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Is the signal peptide always cleaved during protein synthesis in the ER?
My university supervisor said that the signal sequence is always cleaved, however my text book differs.
What I gather from my text book (though it isn't very clearly stated so i'm not sure) is that:

A protein that is meant to be completely extracellular (or go into a membrane-bound organelle) will have only a signal sequence which will be cleaved by signal peptidase.

If there is a protein that is meant to have just one transmembrane domain, it can either:

a) have a single signal sequence, however this will not be at the start of the N terminus that is being translated. If there are more negatively charged amino acids before the signal sequence, then when the signal sequence binds into the translocon complex this beginning 'tail' will be threaded through as it is repelled from the more negatively charged cell interior. The amino acids following the sequence will be more positively charged to stay in the cytosol rather than passing through to the ER lumen. This will determine the directionality of this single-transmembrane-domain strand.
//Alternatively there can be one signal sequence and the amino acids before are more positively charged and after are more negatively charged, so you get the reverse situation where the already synthesised strand remains in the cytosol and the rest of the polypetide is threaded through as it is synthesised. Either way, this involves just one signal sequence.
b)The polypeptide can have one signal sequence and one stop-transfer sequence, with the charges on the surrounding amino acids determining directionailty, and then one of the signal sequcne or stop transfer sequence may be cleaved by signal peptidase.

Multipass proteins have a series of signal peptides/start-transfer and stop transfer.

But if my textbook (or rather what I understand from it!) is correct, then some but not all signal sequences are cleaved. So how does the signal peptidase know which to cleave?
I would really appreciate if someone could tell me answer this and also correct me where I have gone wrong in my understanding.

Would you mind providing a source/page number for the text so I could take a look at it? Having a multitude of transfer signals makes sense to me, but I don't understand the rationale for having multiple SRP-binding sequences.

@kingfishersfire I am using molecular biology of the cell 6th edition, Albert's et al (Garland Science). I do not know where one can get the 6th edition online-I have a hard copy- however I have found the corresponding chapter for the fourth edition https://www.ncbi.nlm.nih.gov/books/NBK26878/

I couldn't find the section you were talking about in that text, however I did find this http://www.zoology.ubc.ca/~berger/B200sample/unit_8_protein_processing/er_targeting/lect27.htm that looks like it might be helpful for you.

This is a rather long question, and I'm still not sure what exactly you're asking. Are you asking what makes a SP different to a TMH, or are there exceptions to SP cleavage? As far as I've understood the topic, signal peptides should be cleaved; it's part of their definition. If not, then there isn't too much distinguishing them from any other TMH post insertion. With a more specific question, I can provide a specific answer.


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Reasoning behind CO2 mouse euthanasia precharge prohibition
I have been at two universities now and the first permitted the precharging of a cage with co2 before a mouse is put in, but the second does not. I was wondering what the reasoning is behind the ban on precharging a cage with Co2.
When I think about this, it seems that it would be less stressful for the mice to fall unconscious very quickly rather than a slow and gradual suffocation. Is there some shock associated with the precharged cage that makes this more stressful in some way?

Upon some research, I have found more guidelines from universities attributing to NOT PRECHARGING the chamber with CO2. Precharging actually results in more distress for the rodents.

Quoting from guidelines to CARBON DIOXIDE EUTHANASIA OF RODENTS from University of Pennsylvania >>

Do not “pre‐fill” the euthanasia chamber with CO2.  Start with room air then slowly fill the chamber with CO2 over several minutes
  (OLAW).  CO2 is heavier than room air, thus the chamber may need to be
  “purged” between groups of cages.
“Because inspiration of high
  concentrations of CO2 is both aversive and painful, a recommended
  procedure is to place animals into a chamber that contains room air
  and then to gradually introduce CO2.” (ACLAM)
CO2 first renders the animal anesthetized and then, with adequate exposure time, will result in death by CO2 narcosis.  Animals should
  be left for additional time within the euthanasia chamber, after
  spontaneous movements have ceased, with CO2 continuing to flow.
“Animals should be left in the container until clinical death has been
  ensured.” (NIH)

Also, according to an article in The Scientist by Kerry Grens >>
It's been realized that at high concentrations, CO2 causes creatures torment. After reaching mucosal surfaces, it transforms into carbonic acid, which stings. Also, in people, even low fixations can be upsetting, bringing about shortness of breath.Therefore, explaining why high levels of CO2 is actually more painful for the rodents.

I know I'm not supposed to use comments for this, but +1 for a very well presented answer.

I have always understood that in all methods of "humanely" euthanising animals, the idea is not to kill them fast, but to first softly get them unconscious and then kill them in their "sleep", as whatever is killing them will usually cause distress in a lethal dose. But this is just from having to watch pets be put down as a child.

@anongoodnurse Thank you. It is nice to get into this community.

@skymningen True, on research, I found that sometimes when the rodents are unconscious, they are killed by a two part neck dislocation. I cant quite remember the steps correctly  now. There is actually research going on to minimize the distress with CO2 as much as possible and there are articles that talk about using anaesthesia instead.

@skymningen in my experience, cervical dislocation (CD) is the most rapid, humane, and cost-efficient method of euthanasia, of course when performed by well-trained researchers or staff. The way I learned it, you keep the mouse in its cage up to the very end, so it doesn't become stressed. You then remove the animal, and (very important) out of sight of any other animals, you place the mouse perpendicular to the wires on the top of an old-fashioned regular cage and grip its tail near the base until it reflexively grabs onto a wire. [...]

[...]  You then quickly place the blades of a closed pair of scissors behind its neck, press down firmly and very slightly forward to immobilize the head, and quickly and smoothly pull on the base of the tail until you feel the pop of the spine disconnecting from the base of the skull. From placing the animal on top of the wire to death should take no longer than 1-3 seconds at the very most. The mice pretty much have no idea what's happening, and they're gone in an instant. There's no worrying about measuring the flow of $CO_2$ or of the killing cage smelling like death or anything.

@MattDMo Cervical dislocation is what I meant. On what I was reading, there were also practices where they would make the mice unconscious with the CO2 and then perform the cervical dislocation. They say it is more easier when the mice are unconscious as they dont fiddle around. Isnt this more easier than having the mice alive while performing this technique?

@ImtiazRaqib knocking out the mice with $CO_2$ kind of defeats part of the purpose of CD, although in times when I've had to euthanize via $CO_2$ I've also done CD on the bodies just to make sure they're dead. Even if you do asphyxiation slowly (in my experience, at least), the mice still get panicked as they realize there's not enough air, but before they're knocked out. Maybe I was just adding the gas too quickly, I'm not sure. The reason I used CD in grad school was because I was in an immunology lab, and stress can activate the immune system, altering your data. Proper CD doesn't do that.

@MattDMo Cervical dislocation is actually prohibited at our institution as a primary means of euthanasia. In many cases a secondary method is required, and CD is permitted as a secondary method where I am. It does seem silly for CD to be used after CO2, but still can be required.

@TheNightman just curious, do you know why it is prohibited as a primary means?

@MattDMo I don't know why this is the case, maybe just to avoid instances where people perform it improperly?

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text:
Generating all possible conformations of an Intrinsically disordered protein
I want to simulate interaction between the bHLH-LZ domain of c-Myc encoded protein and a test ligand. Since the domain is intrinsically disordered, I want to generate all possible conformations of the IDP to run several iterations of simulation, each time with a different conformation. How can I do so? I would really appreciate if you could explain me what is the basis of these conformations and explain the concept?
Thank you!

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text:
Commensalism with Virus bacteria
Why people die of infection from microorganism, when germs can keep breeding for longer if they dont kill host?
Would not millions of years of evolution make germs evolve to not to kill human but feed on them just enough to not to kill them ?

Great question! In fact, some of the most successful pathogens (Herpes viruses are a excellent examples) have evolved with precisely this strategy. Herpes viruses have very low virulence, but infect nearly every human on the planet, and stick around for life.
But there's an evolutionary trade-off to this strategy. Herpes viruses have giant genomes (for a virus), because they need a ton of genes that counteract the immune system and perform other feats of cellular control so that they can stay dormant for long periods of time. While dormant (the technical term is "latent"), the virus is not transmissible, so while it persists  for a long period of time, they actually don't transmit very often.
Other viruses (influenza is a good counter example), are readily transmissible throughout most of their life cycle, but end up being cleared in a few weeks by most people. And yet influenza also spreads around the globe each year, so this also seems to be a pretty effective strategy.
It's really hard to ask questions like "why doesn't influenza behave like herpes?" When it comes to evolution, there are many successful strategies. Might as well ask, "why don't fish have feathers?" "Why don't sea birds have gills so that they can stay under water?" "Why aren't humans single-celled organisms?"

Some of the information contained in this post requires additional references. Please [edit] to add citations to reliable sources that support the assertions made here. Unsourced material may be disputed or deleted.


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Why the total phosphorylation of certain neuronal proteins decrease during development?
Looking at the effects of RIM1a which is a protein involved in neurotransmitter release. Any ideas as to why its total phosphorylation decreases as the rats develop?
Many thanks
Image; https://i.gyazo.com/16170fd79bd1f96517e028dfa2e70fbf.png
Paper; http://www.cell.com/cell/pdf/S0092-8674(03)00727-X.pdf

Here are a couple Wikipedia articles that might help out:
Critical period - Critical period: the idea that certain types of plasticity in the nervous system occur only at certain "critical" times.
Long-term potentiation - LTP, talked a lot about in the paper you linked: it's a mechanism for strengthening of synaptic connections.
Synaptic pruning - # synapses/strength of synapses tend to decrease from adolescence to adulthood
The paper you linked talks a lot about the role of phosphorylated RIM1a in LTP. Without knowing more specifically about this protein, and from just a glance at the paper you linked, I'd suspect that RIM1a is phosphorylated during periods of increased LTP, particularly earlier in development, and as animals age and their brains go into the synaptic pruning phase, LTP is downregulated overall, and one of mechanisms could be the lack of phoshporylated RIM1a.


text:
Why don't we hear ultrasonic sounds as aliased versions of the original signals?
The upper limit of hearing is approximately 15 kHz, dependent on age and other factors. According to the principles of digital signal-processing, such an upper limit would mean that the auditory system samples at least at 30 kHz or more.
Now suppose an ultrasonic signal, say a 40-kHz acoustic frequency - why would I hear nothing, instead of that signal aliased at a 30 kHz sampling rate?

one thing i could not understand... if you can't hear above 15kHZ  ("upper limit") then your auditory system should sample below 15 kHz.  isnt?

In order to hear a sound of a given frequency, you have to sample at twice that frequency (really, above twice that frequency). This is the Nyquist rate. Not sure if you're interested enough, but this Youtube video on the concept is really good: https://www.youtube.com/watch?v=yWqrx08UeUs

When a digital sound is processed by a speaker, the speaker diaphragm travels through every point in space between the two digital bits of data. therefore, all sounds transmitted in air are generated and heard non-digitally, they are continuous signals limited by atomic size, which is bigger than HDD requirements. Frequency is mathematical, but the human cellular ear structures are not mathematical so you can't rate an ear in mathematical way very clearly.

The answer to your question is in here. I scanned through it, but I don't have time right now to write up a formal answer (someone else is welcome to if they would like). Short answer is that, according to this, the exact mechanics of sound perception are still not pinned down, but it likely has something to do with a lack of space within in the cochlea since vibrations at different areas correspond to the perception of different frequencies.

I don't have time to type up a whole answer right now, but the premise of your question has a major flaw: the Nyquist rate that you are referencing by talking about necessary sampling rates applies to discrete sampling of a waveform; this isn't how auditory information is represented in the cochlea or auditory nerve or anywhere in the brain that we know of, so it does not apply. You could look into "phase locking" which occurs at lower frequencies, but higher frequencies can just as easily be represented by their envelope, or phase information can be distributed across a population.

@BryanKrause I would like to see your entire answer later. It is a conceptual simplification but there are discrete aspects to how sound is received and encoded, at least potentially: since frequency is tonotopically represented, and the spiral ganglion has fibers that innervate different sections of it, they could potentially be 'sampling' that section of the basilar membrane even though the entire waveform is complex and excites many places on the cochlea.

@BryanKrause The auditory nerve conserves that tonotopy: http://images.slideplayer.com/18/5700795/slides/slide_38.jpg
Relatedly, the actual auditory neurons fire discretely, e.g. at a certain rate, not continuously, and presumably some aspect of auditory perception is limited by the max rate (~1 kHz) although this could be overcome by groups of neurons (volley principle).

@kingfishersfire I have found that page before and love it, thank you for reminding me of its existence. It's getting bookmarked.

@Bzrs I am quite familiar with tonotopic organization of the cochlea and auditory nerve, my point is that this has NOTHING to do with the sampling rate. You can have a part of the cochlea respond to 50kHz tones (humans don't, but mice do, and vocalize in that range), but no need to fire at 50kHz. Also although action potentials are (roughly) point processes, that is not the same as discrete sampling...

...Discrete sampling  of a point process would imply you have a series of 0s and 1s, but an action potential, even though it is a point process, can occur at any arbitrary time point: even if your maximum firing rate is 1000 Hz, you could have a spike at t=0s, or t=.001s, or t=.0001s, or t=.00001s. This is actually a necessary concept behind the "volley principle" you mention. At the highest frequencies, there is no evidence for volley principle, instead cells sensitive to basilar membrane vibrations in the high freq area spike w/ respect to the amplitude of those vibrations, not phase.

@BryanKrause I get what you are saying, just a few points: (1) detection of up to 90 kHz has been reported in humans through bone conduction, see https://www.ncbi.nlm.nih.gov/pubmed/2063208 (2) amplitude would seem to be a poor way to code high frequencies given their greater attenuation....

For echolocating animals which hear well into the hundreds of kHz it seems particularly problematic. I doubt you could get large displacements of the BM in response to high frequencies without help (active amplification), but immunogold labeling has shown similar amounts of prestin in the base and apex which seems inconsisent with amplification being more important at the base. https://www.researchgate.net/publication/44651053_The_ultrastructural_distribution_of_prestin_in_outer_hair_cells_A_post-embedding_immunogold_investigation_of_low-frequency_and_high-frequency_regions_of_the_rat_cochlea

Let us continue this discussion in chat.

Short answer
The cochlea is a tonotopic map with certain physically determined boundaries that determine the range of frequencies perceived. Ultrasonic soundwaves simply do not have a correlate on this map.
Background
The cochlea is a frequency analyzer that basically translates acoustic frequencies into a place-map. High frequencies are encoded basally (up to 20 kHz), low-frequencies apically (down to 20 Hz or so). Hence, it is pretty much a Fourier analyzing system (Fig. 1). This way of analyzing sounds is referred to as the place-coding theory of pitch. The place where a frequency is encoded is mainly dependent on physical characteristics of the basilar membrane in the cochlea. Every part is sensitive to a slightly different frequency then the next. This is caused by gradual variations in the stiffness and width of the basilar membrane, among other less important factors like hair cell length and so forth. The specific physical characteristics determine what specific resonant frequency a particular part of the basilar membrane has. Hence, incoming sounds are torn apart with standing waves, where each frequency results in a standing wave at a particular spot in the cochlea.

Fig. 1. Tonotopic map of the inner ear. source: Ternopil State Medical University
The frequencies mentioned are physical wavelengths of the acoustic air pressure differences entering the outer and middle ear. The cochlea translates these into fluid-based pressure differences. Hair cels in the cochlea pick up these fluid pressure differences and tranlate them into potential gradient differences.
The sampling rate of hair cells is pretty much infinite, as they work on a continuous membrane voltage, i.e., they are analogue.
The secondary neurons, the spiral ganglion cells, translate these voltage differences into neural spikes and lead them through the auditory nerve to the brain.
Neural spiking follows the acoustic frequencies up to, say 1 kHz (frequency following response). This phenomenon is referred to as the temporal code of pitch hearing. After that, the refractory characteristics cause single fibers to fire only to one in a few wavelength periods. So at the upper limit of hearing, say 20 kHz, a ganglion cell may only fire once every 20 wavelengths or so. No problem, as many others do the same thing. Stochastics cause the wavelength to be nicely encoded in a population of responsive fibers. Furthermore, the auditory cortex contains a tonotopic map, meaning that high frequencies are processed elsewhere then lower frequencies. In other words, the auditory nerve doesn't need to faithfully encode the incoming wave.
A nice example in this are cochlear implants; they stimulate the auditory nerve with electrical currents. The place of the electrodes determines the pitch, not their pulse rate (although it can have an effect).
Now why are you not hearing ultrasounds? Simply because the basilar membrane does not contain regions sensitive to frequencies above 20 kHz or so. This is referred to as the Greenwood map, which depends on species.

Thanks for the answer. Just a few questions: re: "The sampling rate of hair cells is pretty much infinite, as they work on a continuous membrane voltage, i.e., they are analogue" don't they have to depolarize, though, which is a discrete event? Is your statement that there is no real limit at all related to this study which showed that OHCs are not limited by their membrane time constant? https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3143834/

@Bzrs The point is that hair cells voltage is continuous - those cells don't fire spikes. So, no, depolarization is not a discrete event. The most likely explanation is that mechanical deflection of the hair cells causes a channel to open; that open probability is a function of the magnitude of the deflection. The depolarization is analog meaning that it is continuous. You could depolarize by 1 mV, or 2 mV, or 0.5 mV, or 0.1 mV, or anything between. Here we are talking about the inner hair cells, the primary sensory cells, not the OHCs.

@BryanKrause I know IHCs actually transduce the sound, just was thinking there would have to be a similar mechanism behind their analog quality and it appears that there is (it being the probability of open channels). It's a bit confusing to me since one could see discreteness in some aspects of this, e.g. neurotransmitter release from the IHC is also continuous/analog due to channel state being so, but the release itself is quantal (released in packets of constant quantity) according to "Neurotransmitters and Synaptic Transmission" by Sewell in "The Cochlea" (Springer Auditory Handbook).

@Bzrs Yes, there are some aspects that are still somewhat discrete, like neurotransmitter release, but even that is continuous on average: see law of large numbers. Essentially, the membrane potential is setting a probability of release, and release events are frequent enough that the output is roughly continuous, especially because there will be some postsynaptic temporal filtering that smooths the individual release events.

@Christiaan if freqs above 20 kHz have no representation in the human cochlea, what is your interpretation of the human ultrasound via bone conduction studies? This study claims to rule out lower freq stimulation (https://www.ncbi.nlm.nih.gov/pubmed/23384569) and another by the same group shows inhibition of tinnitus after 30 kHz BCU, which they say is evidence that their BCU stimulus activated the cochlea base (https://www.ncbi.nlm.nih.gov/pubmed/24530434). Your answer http://biology.stackexchange.com/a/27901/28436 invokes ossicles and not cochlear representation as the limiter on high freqs.

Also, some interesting findings: BM motion of up to 100 kHz detected in guinea pig, despite it being well over the upper freq limit for them: https://www.ncbi.nlm.nih.gov/pubmed/16603325
Responses of up to 100 kHz recorded in single OHCs: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC16347/
Presumably the analog/continuous voltage changes induce conformational changes in prestin particles such that the OHCs can change length at this rate. Perhaps, as with volley principle, there are enough prestin particles that only a subset need to be shrinking/enlarging to cause movement each cycle?

Why should the OHCs amplify at such high rates (essentially following a 100 kHz signal) if detection at this high frequency will only matter on the place code? At this point we are obviously butting against the limit of knowledge on the topic, but...it's fascinating stuff.

Sorry, final comment: the OHCs amplifying 100 kHz signals is not inconsistent with the place code. Rather, it serves to boost the strength of the response which is likely needed for high frequencies. So its purpose is not encoding frequency so much as it is amplifying the signal; and failing to keep up with the high frequency would cause distortion through subtraction/addition (similar to what is posited for prestin's mechanism of conferring frequency selectivity).

@Bzrs  Per this answer: http://biology.stackexchange.com/a/27901 , "the transfer function of the ossicle chain in the middle ear is a suspected culprit in setting the upper frequency limit to 20 kHz (Hemila et al., 1995)." The answer has a link to that paper. So... we have a 20kHz LP filter in the acoustic path to the hair cells; even if the latter were doing "sampling", we still wouldn't get aliasing. otoh, bone conduction bypasses the middle ear, explaining how we can "hear" ultrasonics by that path.

@JamieHanrahan The ossicles do not set the upper frequency limit. That's an outdated idea. See http://www.pnas.org/content/99/20/13206.full.pdf

I think that you are misquoting Aliasing.
Digital acoustics is explained in a mathematical sense, Aliasing is a maths concept. Real life acoustics is explained in a physical sense, which talks about reflection, absorption, phase change, harmonic modes, weights... the perception of sound is discussed as psychoacoustics and cortical structures and individual nerve impulse detection thresholds. consider for example the explanation of drum acoustics, it is not digital and on no physical objects will you see the word "Aliasing" used: https://en.wikipedia.org/wiki/Vibrations_of_a_circular_membrane
Aliasing refers to a digital concept, whereby we devide screens into pixels, and you can't make out objects narrower than a pixel. A wave is at least 2 "/////" points of data, so it requires a 2x window so we have 44k CD's to code 22Khz sounds.
I'll just tackle this precise question, aside from the mis-use of the term Aliasing: why would I hear nothing instead of the signal aliased at a 30 kHz sampling rate?
Pressure waves are continuous and physical sounds... A continous sound or physical object can't be subject to the digital distortion effect "Aliasing" which for example refers to the generation of infinitely high frequencies in between two sampled points of a clock rate...
Because physical sound is continuous, it can't have frequency distortion related to it's sampling rate of 15/30 Khz, it can attenuate and physically react with physical objects including other sound pressure waves and cause physical objects to resonate in different modes of movement.
The sound detection depends on the physical excitation of hairs and nerves that must exceed a threshold of detection. physical objects don't have radical and odd excitation modes when they absorb a frequency that is too high, they can resonate in different modes, but they wack about wildly and produce volume clipping and sound artefacts. Most of the time they don't have a limit of frequency after which they go crazy. the closest you can get to strange frequency modes in physical objects is resonance where the movement builds up into a high kinetic movement like the Tacoma Narrows Bridge. You have to approach the ear as a physical model and not a digital one. I think of the resonant modes of structures in the ear similar to a guitar string or a gong moving in 3D space. This gives you an idea of the nerve signals in the ear:
https://www.youtube.com/watch?v=1JE8WduJKV4&t=17s
Almost all sound that is detected inside an ear is distorted by reflection from it's initial shape and source, and thereby it is smudged into reverb similar to light travelling through frosted windows.
Human brains and tissues are not digital and quantized, they aren't even analog, the are cellular with different types/sizes of receptor cells and nerves, variable and organic. You can say they alias only when you talk about perfectly equal sized cell matrix in 2d/3d pattern, like photoreceptors, except that our minds disregard information on cellular scales that aren't useful to us, like a biological version of aliasing would be.
If you study the function of the cochlea you will find that the structures, hairs, membranes are so different from a digital aliasing concept.
Human ears collect high frequency sounds unlike the dished ears of bats and cats and dogs, which are made of stiff cartilage that reflects higher frequencies well, into the ear canal. high frequencies are absorbed very fast by the skin and it takes specialized organs to reflect them to stiff cartilage chambers lined with hairs, each part of which is adapted to further reflect and absorb different frequencies.
The cochlea is organic and cellular, and it is similar to multiple electret microphone diaphragms and cilia all existing inside a complex organ which sends the vibrations to nerves. Sounds have to be collected by dishing and focused onto light and rigid membranes.
There is very much artifacting from all frequencies as they reach the ear. The sounds reflect of different surfaces, although high frequency ones absorb more easily and therefore are heard more linear from the source to the sensor, and have more time precision and more binaural precision.
Sounds don't tend to be generated in the exact same spot(point sources), so if you have for example an insect generating high frequencies, it will make a complex wave shape, that excites a large envelope of air around it, like dropping 5-10 stones into some water, and the outgoing wave will not be a simple form, but a complex series of phase interactions similar water that is excited by a swimmer. In that sense it has some properties of a moiré pattern, but it isn't aliasing, it's complex wave and phase interaction.
An Aliased oscillator on the other hand is a digital sound which contains infinitely high frequencies, because digital encoding forces sudden changes in amplitude to be abrupt, which is different to nature, where sounds are continuous and not discrete sets of values.
As sound travels through air and through flesh, the high frequencies which are all pure sine wave components of the overall sound, will simply be attenuated according to complex spectra of attenuation which correspond to the ambient air conditions, the angle of incidence towards the reflective and transmitting ear vestibules.

Nice answer, but can you add a couple of references or a good textbook to provide support/further information?

I don't know that I understand what you're saying some of the time, but from your analogies I would guess you come from a visual background.
Human ears also have cartilaginous pinnae that help amplify sound. The cochlea is not lined with hairs (did you mean hair cells?). And with regard to high frequency sounds, the place-code of the cochlea does come with particular frequencies being represented in a particular place.
I know the ear is not digital and that signals do not come in without a lot of modification. It's a simplification, but my question was conceptual.

You can actually bypass the entire impedance from air to fluid/ossicle transfer function aspect of it if you transmit a signal through bone conduction, and indeed studies show that people (even the deaf) can hear higher frequencies this way. In which case the limitation may not be pre-cochlear.
https://www.ncbi.nlm.nih.gov/pubmed/2063208
https://www.ncbi.nlm.nih.gov/pubmed/11234768

This answer makes some good points but a lot of the details are misleading or wrong, especially the comparisons between human and other animal hearing. I think it would be greatly improved if @comprehensible was able to source the real stuff and remove anything they can't find sources for.

Bzrs,that study talks about brain implants of some kind, ultrasound hearing aid cortical implants. Cats can and bats can hear above 60Khz. they have forward pointing ears with round dish structures that point towards the ear canal. some primates have dished ears, but almost all the human ear convex shape points away from the inner ear. The major mistake in the text is that i have not considered how the human auditory cilia can react to signals of 15Khz in a way that can be compared to a digital encoding of 30Khz which is necessary to detect a peak and trough at 15Khz.

Most of my understanding of sound is from many years of backwards engineering digital audio synthesizers, and knowledge of physical modelling in audio, reverb, direct versus indirect audio. Vibration modes of a gongs and drums and the function of speakers and microphones. Most of the information is so obvious to me, that the human nervous system doesnt have a digital clock rate at 44khz, or a binary function, you have to tell me what i have stated too vaguely so that i can reference it.

@comprehensible "Human ears collect high frequency sounds unlike the dished ears of bats and cats and dogs" - All of those non-human animals hear at higher frequencies than humans. This has to do with the physical properties of the cochlea, not the pinnae. "The sounds reflect of different surfaces, although high frequency ones absorb more easily and therefore are heard more linear from the source to the sensor, and have more time precision and more binaural precision." - The logic here is incorrect, and I'm not sure what point you are even making.

@comprehensible "High frequency sounds don't tend to be generated in the exact same spot" - By "exact same spot" I think you mean "precise frequency" - however the OP isn't talking about natural sounds necessarily, and it is certainly possible to artificially present tones fixed to any frequency. And your last paragraph is mostly jibberish, there is no difference in the "pureness" of sine waves at different frequencies, and probably the head itself is the main attenuation source, allowing for sound localization based on interaural level differences.

High frequencies are absorbed more readily by air, trees, stone, the ground, water, etc. they don't travel so far. that's simple. what that means is that the higher pitched the sound, the more likely that you will not have heard it as an Nth reflection... Aliasing is a kind of distortion, and indirect hearing is a temporal and spacial distortion, so I thought it was relevant to try and explain that.... Animals have reflective objects surrounding their ear, which transmit an imprecise reflection of the sounds, and it further illustrates that we have temporal and phase distortions, not Aliasing.

You presume that i mean Frequency when i say "generated in the same Spot" ? I mean Point Source of sound that doesnt exist in nature. you presume Gibberishly yourself. Your judgement of giberrish seems to arise from a mind that doesnt even understand the concept of a "point source" of sound, you are confused. You need to consider that SOUND SOURCES aren't really idealised point sources. Depending on the application, you can shape speaker(s) so you have cylindrical waves, or dipole waves, or sections of a monopole wave ..., or a combination of several patterns.

I'm sorry, you're right, it was dismissive to say gibberish, I apologize. What I meant to say was that I don't think your points actually go toward answering the OP, because the OP was talking about tones, and in that context it doesn't matter what naturalistic sources of sounds are: I totally agree with you that pure tones are not directly relevant to natural hearing. There are still misunderstandings by the OP that are more relevant to answering the actual question.

Sorry for not writing it more sensibly. Having programed anti-aliased oscillators and studied physical acoustics, I was confused by the question and it left me in a state of incomprehension when i tried to interpret the wording. I have rewritten paragraphs 3/4 to take up and answer his question properly.

I actually think I realized the answer this morning. The biological equivalent of 'sampling' should occur at the neural level, e.g. after successful transduction. Since properties of the basilar membrane (e.g. stiffness/thickness) AND the transfer function of the ossicles would need to allow passing of a high frequency sound into the cochlea prior to sampling, the excessively high signal may never make it there in the first place.

I would agree with what you've said about the properties of the ear, but I'm not sure that the concept of sampling is a good fit on a neuronal level either. Though I would be very interested if you had some info about how it would relate.

I just found this and will be digging into it as best I can with my limited neuro background:  http://audiology.pagesperso-orange.fr/en/cochlear-sampling-theory.pdf

Also, not sure if you saw my answer above, but considering the nature of spiral ganglion fibers innervating different places along the cochlea, and the tonotopic representation of frequency, there's at least potential for these to act as 'channels' which are sampled/filtered/processed in different ways. This was obviously the thought behind some cochlear implants but I admittedly don't know how much it is an accurate reflection of the biological ear.

This looks interesting. Thanks for sharing. It looks like our supposition about the limits of the cochlea may have been premature.

From what I can gather from skimming the paper is that there isn't a practical limit to high frequency detection. The multiplexing that is proposed (p. 53) that got us to 15-20 kHz could get us much higher. Though it seems like the paucity of cochlear space devoted to higher frequencies means the cochlea has a functional high pass filter. Fascinating paper though, I'm going to dive into it later when I have more time!

Yeah, that 'multiplexing' is essentially the volley principle as explained in the link you provided above. It does not satisfactorily explain the hearing of other mammals, however, such as echolocating bats and whales. To hear 200 kHz you'd need 200 IHCs responding (to be strict) or else have enough of them firing such that the brain could still reconstruct the signal from the incoming periods (e.g. for a 10 Hz signal you wouldn't need firing on all 10 cycles but if you got 1, 2, 5, 6, 9, the brain might still deduce the frequency). Harder with 1, 3, 5, 7, 9, though (would look like 5 Hz).

Multiplexing and volley principle is not necessary for detecting or perceiving sounds; phase information is not needed to perceive a sound at a particular frequency, only amplitude. There is no need for the brain to be able to reconstruct the exact waveform of an incoming sound to be able to perceive it, a spectrogram is almost certainly sufficient. Phase information is important for localization of low frequency sounds, however, so it is still important, just not necessary at all frequencies.


text:
How to find the location of a gene, starting with the gene name and the DNA sequence of nucleotides?
I'm not a professional biologist, I'm just trying to analyze some actual data. Where should I look up the location of a gene and nucleotides it consist of? How can I find it in DNA? Is there an algorithm that can be used?

This is not clear. You have a gene and its sequence? You have a gene name and a genome sequence that could or could not have this gene? What type of "gene name" do you have? There are different identifiers for genes. If it is a standardised one, yes, you can get the gene sequence for example from Genbank and you can align the gene to a genome. But please try to make the question more specific and add more research.

To find the genomic location of a gene when you start with a gene name;
Use the UCSC Genome browser. This has a number of advantages. There are a number of species to choose from. It provides a representative image of the gene and regulatory elements that surround it. It can display a lot of extra information if you want to see it. The disadvantage ot the UCSC Genome browser is that the information density may overload non-professional users.
To find the genomic location of a gene when you start with a DNA sequence;
Use the search tool that links to the UCSC browser.
The alternative option is to search for your gene ID or sequence in NCBI Gene.
To search for a DNA nucleotide sequence using the link above, select Reference genomic sequences (refseq_genomic) from the pull-down tab in the Database field. Limiting the search to a species using the Organism field is also wise.
Both of these sites provide the information you are after. Taking time to read the help instructions will be useful.


text:
Help understanding the word 'glycosaminoglycan'?
In my biochemistry course I have to know about various polysaccharides and variants, and I am struggling with remembering them. I think it would help if I could break down their names.
For 'glycosaminoglycan' i think
-glycan just refers to the fact that it is a polysaccharide. Some, but not all polysaccharides have glycan in their name, e.g. glycogen vs amylase and amylopectin
-amino means there is an amino group somewhere in there?
That's all I can think of...

Find a booklet about chemical nomenclature, I used to get one for free as a scientific bookshop. https://en.wikipedia.org/wiki/Chemical_nomenclature I am sure there are also plenty websites with catalogs of this.

There is a specific method for drawing a molecule based on it's named components. Organic Chemistry generally requires that you understand the main nomenclature, look for videos on it if you need different infos.

Glycosamines (or amino-sugars) are monosaccharide derivatives with an amino group substituting the hydroxyl group at second carbon. Glycosaminoglycans (GAG) usually contain repeats of a disaccharide unit one of the component of which is an amino sugar. GAGs are not strictly polymers of amino sugar monomers as the name might misleadingly suggest.


text:
Why can't I smell things that aren't there?
I can close my eyes and imagine a red cube with a yellow star on it. Although I don't literally see it -- if there was a red cube with a yellow star on the inside of my eyelids, I'd know the difference -- I can experience it in much the same way as if I was seeing it.
I can do much the same thing with sound, imagining (say) the sound of a bird, or of a bell ringing.
But I can't imagine any tastes, or smells. I know what cinnamon smells like: if several spices were placed in front of me, I could readily identify the cinnamon. But I can't call a familiar smell or a taste to mind in the same way I can call a familiar sight or sound to mind.
I don't think it's merely a memory thing. Even if I've never seen the box, I can still imagine it. I can imagine the sound of a bird tweeting in a large echoing hall, even though I've never heard it. But I can't synthesize unknown smells or tastes in my imagination in the same way I could unknown sights or sounds. I don't think I'm unusual in this respect (correct me if I'm wrong).
Are there any theories as to why this is?

I think you may be unusual.  Or perhaps I am: I can recall smells & tastes with no difficulty.  Imagining new ones is more difficult, but I think any creative cook can do it to some extent, when figuring out what foods & spices to use in a dish.

@jamesqf exactly. smells, tastes, touches, temperature etc could be recalled and imagined. But for me they are quite less-easier  to deal in mind than vision (shape, colour, motion) and sounds. Maybe it is due to we  (modern human) are  evolved to 'think' mainly visually and auditorily (such as verbally) than we use the other senses.

Interestingly, when I read the word "cinnamon" in your question, I automatically imagined smelling cinnamon. I would not consider myself a great smeller or taster - I can rarely guess the flavor of something without knowing ahead of time, but I still had this experience. It may be that smells are more difficult to imagine for humans, and that you are an extreme example, but it seems like it isn't truly an inability.

@Always Confused: It doesn't seem much different to me, but of course that's just an unscientific anecdotal opinion :-)  Could be it's just a function of practice, and many people get more practice with vision & hearing than with taste & smell.

@jamesqf yes that was a speculation and not an answer.

the continuous nature of sound and visual stimuli--compared to the discrete nature of chemical detection--is likely at the root of your observation, which I agree with.  the specific way each of us represents odor, for instance, in the brain, is unique (see recent work by Axel lab on piriform cortex).  the direct representation of a box or sphere or whatever object is not unique.  and you can easily play with a shape in your mind, while smell is not easy to play with mentally because we have so much unexplored chemical space, in part because of the limited number of environmental chemicals.

Couple of contributing theories:

The olfactory system does not project to the thalamus, which serves as a relay to other higher processing areas.
Lack of a specialized working memory subsystem; we have fairly robust subsystems for movement,visual and auditory buffers of information, what is normally called working memory, things we can hold on for a little while, but it seems they are not as developed or engage the same areas for smell. see for instance:Working Memory in Another Dimension
It is not as useful,used or adaptive ( beyond recognizing odors) as the other senses, there is a relationship in between how much we use something ( could also be the above working memory systems )and the cortical real state devoted to it's processing, this is a competitive part of the brain and in comparison to other senses like vision the portion of the cortex devoted to olfaction is small.
Another way of looking at it, is that we do have the capability to imagine smells and gustation, but they are not as developed as the others since we don't use them as much.
Anectodally, I would argue that people whose jobs revolve around combining nice smells or tasty things do develop certain abilities like those in vision as well as for those who have been exposed to the same odor repeteadly and can imagine it at will.

Some interesting theories, but I am wondering if you can cite any academic work to back any of these suggestions up with supportive evidence? Specifically, for whether the phenomenon the OP reports is actually a real thing beyond OP's own experience, or the lack of working memory for smells?

From the citation you just added: "the results showed that prefrontal regions identified during a visual working memory task were also engaged during olfactory working memory" - This does not support your statement at all that working memory is "not as developed for smell" (edit: I see you have edited again. I still don't think what you are saying is at all supported, I see no evidence that working memory is any less specialized for any of the modalities you mention...I think it is simply true that olfactory working memory is not well studied in humans)

Also, thalamus is a relay to all areas of cortex, not just higher processing areas, and there are olfactory connections with the thalamus(for example), it is just that the olfactory bulb itself does not project through thalamus to cortex like other sensory modalities, and I am not certain the role of the thalamus in working memory is well understood


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What is the difference between RFLP and DNA fingerprinting?
Is RFLP (restriction fragment length polymorphism) analysis the same as DNA fingerprinting? I looked for information online and I don't understand the difference.

What do you understand about each concept, and where exactly are you stuck? In particular, have you read through the Wikipedia article on DNA profiling, the very first result when googling DNA fingerprinting?


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How does low cysteine conditions affect pheomelanin production?
So we were studying this amino acid called cysteine. Specifically we were studying it's effect on melanin genesis.
Our teacher told us how excess of cysteine affects the melanin synthesis  by generating more pheomelanin. Low amount of cysteine promotes formation of eumelanin.
 He told us that if the concentration of cysteine is increased in cells then the above reaction starts producing pheomelanin in brown/black skinned people. I searched it on net and it seems to be true.
The question is that if someone who has fair skin (produces more pheomelanin) is forced to live in low cysteine condition, then what happens? Eumelanin production should increase. His complexion must change. But it doesn't occur anywhere. Fair skinned people affected by malnutrition remain fairskinned. How is this possible? The pheomelanin production must stop since they aren't getting enough cysteine. Then how...?
He also told us that onions contain large amount of cysteine yet it can't be used since it is destroyed by stomach acids.

First: Your teacher is right with the statement that a low cysteine concentration affects the synthesis of pheomelanin. To understand this, you need to take a look at the biosynthesis pathway of melanin (from here):

The first steps for both melanin forms are the oxidation of the amino acid Tyrosine to DOPA (L-3,4-Dihydroxyphenylalanine) and the to DOPA quinone by the enzyme Tyrosinase (abbreviated Tyr). In the following step the branches divert, if there is enough cysteine present in the cells, then Cysteinyl-DOPA and subsequently Pheomelanin are synthesized.
If the cysteine concentration in the cell falls below the threshold of 0,13µM (this is taken from this paper), then the switch to eumelanin production occurs.
In the case of you second question, there is a different setting. The overall rate of the melanin production (no matter which flavor) depends on the amount of active Tyrosinase (for the production of the first steps in the synthesis cascade). The production of this enzyme is regulated by receptors in the cellular membrane (and different other factors).
In fair skinned people (classically red-haired and with freckles) these receptors are not fully functional, resulting much less Tyrosinase enzyme in the cells. This results in fewer available precursors for the melanin production and in turn in less need for cysteine. The reason is that the cysteine pool of the cell is not getting exhausted.

Sorry. But I couldn't understand the last paragraph.Tyrosinase affects melanin production. If fair skinned people have less tyrosinase ,wouldn't it mean that the production of melanin itself decreases ,regardless of its type. Also would cysteine deprivation affect the color of fair skinned people? Also would cysteine deprivation affect the skin color? Is the cysteine in onions unusable since it is destroyed by stomach acids? How can this be true? I mean ,shouldn't all amino acids be destroyed since they have to pass through stomach. Once again thx for ur help

@AScientist Yes, they also produce less pigment in total, that's why these people have a much lighter skin type. But it also affects the type of melanin produced. Without enough cysteine the pathway would be shifted to eumelanin.

"Pheomelanogenesis may have evolved as an excretory mechanism to remove excess cysteine, and in humans this might potentially confer a greater ability to avoid disease such as Parkinson's and Alzheimer's disease, in which excess cysteine is a contributory cause." Source:https://onlinelibrary.wiley.com/doi/full/10.1002/bies.201200017
In this instance your teacher has his information incorrect. L-Cysteine has nothing to do with the production of Eumelanin. "Melanocortin 1 receptor (MC1R) is a key signaling molecule on melanocytes that responds to α-MSH by inducing expression of enzymes responsible for eumelanin synthesis. Some forms of Pheomelanin production lack the MC1R receptor to form eumelanin entirely; others have a weak signal if they have mixed Pheo/Eumelanin. Eumelanin has a strong MC1R receptor connected to the (Melanin Stimulating Hormone) α-MSH. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4299862/
Pheomelanin and Eumelanin have completely different pathways of formation. "Pheomelanin, consists mainly of sulfur-containing benzothiazine and benzothiazole derivatives (Figure 1a). L-cysteine is the chief source of sulfur and is, therefore, essential for the pheomelanin synthesis (12). Eumelanin, on the other hand is an extremely heterogeneous polymer comprising of 5,6-dihydroxyindole (DHI) and or 5,6-dihydroxyindole-2-carboxylic acid (DHICA) units (Figure 1b)."https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4299862/
Individuals with Eumelanin maybe less able to synthesis Sulfur based Amino Acids like: Methionine, Cysteine, Homocysteine, Taurine, and Glutathion. :)

First: Both pathways have the common starting point of tyrosine and its oxidation. Then: As I said in my answer (and referenced there as well) availability of cysteine does influence which of the melanins is produced. If there is excess cysteine available, no eumelanin is produced. So your answer is wrong in the way it is written. Please correct it. Also: Please stop giving unreferenced health advices, these are off-topic here.

Pheomelanin and Eumelanin have completely different pathways of formation. "Pheomelanin, consists mainly of sulfur-containing benzothiazine and benzothiazole derivatives (Figure 1a). L-cysteine is the chief source of sulfur and is, therefore, essential for the pheomelanin synthesis (12). Eumelanin, on the other hand is an extremely heterogeneous polymer comprising of 5,6-dihydroxyindole (DHI) and or 5,6-dihydroxyindole-2-carboxylic acid (DHICA) units (Figure 1b)."https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4299862/

Have you taken at least a short look at the diagram in the answer above? It shows the schematical pathway (not in all details, but still enough).

So you contend that if one born with only Pheomelanin "falls below the threshold of 0,76µM in L-Cysteine" one would gain Eumelanin? Even though L-Cysteine has nothing to do with Eumelanin production. Even in the figure you posted that theory makes no sense.

Read the paper of Land. BTW: Ito and Wakamatsu (the authors of the 2008 paper you copied above) are co-authors of this study. The concentration of cysteine is the decision point which melanin is made from the common precursor dopa-quinone. Both ways have a common starting point.

I did I actually posted it and it says nothing about L-Cysteine levels dropping and turning into Eumelanin.

Once more: You go from DOPA-quinone either in the direction of cysteinyl-DOPA (and then Pheomelanin) or DOPAchrome (and then to Eumelanin). The decision which way you go is influenced by the Cysteine concentration. And exactly this is described in the Land paper on page 4. Is this so hard to understand?

Another thing: The Nasti review (where you took the images from this answer from, also contains what I am saying: "Melanogenesis produces mixtures of eumelanin and pheomelanin at different mixed ratios. The ratio is determined by tyrosinase activity and the substrate concentrations of tyrosine and cysteine (27)." Reference 27 is this one: https://www.ncbi.nlm.nih.gov/pubmed/19627559/ Which also gives this explanation.

Basically you are saying that a white person can turn black if their sulfur levels drop. Now tell me if that makes sense to you.

No, this is not what I am saying. I say (and the papers back this) that low cysteine concentrations affect the synthesis of Pheomelanin. Regulation of pigmentation also happens on other levels as well, which play an important role,  too. And please, don't start to tell this is all MC1R. There are more factors (transcriptional) involved here.

I will read the Land paper give me one moment...

That study is nearly a decade old and new information has been attained on the subject. The information I posted is current information from 2016 on melanin. I can show you more.

Then show me the paper which proofs this connection wrong. BTW: That a paper is old doesn't necessarily mean it is wrong. The Nasti paper itself shows this connection (in the text and also via reference 27).

I don't think you a factoring into account that Genes play the top role in this as stated above. Next there are 3 different types of melanogenesis. Eumelanogenesis, Pheomelanogenesis and MIXEDmelanogenesis; all three do not occur in the same fashion. The synthesis is different for each. Yes in mixed melanin a lower amount of the Sulfur amino acid L-Cysteine would produce a person with darker skin however, you cannot take a person with only Pheomelanin put them in an environment with no Cysteine and think that Eumelanin will spontaneously occur due to a "drop in sulfhydryl compounds."

The melanocortin 1 receptor controls which type of melanin is produced by melanocytes. When the receptor is activated, (by the MSH) it triggers a series of chemical reactions inside melanocytes that stimulate these cells to make eumelanin. If the receptor is not activated or is blocked, melanocytes make pheomelanin instead of eumelanin. https://ghr.nlm.nih.gov/gene/MC1R

This is nice statement, but an overall simplified as well.

This is the UPDATED information on L-Cysteine production for Pheomelanogenesis, which says nothing about L-Cystenine levels falling and creating Eumelanin as this "guess" (not even a theory) makes no sense published May-Jun 2008
Chemistry of mixed melanogenesis--pivotal roles of dopaquinone.
Ito S1, Wakamatsu K.
Author information
Abstract
Melanins can be classified into two major groups-insoluble brown to black pigments termed eumelanin and alkali-soluble yellow to reddish-brown pigments termed pheomelanin. Both types of pigment derive from the common precursor dopaquinone (ortho-quinone of 3,4-dihydroxyphenylalanine) which is formed via the oxidation of l-tyrosine by the melanogenic enzyme tyrosinase. Dopaquinone is a highly reactive ortho-quinone that plays pivotal roles in the chemical control of melanogenesis. In the absence of sulfhydryl compounds, dopaquinone undergoes intramolecular cyclization to form cyclodopa, which is then rapidly oxidized by a redox reaction with dopaquinone to give dopachrome (and dopa). Dopachrome then gradually and spontaneously rearranges to form 5,6-dihydroxyindole and to a lesser extent 5,6-dihydroxyindole-2-carboxylic acid, the ratio of which is determined by a distinct melanogenic enzyme termed dopachrome tautomerase (tyrosinase-related protein-2). Oxidation and subsequent polymerization of these dihydroxyindoles leads to the production of eumelanin. However, when cysteine is present, this process gives rise preferentially to the production of cysteinyldopa isomers. Cysteinyldopas are subsequently oxidized through redox reaction with dopaquinone to form cysteinyldopaquinones that eventually lead to the production of pheomelanin. Pulse radiolysis studies of early stages of melanogenesis (involving dopaquinone and cysteine) indicate that mixed melanogenesis proceeds in three distinct stages-the initial production of cysteinyldopas, followed by their oxidation to produce pheomelanin, followed finally by the production of eumelanin. Based on these data, a casing model of mixed melanogenesis is proposed in which a preformed pheomelanic core is covered by a eumelanic surface. Source: https://www.ncbi.nlm.nih.gov/pubmed/18435614
As stated above Eumelanin and Pheomelanin are two chemically different compounds. So even if Pheomelanin levels dropped one would not attain Eumelanin through the depletion of sulfhydryl compounds, because they follow completely different pathways of synthesis. This is determined by Genetics, one would have to turn on the SLC24A5 and SLC45A2 genes as a start.
α-MSH/MC1R plays a major role in the production of Eumelanin. MC1R Variants
"Melanocortin 1 receptor is a highly polymorphic protein, and in humans many of the loss-of-function variants are associated with the “red hair color” (RHC) phenotype. Individuals with a dysfunctional MC1R may have decreased eumelanin synthesis leading to fair skin and an increased sensitivity to UV exposure."
MC1R and Pigmentation
"There are two major types of pigment present in the skin, the darkly pigmented eumelanin and the red/yellow sulfated pheomelanin. Eumelanin is chemically inert and is highly photoprotective by absorbing UV radiation and oxidants. In contrast, pheomelanin is much less efficient at blocking penetration of UV radiation into the skin and can promote UV-induced cellular damage by contributing to free radical and oxidative injury. MC1R signaling is a major determinant for the amount and type of melanin pigments synthesized by melanocytes, regulating both basal pigmentation and the UV induced tanning response. **MC1R signaling increases **eumelanin synthesis****, the ratio of eumelanin-to-pheomelanin, and enhances melanosome transfer to enhance melanin deposition in keratinocytes.
Both eumelanin and pheomelanin derive from the sequential cyclization and oxidation of the amino acid tyrosine (Figure Figure33) (Ito, 2003). The first two biosynthetic steps are shared between the two pathways: the conversion of tyrosine to DOPA and then to DOPAquinone by the enzyme tyrosinase. Eumelanogenesis and pheomelanogenesis diverge after formation of DOPAquinone. Other enzymes beside tyrosinase are needed for melanin synthesis including dopachrome tautomerase and tyrosinase-related protein 1. Defects in many pigment enzymes yield hypomelanotic phenotypes such as albinism. Pheomelanin production is dependent upon the incorporation of a cysteine and retention of sulfur after the synthesis of DOPAquinone, which may explain why mature pheomelanin pigments are reddish/yellow rather than dark brown/black as eumelanin is. Although the control of the pigment switch between eumelanin and pheomelanin is regulated by multiple factors including the pH of the cellular milieu and the levels of tyrosinase (Burchill and Thody, 1986; Ancans et al., 2001), the presence of a functional MC1R is required for effective synthesis of eumelanin. Since eumelanin absorbs UV radiation, the more eumelanin the skin has, the more protected it is from UV damage." Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4885833/

I know this paper - and it says it itself: "Regarding the production of pheomelanin, the intervention of sulfhydryl compounds (such as cysteine) gives rise exclusively to thiol adducts of dopa (cysteinyldopas) among which
5-S-cysteinyldopa (5-S-CD) is the major isomer (38). Further
oxidation of the thiol adducts leads to the formation of
pheomelanin via benzothiazine intermediates." Without cysteine the formation of cysteinyl-DOPA and subsequently pheomelanin is not possible. Also: Read the paper of Land from 2003 which explains the mechanism. If you don't have access, let me know.

You can down my comment because you do not agree with it but you are interpreting the information incorrectly. A fall in L-Cysteine levels will not change to  Eumelanin because you want it to, thats not how genetics works.

This is not genetics, is regulation of enzymes. Genetics is the layer above this step. And here a lot of other factors come into play. So your comment is pointless and your answer doesn't really answer the question.

The question is that if someone who has fair skin (produces more pheomelanin) is forced to live in low cysteine condition, then what happens? He is not asking about MIXED melanin which is something altogether different than the figures you or I have posted.

The melanocortin 1 receptor controls which type of melanin is produced by melanocytes. (NOT CYSTEINE) When the receptor is activated, it triggers a series of chemical reactions inside melanocytes that stimulate these cells to make eumelanin. If the receptor is not activated or is blocked, melanocytes make pheomelanin instead of eumelanin. https://ghr.nlm.nih.gov/gene/MC1R

Nope. The receptor regulates the major transcription factor important for pigmentation: MITF. This one regulates the transcription of genes involved in pigmentation, for example the tyrosinase (which is the first enzyme in both cascades). If tyrosinase is missing or inactive you would be an albino. Little MC1R signalling (as in red haired people) due to mutations leads to little production of tyrosinase and subsequently little DOPAquinone. Therefore the cysteine levels are not depleted below the critical threshold and only the red pheomelanin is made.

all_licenses: Creative Commons - Attribution Share-Alike - https://creativecommons.org/licenses/by-sa/4.0/


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Is it possible to completely puncture a human hand and have no blood come out?
Illusionist David Blaine sometimes performs a trick where he takes a very long and thin ice pick, insterts it in his hand, and comes out the other side (the palm). However, there is no blood present. Is this possible at all? (Warning: Graphic Content) Here is the video (already timestamped)

Yes, it is possible.
The needle should be passed through Fistula, which is an abnormal or surgically made entry between an empty or tubular organ and the body surface, or between two empty or tubular organs.
According to Magic Secrets Explained >>

This provides us with a reasonable explanation for Blaine's needle
trick. He has a fistula through his arm. He created this fistula to
himself, by repeatedly causing small damage to his arm in the same
direction, probably by actually stabbing a needle into it.
He basically drilled a tube of scar tissue through his arm just so he could perform this one trick.

In order to further cement their logic, they attached another video of a man who had a fistula through his body which empowered him to have swords cut through his body without hurting him.
Fistulas are also incorporated in dialysis, and infact referred to as dialyses’ lifeline. An article by Big D and Me expands more on this plus explains how it also threatens lives.


text:
Why is trisomy a problem?
I understand that a missing part of genetic information is a problem - the cell does not know how to synthesize a specific protein. But why is it a problem when there's one more copy of a chromosome?
Let's say a trisomy of the 21st chromosome occurs, so the person has Down syndrome. What happens on the molecular level that the person develops the way they develop?

The biggest reason is that excess of chromosomes would disrupt the proportion just like lack of chromosomes do. Over-expression of some genes inteferes with normal cell function.

where have you tried looking for an answer to this question? have you looked in any genetics texts, specifically the concepts of gene dosage, etc?

I tried googling several similar things but I don't think I came across gene dosage. Neither I remember hearing about it at school - that's why I asked the question but now it makes more sense. My bad.

Without going into Down syndrome specifically, let's address the title of your question: Why is trisomy a problem? Or, more specifically, why can it be a problem to have extra copies of genes?
Let's imagine biology to be just a really complicated cake. If you are trying to bake a cake, and you leave out the flour, I think mostly everyone would agree that the outcome product wouldn't be much of a cake at all: that's the condition where you are completely lacking an ingredient, both copies of the same chromosome, a nearly assured fatality.
But let's say you instead include 50% too much flour. What results? You might still get a cake, but it might not taste perfect: maybe a little too bread-like or not sweet enough.
In short: having an extra chromosome means genes on that chromosome are overexpressed. Those gene products could themselves have deleterious effects in excess, or they could affect expression of other genes and cause over- or under-production of those products. Of course it isn't as simple as "+50% expression!" because of regulatory mechanisms ubiquitous in biology, but there is sufficient overexpression to cause some issues.
Really, someone with Down syndrome develops almost completely normally - many other trisomys are fatal in the early stages of development, so we don't become familiar with them. For Down syndrome in particular, you can check out some of the proposed mechanisms on Wikipedia. One suggestion is that some of the cognitive deficits resemble Alzheimer's disease, implying a causative function for amyloid beta in both circumstances. The hypothesis is that amyloid beta accumulates in aging brains, but people with Down syndrome overproduce amyloid beta so they show dementia symptoms much earlier. This comparison is certainly not the only factor in Down syndrome, however.


text:
Why use embryonic neurons to study protein knockouts/mutants in long term potentiation?
Just wondering if anyone had some ideas about the question in the title. I'm just wondering why some papers use embryonic cultures of specific brain regions for neurones to test the effects of knockouts/mutations on synaptic plasticity (for example, long term potentiation, LTP) instead of adult cultures?
Many thanks

Could you edit your question to include a definition for LTP?

@Michael_A I think adding a definition for LTP to the question isn't necessary for the OP, but I made a clarifying edit that LTP is a type of synaptic plasticity and added a link to wikipedia for anyone who is unsure. These edits are pending. I also previously spelled out the abbreviations in OP, and it looks like that edit was accepted just after your comment.

@BryanKrause,  nice. My request was a nudge to help keep this interesting question as accessible as possible.

Some suggestions, there may be more:
1) The knockout may not be viable to adulthood (the animals die). Perhaps heterozygotes are viable, but to test the full knockout you need a homozygote.
2) Even if the knockout is viable to adulthood, the brain may develop adaptations to the knockout that aren't specific to the knockout itself: up- or down-regulation of certain channels, for example.
3) Plasticity is upregulated in developing brains compared to adult brains, so the effects may be more pronounced in the young tissue.
4) Younger tissue cultures better - you can keep cells alive longer, more easily.
Also good to note is that undifferentiated stem cells tend to be "neuron-default" - that is, if you just culture embryonic stem cells and you don't do anything special to them, they will tend to generate neuron-like cells. In the adult, neurons are always going to be alongside other types of cells: glia, vascular tissue, etc.


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Is the term 'allele' specific to sexual populations?
I had always thought that 'allele' simply meant a variant of a gene and thus could be used in the context of either asexual or sexual populations. With it only being slightly less useful as a concept in asex because of the lack of recombination and thus no reshuffling of allele among offspring. Recently, I was reading a paper that wrote:

In the asexual and sexual populations mentioned earlier, the implicit model space is simply a point in genotype frequency space or allele frequency space, respectively.

Suggesting that alleles should primarily be used in the context of sexual populations. Wikipedia gives a general definition consistent with both asex and sex use, but all examples listed are sexual.
Hence my terminology question:
Should I use the word 'allele' for variants of genes only in the case of sexual populations? Or is it alright to use 'allele' in populations of obligate asexuals?
I realize why recombination forces us to represent a whole population as allelic frequency instead of talking about individual genotypes, and why asex lets us focus on just the latter. In this question, I am not curious about this distinction, just the purely terminological question.

No, it's fine to use for asexuals too. There's an ambiguity in the term "locus" for asexuals, but "allele" is fine, and "gene" is not much more ambiguous than it is for sexuals (which isn't saying much).
Your final paragraph seems confused though, and I think it's related to your main question. When recombination is sufficiently frequent to keep the population in linkage equilibrium, it allows us to represent the population simply as a point in allele frequency space, rather than in the full, exponentially-larger genotype space. So Watson and Szathmary are using different terms for the two cases not because they can't use "allele" in an asexual context, but because alleles are not sufficient to describe an asexual population.
In general sexual populations are not in linkage equilibrium and cannot be simply described by allele frequencies either, as W&S note later in that paragraph.

Thank you for that answer. I want repeat back and see if I got your second point correctly: the allele frequency representation is noted separately in the example sentence because it is a more compact representation that can be used in the special case of a sexual population that is at linkage equilibrium (something special even for sexual pops).

Yup, that's it!


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Can species be paraphyletic?
I thought that according to cladistics, only monophyletic groups were valid as species or any other taxa. But extinct species, like say H Erectus must be paraphyletic, as the common ancestor of H Erectus is also the common ancestor of modern man. So if species are frequently paraphyletic, how can cladistics be tenable?
Edit. Also, I'm new to this forum. The people responding here, I'm assuming are actually biologists with a specific knowledge of cladistics, right? I'm a post-grad (philosophy of biology rather than biology per se) so I'm not really looking for links which explain what cladistics is, and certainly not wikipedia. I can access most journals if there is a paper on this subject. I can't find anyone in our dept who can give me a steer on this. I realise thhis is a slightly unorthodox research method, but I'm at a bit of a dead end here!

Right, thanks. But I don't see that the species concept is the issue here. I'm really questioning whether cladistics is coherent, given that it prioritises clades (which are by definition monophyletic) as being the only valid taxa. Now, as far as I understand, it doesn't really matter which species concept we use. Cladistics doesn't seem to rely on any once species concept (Hennig's Tokogenetic concept aside)but does absolutely insist on monophyly. The vast majority of species, though, over evolutionary history, are paraphyletic, right? Just want to check I'm not making some stupid error here.

For your example; I don't think it is obvious that H. erectus is paraphyletic. The question is if H. erectus is the direct ancestor of modern man (if so H. erectus would be paraphyletic), or if H. erectus and H. sapiens share a common ancestor (which would make them related, but none of them would have to be paraphyletic). Extinct species don't have to be paraphyletic, as you seem to claim. I'm not an expert in this specific case though (human systematics), and this is merely a conceptual point.

You say that "only monophyletic groups are valid as species"... That is according to a certain interpretation of evolution that is not necessarily mainstream, (you wouldn't be taught that definition of species in Oxford or Yale) and which idealizes cladistics into simple trees, which don't reflect reality of hybridizing species like orchids and hominids, where simple tree like branching has been proven to not exist. Inflexible definitions of phylogeny should be taken with a pinch of salt, because pollen and other reproductive systems cause many species to be flexible. It's unwise to state that definition of species without being well aware of the mainstream one: Ernst Mayr definition.
Strict interpretations of species lead to problems, because
Darwin wrote:
No one definition of species has satisfied all naturalists; yet every naturalist knows vaguely what he means when he speaks of a species. Generally the term includes the unknown element of a distinct act of creation.
If you check the Wiki page on species, they state 11 contrasted definitions of species which are not necessarily cross compatible.   https://en.wikipedia.org/wiki/Species#Standard_definition:_Mayr.27s_Biological_Species_Concept
The definition of species that i was taught had nothing to do with the parental mechanisms that shaped the species differentiation from other species, and that it is a practical concensus to effectively group animals methodically, which doesnt actually reflect natures unmethodical reality.
Seeing as humans interbred with neanderthal and denisovan species, and orchids interbreed very commonly, the following image refers to an idealized phylogenetic model which is not applicable to all reproductive systems, and it isn't applicable to humans.

I think it's pretty mainstream to say that species have to be monophyletic, but not all monophyletic groups have to be species. In fact, I would even argue that Mayr's species concept is pretty close to that notion as 'reproductively isolated groups' and a monophyletic species (taxon) are not that different (of course without hybridisation across cladistic barriers). Additionally, you should avoid using terms like 'creation', especially when assuming that most natural scientists include this as an 'unknown element' to their idea about species. -1

Thanks. But it seems, then, like the vast majority  of species are actually paraphyletic? Extamt species are monophyletic, and extinct species which are 'dead ends' as it were. But all other species are parphyletic. The species concept isn't the issue here.My qusetio

Sorry. Can't delete the previous comment which I posted by mistake....Yes. That's what I thought. It's just orthodoxy that species must be clades. And that higher taxa must also be clades. I'm pretty sure they would teach me that at Oxford.

Indeed, a research professor who has been very busily involved in naming new species (i.e. nematodes) and phylogeny would rave on and on about all the amazing funny facts about species diversity, like one researcher getting revenge on another researcher by calling a species "johnsonus sillius" and the russian classification system which has 8 times more species than us, and they go through all the reproductive intricacies that mean that clades, i.e. bear species, sometimes intertwine, whereas some species have very specialized reproductive organs with barbs and where clades are better defined.

In short i suggest that the rigorous phylogeny terminology that you quote is useful for genetic measurements and in depth phylogeny study. It's recommended to first learn at least 3-4 alternate definitions of species, and first do case studies of dozens of different speciation routes, physiologies, read about actual animals and surprises and conflicts in research based on certain evolution theories, to make it more of a fun topic that logic of branching terminology. By actually reading topical zoology and botany case studies, i think that someone gains a lot of useful background knowledge.

You have to understand that a fossil "species" is very different than the common usage. A species is not really a real thing. Paleontology (and other fields) accepts the vague nature of the classification of species. All life that has ever existed on earth is really one huge messy ring species on the long scale once time is included. phylogeny is a way of imposing a classification system that helps us understand life, any such classification will have arbitrary cut off points becasue WE use them to help understand relationships on the large scale. Species is one such arbitrary distinction, it is convenient and works on the large scale with living organisms just fine, but breaks down on the finer scale or once deep time is included.
For fossils you group by noticeable/measurable differences, while trying to make allowances for differences that should occur within a population (like sexual dimorphism). Paleontologists accept that a "species" is just an approximation, which is why the finer the scale of the cladistic analysis, you rely on individual specimens and not grouping them into a species. Ideally all cladistics would be done this way but it is completely impractical, in extant life becasue of huge population numbers in fossils becasue of incomplete specimens causing missing variables. On an analysis using any group as taxa, including species, it's fine if they are paraphyletic becasue they are only approximations.
You can find a more in depth exploration of  cladistics here enter link description here
And a general review of cladistics here enter link description here

Right. Which is why I'm asking, really. Hennig (and many others since,  such as Wiley and Lieberman, Baum and Smith, Ridley, Tudge, Ghiselen etc etc)  explicitly claim that Claude based species are the natural (as opposed to merely nominal) kinds of biology. So,  as a philosopher, it is of interest to me that this isn't really coherent,  and as a philosopher  of science it is of interest that this has occurred. It seems to me that it could work if we defined monophyletism synchronically, and allow groups which were at one point monophyletic, but as far as I know,  no one does this.

Ah I see a bit more of what your asking. You might want to change your question to reflect this. Part of the difference is how a clade is defined, in Paleontology the most common usage is: X plus Y and there most recent common ancestor and all of its descendants , becasue the assumption is you will never find a direct ancestor, or at least if you do you will never be able to demonstrate it.  species and clade are not interchangeable. and by their own definition all defined clade are monophyletic.

Species which are defined as a clade have to be monophyletic but  that way of defining a species are not commonly used. Mostly because while very accurate is is also largely useless in practice.

The boring but probably most correct answer is: it depends on the species concept that you accept.
Basic evolutionary theory predicts that paraphyletic species (as defined by a variety of concepts) should be generated under a wide range of processes.
The vast majority of species is described from gross morphological states ("morphospecies"). They can be wholly paraphyletic, as can species under nearly all concepts, except those that insist on monophyly (e.g. phylogenetic species concept of Cracraft 1989, deQueiroz and Donoghue 1990).
A problem to consider is one of the source of data. For example, a species can be monophyletic at a particular gene, but not at great many others. Broadly speaking, this is known as the "gene tree vs. species tree" problem.  A particular set of relationships can be recovered from analyses of a single genetic region, drawn from a wide statistical distribution of (for example) genealogies. Ideally we would have the genetic sequence within region(s) that cause(s) populations and species to be differentiated.
Depending on population size, after some amount of time (potentially very large), all genes are expected to be monophyletic in each descendant species, a condition that is then called "reciprocal monophyly."
Separately, you can take a look at https://en.wikipedia.org/wiki/Paraspecies for a straightforward treatment. As for your specific example, here is a great treatment of the subject: http://evolution.berkeley.edu/evolibrary/news/100501_xwoman

Can species be paraphyletic?

Yes, as you have explained in your post.

So if species are frequently paraphyletic, how can cladistics be tenable?

The grouping of lineages into species is necessarily somehow arbitrary. However, the relationship between lineage is free from any subjectivity. The reconciliation you need to go through is to accept that the concept of species, despite being so much used, is of no use to phylogenetic (or only to facilitate naming).
Cladistic and phylogentics is tenable because it does not depend on the concept of species which itself is arbitrary. You can learn more about the semantic of the concept of species in How could humans have interbred with Neanderthals if we're a different species?

Right. So if species are frequently paraphyletic, why is it regarded as unacceptable for higher taxa (which are usually seen as more arbitrary) to be paraphyletic? As in the idea that reptilia are not a legitimate grouping.  How can the fact that even species are not by nature monophyletic be reconciled with cladistics claim that only monophyletic groups are legitimate? Many thanks, by the way.

Probably because as you go to the detail, it becomes harder (impossible?) to really name monophyletic groups only. This is even more problematic as we would ought to rename groups at every small discovery about the ancestry of a lineage.


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What is a centrosome?
I know that a centrosme is composed of two perpendicular centrioles, but the following sentences of Wikipedia confuse me:

Interestingly, centrioles are not required for the progression of mitosis.
Many cells can completely undergo interphase without centrioles.
Unlike centrioles, centrosomes are required for survival of the organism.

If centrosomes are essential then does this doesn't imply that centrioles too are necessary since centrosome is made of two centrioles, if not then what is it made of?

Reading the specified Wikipedia article about Centrosome, actually explains why centrioles are NOT IMPORTANT for the PROGRESSION OF MITOSIS.
To better understand what wiki meant, let us look at both centrioles & centrosomes.
According to Biology Pages for Centrioles and Centrosomes >>

Centrioles are built from a cylindrical array of 9 microtubules, each of which has attached to 2 partial microtubules.
The Centrosome

is located in the cytoplasm usually close to the nucleus.
It consists of two centrioles — oriented at right angles to each
other — embedded in a mass of amorphous material containing more than
100 different proteins.
It is duplicated during S phase of the cell    cycle.
Just before    mitosis, the two centrosomes move apart until    they
are on opposite    sides of the nucleus.
As mitosis proceeds,       microtubules grow out    from each
centrosome with their plus ends       growing toward the    metaphase
plate. These clusters of microtubules    are called spindle
fibers.

So, now we know that during mitosis, the nuclear membrane separates and the centrosome nucleated microtubules (parts of the cytoskeleton) can associate with the chromosomes to fabricate the mitotic spindle.
Understanding the conceptual working of centrosome, the Wikipedia article states >>

Interestingly, centrioles are not required for the progression of
  mitosis.
When the centrioles are irradiated by a laser, mitosis
  proceeds normally with a morphologically normal spindle.
In the absence of the centrioles, the microtubules of the spindle are
  focused by motors allowing the formation of a bipolar spindle. Many
  cells can completely undergo interphase without centrioles.

Therefore, even in the absence of centriole, centrosomes develop Astral microtubules which just exist amid and quickly before mitosis. Astral microtubules are characterized as any microtubule beginning from the centrosome which does not interface with a kinetochore.
Astral microtubules are not required for the movement of mitosis, but rather they are required to guarantee the devotion of the procedure. The capacity of astral microtubules can be by and large considered as assurance of cell geometry. They are totally required for right situating and introduction of the mitotic spindle assembly, and are in this way required in deciding the cell division site in light of the geometry and extremity of the cells.
An important note from the the Wikipedia article >>

Unlike centrioles, centrosomes are required for survival of the
  organism. Acentrosomal cells (i.e. cells without centrosomes) lack
  radial arrays of astral microtubules.
They are also defective in spindle positioning and in ability to
  establish a central localization site in cytokinesis.

so if we irradiate the centrioles then, what is left to be called as centrosome? The only constituents of centrosome are 2 centrioles , if we destroy them with laser,  then directly we are destroying the whole centrosome too.

@JM97 that is not entirely correct. If you read the answer, it says centrosome includes 2 centrioles PLUS 100 different proteins. The only constituents of centrosomes are not centrioles.


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Rate of growth of an RNA or DNA sequence
Given, e.g., a mixture of the necessary components in optimal conditions, what would be the average rate of attachment of nuceotides to ribose molecules?  This is related to the study of how long it would be expected take for a particular genome to evolve.

Your question is too vague and unclear. What exactly are the "necessary components"? Are there polymerases involved? Is there a template sequence? If you just take some RNA and mix it with ribonucleotides, exactly nothing is going to happen unless you have some sort of catalyst present, like an enzyme or ribozyme. The same is true of DNA. It takes energy to attach both nucleotides to ribose, and to attach (deoxy)ribonucleotides to each other. Please [edit] your question and clarify exactly what you're asking.

Also, this has nothing to do with how genomes evolve.


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If someone's arm is cut off, how does that affect blood circulation throughout their body?
Essentially what I'm asking is that if someone's arm is amputated, doesn't that cut off a significant part of their blood flow because the blood vessels that normally flowed up to the hand of the amputated arm and back can't anymore?  If it heals, does that mean the body has to grow more vessels to sort of complete the circuit again?  Does the body just compensate by putting more stress on the rest of the body's blood vessels?

Is it in reference to surgical amputation?

please mention the source from  where you found the information that cut at one place affect circulation at rest-portion of the body. However not much answer but from very common sense it seems logical. If you have a pipeline for water at your home and the pipe leaks, the water pressure would fall, so you would get slower water. Also in case of that healing; certainly some new blood capillaries regenerate but when the hand is no more, I think there is no need to regenerate the long arteries and veins for hands. just 'sealing' wounds and make a close-circuit with capillaries seemingly enough

If I understand your question correctly, you ask how does the body deals with released blood volume after the removal of part of blood vessels?
The simple answer is the body decreases the blood volume. Our body is able to alter blood volume significantly in response to different factors.
For example, take a look at this paper: Blood volume changes in normal pregnancy. It states that:

A healthy woman bearing a normal sized fetus, with an average birth weight of about 3.3 kg, will increase her plasma volume by an average of about 1250 ml, a little under 50% of the average non-pregnant volume for white European women of about 2600 ml.

So, after the arm cutting, an organism will decrease its blood volume. Although it will take some time, blood volume altering is more probable way than new vessels generation.

Amputation of a limb or more will cut off both the arteries and veins to and from that limb. The body will compensate by reducing the amount of the circulating blood in it in order to maintain normal blood pressure. The best analogy I can provide would be electrical circuits: In amputation you are removing a circuit that is connected as a parallel circuit, not as a series circuit, therefor there is no need to create new connection after amputation to allow the circuit to complete, you just need to block the loose ends (ligate the main artery and vein to the amputated limb).
Amputation does not lead to increased stress on the remaining part of the system, in fact it has the exact opposite effect. The heart as a pump becomes more efficient as the "piping system" is now shorter with less resistance, and people with cardiac failure report feeling improved cardiac symptoms after amputation, and those with high blood pressure require less medication to control their blood pressure. In fact, the functional efficiency of all other vital organs like the kidneys, pancreas and liver improve as a result of reduced body mass (they now need to service and detox less cells). If the person was diabetic, their requirements for external insulin reduce, and people who suffer kidney failure might no longer require dialysis as the remaining kidney function -although compromised- becomes sufficient to filter the smaller amount of blood which includes less -waste chemicals- due to reduced muscle and fat mass.

I'd like to see references for the core statements (blood amount is reduced in response to limb loss, and improved heart function after limb loss), but the main point is correct: our circulatory system consists of thousands of smaller parallel circuits that branch off the main vessels in the trunk. As soon as blood clotting has taken care of the actual leakage, the rest of the system goes back to stable.

There are limited references in peer reviewed journals in relation to this subject. Studies related to amputees are very limited due to this area of science being too specific as amputees represent a relatively a small percentage of the population. However, total blood volume is generally calculated based on the person's weight as the main predictor, and limb amputation clearly reduces weight leading to reduced circulating blood volume: https://reference.medscape.com/calculator/estimated-blood-volume https://www.medicalalgorithms.com/blood-volume-after-amputation

Fair point about blood volume. I was still wondering about the improved heart function though, and I haven't been able to find evidence for that. To the contrary, when looking at the risk of heart attacks, it seems patients who lost a limb due to peripheral vascular disease have an even increased risk, and patients with limb amputation for other reasons have no change in risk (https://jneuroengrehab.biomedcentral.com/articles/10.1186/s12984-018-0400-0). For leg amputees, cardiovascular complications seem to be increased generally (https://academic.oup.com/qjmed/article/101/4/251/1544580).

Cardiac function improvement refers to the immediate improved efficiency of the heat as a pump following amputation, due to the reduction in the vascular tree this pump needs to service, while the cardiac muscle remains unchanged, and still at a high risk of further clots leading to future deterioration of cardiac function. Unfortunately I couldn't find references to support this statement, but if you ever meet a vascular amputee I expect you will be able to confirm that it is true.

You are absolutely right about the increased risk of cardiovascular complications following vascular amputations, but this is different from "improved cardiac function following amputation".Vascular amputees had narrowing in the main artery leading to the limb, and this is usually part of the systematic vascular problem. These people will continue to be at high risk of vascular complications in other organs following a vascular amputation, and statistically speaking, a vascular amputation is considered a predictive risk factor for further vascular problems in other organs.


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Why does a centrocyte have a cleaved nuclei?
Why does a centrocyte have a cleaved nuclei? Is there a biological reasoning behind this phenomenon or is it the nature of the centrocytes? Does the selected centrocytes proliferate too?


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Biggest change in size from birth
Which mammal has the largest change in size from birth to fully grown percentage wise?

I  guess it maybe a marsupial for example red kangaroo.

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@JM97 is correct.
According to National Geographic >>
The gestation period of a Red Kangaroo is 33 days and it's baby at birth weighs a mere 0.03 oz. To put it into a more precise perspective, on birth, the baby weighs 1/100,000 of an adult red kangaroo's weight.
Second place goes to the baby of a Giant Panda; at birth it weighs 3.2oz which is 1/900 of an adult giant panda's weight.

How about platypus?

Although platyplus babies are almost the size of a jellybean, their baby to adult ratio isnt much. Because adult platypus usually extend upto 15 inches.


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Can jellyfish sting outside of water?
According to my understanding of the Wikipedia page on the stinging cells of the jellyfish, the mechanism of delivering the toxic missile is largely due to water pressure. Does that mean that a jellyfish on land (or brought out water) is unable to, or perhaps less efficient at, delivering its stings?

The wiki article did state the cnidoblasts uses the chemical gradient and osmosis to sting. So i guess it needs those two factors to work.

Short answer
Jelly fish can sting out of the water and even when they are considered to be dead.
Background
I do not have detailed scientific literature available. However, popular sources generally and equivocally warn against touching jelly fish, even on land and even when they appear to be dead. In fact, dead box jelly fish can be as dangerous as live ones (ABC News).
Credible sources
 - National Poison Control Center
 - UK Telegraph
 - ABC News