Search is not available for this dataset
text
stringlengths 1
134k
| id
stringlengths 11
16
| article_id
stringlengths 8
10
| section_title
stringlengths 1
1.35k
| educational_score
float64 0.52
5.16
| domain
stringclasses 3
values | document_type
stringclasses 4
values | domain_scores
listlengths 3
3
| document_type_scores
listlengths 4
4
| language
stringclasses 38
values | language_score
float64 0
1
|
|---|---|---|---|---|---|---|---|---|---|---|
The work presented herein demonstrates for the first time that inhibition of GSK-3 is required for complete insulin regulation of IGFBP-1, while we have identified the DNA element by which GSK3 targets this gene promoter. As such, GSK-3 inhibition will mimic the insulin regulation of IGF1 bio-availability, as well as reducing the expression of hepatic gluconeogenic genes. It remains to be seen how many other insulin-regulated (and/or TIRE-containing) gene promoters are sensitive to these inhibitors.
|
15350195_p15
|
15350195
|
Conclusions
| 4.166633 |
biomedical
|
Study
|
[
0.9996486902236938,
0.00019133681780658662,
0.00015992783301044255
] |
[
0.9990301132202148,
0.00036619609454646707,
0.0005314574809744954,
0.00007217399252112955
] |
en
| 0.999998 |
Radioisotopes were obtained from Amersham, Bucks, UK ({γ 32 P}-ATP) and ICN, Thame, Oxfordshire, UK ({α 32 P}-UTP). Insulin was purchased from Novo Nordisk, (Crawley, West Sussex, UK), kenpaullone and alsterpaullone from Calbiochem (La Jolla, CA) and the RNase Protection Assay Kit II from AMS Biotech/Ambion, (Austin, Texas). All other chemicals were of the highest grade available.
|
15350195_p16
|
15350195
|
Materials
| 1.312887 |
biomedical
|
Other
|
[
0.9862927198410034,
0.0017649304354563355,
0.011942368932068348
] |
[
0.16726656258106232,
0.8278705477714539,
0.0024997189175337553,
0.002363177016377449
] |
en
| 0.999997 |
CHIR99021 (6-{2-[4-(2,4-Dichloro-phenyl)-5-(4-methyl-1 H -imidazol-2-yl)-pyrimidin-2-ylamino]-ethylamino}-nicotinonitrile) was synthesized in 7% overall yield using a convergent approach from 2,4-dichlorobenzoyl chloride and 6-chloro nicotinonitrile respectively ( and refs within).
|
15350195_p17
|
15350195
|
Synthesis of CHIR 99021
| 3.454244 |
biomedical
|
Study
|
[
0.9980313181877136,
0.0004905909299850464,
0.00147810869384557
] |
[
0.9059793949127197,
0.09220108389854431,
0.0008652309188619256,
0.000954293820541352
] |
en
| 0.999997 |
The rat hepatoma cell line H4IIE was maintained in Dulbecco's Modified Eagle's medium (DMEM) containing 1000 mg/l glucose, 5% (v/v) foetal calf serum, as described previously . Cells were incubated with hormones, at 37°C, for the times and at the concentrations indicated in the figure legends.
|
15350195_p18
|
15350195
|
Cell Culture
| 3.979672 |
biomedical
|
Study
|
[
0.9994789958000183,
0.00017743839998729527,
0.00034357464755885303
] |
[
0.9954056739807129,
0.004104274790734053,
0.00038962691905908287,
0.00010037006722996011
] |
en
| 0.999997 |
H4IIE cells were serum-starved overnight and treated with hormone/inhibitor for the times and at the concentrations indicated in the figure legends. Total cellular RNA was isolated using TriReagent™ (Sigma) following the manufacturer's instructions. An RNase Protection Assay (RPA) was performed to determine the relative amounts of IGFBP-1 and cyclophilin mRNA in each sample . Band intensity was quantified on a phosphorimager (Fuji), data calculated as a ratio of IGFBP-1 to cyclophilin mRNA and presented as fold activation (for induced samples) where the intensity of control samples were set at one, or as % gene expression (for non-induced samples) where the level of gene expression in untreated cells is set at 100%.
|
15350195_p19
|
15350195
|
RNA isolation and RNase protection assay
| 4.103005 |
biomedical
|
Study
|
[
0.999596893787384,
0.00021393354109022766,
0.00018918733985628933
] |
[
0.9990979433059692,
0.0005044103018008173,
0.00033508651540614665,
0.00006267345452215523
] |
en
| 0.999997 |
H4IIE cells were incubated in serum-free medium with hormones and inhibitors for the times and at the concentrations indicated in the figure legends. Cells were then scraped into ice-cold lysis buffer (25 mM Tris/HCl, pH 7.4, 50 mM NaF, 100 mM NaCl, 1 mM sodium vanadate, 5 mM EGTA, 1 mM EDTA, 1% (v/v) Triton X-100, 10 mM sodium pyrophosphate, 1 mM benzamidine, 0.1 mM PMSF, 0.27 M sucrose, 2 μM microcystin and 0.1% (v/v) 2-mercaptoethanol). Cell debris was removed by centrifugation at 13000 × g for 5 min and the protein concentration determined by the method of Bradford, using BSA as an internal standard.
|
15350195_p20
|
15350195
|
Preparation of cell extract for western blot
| 4.104763 |
biomedical
|
Study
|
[
0.9995651841163635,
0.00021289226424414665,
0.0002218135487055406
] |
[
0.997343122959137,
0.00209081475622952,
0.0004668142646551132,
0.00009932064858730882
] |
en
| 0.999997 |
Antibodies to phospho ribosomal protein S6 (Ser-235), phospho-FKHR-L1 (Thr-32) and GSK-3β were purchased from Upstate (Lake Placid, USA), while the phospho-specific Ser9/Ser21 GSK-3, Thr-308 PKB, Thr389-S6K1, and Thr-183/Tyr185 p42/p44 MAPK antibodies were purchased from Cell Signalling Technologies (Hertfordshire, UK). H4IIE cell lysates were prepared following incubation with hormones as described in figure legends and analysed by Western blot analysis.
|
15350195_p21
|
15350195
|
Antibodies for western blot analysis
| 3.396306 |
biomedical
|
Study
|
[
0.9990484118461609,
0.00017618609126657248,
0.000775403343141079
] |
[
0.9638679027557373,
0.03473702818155289,
0.0011093802750110626,
0.00028565298998728395
] |
en
| 0.999995 |
The plasmids BP-1 WT and BP-1 DM5 were a gift from Dr Robert Hall and Professor Daryl K. Granner (Vanderbilt University, TN, USA) . The BP-1 WT plasmid represents a luciferase reporter construct under the control of a thymidine kinase promoter containing the IGFBP-1 TIRE wild-type sequence (5'-CAAAACAAACTTATTTTG). Two base pair mutations of the wild-type TIRE sequence at residues equivalent to position 5 of each A and B site (5'-CAAAA G AAACTT C TTTTG) produces a mutant promoter (BP-1 DM5) that is no longer responsive to insulin . The FOXO-1 constructs have been described previously (10).
|
15350195_p22
|
15350195
|
Plasmids
| 4.088953 |
biomedical
|
Study
|
[
0.9995813965797424,
0.00013928608677815646,
0.00027934429817833006
] |
[
0.9956087470054626,
0.003888825885951519,
0.0003870745422318578,
0.00011539001570781693
] |
en
| 0.999997 |
The TOPflash reporter plasmid kit were obtained from Upstate Biotechnology (Lake Placid, USA). TOPflash has Tcf binding sites driving luciferase expression. Tranfections were performed using the calcium phosphate procedure as described previously . H4IIE cells were transfected in 10 cm dishes with BP-1 WT (10 μg), BP-1 M5 (10 μg), TOPFlash (10 μg), plus or minus 2 μg of GST-FOXO-1 as indicated. Cells were then incubated for 24 h in serum free media with or without hormones or inhibitors as described in figure legends. Cells were lysed in 300 μl lysis buffer (Promega, UK), the cell debris removed by centrifugation at 13000 × g for 2 min and the supernatant stored at -70°C. Luciferase assays were performed using the firefly luciferase assay system (Promega, UK), as per manufacturer's instructions, with luciferase activity being corrected for the protein concentration in the cell lysate.
|
15350195_p23
|
15350195
|
Transient transfections
| 4.120195 |
biomedical
|
Study
|
[
0.9995632767677307,
0.00017269734235014766,
0.0002640827151481062
] |
[
0.9978603720664978,
0.0017553014913573861,
0.0003075666609220207,
0.00007669385377084836
] |
en
| 0.999998 |
H4IIE cells were infected with virus between a titre of 10 8 and 10 9 plaque forming units per ml, incubated at 37°C for 16 hr. Cells were then transfected with 10 μg of BP-1 WT as described above and incubated for a further 24 hr in the presence or absence of 10 nM insulin. Luciferase was harvested and assayed or cell extracts were prepared for western blot analysis, as described earlier.
|
15350195_p24
|
15350195
|
Adenoviral infection
| 4.056638 |
biomedical
|
Study
|
[
0.9995452761650085,
0.00022970394638832659,
0.00022501309285871685
] |
[
0.9989334940910339,
0.0007402541814371943,
0.0002649629022926092,
0.00006123082130216062
] |
en
| 0.999997 |
As a measure of statistical significance of differences in experimental groups, student t-tests were performed and 5% confidence limits applied.
|
15350195_p25
|
15350195
|
Statistical analyses
| 3.198594 |
biomedical
|
Study
|
[
0.9983356595039368,
0.0003395281091798097,
0.001324881101027131
] |
[
0.980730414390564,
0.017077714204788208,
0.0019402308389544487,
0.0002516463282518089
] |
en
| 0.999997 |
G6Pase, glucose 6-phosphatase; IGFBP-1, IGF-binding protein-1; phosphatidyl inositol 3, kinase, PI 3-kinase; TIRE, thymine rich insulin response element; PKB, protein kinase B; PEPCK phosphoenolpyruvate carboxykinase; GSK-3, Glycogen synthase kinase 3
|
15350195_p26
|
15350195
|
Abbreviations
| 2.748307 |
biomedical
|
Other
|
[
0.9934485554695129,
0.0021151164546608925,
0.004436278250068426
] |
[
0.006447043269872665,
0.9924754500389099,
0.0004254429950378835,
0.0006519845919683576
] |
en
| 0.999998 |
The majority of the data was obtained in equal measure by D.F. and S.P, the CHIR99021 was synthesised, purified and analysed by N.S. and R.M., the adenoviral vectors were produced and characterised by L.M.D. and C.J.R., while the project was conceived and supervised by C.S.
|
15350195_p27
|
15350195
|
Authors contributions
| 0.90361 |
biomedical
|
Other
|
[
0.7769085764884949,
0.004198974464088678,
0.2188924252986908
] |
[
0.046354807913303375,
0.9486764669418335,
0.0037855461705476046,
0.001183210639283061
] |
en
| 0.999997 |
The use of chemical fertilizers has been responsible for dramatic increase in the stem wood production of forest trees . In an 8-year-old stand of loblolly pine growing on an infertile site in Scotland County, North Carolina, for example, stem volume increment increased 152% after the fourth year of fertilization treatment . However, little is known about the mechanistic basis for such favorable effects of fertilization. One hypothesis is that improved nutrient availability leads to increases in leaf area growth and photosynthetic capacity, thus producing more photosynthate that can be allocated to the stem wood. This hypothesis has been supported by a number of physiological studies and used as a conceptual model for plant nitrogen acquisition and cycling . However, forest trees can consume as much as 60–80% of annual net primary productivity in the turnover of fine roots . Fine roots are a tissue with high maintenance respiration tissue whose primary function is to absorb and metabolize water and nutrients from the soil . A number of previous studies have shown that the production of fine roots is sensitive to the availability and distribution of nutrients within the soil . In this study, we test a second hypothesis that the capacity of fine roots to respond to nutrient availability, referred to as phenotypic plasticity , can potentially increase forest-tree productivity.
|
15353004_p0
|
15353004
|
Background
| 4.181671 |
biomedical
|
Study
|
[
0.9305095672607422,
0.0011548454640433192,
0.06833554059267044
] |
[
0.99912029504776,
0.0004583687987178564,
0.0003572364803403616,
0.00006414725794456899
] |
en
| 0.999997 |
Phenotypic plasticity is the potential of an organism to alter its phenotype in changing environments . Phenotypic plasticity may play an important role in plant adaptation and evolution by combining a physiological buffering to poor environmental conditions with an improved response to favorable conditions . The understanding of how phenotypic diversity is generated by the coherent change of other integrated traits is a key challenge in evolutionary biology. In much plant literature, studies of adaptive phenotypic plasticity have focused mainly on morphological and fitness traits above ground . It is unclear how phenotypic plasticity exerts a significant effect on plant growth and production through the alteration of root systems below ground. Studies strongly suggest that plant root systems are adapted to different environments , and their diversity represents one important form of morphological evolution . Fine roots are unique organs with great environmental and developmental plasticity which are subject to strong natural selection and are amenable to genetic and developmental study .
|
15353004_p1
|
15353004
|
Background
| 4.047693 |
biomedical
|
Study
|
[
0.9973196387290955,
0.0003788198810070753,
0.0023015534970909357
] |
[
0.9528753757476807,
0.0009018188575282693,
0.04607048258185387,
0.00015231026918627322
] |
en
| 0.999996 |
Loblolly pine is the most important tree species for fiber production in the southern US . Because of its wide natural distribution from the moist Atlantic Coastal Plain to the dry "Lost Pines" region of Texas, this species displays strong adaptability to a range of environmental conditions. However, detailed ecophysiological and developmental mechanisms for the adaptive response of loblolly pine from a perspective of fine roots remain unknown. In the study, we integrate the conceptual theory of phenotypic plasticity into the test of the hypothesis that the reduced production of fine roots under high fertilization can increase stem productivity in loblolly pine.
|
15353004_p2
|
15353004
|
Background
| 2.362014 |
other
|
Study
|
[
0.3183850646018982,
0.0013961595250293612,
0.6802188158035278
] |
[
0.9932790398597717,
0.006187740247696638,
0.0003194312157575041,
0.00021374440984800458
] |
en
| 0.999996 |
After 4 weeks of treatment, trees receiving the high nutrient treatment displayed 22% ("xeric") and 47% ("mesic") greater stem biomass than those under the low fertilizer treatment ( P < 0.001). These values increased to 102% and 199% for these two ecotypes, respectively, when the trees were treated for 14 weeks ( P < 0.001).
|
15353004_p3
|
15353004
|
Results and Discussion
| 3.555693 |
biomedical
|
Study
|
[
0.7835986614227295,
0.0014160351129248738,
0.21498528122901917
] |
[
0.9985685348510742,
0.0009425390162505209,
0.00041268407949246466,
0.00007623451529070735
] |
en
| 0.999997 |
Allometric analysis was used to evaluate the influences of foliage and fine-root biomass partitioning on stem growth which arise from differences in nutrient supply. On both harvesting dates, the proportion of foliage biomass to total plant biomass increased markedly, whereas the proportion of fine root biomass decreased significantly, with better nutrient supplies. As an illustration, we use Figure 1 to demonstrate the phenotypic plasticity of stem growth and biomass partitioning between two treatments on the second harvesting date. However, the degree of plasticity, defined as the absolute difference between the two treatments , was strikingly greater for the fine-root proportion than foliage proportion, especially for the "xeric" ecotype. The significance levels for the treatment effect on stem biomass decreased when the proportion of foliage or fine-root biomass was held constant ( P < 0.01), as compared to the significance level when the proportion was not held constant . These dependent relationships suggest that increased stem biomass due to better nutrient supplies was attributable to both increased foliage investment and decreased energetic costs of fine root construction.
|
15353004_p4
|
15353004
|
Results and Discussion
| 4.129034 |
biomedical
|
Study
|
[
0.9893981218338013,
0.0007423019269481301,
0.00985949207097292
] |
[
0.9992998838424683,
0.00019483634969219565,
0.0004567133146338165,
0.00004857933527091518
] |
en
| 0.999998 |
We analyzed genetic differences in how foliage and fine-root biomass partitioning affect stem biomass through changes in nutrient level. We used correlations of family means in the two treatments to calculate path coefficients of the nutrient-induced plasticity of foliage and fine-root biomass partitioning to the plasticity of stem biomass. For "mesic" families, the plasticity of foliage biomass partitioning did not give rise to a change in stem biomass ( p y ←1 = -0.09), whereas the plasticity of fine-root biomass partitioning, i.e ., decreased partitioning of biomass to fine roots under higher fertilization, had a significant impact on the corresponding increase of stem biomass . For "xeric" families, both increased biomass partitioning to foliage and decreased partitioning to fine roots as a consequence of more nutrients favorably affected stem biomass. The path coefficients derived from foliage and fine-root biomass partitioning accounted for most of the variation in stem biomass as indicated by a small residual effect (0.09–0.12), suggesting that no additional traits are required to explain stem biomass. Results from path analysis suggest that the two ecotypes have different physiological mechanisms that determine the nutrient-dependent influences of foliage and fine-root biomass partitioning on stem growth.
|
15353004_p5
|
15353004
|
Results and Discussion
| 4.222278 |
biomedical
|
Study
|
[
0.9904667735099792,
0.0007352480315603316,
0.008797912858426571
] |
[
0.9992856383323669,
0.0002153967652702704,
0.0004408724489621818,
0.00005815931945107877
] |
en
| 0.999998 |
Foliage and fine roots have complementary roles in uptake of resources; the former in energy and carbon uptake and the latter in water and nutrient uptake . Mechanistic modeling of resource uptake suggests that the most efficient deployment of plant biomass is to form minimal fine roots that supply water and nutrients for the production of maximum leaf area . However, there are important trade-offs in generating few fine roots. We used the ratio of foliage biomass to fine-root biomass (RFF) as an architectural trait to describe the allocation of biomass within ephemeral tissues. This ratio reflects the degree to which plants display a balance of resource investment vs. resource acquisition. It was highly plastic to nutritional levels and tree development. The ratio was larger in the high nutrient treatment (RFF = 6.0–7.0) than in the low treatment (RFF = 3.0–3.5). Under the higher nutrient treatment, trees tended to invest increased energy on foliage with their growth. All these trends differed between the two ecotypes, as shown by significant interaction effects between ecotypes, treatments and harvesting dates ( P < 0.001). Plasticity between different growth stages indicates the dependence of plastic responses on the timing and sequences of developmental events. Ecotypic variation in developmental plasticity represents different genetic bases involved in relevant developmental events .
|
15353004_p6
|
15353004
|
Results and Discussion
| 4.178997 |
biomedical
|
Study
|
[
0.9901285767555237,
0.0006339236861094832,
0.009237509220838547
] |
[
0.9990869760513306,
0.0002633566618897021,
0.000595239398535341,
0.000054426542192231864
] |
en
| 0.999996 |
Ecotypic differentiation of loblolly pine could be explained by limits of plasticity. Quantitative evolutionary genetic models predict that the phenotypic plasticity of a trait is costly or physiologically limiting when the trait is forced to respond to environmental variation ("passive" response). DeWitt et al. delineated five costs (maintenance costs, production costs, information acquisition costs, developmental stability costs and genetic costs) and three limits (information reliability limits, lag-time limits and developmental range limits) of plasticity. A limit of plasticity occurs when facultative development cannot produce a trait mean as near the optimum as can fixed development. A negative relationship between the degree of plasticity and the fitness residuals (calculated from the regression of fitness on mean phenotype) identifies a limit of plasticity.
|
15353004_p7
|
15353004
|
Results and Discussion
| 4.172163 |
biomedical
|
Study
|
[
0.9916886687278748,
0.0003491456154733896,
0.007962220348417759
] |
[
0.9983946681022644,
0.0005791820003651083,
0.0009758859523572028,
0.00005034434434492141
] |
en
| 0.999999 |
Our analysis suggests that the plasticity of fine-root biomass proportion is physiologically limiting, whereas the plasticity of foliage biomass proportion is not. The relationship of the shoot biomass residuals was positive with the degree of plasticity of foliage biomass proportion , but negative with the degree of plasticity of fine-root biomass proportion . Thus, when nutrient supply changes, foliage and fine roots will respond in different ways, with the former in a constitutive (active) way and the latter in an inducible (passive) way . For both "xeric" and "mesic" ecotypes, the families that reduced fine root biomass the least had the highest stem biomass on the high nutrient treatment. Larger limits of fine-root plasticity for "xeric" than "mesic" could explain why the stronger plasticity of fine root growth for the former ecotype did not result in more stem growth as expected . Perhaps, for these "Lost Pines" from infertile sites, under improved nutritional conditions there is strong conflict between energetic savings due to reduced fine root production and energetic costs associated with higher efficiency of absorbing and metabolizing nutrients with fewer fine roots.
|
15353004_p8
|
15353004
|
Results and Discussion
| 4.183166 |
biomedical
|
Study
|
[
0.9868039488792419,
0.0006172338034957647,
0.012578796595335007
] |
[
0.999382495880127,
0.00027583676273934543,
0.0002917131350841373,
0.00004984753468306735
] |
en
| 0.999998 |
Forest tree form (biomass partitioning) is highly plastic in response to changes in nutrient levels. The carbon budgets for forest trees show a surprisingly large role of roots. Under low nutrient conditions that predominate in natural forests, 60–80% of photosynthate is allocated below ground, compared with 30% for high nutrient levels . Our path analysis for loblolly pine seedlings showed that phenotypic plasticity of roots had a major influence on the plasticity of stem biomass, supporting the hypothesis that roots play a crucial role in forest productivity. Current selections when grown on high nutrient sites could have relative proportions of roots and stems and foliage that are unfavorable for high yield.
|
15353004_p9
|
15353004
|
Results and Discussion
| 3.827079 |
biomedical
|
Study
|
[
0.789128303527832,
0.0009981143521144986,
0.20987364649772644
] |
[
0.9978006482124329,
0.001643832540139556,
0.00046514152199961245,
0.0000904168700799346
] |
en
| 0.999997 |
Progress towards domestication in trees will be slowed by long generation times, but is likely to be based on the exploitation of interactions between genotypes and yield associated with various types of agronomic methods (e.g., fertilizer levels), as have been shown for herbaceous crop plants. However, the environmental uncertainties during the long life span of trees have caused some breeders to consider the value of plasticity as a trait itself. And plasticity could obscure the relationship between phenotype and genotype, making selection less efficient. Efforts to domesticate forest trees will be enhanced by a deeper knowledge of phenotypic plasticity .
|
15353004_p10
|
15353004
|
Results and Discussion
| 3.10522 |
biomedical
|
Other
|
[
0.6953006982803345,
0.0008585829054936767,
0.3038407266139984
] |
[
0.3626832365989685,
0.6017164587974548,
0.034992896020412445,
0.0006074379780329764
] |
en
| 0.999999 |
Our study of biomass partitioning in relation to varying nutritional levels in loblolly pine supports the previous hypothesis, proposed by Linder and Axelson , that the reduced production of fine roots under fertilization results in the increase of stem production through the optimal use of energy. Yet, supporting this hypothesis does not imply that we should reject a more commonly accepted hypothesis that greater plant production due to fertilization stems from increased foliage and photosynthetic capacity. We explained the discrepancy of these two hypotheses from an ecophysiological perspective using a well-established conceptual model of phenotypic plasticity. The pattern of biomass partitioning is under environmental control and exhibits considerable ecotypic differentiation for the best utilization of available resources. In this study, we observed that biomass partitioning in loblolly pine is also under ontogenetic control, as well documented in other species . Although our study of fine roots was performed using young loblolly pine seedlings in controlled conditions, results promise to enhance a fundamental understanding of evolutionary changes of tree architecture under domestication and to design sound silvicultural and breeding measures for improving plant productivity.
|
15353004_p11
|
15353004
|
Conclusions
| 4.17334 |
biomedical
|
Study
|
[
0.9812317490577698,
0.0008396077901124954,
0.0179285928606987
] |
[
0.9990447163581848,
0.00024206652597058564,
0.0006586897652596235,
0.00005447710645967163
] |
en
| 0.999999 |
Phenotypic plasticity was evaluated for fine roots and biomass partitioning of a commercially important forest tree species, loblolly pine ( Pinus taeda L.). We used two contrasting loblolly pine ecotypes from regions that differ in soil resource availability. One of the ecotypes, known as the "Lost Pines" of Texas, is adapted to droughty conditions and low soil fertility and is denoted by "xeric", whereas the other, Atlantic Coastal Plain, is adapted to more moderate conditions and is denoted by "mesic". Adaptive differentiation between the contrasting "xeric" and "mesic" ecotypes has been previously characterized .
|
15353004_p12
|
15353004
|
Plant material
| 3.038883 |
biomedical
|
Study
|
[
0.5699812769889832,
0.0014947422314435244,
0.4285239577293396
] |
[
0.9970679879188538,
0.0025342002045363188,
0.0002883329289034009,
0.00010945762187475339
] |
en
| 0.999997 |
In May 1997, the seeds from the two ecotypes of loblolly pine were germinated in vermiculite, the seedlings were transplanted to 40 cm deep by 20 cm diameter plastic pots filled with pure sand, and placed in an open site at the Horticulture Field Laboratory at North Carolina State University, Raleigh. Pine seedlings from each ecotype were assigned to two different treatments: low nutrients and high nutrients . The experiment was laid out in a complete randomized design with two different nutritional treatments and with five half-sib families from each ecotype in each level (8 seedlings were included per family per ecotype in each treatment). The seedlings in the high nutrient regime were fertilized at 50 ppm N solution (Peters 15-16-17) every morning, and those in the low nutrient level at 10 ppm N every other morning. The two treatments received the same amount of water. Half of the trees were harvested after 4 weeks of treatment, whereas the other half, after 14 weeks of treatment. Plants were separated into foliage, branches, stem, tap root, coarse roots and fine roots. Fine roots are defined as those of diameter ≤ 2 mm.
|
15353004_p13
|
15353004
|
Plant material
| 4.003161 |
biomedical
|
Study
|
[
0.909345805644989,
0.0010026092641055584,
0.08965151757001877
] |
[
0.9990552067756653,
0.0007144427509047091,
0.00018051188089884818,
0.00004979833465768024
] |
en
| 0.999997 |
The differences of stem biomass between the two nutritional levels were statistically analyzed using an allometric model that characterizes allometric relationships between plant parts and wholes. The model is based on an exponential function, y = ax b , where x and y are total plant biomass and stem biomass, respectively, and a and b represent the coefficient and exponent of the allometric equation, respectively .
|
15353004_p14
|
15353004
|
Data analysis
| 4.040236 |
biomedical
|
Study
|
[
0.9861611127853394,
0.0003441490407567471,
0.013494761660695076
] |
[
0.9984583854675293,
0.0011914164060726762,
0.0003082438779529184,
0.0000418737945437897
] |
en
| 0.999997 |
Path analysis was used to identify the cause-effect relationships in a complex system . Path analysis partitions the correlation of component traits with a yield trait into two parts, direct and indirect. We performed path analysis to detect the direct and indirect effects of the plasticity of foliage biomass and fine root biomass on the plasticity of stem biomass. The path coefficients for foliage biomass ( p 1← y ) and fine root biomass ( p 2← y ) to stem biomass through the change of nutritional levels were estimated by solving the following regular equations:
|
15353004_p15
|
15353004
|
Data analysis
| 4.025201 |
biomedical
|
Study
|
[
0.9622241854667664,
0.0005148305790498853,
0.03726102411746979
] |
[
0.9984063506126404,
0.0012160635087639093,
0.00033274907036684453,
0.00004482513395487331
] |
en
| 0.999997 |
p 1← y + r 12 p 2← y = r 1 y
|
15353004_p16
|
15353004
|
Data analysis
| 1.361632 |
other
|
Other
|
[
0.37646612524986267,
0.004253403749316931,
0.6192804574966431
] |
[
0.025357652455568314,
0.9718376398086548,
0.0018020031275227666,
0.001002678764052689
] |
cy
| 0.999999 |
r 12 p 1← y + p 2← y = r 2 y
|
15353004_p17
|
15353004
|
Data analysis
| 1.279844 |
other
|
Other
|
[
0.2249038815498352,
0.003533880924805999,
0.7715622782707214
] |
[
0.019281500950455666,
0.9778358340263367,
0.0019335858523845673,
0.000949056469835341
] |
cy
| 0.999998 |
where r 1 y and r 2 y are the family correlation coefficients of the plasticity of foliage biomass and fine-root biomass with the plasticity of stem biomass, respectively, and r 12 is the family correlation coefficient between the plasticity of foliage biomass and fine-root biomass. Residuals were estimated to evaluate the degree of determination for the path analysis . All data analyses were performed using software SAS .
|
15353004_p18
|
15353004
|
Data analysis
| 2.688578 |
biomedical
|
Study
|
[
0.6862064599990845,
0.001091538812033832,
0.312701940536499
] |
[
0.94524085521698,
0.05340820923447609,
0.0009845695458352566,
0.0003662860253825784
] |
en
| 0.999998 |
RW designed the study, carried out the experiment, analyzed the data and drafted the manuscript. JEG participated in the experiment. SEM participated in the design of the study. DMO participated in the design and coordination. All authors read and approved the final manuscript.
|
15353004_p19
|
15353004
|
Authors' Contributions
| 0.854368 |
other
|
Other
|
[
0.18922218680381775,
0.0022329248022288084,
0.8085449934005737
] |
[
0.007284028921276331,
0.991193950176239,
0.0009787355083972216,
0.0005433389451354742
] |
en
| 0.999997 |
In recent years, the number of patients suffering from allergic asthma has increased , and allergic diseases including asthma have become a social problem affecting medical costs and quality of life. Allergic asthma is a complex disorder characterized by airway inflammation, bronchial hyperresponsiveness and reversible airway obstruction. Elevated numbers of activated Th2 cells, mast cells and eosinophils in the bronchial mucosa cause certain features of asthma, including increased serum IgE levels in allergic asthma. The available data suggest that there are many potential susceptible genes for allergic asthma, including genes for cytokines, receptors, transcription factors, immune recognition and regulation of lipid mediator generation. A few susceptible genes for allergic asthma have been identified that may be associated with the asthmatic phenotype , but definite susceptible genes have not been identified yet. Thus, large-scale analysis of gene markers is needed, along with identification of association between these genetic polymorphisms and the asthmatic phenotype, and its development mechanism. It has been reported that the human genome has 3 to 10 million single nucleotide polymorphisms (SNPs). A SNP in a coding region can cause amino acid substitution, resulting in functional modification of the protein; a SNP in a promoter region can affect transcriptional regulation; and a SNP in an intron region can affect splicing and expression of the gene. Thus, SNPs can be highly informative for identifying genetic factors of multifactorial disease such as allergic asthma.
|
15339344_p0
|
15339344
|
Background
| 4.421881 |
biomedical
|
Study
|
[
0.9990672469139099,
0.0005705521325580776,
0.00036215592990629375
] |
[
0.6223739385604858,
0.002907478716224432,
0.37398651242256165,
0.0007320523727685213
] |
en
| 0.999997 |
In the present study, we analyzed associations between SNPs and childhood allergic asthma (CAA), which is more strongly influenced by genetic factors than other types of allergic asthma. We performed this analysis using an artificial neural network (ANN), which is a computer-based algorithm that can be trained to recognize and categorize complex patterns . ANNs have been used for discrimination between subtly different clinical disease lesions; e.g., premalignant lesion Barrett's versus esophageal cancer, based on microarray data . In a previous study, we performed severity assessment of senile dementia of Alzheimer type using ANN modeling of electroencephalogram data. The average error of the ANN model for assessment scale (HDS-R) score was 2.64 points out of 30 . We have also used an ANN for prediction of 4 allergic diseases using SNP data ; 82 subjects with data for 6 SNPs were analyzed, and the ANN model predicted diagnosis with accuracy of more than 78%. Thus, we have achieved sufficiently high accuracy with ANNs using relatively little SNP data.
|
15339344_p1
|
15339344
|
Background
| 4.10111 |
biomedical
|
Study
|
[
0.9995112419128418,
0.0002642085019033402,
0.00022454348800238222
] |
[
0.9994519352912903,
0.0001595291105331853,
0.0003287340223323554,
0.000059792619140353054
] |
en
| 0.999997 |
Here, we propose an ANN model suitable to diagnostic prediction of 172 subjects with CAA and 172 healthy subjects, using 25 SNPs in 17 genes shown in Table 1 . For comparison with ANN, we also used logistic regression (LR) analysis, which is currently used to analyze medical statistics and equivalent to ANN with a single hidden node . In order to selectively identify susceptible SNPs, a susceptible marker-selectable ANN is proposed, in which a parameter decreasing method (PDM) is incorporated. Information on obtaining the execute code, example data and documentation of this software is available at . Associations between combinations of important SNPs and CAA pathogenesis were investigated. A χ 2 test was performed for all 2-SNP and 3-SNP combinations.
|
15339344_p2
|
15339344
|
Background
| 4.075098 |
biomedical
|
Study
|
[
0.9995337724685669,
0.0002337999176234007,
0.0002324255765415728
] |
[
0.9994747042655945,
0.00023374619195237756,
0.00023830893042031676,
0.00005326043537934311
] |
en
| 0.999996 |
Several reports have suggested linkage between asthma and chromosomes. For example, genes in the 5q31-5q33 region code for Th2-type cytokines (IL-4, IL-13, which regulate B cell heavy-chain class-switching to IgE production) and ADRB2 (which mediates airway smooth muscle relaxation and protects against bronchial hyperreactivity) . IL-4 operates via the IL-4 receptor (IL-4R), which is encoded by a gene in chromosomal region 16q12. Mice deficient in the IL-4Rα chain lack IgE production and Th2 inflammatory reactions, and it has been shown that total IgE level is dependent on Ile50Val substitution . In the present study, we analyzed 25 SNPs (Table 1 ) in 17 genes known to be associated with development of asthma. Association between these SNPs and CAA was assessed by P -value. As shown in Table 1 , 21 of these 25 SNPs had a P -value greater than 0.1. The P -values of CysLT2 (108 C/A), IL-4Rα (148 G/A), ADRB2 (265 A/G) and C5 were 0.0036, 0.0155, 0.0541 and 0.0581, respectively. When CysLT2 (108 C/A), which had the lowest P -value of 25 SNPs, was used for discrimination between case and control as a sole factor, prediction accuracy was 54.4%, and the sensitivity and specificity was 12.8% and 95.9%, respectively, compared with the number of case and control subjects to assess discrimination performance (genotype CC; case 150, control 165, genotype CA or AA; case 22, control 7). Thus, we constructed a susceptible marker-selectable ANN model, which can discriminate between cases and controls using the selected susceptible SNPs, and which can include the association between combinations of SNPs and development of CAA.
|
15339344_p3
|
15339344
|
SNPs selected for diagnostic prediction with ANN
| 4.218392 |
biomedical
|
Study
|
[
0.9995359182357788,
0.0002831387391779572,
0.00018105245544575155
] |
[
0.9993160963058472,
0.00022231558978091925,
0.00037817860720679164,
0.00008339681517099962
] |
en
| 0.999997 |
We used a three-layered ANN with input, hidden and output layers . An ANN model and LR model, with 25 SNPs as input variables, were constructed with learning data, and we performed diagnostic prediction with evaluation data. The results of diagnostic prediction are shown in Figure 2a,2b and Table 2a . The ANN had higher prediction accuracy than LR. Accordingly, sensitivity and specificity, with both evaluation data and learning data, were higher for the ANN than for LR (Table 2a ). In LR analysis, Monte Carlo study was performed to evaluate the effect of number of events per variable (EPV) . It suggested that at least 10 events per variable analyzed were desirable to maintain the validity of the model. In the present study, we used 172 events per group and 51 variables (25 SNPs and 1 teacher value). LR would not have an enough power for parameter selection, because 172 events per group is small compared with that of variable. The construction of optimized LR model should be furthermore investigated.
|
15339344_p4
|
15339344
|
Diagnostic prediction using 25 SNPs
| 4.112041 |
biomedical
|
Study
|
[
0.999210000038147,
0.00030399393290281296,
0.0004859843465965241
] |
[
0.9996345043182373,
0.0001304393372265622,
0.00019151812011841685,
0.00004356272620498203
] |
en
| 0.999999 |
Ritchie et al . reported the optimization of the architecture using genetic programming neural networks (GPNN) . If important SNPs were previously determined, optimization of network architecture should be carried out. Genetic programming neural networks have contributed the construction of ANN model with high performance. In the present study, however, many candidate SNPs were used and the selection of SNPs is firstly desired. Therefore, in order to extract SNPs closely associated with CAA, we tried optimization of input variables by PDM in the ANN model, while the architecture of a neural network was not modified. Five PDM trials were performed. Figure 3 shows typical results for change of accuracy during PDM procedure. When input variables were excluded one by one to preserve prediction accuracy (as described in Methods), the accuracy began to decrease after the number of SNPs used for modeling reached 10. When the number of SNPs used for modeling decreased, coincidence of genotyping pattern between cases and controls inevitably occurred. When genotyping pattern of a case was coincident with that of controls, the learning for model construction did not progress well. We investigated the rate of case subjects whose genotype patterns were coincident with that of control subjects at each step of PDM . Rate of case subjects [%] in Figure 3 means N' case / N case . In this case, N' case is the number of cases whose genotype pattern is match to control's genotype pattern at least one control ( N case = 172 subjects). As shown in Figure 3 , there was little coincidence of genotype patterns when more than approximately 7 SNPs were used in ANN modeling. Therefore, the decrease in accuracy was considered to be due to omission of a highly important SNP. The remaining 10 SNPs were worth investigating as important factors.
|
15339344_p5
|
15339344
|
Selection of susceptible SNPs for CAA
| 4.102558 |
biomedical
|
Study
|
[
0.9993762373924255,
0.00026397639885544777,
0.0003597925533540547
] |
[
0.9996376037597656,
0.0001589423045516014,
0.0001579502859385684,
0.0000455687077192124
] |
en
| 0.999995 |
To investigate the important SNPs, we counted the number of SNPs that remained within the last 10 input variables in 5 trials. The significance order of remaining SNPs was listed, and a score of order ranging from 1 to 10 points was determined, based on the significance order. The remaining SNPs were reordered according to sums of scores, as shown in Table 3 . We believe that SNPs with higher scores are more important for development of CAA, because significance of SNPs correlated with the order of elimination via the PDM procedure described in methods section. ANN models were reconstructed using SNPs listed in Table 3 . The number of input SNPs varied from three ( IL-4Rα (148 G/A), CysLT2 and IL-10 (-571 C/A)) to 17 SNPs (all listed SNPs) according to the order of Table 3 . When more than 10 SNPs were used as input variables, average accuracy for learning and evaluation data was high , and was almost equal to that of the model using 25 SNPs. These results suggest that the 10 SNPs selected in Table 3 are very important for prediction of development of CAA.
|
15339344_p6
|
15339344
|
Selection of susceptible SNPs for CAA
| 4.107833 |
biomedical
|
Study
|
[
0.9994163513183594,
0.00028801403823308647,
0.00029566630837507546
] |
[
0.9995207786560059,
0.0001409023388987407,
0.0002859604137483984,
0.00005235942080616951
] |
en
| 0.999997 |
The results of diagnostic prediction using the 10 SNPs selected by PDM are shown in Figure 2c , and the accuracy, sensitivity and specificity are shown in Table 2b . In the ANN model, the accuracy, sensitivity and specificity with evaluation data were again sufficiently high, and were somewhat similar to the results from the analysis using 25 SNPs, although the number of input variables was markedly smaller than in the analysis using 25 SNPs. In particular, sensitivity was significantly high (77.9%), indicating that case subjects were more correctly diagnosed by this model. To compare with the LR model, LR model consisting of 10 SNPs selected by ANN was constructed . As shown in Table 2b , the LR model constructed showed low accuracy. This result indicates high performance of ANN modeling for CAA prediction although selected SNPs would not be suitable for LR analysis. We concluded that the ANN model constructed with 10 SNPs could discriminate between cases and controls as precisely as the model constructed with 25 SNPs.
|
15339344_p7
|
15339344
|
Selection of susceptible SNPs for CAA
| 4.08744 |
biomedical
|
Study
|
[
0.9993888139724731,
0.00034837712883017957,
0.00026276931748725474
] |
[
0.999386191368103,
0.0001376627042191103,
0.0004153853515163064,
0.00006069490700610913
] |
en
| 0.999996 |
To understand the importance of the 10 SNPs selected, we analyzed combinations of these 10 SNPs. We paid particular attention to SNP combinations associated with CAA, and assessed whether any combinations consisting of SNPs selected by ANN were associated with CAA. The relationships between 2-SNP or 3-SNP combinations and CAA development were examined by calculating P -value using the χ 2 test. In models using 10 SNPs selected by PDM or the other 15 SNPs, the total number of 2-SNP combinations and 3-SNP combinations ( N comb ) is 90 ( 10 P 2 ) or 210 ( 15 P 2 ), and 360 ( 10 P 3 /2) or 1365 ( 15 P 3 /2), respectively. With respect to 2-SNP combination between the SNP of interest and SNP A, P -value was calculated as follows. When patients were limited with certain pattern of another SNP, such as AA major homozygote of SNP A, patient distribution of the SNP of interest was investigated. With respect to 3-SNP combination, between the SNP of interest, and SNP A and B, P -value was calculated as follows. When patients were limited with certain pattern of two other SNPs, such as AA major homozygote of SNP A and BB major homozygote of SNP B, patient distribution of the SNP of interest was investigated.
|
15339344_p8
|
15339344
|
Interaction between SNP and another SNP for CAA
| 4.08324 |
biomedical
|
Study
|
[
0.9994645714759827,
0.0002786409459076822,
0.0002567271585576236
] |
[
0.9995737671852112,
0.00016904997755773365,
0.00020855068578384817,
0.000048690482799429446
] |
en
| 0.999997 |
To evaluate P -value of the combination, the usual Bonferroni correction of P -values was first investigated. To select the 2-SNP combination accompanied with minimum false positive, the criterion was P < 0.05/300. Here 300 cases correspond to 25 C 2 . Under this severe condition, there were no significant SNPs. As the same as 2-SNP combination, any significant combination was not obtained on 3-SNP combination under the threshold of P < 0.05/2300. Next, to determine important combination, P -value without Bonferroni correction was used, that is P < 0.05. Results are shown in Table 4 . In 2-SNP combination, there were 13 combinations with P < 0.05 among total 90 combinations. In the case of 3-SNP, 72 combinations with P < 0.05 were existed in 360 exhaustive combinations. However, combinations possibly include several false positive significant combinations. Therefore, we paid attention to the SNP, of which P -value effectively decreases by combining with genotype or allele of other SNPs. We defined effective combination value (ECV). ECV2 or ECV3 is the ratio of 2 or 3-SNPs P -value to the product of each P -value. ECV is not indicator for avoiding false positives but for evaluation of interaction. For example, in 2 SNP combinations, when patients were limited with certain pattern of another SNP, such as AA major homozygote of SNP A, patient distribution of the SNP X of interest is investigated ( P = P ax ). If the 2-SNP combination is independent (no interaction) each other, P ax equals multiplication of P a and P x . ECV<1 means that the 2-SNP combination is not independent and two SNPs have any interaction each other.
|
15339344_p9
|
15339344
|
Interaction between SNP and another SNP for CAA
| 4.16399 |
biomedical
|
Study
|
[
0.9993376135826111,
0.00024936176487244666,
0.0004130261659156531
] |
[
0.9995163679122925,
0.0002465735888108611,
0.00019227690063416958,
0.00004472739965422079
] |
en
| 0.999997 |
The effect of ECV on number of effective combinations is shown in Table 4 . About half number of 2-SNP combination satisfied the condition ECV2<1 ( N ECV 2<1 = 47). Among 13 combinations with P < 0.05 mentioned above, 11 combination also satisfied the same condition ( N ECV 2<1, P = 11). When ECV2<0.5, N ECV 2<0.5 decreased the number to 27 and 10 of N ECV 2<1, P = 11 still remained. When ECV2<0.1, N ECV 2<0.1 became small and it was thought that positive combination may be lost. In the case of 3-SNP combination, only 20% of the total combination satisfied the condition P < 0.05. The combinations of 12% among the total combinations (43 combinations) satisfied ECV3<1. All of these 43 combinations also satisfied the condition P < 0.05. From these results, it was concluded that P < 0.05 is not strict criterion for 3-SNP combination analysis. In the case of 2-SNP combination, ECV2<0.5 was adequate as a selection of effective combination, because 77% of the combination with P < 0.05 still remained. From these consideration, we selected these two evaluation bases ( P -value and ECV) in order to determine effective combinations and the combination with N ECV <0.5, P ( P < 0.05 and ECV<0.5) was picked up. The combinations were used for the following investigation. The number of combination which satisfies the condition, P < 0.05 and ECV2<0.5 in 2-SNP combination and P < 0.05 and ECV3<0.5 in 3-SNP combination was designated as N ef , the number of effective combination, respectively (Table 5 ).
|
15339344_p10
|
15339344
|
Interaction between SNP and another SNP for CAA
| 4.043865 |
biomedical
|
Study
|
[
0.9937520623207092,
0.00038017245242372155,
0.005867835599929094
] |
[
0.9996021389961243,
0.00022698205430060625,
0.00013664319703821093,
0.0000342706662195269
] |
en
| 0.999999 |
It is very important to clearly determine whether effective combinations frequently occur among groups of 10 SNPs selected by ANN modeling with PDM. It would be difficult to investigate the phenotypes associated with each of such a large number of combinations. Identifying effective 2-SNP combinations using the conditions described above is a useful method of identifying 2-SNP combinations that merit further investigation. Ten effective combinations were found among the 10 SNPs selected by ANN; 23 effective combinations were found between those 10 SNPs and the remaining 15 SNPs; and 3 effective combinations were found among the remaining 15 SNPs. It is likely that the former 10 combinations are more important than the latter 26 combinations, because the ANN model constructed using only the selected 10 SNPs exhibited sufficiently high accuracy to predict development of CAA. Susceptible genes for development of a multifactorial disease like CAA can correctly classify many subjects as cases or controls, and it is very important that those genes involve SNP combinations that have important interaction with high concentration ratio. We defined the concentration ratio as the ratio of effective rate to random selection rate . When the effective rate, N ef /Σ N ef , was calculated, it was found to be 0.28 (10/36) for the 10 SNPs selected by PDM, 0.64 (23/36) for combinations between the 10 selected SNPs and the remaining 15 SNPs, and 0.08 (3/36) for combinations of the remaining 15 SNPs (Table 5 ). The random selection rate, N com / 15 P 2 shown in Table 5 , represents the rate which the combination is selected from all 2-SNP combinations independently, 0.15 (90/ 15 P 2 ) for the 10 SNPs selected by PDM, 0.5 (300/ 15 P 2 ) for combinations between the 10 selected SNPs and the remaining 15 SNPs, and 0.35 (210/ 15 P 2 ) for combinations of the remaining 15 SNPs (Table 5 ). The concentration ratio was found to be 1.85 for the 10 SNPs selected by PDM, 1.28 for combinations between the 10 selected SNPs and the remaining 15 SNPs, and 0.24 for combinations of the remaining 15 SNPs (Table 5 ). The concentration ratio was higher for combinations among the 10 selected SNPs than for other combinations, so we can select 2-SNP combinations associated with CAA with high rate. The results are shown in Table 6 .
|
15339344_p11
|
15339344
|
Interaction between SNP and another SNP for CAA
| 4.169306 |
biomedical
|
Study
|
[
0.9994720816612244,
0.00025275489315390587,
0.00027518568094819784
] |
[
0.9994937181472778,
0.00016352433885913342,
0.0002851156168617308,
0.00005760172280133702
] |
en
| 0.999998 |
In the next step, 3-SNP combinations were analyzed. The effective rate, the random selection rate, and the concentration ratio were calculated as well as the case of 2-SNP combination (Table 5 ). It was found to be 2.28 for each of the 10 selected SNPs alone (3:0 in Table 5 ), 1.33 for 2 of the 10 selected SNPs and 1 of the remaining 15 SNPs (2:1 in Table 5 ), 0.67 for 1 of the 10 selected SNPs and 2 of the remaining 15 SNPs (1:2 in Table 5 ), and 0.94 for the remaining 15 SNPs alone (0:3 in Table 5 ). The concentration ratio was higher for combinations among the 10 selected SNPs than for other combinations, so we can select 3-SNP combinations associated with CAA with high rate. The combination with the lowest ECV3 consisted of the genes IL-4Rα , and C3 . This is about 3% of the value multiplied each P -value of 2-SNP combination . For patients with genotype GA of IL-4Rα (148 G/A: Val50Ile) and genotype CT of C3 , patient frequency against genotype of C3 had a P -value of 0.01784. For C3 alone, a P -value of 0.6993 was obtained, which was 40 times greater than the P -value of the 3-SNP combination. Thus the rate of correct identification of effective combinations evaluated by adjusted P -value and ECV selected based on PDM trials was higher than the corresponding randomized rate, implying that the ANN can reliably select SNP combinations that are associated with CAA.
|
15339344_p12
|
15339344
|
Interaction between SNP and another SNP for CAA
| 4.142098 |
biomedical
|
Study
|
[
0.9994450211524963,
0.00030960459844209254,
0.0002453725610394031
] |
[
0.9994296431541443,
0.000177076188265346,
0.0003330246836412698,
0.000060246908105909824
] |
en
| 0.999995 |
The 2-SNP combinations with the conditions described above among selected 10 SNPs are shown in Table 6 . For example, in Table 6 , for combinations between CysLT2 and IL-4Rα (148 G/A: Val50Ile), among subjects with a CysLT2 genotype of AG or GG (CAA, 107 subjects; healthy controls, 103 subjects), there was an important correlation with IL-4Rα (148 G/A: Val50Ile) genotype of GG, GA, AA . We examined the distributions of important combinations among subjects. A total of 52 CAA subjects and 24 healthy controls had genotype AG or GG at CysLT2 and genotype GG at IL-4R α (148 G/A) .
|
15339344_p13
|
15339344
|
Interaction between SNP and another SNP for CAA
| 4.064765 |
biomedical
|
Study
|
[
0.9994428753852844,
0.0002565664181020111,
0.00030059312121011317
] |
[
0.9995701909065247,
0.00024628039682284,
0.00013244073488749564,
0.00005112876169732772
] |
en
| 0.999997 |
The present findings also indicate that the 3-SNP combination consisting of IL-10 (-571 C/A), IL-4 (-590 C/T) and C3 is a susceptible factor of CAA . No association with CAA was found for any of these 3 SNPs alone or for any 2-SNP combinations of them . Subjects with genotype CA at IL-10 (-571 C/A), genotype CT at IL-4 (-590 C/T) (CAA, 34 subjects; healthy controls, 38 subjects) and genotype GG at C3 (CAA, 12 subjects; healthy controls, 6 subjects) were estimated to be at high risk for pathogenesis of CAA. Furthermore, among the subjects with the same genotype pattern, the number of subjects with genotype AA at C3 were CAA, 3 and healthy controls, 13, respectively .
|
15339344_p14
|
15339344
|
Interaction between SNP and another SNP for CAA
| 4.083951 |
biomedical
|
Study
|
[
0.999570906162262,
0.00022213169722817838,
0.0002069210313493386
] |
[
0.9995003938674927,
0.0001979303197003901,
0.0002487351594027132,
0.00005288124884827994
] |
en
| 0.999995 |
Other remarkable combinations shown in Table 6 were also found among the 10 selected SNPs. For example, the number of cases with GG genotype at IL-4Rα ( 148G/A) and TT genotype at C3 was 4 times the number of controls with that genotype combination (CAA, 20 subjects; healthy controls, 5 subjects) . There are no previous reports of association between these genotype combinations and CAA. The combination of IL-4Rα (148 G/A: Val50Ile) and IL-4 (-590 C/T) was also associated with CAA ; association between allergic asthma and this combination has previously been reported .
|
15339344_p15
|
15339344
|
Interaction between SNP and another SNP for CAA
| 4.024193 |
biomedical
|
Study
|
[
0.9995614886283875,
0.00019701564451679587,
0.00024147403019014746
] |
[
0.9994749426841736,
0.00028684260905720294,
0.00018153015116695315,
0.00005668723679264076
] |
en
| 0.999998 |
To characterize the development mechanism, we investigated several relationships between SNPs and development of CAA, referring to previous papers, as described below. IL-4 is produced by Th2 cells, and exerts its activity by interacting with the receptor IL-4Rα, located on the surface of B cells. It has been reported that the V50 (148G)/R551 combination of IL-4Rα polymorphisms may be associated with enhancement of IL-4Rα function . As concerns the polymorphisms on IL-4 , it was reported that the -590T allele increases the strength of the IL-4 promoter compared with the -590C allele . C3 is a proinflammatory mediator that binds to specific cell surface receptors and causes leukocyte activation, smooth muscle contraction and vascular permeability . C3 -deficient mice challenged with allergen show diminished airway hyperresponsiveness and lung eosinophilia, with dramatic reduction of the number of IL-4-producing cells and attenuation of IgE responses . In the present study, we found that interaction between genotype TT at C3 and genotype GG at IL-4Rα (148 G/A) may be associated with CAA, but details of interaction between these polymorphisms combinations and development mechanisms have not been clarified. The present findings indicate that, among subjects with an IL-10 (-571 C/A) genotype of CA and an IL-4 (-590 C/T) genotype of CT, there is important correlation with a C3 genotype of GG or AA .
|
15339344_p16
|
15339344
|
Discussion
| 4.163643 |
biomedical
|
Study
|
[
0.9994931221008301,
0.00027902305009774864,
0.0002277817256981507
] |
[
0.9995261430740356,
0.00018201583588961512,
0.0002242966293124482,
0.00006758617382729426
] |
en
| 0.999996 |
CysLTs, which are produced by inflammatory cells including eosinophils, are mediators of leukotrienes, and have been implicated in the pathogenesis of allergic diseases. Recently, it has been reported that CysLTs can act as autocrine or paracrine mediators to stimulate rapid, nonexocytotic release of IL-4 . These findings are consistent with the present results, in which subjects with CT or TT genotype at IL-4 (-590 C/T), AG or GG genotype at CysLT2 and GG genotype at IL-4Rα (148 G/A) were estimated to be at high risk for pathogenesis of CAA . However, 2-SNP interaction between CysLT2 and IL-4Rα (148 G/A) markedly affected the 3-SNP interaction.
|
15339344_p17
|
15339344
|
Discussion
| 4.123917 |
biomedical
|
Study
|
[
0.9996241331100464,
0.00019336940022185445,
0.00018242071382701397
] |
[
0.9994218349456787,
0.00024062908778432757,
0.0002749748236965388,
0.0000626291730441153
] |
en
| 0.999997 |
In the present study, we examined correlation between CAA and 25 SNPs in 17 genes using an ANN model. We think that there are not a few main effects and interactions which can explain development of multifactorial disease like CAA, because it is thought that interactions of genetic risk factors might be different individually among CAA patients in spite of same disease. So it is very important to select multiple genetic factor models associated with multifactorial disease like CAA with high concentration ratio. We found that 10 of these SNPs are important factors in development of CAA. Important combinations among these 10 SNPs were also extracted. As described above, several of these combinations (listed in Table 6 etc.) have been found to be important factors in allergic disease, in previous biological and epidemiological studies. We also found several novel important combinations. The present data about important combinations suggests multiple patterns of CAA development. It should be noted that these findings were obtained automatically using an ANN model constructed without priori knowledge. Using an ANN model with 10 SNPs, we were able to discriminate between cases and controls with more than 70% accuracy. We concluded that the ANN is an effective tool for predicting development of CAA, using SNP data. However, further investigation of other genetic and environmental factors associated with CAA is needed. We previously constructed an advanced modeling method, the fuzzy neural network , which is an ANN model. When this model is applied to analysis, the susceptibility rules of interaction can be explicitly and linguistically described. Also, it can be used to describe susceptible interaction between genetic factors such as SNPs and environmental factors such as favorite foods and life style. Using the rules obtained with this model, we can plan protocols for preventive treatment of subjects with high-risk genetic profiles. Network analysis tools such as ANNs can be applied to analysis of multifactorial disease using SNP data such as selection of important SNPs or description of interactions between SNPs.
|
15339344_p18
|
15339344
|
Discussion
| 4.169063 |
biomedical
|
Study
|
[
0.9994625449180603,
0.0003413986414670944,
0.00019606314890552312
] |
[
0.9990286827087402,
0.00022180001542437822,
0.0006634676828980446,
0.00008611030352767557
] |
en
| 0.999997 |
Relationships between CAA and 25 SNPs in 17 candidate genes were analyzed using an ANN. In diagnostic prediction, ANN discriminated cases from controls more precisely than LR. From among the 25 original SNPs analyzed, we selected 10 SNPs that were closely associated with CAA. Calculating P -value using the χ 2 test, we found that 2-SNP and 3-SNP combinations of these 10 SNPs were associated with CAA. The ANN was able to represent associations between CAA and these 2-SNP or 3-SNP combinations using complicated nonlinear relations. Thus, the ANN can be used to characterize development of complex diseases caused by multiple factors.
|
15339344_p19
|
15339344
|
Conclusions
| 4.085513 |
biomedical
|
Study
|
[
0.9996256828308105,
0.00019151972082909197,
0.00018281441589351743
] |
[
0.9993695616722107,
0.00026866630651056767,
0.00030578632140532136,
0.00005595778930000961
] |
en
| 0.999997 |
SNP data were kindly provided by the ethics committees of Tohoku University and RIKEN. We analyzed the SNP data for 25 polymorphisms in the 17 genetic regions listed in Table 1 . Each SNP was detected using the established method based on TaqMan PCR . The study population comprised 172 subjects with childhood allergic asthma (CAA) who were under 17 years of age and 172 healthy subjects with no signs or symptoms of atopy-related diseases selected from general population, all of whom gave written informed consent for SNP analysis. The subjects were diagnosed by experienced doctors, as "positive" (with allergic asthmatic symptoms) or "negative" (without allergic asthmatic symptoms). In the present paper, the subjects with CAA are referred to as "cases" and the healthy subjects are referred to as "controls". Genotype patterns of the 25 SNPs were compared between cases and controls. None of the cases had genotype patterns coinciding with those of controls.
|
15339344_p20
|
15339344
|
Subjects and SNP data
| 4.013065 |
biomedical
|
Study
|
[
0.999382734298706,
0.0003594346344470978,
0.0002577828709036112
] |
[
0.9995821118354797,
0.00021152333647478372,
0.00014757529424969107,
0.000058790195907931775
] |
en
| 0.999997 |
To use SNP data as input data for the ANN, we converted the genotyping data into 2-numeral data. In ANN modeling, input and output variables are normalized into 0.1–0.9 . In SNP data, there are 3 genotypes per locus. Therefore, we provided 2 inputs per SNP: (0.1, 0.1) for homozygote of the major allele, (0.1, 0.9) for heterozygote, and (0.9, 0.9) for homozygote of the minor allele. Since from the genetic point of view it may be difficult to estimate that heterozygote affects a disease by half the extent that homozygote affects it, the coding of (0.1), (0.5) and (0.9) was never used. The diagnosis data were also converted into numerical data, referred to hereafter as "teacher" values: 0.9 for "positive (case)", and 0.1 for "negative (control)".
|
15339344_p21
|
15339344
|
Data preprocessing
| 4.037771 |
biomedical
|
Study
|
[
0.9995806813240051,
0.00013665994629263878,
0.00028266580193303525
] |
[
0.9983088970184326,
0.0013661402044817805,
0.0002616465790197253,
0.00006327272421913221
] |
en
| 0.999997 |
For LR, we converted SNP data into numerical input data as follows: (0.1, 0.1) for homozygote of the major allele, (0.1, 0.9) for heterozygote, and (0.9, 0.9) for homozygote of the minor allele. Positive and negative diagnoses were also converted into numerical data: 0.9 and 0.1, respectively.
|
15339344_p22
|
15339344
|
Data preprocessing
| 3.888315 |
biomedical
|
Study
|
[
0.9995883107185364,
0.00015250869910232723,
0.00025912094861268997
] |
[
0.9967525005340576,
0.0028803502209484577,
0.000271035562036559,
0.00009615622548153624
] |
en
| 0.999997 |
For SNP analysis, we used a three-layered ANN with input, hidden and output layers . For model construction, the performance index of the ANN was assessed using a method we previously proposed , with slight modifications. N error (number of missed points) and Er (sum of squared error) were defined and calculated for learning data and evaluation data as follows:
|
15339344_p23
|
15339344
|
ANN model and model construction
| 3.866953 |
biomedical
|
Study
|
[
0.9989156723022461,
0.0001732625678414479,
0.0009111329563893378
] |
[
0.9988264441490173,
0.0009667145786806941,
0.000155051879119128,
0.000051854814955731854
] |
en
| 0.999997 |
N error = N error , l + N error , e (3)
|
15339344_p24
|
15339344
|
ANN model and model construction
| 1.536568 |
biomedical
|
Other
|
[
0.7413384914398193,
0.0018449148628860712,
0.2568166255950928
] |
[
0.15161490440368652,
0.8447360992431641,
0.0026202464941889048,
0.0010287066688761115
] |
da
| 0.999992 |
where Y and T represent the predicted value and the teacher value, respectively. N l and N e represent the number of subjects as learning and evaluation data, respectively. N error is the number of output data with an error of >0.4 between the predicted value and teacher value as shown above. Er is calculated with the square of error as shown above. For ANN learning, the connection weights were initially randomly set from 0 to 1, and were altered using the back propagation methods with learning data so as to minimize the value of Er l . Learning rates of 0.1, 0.2, 0.3, 0.4 and 0.5 were examined. The maximum learning time was 2000 iterations. The best ANN model (selected for SNP analysis) was that in which N error reached minimum within the maximum learning time. When minimum N error was equal to that of other models within the maximum learning time, the model with minimum Er value was selected.
|
15339344_p25
|
15339344
|
ANN model and model construction
| 3.269307 |
other
|
Study
|
[
0.3630639612674713,
0.0005086387973278761,
0.6364274024963379
] |
[
0.916942298412323,
0.08165255188941956,
0.0011136089451611042,
0.0002915598452091217
] |
en
| 0.999997 |
Prediction accuracy of the constructed model was defined as follows. Threshold was set at 0.5. If the teacher value was 0.9, and the predicted value was greater than 0.5, the prediction was true (true positive; TP); for predicted values lower than 0.5, the prediction was false (false negative; FN). If the teacher value was 0.1, and the predicted value was lower than 0.5, the prediction was true (true negative; TN); for predicted values greater than 0.5, the prediction was false (false positive; FP).
|
15339344_p26
|
15339344
|
ANN model and model construction
| 3.562512 |
biomedical
|
Study
|
[
0.9957226514816284,
0.00036349595757201314,
0.00391384307295084
] |
[
0.9482408761978149,
0.05099175497889519,
0.0005508183967322111,
0.00021650517010129988
] |
en
| 0.999999 |
We calculated the prediction accuracy ( Ac ) as follows:
|
15339344_p27
|
15339344
|
ANN model and model construction
| 2.136029 |
biomedical
|
Study
|
[
0.9691677093505859,
0.001177090685814619,
0.029655221849679947
] |
[
0.9379429221153259,
0.059316739439964294,
0.002066596643999219,
0.0006737544317729771
] |
en
| 0.999998 |
The sensitivity ( Se ) and specificity ( Sp ) of predicted values were defined as follows:
|
15339344_p28
|
15339344
|
ANN model and model construction
| 3.024989 |
biomedical
|
Study
|
[
0.9980893731117249,
0.0004296953266020864,
0.0014809404965490103
] |
[
0.9800142049789429,
0.01903468556702137,
0.0007261052960529923,
0.00022508671099785715
] |
en
| 0.999997 |
where N TP , N FN , N TN and N FP are the number of TN, FN, TN and FP subjects, respectively. N case and N control are the number of case and control subjects, respectively.
|
15339344_p29
|
15339344
|
ANN model and model construction
| 2.327178 |
biomedical
|
Study
|
[
0.9859610795974731,
0.0006761001423001289,
0.013362843543291092
] |
[
0.540547788143158,
0.45703381299972534,
0.0016065979143604636,
0.0008117477991618216
] |
en
| 0.999996 |
In order to extract SNPs closely associated with CAA, we selected the input variables by parameter decreasing method (PDM) after the ANN model with 25 SNPs was constructed. In PDM, 1 SNP was excluded from input variables in turn, and ANN models were constructed with the remaining 24 SNPs by performing the cross-validation described below. From among the 25 models thus constructed, the model with minimum N error averaged in the cross-validation step was selected. When minimum N error was equal to that of other models within the maximum learning time, the model with minimum Er value was selected as described above. The PDM step was repeated until 1 SNP remained as input variable. The PDM procedure was performed 5 times with unifying learning rates of 0.1 and learning time of 2000, and the rank of importance of selected SNPs was determined as described in Results section. We performed 5 PDM trials so that the effects of randomized initial connection weights might be minimized. In 5 PDM trials, data set for cross-validation mentioned below was reconstructed every time.
|
15339344_p30
|
15339344
|
Parameter Decreasing Method (PDM)
| 4.088194 |
biomedical
|
Study
|
[
0.9994220733642578,
0.00020351141574792564,
0.0003744631540030241
] |
[
0.9995349645614624,
0.0002248119271825999,
0.0001980884262593463,
0.00004221634299028665
] |
en
| 0.999997 |
Cross-validation allows estimation of the prediction error of a model by leaving out a portion of the data as an evaluation data . In the present study, to investigate the flexibility of the ANN, learning and evaluation were performed using the ANN and 5-fold cross-validation. With 5-fold cross-validation, the data set for the 172 cases and 172 controls was divided into 5 groups with randomizing and alternating the data. In each group, the number of cases was equal to that of controls. Four groups were assigned as learning data, and 1 group was assigned as evaluation data; this learning and evaluation process was repeated 5 times, so that each group was assessed once as evaluation data. Then, the prediction accuracy of evaluation data across all 5 trials was calculated and averaged for the overall prediction accuracy of the ANN model shown in Table 2 . Sensitivity and specificity were also calculated.
|
15339344_p31
|
15339344
|
Cross-validation
| 4.086065 |
biomedical
|
Study
|
[
0.999206006526947,
0.00024308980209752917,
0.0005508651374839246
] |
[
0.999620795249939,
0.00020667458011303097,
0.00013883045176044106,
0.00003363428550073877
] |
en
| 0.999999 |
An LR model was constructed using SPSS 11.5J statistic software for Windows (SPSS Japan Inc., Tokyo), for comparison with the ANN model. All 25 SNPs were used as input variables of LR. For LR analysis, we used 50 main effects plus an intercept but not any interaction terms. As with the ANN model, the data set was divided into 5 groups and the cross-validation was performed. Prediction accuracy, sensitivity and specificity were calculated.
|
15339344_p32
|
15339344
|
Logistic Regression (LR) Model
| 3.962858 |
biomedical
|
Study
|
[
0.9990794658660889,
0.00018337246729061007,
0.0007370948442257941
] |
[
0.9994279742240906,
0.0003825745661742985,
0.000148779756273143,
0.000040589337004348636
] |
en
| 0.999999 |
We also examined association between CAA and combinations of SNPs by calculating P -value using a χ 2 test. The χ 2 test was used to evaluate the differences in frequencies of alleles or genotypes between cases and controls. The P -values shown in Table 1 were calculated using 172 cases and 172 controls. Degree of freedom (D.F.) (shown in Table 1 ) was 2 for 3 types of subjects; e.g., homozygote of the major allele, heterozygote, and homozygote of the minor allele. In the test with one SNP, when the expectancy for subjects homozygous for the minor allele (calculated from the frequency of the genotype) was less than 5 subjects for both case and control, we regarded the homozygote of the minor allele and the heterozygote as identical and defined degree of freedom as 1. In the tests with 2-SNP and 3-SNP combinations, we used the D.F. shown in Table 1 to find the change of differences in frequency under the same condition of SNP alone. If, in more than 5 subjects, all expectancies for subjects satisfied the test conditions, we calculated P -value with χ 2 test. In order to determine important combinations, we use two evaluation bases ( P -value and effective combination value (ECV)) mentioned in Results section.
|
15339344_p33
|
15339344
|
Determination of differences in frequency of alleles and genotypes
| 4.088964 |
biomedical
|
Study
|
[
0.9995149374008179,
0.00023884819529484957,
0.0002462172124069184
] |
[
0.9995399713516235,
0.00017252999532502145,
0.00024037148978095502,
0.000047144094423856586
] |
en
| 0.999997 |
YT carried out ANN modeling of SNP data including PDM and calculating P -value using a χ 2 test. ST and YH carried out the basic analysis using ANN and data preprocessing. YS and TS participated in providing of SNP data and the design of LR analysis. TK participated in the design of the study. HH conceived of the study, and participated in its design and coordination. All authors read and approved the final manuscript.
|
15339344_p34
|
15339344
|
Authors' contributions
| 1.028477 |
biomedical
|
Other
|
[
0.7911098599433899,
0.0034038161393254995,
0.2054862678050995
] |
[
0.04670843482017517,
0.9491814970970154,
0.002708607818931341,
0.0014014407061040401
] |
en
| 0.999995 |
The success of dopaminergic interventions in the treatment of Parkinson's disease (PD) symptoms has been significant. Nevertheless, a misdiagnosis of PD can cause psychological trauma and unnecessarily expose patients to PD drugs. Additionally, as new, and possibly neuroprotective, drugs become available for the treatment of PD, early and accurate diagnosis will become increasingly important. As the diagnosis of PD is usually based on subjective clinical assessment of overt symptomatology , the need for an objective and reproducible battery of diagnostic tests is great. Medical imagery offers some hope for the objective diagnosis of PD (e.g. 18 F-dopa positron emission tomography ), but these techniques tend to be expensive, and inaccessible to patients living in remote areas. What is truly needed is a low-cost objective test battery that might be used in situations where (a) movement disorder specialists are unavailable to render expert diagnoses, and (b) medical imaging is inaccessible.
|
15361256_p0
|
15361256
|
Background
| 3.987895 |
biomedical
|
Review
|
[
0.9960758090019226,
0.0027922731824219227,
0.0011318831238895655
] |
[
0.01987355947494507,
0.03291483223438263,
0.9459888339042664,
0.0012227798579260707
] |
en
| 0.999999 |
Montgomery et al. have published one of the better known objective PD batteries, incorporating measures of motor performance, olfaction, and mood. The aggregate of all subtests of this battery has demonstrated good diagnostic properties, with a sensitivity of approximately 70%, and a specificity of approximately 90%. Given that the primary symptoms of PD are motoric , however, it is interesting to note that the sensitivity of the motor task in this PD battery is approximately 50% , indicating that diagnoses based solely on this subtest are not much better than chance. As the predictive power of a battery increases with the addition of each valid and independent subtest, it is important to evaluate motor performance paradigms that may produce better predictive validity.
|
15361256_p1
|
15361256
|
Background
| 4.037435 |
biomedical
|
Study
|
[
0.9995008707046509,
0.00018082041060552,
0.00031821857555769384
] |
[
0.9827533960342407,
0.0007059559575282037,
0.016431821510195732,
0.00010884562652790919
] |
en
| 0.999997 |
The global slowing that is consistently demonstrated by PD patients suggests that measures of cognitive or motor speed are logical methods for obtaining quantitative measurements of PD severity. As reaction time (RT) and movement time (MT) have repeatedly been demonstrated to show substantive and significant deficits in PD populations (for a review of this literature, see Gauntlett-Gilbert et al. ), these indicators are (by definition) capable of distinguishing individuals with PD from healthy participants. Despite this fact, however, the motor subtest of the PD battery described by Montgomery et al. remains the only significant attempt at evaluating diagnostic accuracy with these chronometric indicators. Although this subtest measures both RT and MT, the task is performed in a biomechanically complicated fashion that requires the participant to move his/her hand in an arc (i.e. wrist flexion and extension) to aim at LED targets. This test assesses both rigidity and bradykinesia within the same task – and while this is a conceptually defensible measurement decision, the resulting inter-subject variability may overwhelm group differences, and confound diagnostic accuracy. It is, therefore, worth examining the extent to which a simpler paradigm might be used to distinguish PD patients from healthy participants.
|
15361256_p2
|
15361256
|
Background
| 4.133226 |
biomedical
|
Review
|
[
0.9981541037559509,
0.0007516565965488553,
0.001094249659217894
] |
[
0.435782790184021,
0.0011051016626879573,
0.5626767873764038,
0.0004353879194241017
] |
en
| 0.999996 |
The goal of this study, therefore, is to evaluate the diagnostic properties of a choice reaction time task that uses a simple external response console (i.e. a "button box"), similar to other similar response time tasks extant within the PD literature.
|
15361256_p3
|
15361256
|
Background
| 3.104271 |
biomedical
|
Study
|
[
0.9939351677894592,
0.0006579309701919556,
0.005406931508332491
] |
[
0.998670220375061,
0.0009976101573556662,
0.00024338292132597417,
0.00008888609590940177
] |
en
| 0.999996 |
Two independent samples were drawn for this study, the first consisting of 40 PD patients (Age: M = 62.13, SD = 9.59) and 40 healthy participants (Age: M = 65.02, SD = 8.84), and the second consisting of 20 PD patients (Age: M = 64.50, SD = 10.88) and 20 healthy participants (Age: M = 62.65, SD = 12.02). To ensure that no baseline ability differences existed between groups, Wechsler Adult Intelligence Scale (WAIS) full scale IQ estimates were computed for all participants, using the National Adult Reading Test (NART) . No significant age or IQ differences were identified between patients and controls, in either sample. During the course of testing, patients were also assessed by an experienced clinician (using the motor subscale of the Unified Parkinson's Disease Rating Scale; UPDRS), to determine the severity of their motor symptoms . Patients demonstrated mild to moderate motor symptoms in both the first ( M = 24.49, SD = 9.79), and the second sample ( M = 22.73, SD = 7.66), with no significant severity differences demonstrated between samples. The spectrum of motor severity within the clinical group is graphically depicted with an area graph in Figures 1 and 2 , corresponding to the norming sample and the cross-validation sample, respectively. Finally, all participants were demonstrated to have a Mini-Mental Status Examination (MMSE) score of at least 27 at the time of testing.
|
15361256_p4
|
15361256
|
Methods
| 4.092164 |
biomedical
|
Study
|
[
0.9992539286613464,
0.000520851113833487,
0.0002252362173749134
] |
[
0.9994660019874573,
0.00016363522445317358,
0.00029596229433082044,
0.00007438117609126493
] |
en
| 0.999996 |
The response time tasks used in this study started with an instruction to watch a fixation point (asterisk) in the centre of the computer screen, while depressing the home key (measuring 1.905 cm × 1.905 cm) in the centre of the response console. For the 'uncued' task, participants were not given any advance information concerning the location of the upcoming stimulus. For the 'cued' task, an arrow appeared in place of the fixation point (i.e. in the center of the screen) for a period of 2 seconds, immediately following the disappearance of the fixation point, and correctly cued the location of the upcoming stimulus on all trials. The visual stimulus to which the subject responded was presented on the right or left side of the monitor, at a random interval following the fixation point ('uncued') or the arrow ('cued'). Participants responded to the stimulus by moving the index finger of their dominant hand from the home key to a response key (measuring 1.905 cm × 1.905 cm) placed 3.175 cm to the left or right of the home key, as directed by the stimulus placement on the screen. The time measured between the onset of the visual stimulus and a participant's movement from the home key was defined as reaction time (RT), and the time measured between a participant's lift from the home key and depression of the response key was defined as movement time (MT). Each task consisted of 10 practice trials, and 40 experimental trials. A participant's RT and MT was computed as the unit-weighted average of scores on the 'cued' and 'uncued' choice response time tasks. This testing apparatus is described in further detail by Johnson et al. .
|
15361256_p5
|
15361256
|
Methods
| 4.091684 |
biomedical
|
Study
|
[
0.9988075494766235,
0.0004942373489029706,
0.0006981806363910437
] |
[
0.9994584918022156,
0.0002757798647508025,
0.00021012284560129046,
0.000055614284065086395
] |
en
| 0.999994 |
All patients involved in the study were asked to remain drug-free overnight, and to delay taking their morning anti-Parkinsonian medications until after the testing. To avoid any confounding effects resulting from different levels of caffeine intake among participants, all participants were asked to have a normal caffeine-free breakfast prior to testing. None of the participants reported any acute physiological conditions that may have precluded them from putting forth their best effort during the testing session. All procedures and materials were approved by the Health Sciences Research Ethics Board at the University of Western Ontario.
|
15361256_p6
|
15361256
|
Methods
| 2.552521 |
biomedical
|
Study
|
[
0.9922113418579102,
0.006518254056572914,
0.0012704754481092095
] |
[
0.9759071469306946,
0.022579731419682503,
0.0006358125829137862,
0.0008773059234954417
] |
en
| 0.999996 |
In the first sample (40 patients and 40 healthy participants), separate receiver operator characteristic (ROC) curves were generated for the composite RT and MT scores. The best prediction (i.e. the largest area under the ROC curve) was achieved using the composite MT score. The cutoff score was identified as the point on the curve that maximized sensitivity, with a specificity of at least 70%. This cutoff score was determined to be 230 ms (i.e. individuals with a MT of at least 230 ms were identified as having PD). To control for the possibility that classification success in the first sample was the result of a capitalization on sample-specific variability , this classification strategy (i.e. the cutoff score identified from the ROC within the first sample) was cross-validated in the second sample (20 patients and 20 healthy participants). Classification results and diagnostic efficacy variables for both samples are presented in Table 1 .
|
15361256_p7
|
15361256
|
Results
| 4.092055 |
biomedical
|
Study
|
[
0.9993755221366882,
0.00037188781425356865,
0.00025255599757656455
] |
[
0.9994636178016663,
0.0002119576238328591,
0.00026583008002489805,
0.00005866461287951097
] |
en
| 0.999997 |
To identify the extent to which response time predicted disease progression, correlations were computed between the UPDRS and the aggregate RT and MT scores. As the samples demonstrated no significant differences on the UPDRS, correlations were computed across all data collected in both samples. Both RT (r = 0.23, n.s.) and MT (r = 0.59, p < 0.025) were positively correlated with the UPDRS, suggesting that these response time tasks are good predictors of the severity of Parkinsonian symptoms, particularly when considering the MT component of response time.
|
15361256_p8
|
15361256
|
Results
| 4.087101 |
biomedical
|
Study
|
[
0.9993292093276978,
0.00042127404594793916,
0.0002495435473974794
] |
[
0.9993383288383484,
0.00016116222832351923,
0.00043526568333618343,
0.00006519595626741648
] |
en
| 0.999997 |
This study confirms previous research that has shown significant movement time (MT) differences between PD patients and healthy participants . The results of the present study also suggest that MT composites on biomechanically simple response time tasks demonstrate high cross-validated sensitivity and specificity for 'unmedicated' patients (i.e. patients that have been temporarily withdrawn from their dopaminergic medications) – and that these values may be higher than the demonstrated sensitivity and specificity of the motor subtest employed by Montgomery et al. .
|
15361256_p9
|
15361256
|
Discussion
| 4.078234 |
biomedical
|
Study
|
[
0.9993755221366882,
0.00041444451198913157,
0.00021007873874623328
] |
[
0.999249279499054,
0.00017321652558166534,
0.0004981269012205303,
0.00007935672329040244
] |
en
| 0.999994 |
Standardized objective test batteries will be diagnostically useful in two general scenarios: (a) as an adjunct to the physical examination performed by a specialist (to improve diagnostic accuracy), and (b) as a standardized preliminary screening tool, for situations in which a movement disorders expert is unavailable for the physical examination. The latter situation is more important than the former, as primary care physicians are often the first point of contact for these patients. Given the waiting times to see a movement disorders specialist, patients that are considered likely to have PD (based on a screening measure) might be assigned a higher priority in their wait for an initial appointment. This assumes, of course, that primary care physicians will have access to the appropriate motor performance testing devices – and while this is currently prohibitive from a logistical standpoint, it is technologically feasible for the simple tasks described herein to be packaged in smaller (perhaps handheld), less expensive devices.
|
15361256_p10
|
15361256
|
Discussion
| 3.983145 |
biomedical
|
Study
|
[
0.990437924861908,
0.00896536186337471,
0.0005966946482658386
] |
[
0.5734429359436035,
0.3972557783126831,
0.025563383474946022,
0.0037378680426627398
] |
en
| 0.999999 |
A MT battery may also allow for the communication of results in a "common metric" – without relying on subjective clinical judgments, thereby complementing other clinical tools. Aside from its diagnostic utility, MT batteries may also be useful in tracking a patient's progress as he/she undergoes treatment. At present, motor evaluations conducted during the clinical exam are the only method for tracking change, and this is considerably more qualitative than the MT measures described herein. Along similar lines, MT batteries could make useful adjuncts to clinical drug trial protocols, as they provide good quantitative measures of motor skill that may be used to gauge the effectiveness of the medication under study – in the present study, MT was able to explain 34.81% of the variability in UPDRS motor scores.
|
15361256_p11
|
15361256
|
Discussion
| 4.0699 |
biomedical
|
Study
|
[
0.9994675517082214,
0.00038943879189901054,
0.00014303321950137615
] |
[
0.9967696666717529,
0.0009986583609133959,
0.0021045871544629335,
0.0001271138753509149
] |
en
| 0.999998 |
It should, of course, be noted that the present research was only used to separate PD patients from healthy participants, and so it has not been demonstrated to have any differential diagnostic capabilities (e.g. distinguishing PD from progressive supranuclear palsy). Future research in this area should, therefore. investigate the differential diagnostic power of response time batteries – it may be that the MT battery administered in this study are detecting a general 'impairment' factor, and is not useful as a standalone instrument for the diagnosis of Parkinson's disease. Extending the study base to include patients with disorders such as progressive supranuclear palsy would provide important information concerning appropriate norming that may be done to maximize diagnostic utility.
|
15361256_p12
|
15361256
|
Discussion
| 3.915058 |
biomedical
|
Study
|
[
0.9994449019432068,
0.00013028555258642882,
0.0004247273609507829
] |
[
0.9952905178070068,
0.002245170995593071,
0.0023862402886152267,
0.00007808057125657797
] |
en
| 0.999997 |
At the very least, however, these results suggest that the use of simple response time batteries may serve as a useful adjunct to other clinical assessment batteries, and may also open interesting avenues of exploration into the consideration of the biological underpinnings of reaction time, and its relationship to movement disorders in general.
|
15361256_p13
|
15361256
|
Discussion
| 3.346745 |
biomedical
|
Study
|
[
0.9967404007911682,
0.0003579510375857353,
0.002901599509641528
] |
[
0.8136882781982422,
0.15421216189861298,
0.03135572373867035,
0.0007437616586685181
] |
en
| 0.999997 |
None declared.
|
15361256_p14
|
15361256
|
Competing interests
| 0.828596 |
other
|
Other
|
[
0.19056588411331177,
0.00526782963424921,
0.804166316986084
] |
[
0.017649328336119652,
0.97890704870224,
0.0020668187644332647,
0.0013767849886789918
] |
it
| 0.857139 |
AJ conceived and designed the study, collected all data in the norming sample, supervised data collection in the cross-validation sample, supervised data analysis, and contributed to the writing of the paper. PV supervised data collection in the norming sample, assisted in the development of the response time tasks, contributed to the data analysis, and to the writing of the paper. QA assisted with data collection in the cross-validation sample, and contributed to the writing of the paper. LG did all clinical testing on patients in the norming sample. RS assisted with data collection in the cross-validation sample. MJ provided patient diagnoses for participants in the norming sample and the cross-validation sample, and contributed to the writing of the paper.
|
15361256_p15
|
15361256
|
Authors' contributions
| 0.960196 |
other
|
Other
|
[
0.20857663452625275,
0.0037621408700942993,
0.7876612544059753
] |
[
0.027612753212451935,
0.9704861044883728,
0.0010814309353008866,
0.0008198274881578982
] |
en
| 0.999998 |
All authors have read and approved the final manuscript.
|
15361256_p16
|
15361256
|
Authors' contributions
| 0.884907 |
other
|
Other
|
[
0.04356927424669266,
0.002697407267987728,
0.9537333250045776
] |
[
0.002202090807259083,
0.9948587417602539,
0.0020482451654970646,
0.0008908432791940868
] |
en
| 0.999997 |
The pre-publication history for this paper can be accessed here:
|
15361256_p17
|
15361256
|
Pre-publication history
| 1.031347 |
other
|
Other
|
[
0.013091341592371464,
0.0014214670518413186,
0.9854872226715088
] |
[
0.0015875872923061252,
0.997281551361084,
0.0006836647517047822,
0.0004471398133318871
] |
en
| 0.999997 |
Neurofibromatosis type-1 (NF-1) is a common autosomal dominant disorder characterized by multiple neurofibromas, café-au-lait spots, freckling of the inguinal or axillary regions, gliomas, iris hamartomas, and malignant peripheral nerve sheath tumors . Neurofibromas are typically well-delineated and are composed of an admixture of various cell types, such as Schwann cells, fibroblasts and perineural-like cells and cells showing intermediate features . Although as outlined above, multiple neurofibromas are characteristic of patients with NF-1, however, most cases of neurofibroma which are diagnosed in general are sporadic in nature. The vast majority of neurofibromas are cutaneous and less commonly are intraneural, within the soft tissues or viscera. Presacral neurofibromas or neurofibromas with presacral involvement are uncommon in patients without NF-1, and have been the subject of sporadic case reports over the past half-century . Likewise, spitzoid melanoma or melanomas showing spitzoid-like features form only a small percentage of all malignant melanomas. This diagnosis is based on the rare finding that some melanomas displays cytologic features that are similar to those identified in the benign Spitz nevus . The controversy associated with this lesion stems from the fact that some dermatopathologists do not believe in its existence and prefer to designate melanocytic proliferations meeting traditional criteria for malignancy as malignant melanomas, irrespective of the Spitzoid features . To our knowledge, a synchronous presacral neurofibroma and cutaneous spitzoid melanoma have never been reported in a patient without neurofibromatosis. More importantly, the absence of NF-1 in our patient may have implications for the potential association between malignant melanoma and NF-1.
|
15363097_p0
|
15363097
|
Background
| 4.429018 |
biomedical
|
Study
|
[
0.9943491816520691,
0.005411484744399786,
0.00023931986652314663
] |
[
0.9496126770973206,
0.014033769257366657,
0.006733729969710112,
0.029619723558425903
] |
en
| 0.999996 |
In September 2000, a 35-year-old female without any history or clinical stigmata of NF-1 presented to her primary physician with complaints of a dull, localized left upper leg pain of several months' duration. An abdominal mass was palpated during a physical examination. Magnetic resonance imaging (MRI) as well as a computed tomographic (CT) scan of the abdomen and pelvis showed a large well-defined, near spherical mass in the left false pelvis which enhanced heterogeneously at a mean Hounsfield value of 44 units . The mass displaced the external iliac vein medially and psoas muscle laterally. It also abutted the upper surface of the left ovary without truly invading any of these or other surrounding structures. However, the mass was believed to be in the course of the left genitofemoral nerve and lumbar plexus. The decision was made to resect the mass. Intraoperatively, the tumor's capsule was found to be densely adhered medially to the external iliac vessels, with at least 10 external venous branches directly supplying the tumor. The tumor was carefully marsupialized out of the retroperitoneal area and the decision was made to leave the residual capsule, since an attempt at its removal would have entailed a highly morbid procedure that was not felt to be justified based on the histopathologic appearance of the tumor on frozen sections. Intraoperatively, a pigmented macular lesion with faintly irregular edges was noted in the left upper thigh, which was biopsied. Pathologic examination showed a malignant melanoma with spitzoid features. The precise circumstances regarding the duration of the lesion and whether there had been any increase in its size was unclear. She subsequently underwent a wide local excision (4 × 12 cm skin ellipse was removed) and sentinel lymph node biopsy, both of which showed no residual melanoma. The patient's postoperative course over the subsequent 2 years was remarkable for a relatively slow but progressive improvements in the neurologic symptoms related to her surgery. However, she showed no evidence of either tumor recurrence at last follow-up, 26 months postoperatively.
|
15363097_p1
|
15363097
|
Case presentation
| 3.941712 |
clinical
|
Clinical case
|
[
0.0819859430193901,
0.9142793416976929,
0.0037347052711993456
] |
[
0.006977913435548544,
0.0072780791670084,
0.005443372763693333,
0.9803006052970886
] |
en
| 0.999998 |
The resected mass was spherical, weighed 270 grams and measured 8.5 × 7 cm × 7 cm . The specimen was sectioned to reveal a myxoid tan-yellow cut surface . Microscopically, the specimen was uniformly hypocellular, and showed a haphazard admixture of wavy Schwann cells and collagen fibers dispersed in a mucopolysaccharide matrix . No increased cellularity, nuclear pleomorphism, increased mitotic activity or tumor coagulative cell necrosis was identified. On immunohistochemistry the tumor was positive for S100, Neurofilament, vimentin, and negative for epithelial membrane antigen, in combination with the morphological features a diagnosis of neurofibroma was made. Pathologic examination of the skin lesion showed a malignant melanoma (6 mm in diameter) with spitzoid features: epithelioid and spindle atypical melanocytes growing in a solid, asymmetric, non-maturing pattern with deep mitotic figures . The individual cells displayed nuclear pleomorphism with prominent nucleoli and the epithelioid forms showed abundant cytoplasm . Immunohistochemically, both the spindle and epithelioid cells showed strong and diffuse immunoreactivity for S100 and HMB-45. The proliferative index of the tumor was 30–40% as assessed with the immunohistochemical marker ki-67. This lesion was at a Clark's level IV and at a depth of 2.1 mm. Growth phase was vertical and ulceration was absent. A few tumor-infiltrating lymphocytes were present and there was no definitive evidence of regression.
|
15363097_p2
|
15363097
|
Pathologic findings
| 4.208225 |
biomedical
|
Clinical case
|
[
0.7411032319068909,
0.2570543587207794,
0.0018423403380438685
] |
[
0.151383176445961,
0.019520988687872887,
0.007498584222048521,
0.8215972185134888
] |
en
| 0.999997 |
The potential association between NF-1 and malignant melanoma has been the source of controversy in the medical literature. The common neural crest origin of these conditions has provided an attractive framework for this discussion. However, it is unclear whether patients with NF-1 have an inherently higher propensity to develop malignant melanomas than the general population. In a follow-up study of 70 NF-1 patients reported to the Swedish Cancer registry, 24% of the 70 patients developed 19 malignancies, only 1 of which was a melanoma . However, the precise prevalence of melanomas in NF-1 patients is largely unknown. Most melanomas that arise in the setting of NF-1 are ocular. In a recent literature review, Honavar et al identified only 19 reported cases overall. Cutaneous and anorectal melanomas have also been rarely reported in patients with NF-1 . The rarity of this association given the frequency of NF-1 suggests that the probability of NF-1 patients developing malignant melanoma is no more than the general population. However, this needs to be tested in a rigorous population-based study. Ishii et al recently reported a loss of heterozygosity (LOH) at the NF-1 gene in an anal melanoma occurring in an NF-1 patient. This suggests that the well-known Knudson's two-hit hypothesis may be operational, and that somatic loss of the second allele of the putative tumor suppressor function of the NF-1 gene causes development of this particular somatic malignancy. Again, more cases need to be studied to exclude the possibility that LOH for NF-1 occuring as a late event in the tumorigenesis of sporadic melanomas.
|
15363097_p3
|
15363097
|
Discussion
| 4.357493 |
biomedical
|
Review
|
[
0.998163640499115,
0.0008664850029163063,
0.0009698495268821716
] |
[
0.39207273721694946,
0.0012706934940069914,
0.6060914993286133,
0.0005650576204061508
] |
en
| 0.999997 |
Our case provides another framework for the discussion of the potential association between NF-1 and malignant melanoma. Our patient has no evidence of either of the neurofibromatosis syndromes. The rarity of the clinicopathologic features of both lesions identified in this patient (the unusual presacral location of the neurofibroma and the spitzoid melanoma) suggests that their association in this patient is coincidental, even though both are neural crest derived neoplasms. This presumption contradicts the notion that in patients with NF-1, malignant melanomas that rarely develop are part of their neurocristopathy. For residents of the United States, the lifetime probability of developing cutaneous melanoma is 1 in 55–82 (approximately 1.5%) . As previously noted, NF-1 is a relatively common condition with a prevalence of 1 in 3000. Since no more than 100 cases of melanoma (all sites combined) developing in NF-1 patients have been reported, the incidence is significantly lesser than the 1.5% that can be attributed to chance alone.
|
15363097_p4
|
15363097
|
Discussion
| 4.216338 |
biomedical
|
Clinical case
|
[
0.840984046459198,
0.15788407623767853,
0.0011318629840388894
] |
[
0.16940410435199738,
0.06743023544549942,
0.00971249584108591,
0.7534531354904175
] |
en
| 0.999995 |
Although the patient described in this report did not have characteristic clinical features of NF-1, an important possibility that requires consideration is that she has segmental NF-1. Segmental NF-1 is thought to result from a post-zygotic mutation in the NF-1 gene resulting in a somatic mosaicism . In these patients, characteristic NF-1-associated diseases are limited to a localized part of the body . In our patient, a presacral neurofibroma was associated with an upper thigh cutaneous melanoma, putting both lesions in the general same region, albeit without true co-localization. Additionally, melanoma is not a diagnostic criteria for NF-1, as associated lesions are required to be for the definition of segmental NF-1. The location of the current patient's neurofibroma is also somewhat unusual for segmental NF-1. In two combined series that investigated 163 patients with segmental NF-1, there was not a single case of a retroperitoneal neurofibroma . In one of these series , neurofibromas alone were the most common manifestation of segmental NF-1. However, in all such cases, the neurofibromas were either dermal, on major peripheral nerve trunks or both. Although these findings argue against segmental NF-1 in the current patient, the possibility certainly remains. Thus, the findings in this case should be viewed within the context of that possibility.
|
15363097_p5
|
15363097
|
Discussion
| 4.178814 |
biomedical
|
Study
|
[
0.950040876865387,
0.04939093813300133,
0.0005681487964466214
] |
[
0.488267183303833,
0.06908148527145386,
0.007813939824700356,
0.4348374307155609
] |
en
| 0.999998 |
In conclusion, we report here the previously unreported synchronous diagnosis of a presacral neurofibroma and a spitzoid malignant melanoma in a patient without NF-1. Furthermore, the finding of a sporadic neurofibroma and malignant melanoma occurring in a patient without NF-1 lends credence to the view that when these lesions occur in patients with NF-1, the association may be coincidental.
|
15363097_p6
|
15363097
|
Discussion
| 4.01689 |
biomedical
|
Study
|
[
0.9726758003234863,
0.027014700695872307,
0.0003095272113569081
] |
[
0.6491138935089111,
0.07818412035703659,
0.005940146278589964,
0.26676180958747864
] |
en
| 0.999996 |
None declared.
|
15363097_p7
|
15363097
|
Competing interests
| 0.828596 |
other
|
Other
|
[
0.19056585431098938,
0.005267809145152569,
0.804166316986084
] |
[
0.017649320885539055,
0.97890704870224,
0.002066816668957472,
0.0013767824275419116
] |
it
| 0.999995 |
OF and DH made substantial contributions to the intellectual content of the paper. Both co-wrote the manuscript. Both the authors have seen the final version of the manuscript and approved it for publication.
|
15363097_p8
|
15363097
|
Authors' contributions
| 0.966087 |
other
|
Other
|
[
0.004455659072846174,
0.0011246193898841739,
0.9944196343421936
] |
[
0.0007708158809691668,
0.9977387189865112,
0.0008767416002228856,
0.0006137625314295292
] |
en
| 0.999997 |
During development of the central nervous system (CNS), all types of neuronal and macroglial cells derive from neuroepithelial neural stem cells (NSCs) . NSCs self-renew and continue to function as source of new cells in adults . The fate determination of neural stem cells is regulated by cell-intrinsic programs as well as extrinsic cues from the surrounding environment . In the adult, the molecular mechanisms that regulate the production of new neurons in the dentate gyrus or in the subventricular zone are still unknown, although extrinsic factors expressed for example by astrocytes could play a role .
|
15369599_p0
|
15369599
|
Background
| 4.183908 |
biomedical
|
Study
|
[
0.9995236396789551,
0.00020582170691341162,
0.0002705937367863953
] |
[
0.9371472001075745,
0.006264179479330778,
0.05624610185623169,
0.000342533370712772
] |
en
| 0.999998 |
BMPs (Bone Morphogenetic Proteins) are secreted members of the TGF-β superfamily. Together with their receptors, they are abundantly expressed in the brain both during embryogenesis and in the adult . More specifically, an expression of BMP4 was demonstrated in different cell types like ectodermal cells , radial glia , haematopoietic cells , chondrocytes and stromal cells . As for other members of the TGF-β superfamily, BMPs signal transduction is triggered by binding to type 1 and type 2 serine-threonine kinase receptors, inducing their dimerization. In this manner, BMP2 and BMP4 signalling specifically leads to the formation of BMPR-1A/BMPR-II and BMPR-1B/BMPR-II heterodimers . BMPs have been shown to play a role in patterning and cellular fate determination in many tissues . For examples, during development, BMPs are involved in the induction of the neuroectoderm, the patterning of the dorsal roof of neural tube, the development of neural crests and of the peripheral nervous system . In postnatal animals, they promote the differentiation of neuronal precursors in the spinal cord and in the cortex . Finally, they facilitate an astroglial lineage commitment of forebrain subventricular zone progenitor cells .
|
15369599_p1
|
15369599
|
Background
| 4.846458 |
biomedical
|
Study
|
[
0.9977874755859375,
0.0010385261848568916,
0.0011739549227058887
] |
[
0.5876555442810059,
0.00412429915741086,
0.40690672397613525,
0.0013135208282619715
] |
en
| 0.999998 |
Cellular therapies using stem cells are promising approaches for the treatment of several chronic or acute neurological diseases such as Parkinson's or Huntington's diseases or spinal cord injuries . One main problem relates to the origin and the nature of the cells to be used for such procedures. Foetal brain tissue has already been shown to have significant effects in patients with Parkinson's disease. Clinical use of the foetal brain tissue is, however, limited by ethical and technical problems as it requires high numbers of grafted foetal cells and a possible immunosuppression. Alternatively, somatic stem cells derived from adult tissues seem to be better candidates for cell replacement therapy . These observations raise hopes in cell replacement strategies based on an autograft approach. However, the exact mechanism by which mesenchymal stem cells (MSCs) adopt a neural fate is not completely understood as recent in vivo studies demonstrated that MSCs fuse with host neuronal cells . These observations impose a better knowledge of the mechanisms underlying the phenotypic plasticity of somatic stem cells and the characterization of their daughter differentiated cells is a prerequisite before considering their use in the treatment of human patients.
|
15369599_p2
|
15369599
|
Background
| 4.30411 |
biomedical
|
Review
|
[
0.9980008006095886,
0.0009310906170867383,
0.0010681303683668375
] |
[
0.18625624477863312,
0.002376424614340067,
0.8108339309692383,
0.0005333991139195859
] |
en
| 0.999999 |
Recently, we demonstrated that two phenotypes of MSCs could be obtained in culture: nestin-positive MSCs (npMSCs) which are able to integrate some extrinsic signals when co-cultured with neurons leading to a differentiation into astrocyte-like cells and nestin-negative MSCs (nnMSCs) which are unable to adopt a neural phenotype but remain able to differentiate into adipocytes, chondrocytes or osteocytes . When considering the use of MSCs as a source of material for cell replacement protocols in neurological diseases, one has also to be concerned by a possible effect of these MSCs on the host nervous tissue and more particularly on immature resident neural cells. In several models of neurological diseases, grafted MSCs were shown to favour host CNS regeneration rather than to express themselves a neural phenotype . This positive effect of MSC grafts could result from the release of factors acting on resident immature cells in the adult brain. Recently, it has been demonstrated that following ischemia in the adult striatum, intra-ventricular EGF injections are able to stimulate neurogenesis from resident neural stem cells, although EGF is devoid of any effect in non-ischemic striatum . These observations emphase the importance of the lesion priming in order to respond to extrinsic factors or cytokines. In this paper, we address the question of the influence of MSCs on neural stem cells in vitro and demonstrate that MSCs favour astroglial lineage. We observe that npMSCs are able to stimulate astroglial fate in striatal progenitor cultures and to repress neuronal and oligodendroglial fate through the release of diffusible factor(s). Using BrdU incorporation, we demonstrate that this npMSC conditioned medium has no effect on the astrocytic or oligodendrocytic progenitor proliferation. Propidium iodide incorporations suggest that the npMSCs conditioned medium protect GFAP-positive cells from cell death in comparison to the effect of nnMSCs conditioned medium or to the control condition. Meanwhile, no increase of cell death is observed in neuronal and oligodendroglial populations. We then demonstrated that BMP4 is present in a biologically-active form in the npMSCs but not in nnMSCs conditioned medium and is responsible for both the increase of astroglial numbers and the inhibition of oligodendrocyte differentiation in striatal NSC cultures.
|
15369599_p3
|
15369599
|
Background
| 4.530959 |
biomedical
|
Study
|
[
0.9992110729217529,
0.0005540295969694853,
0.00023488368606194854
] |
[
0.9984973669052124,
0.00032929066219367087,
0.000993520487099886,
0.00017977871175389737
] |
en
| 0.999996 |
Neurosphere-derived cells from GFP-positive E16 green mouse striata include neural stem cells and progenitors which are still proliferating but already committed to a given cell fate. Upon transfer on adherent surfaces (poly-ornithine coated dishes), these cells spread and spontaneously differentiate as follows after 5 days of culture: 44.2 ± 2.5% GFAP-positive cells (astroglial cells), 15 ± 2.1% Tuj1-positive cells (neuronal cells) and 5.86 ± 0.6% 04-positive cells (oligodendroglial cells). When co-cultivated with nestin-positive MSCs (npMSCs), phenotypic allocation of neurosphere-derived cells (identified as GFP-positive cells) become strikingly different: GFAP labelling is increased to 78.5 ± 3.9% (n = 12, ***Student T-test, P < 0.001), while Tuj-1 and O4 are decreased to respectively 3.2 ± 1.1% and 2.9 ± 0.5% . On the other hand, if neurospheres are co-cultured with nestin-negative MSCs (nnMSCs), the percentage of labelled cells were 52.1 ± 2.9%, 4.7 ± 0.8% and 7.8 ± 1.5 for respectively GFAP, Tuj-1 and O4. These numbers are not significantly different from the numbers obtained in control cultures for GFAP- and O4-positive cells (n = 8, Student T test, P > 0.05), while significantly lower for Tuj-1-postive cells .
|
15369599_p4
|
15369599
|
Nestin-positive MSCs increase astrocytes number in differentiating neural stem cell cultures
| 4.21629 |
biomedical
|
Study
|
[
0.9994999170303345,
0.00029132061172276735,
0.00020876011694781482
] |
[
0.9992212057113647,
0.00021255695901345462,
0.0004938829224556684,
0.00007239497062982991
] |
en
| 0.999997 |
Subsets and Splits
SQL Console for rntc/test-pp-aa
The query retrieves a sample of documents that are clinical cases with an educational score above 3, providing limited analytical value.
Clinical Cases Sample
Returns a sample of 100 clinical case documents, providing a basic overview of the document type's content.