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Why is the SARS-CoV-2 target receptor ACE2 not endocytosed when bound physiologically?
The COVID-19 coronavirus SARS-CoV-2 enters cells by receptor-mediated endocytosis.
See, e.g.  here.
Why doesn’t the enzyme ACE2 — SARS-CoV-2’s target receptor — undergo endocytosis when bound by its physiological ligand, angiotensin II? If ACE2 triggers endocytosis on binding SARS-CoV-2, why doesn’t it trigger endocytosis on binding its physiological ligand?
For instance, from
https://www.nature.com/articles/cr200815
I know what receptor-mediated endocytosis is. However, I just cannot imagine just the opposite, in my wording:  non-receptor mediated (endocytosis). My guess is that the virus contacts a receptor and gets endocytosed, however I imagine the receptor as being left behind, on the membrane, where it remains, it's just some anchor. In other words: does there exist some mechanism that uses a receptor for attaching the virus like a  rod to get - not  the spike  but - the virus membrane  close to the membrane of the cell so fusion of   membranes might happen. Would that be endocytosis, fusion of membranes?
Some idea to get into it deeper, so to speak: ACE2 is special as it's an enzyme - and it does not have, alternatively: does not need any communication channel behind the membrane as it does not trigger anything inside the cell. Thus, ACE2 does not appear as a receptor leading to signaling, and tentatively I suggest that  signaling might lie in the endocytosis of the receptor, in a broader sense of signaling (maybe earlier staged in evolution: no G-proteins, no cascade...)  and in contrast to just blindly harbouring  an enzmye on the membrane. Edited, see comments: it's not blindly that ACE2 has been "expressed", I realized that  the very expression of proteins - be it on surface or not or not at all -  can be seen as signaling.
Interestingly, especially Sars-Cov-2's spike is known to be cleaved by other enzymes on the cell's membrane (furine). Edited: Another exciting perspective: ACE2 which is a cleaving enzyme isn't used by the virus in its cleaving function, it looks like some exchange of "enzyme", not receptor. This is interesting in the context of CoV-2 mutations which add to specifity. Compare newer comment below: what normal interaction is "perturbed" by binding of CoV-2 to ACE2? My point is that there is no signaling cascade after ACE2 which could be perturbed - however, there is "competitive binding", as it is known with any other receptor, so a new way to look at CoV-ACE2 is to see a longer lasting state of blocking the receptor, shielding it away from its natural ligand (sorry, edited: such kind of poetrick is very familiar "competitive binding") Angiotensin II, and I couldn't tell if such kind of non use might trigger endocytosis, haven't heard of any "De-Overexpression", i.e. endocytosis of receptors that are not bound or used physiologically - which makes sense, as competive binding molecules are homologues, identical, how could one cell tell the difference? Aha, it's the "intrinsic effect" (you call it?) in contrast to just blocking - which in case of ACEII does not exist! Nothing behind ACE2 as some follow up cascade.) To me it's a possibility that the getting used of Furine triggers endocytosis of ACE2 (I don't think it does, End of editing).
That should bring up some other question - importance of receptor expression (that is discussed in the context of blood pressure medication, i.e. ACE antagonists as medication). Now, in context of this question, the expression as such just as the opposite, the endocytosis (which physiologically does not seem to be undertaken)  might be seen as a way of  regulation. So, why is ACE2 endocytosed, and why isn't it...
Also see
https://science.sciencemag.org/content/early/2020/10/19/science.abd2985

...however, it is also possible that SARS-CoV-2 can enter cells independently of ACE2 when viral loads are high.

This might be explained by SARS-CoV-2 not searching for a receptor that is  endocytosed to facilitate entry by receptor-mediated endocytoses  but attaches to any antigen that fits its spike, which speaks in favour of my assumption that it is the closeness of membranes. This is quite exciting as it's on the side of the victim - as I postulated - if ACE2 is prone or not to be endocytosed as the opposite of overexpression i.e. diminishing ACE2 is the way (to go away the way to go :-))
Edited, found https://pubmed.ncbi.nlm.nih.gov/15897343/
Confer at figure 4. Endocytosis of receptor not necessary(?)

I have reframed your question in a more scientifically formal manner to make your argument clearer. You will see I have made explicit an implicit assumption in your argument. I suggest that before posting this question it might have been reasonable to read about endocytosis.

I've also corrected your terminology. The disease COVID-19 is caused by infection with a member of the coronavirus family known as SARS-CoV-2. There is no such thing as "CoV-19."

Thank you. To David: you might be right in your reproach, as I am still a beginner, I have read a whole lot of stuff and learnt about endocytosis - clathrins and all that. I'm bringing up because it seems seems such an easy and basic question - but I just can't answer it but know I ought to. Please help...

To David again: by the way, I liked "to trigger", I do not like the "it", though :-) It's free speech anyway, so why use those - äh, I guess you call them - citation marks. "Did I make myself understood" (just kiddin'). Thank you. I'll consult the guidelines as a newbie around, as I guess al this is from the land of the free speakers, To be serious and true: I cannot really assume that, here at stackexchange, it's not up to the author, to have the "the last word". I wouldn't want to feel like a worker for a newspaper. Talking of non author editing which means non authorized editing to me.

To whom it may concern: I' m excited as I believe I have found some anwer, it's within my editing. ACE2 is an enzyme - some implication added here, please forgive me: the very proneness to Covid-disease might be some tendency - coming from within the host cell - to endocytose that ACE2-enzyme so that it does not exist any more as it is not needed. So, receptor-mediated endocytosis in that sense is just the opposite of so called expression, of over-expression of receptors.

If you wish to answer your own question that is permitted and would be infinitely preferable to the additions you have made that, quite frankly, nobody will read and are unsuitable in a question.

To David. Thank you! I will take the tour - it's permitted to use the answer format to answer one's own question... So I declare my further amending as "suggestions for possible answer" as I'm not sure yet if it does make sense what I think the answer could be.

To add to the noise -- a good answer would reframe the question.  How is SARS-CoV-2 endocytosed when it binds ACE2?  After all, if we assume that the normal state of the system is the absence of endocytosis when ACE2 interacts with its ligand, then it is more useful to ask how that normal interaction is perturbed to induce endocytosis when the virus is introduced.

...a good answer - I mean mine, of course, see above - did reframe the question? We assume the normal state is the working of ACE2 with its substrate - so what we see is some non-"cleaving" of e.g. the spike protein. Normal state would be just to cut the spike (least, not the virus) into two pieces (cp. insuline, and in this case Angiotensin II as the physiological ligand which is cleaved to AT1-7). I will think about "normal interaction" - there is no normal interaction "perturbed" (just competitive binding)  - I would say there is some new interaction "we do not know of yet".

To acvill:  your refer to the wording of my question? I thought about it, the other way round. For the time being one could answer: "why should it be" (endocytosed, as ACE2 just isn't). A more convenient wording would be: why is ACE2 endocytosed when bound by the virus. Indeed, my way to put the question is the very "edding to noise".

@acvill This paper discusses clathrin-mediated endocytosis and suggests that the first event initiating endocytosis is not well understood. Also many papers say that in cells with ACE2 and TMPRSS2 the virus doesn't really enter into the endocytosis vesicles and does the entry in a more active way (the S2' cleavage does release the fusion peptide, when such transmembrane serine protease is lacking the virus may wait to be endocytosed and the cleavage achieved latter by cathepsin, activated by the acidified endosome)

To @acvill: exiciting news to me, dont' be irritated by the way I framed the question, and put that up as an answer? Question was why ligand ATII is  - now: - never :- endocytosed. The receptor without the substrate may well be as I just see. Wow, you made me see: it's the receptor "with or without" the "u" as just the opponent of the cleft that's can or is not be endocytosed. This means... why does CoV-2 seem to fake  a non usage of receptor (given assumption  that endocytosis in case of non-landing, non-usage by ligand ATII).

To @acvill: also, "with ACE2 and TMPRSS2" it should be in the paper cited if the cleaving by TMPRSS2 differs from cleaving by Furin (and there is even cathepsin - all three cleaves cleave the same way, "I am not a believer". Once again, an open unused receptor should be recycled and endocytosed one day, physiologically. How can the spike hasten that time by suspension? Maybe by some conformational change that resembles oxidation or degradtion that comes wiht time or environment and lets recycling start; endocytoses then just doesn't realize that "there is something on".

So, the question is

Why doesn’t the enzyme ACE2 — SARS-CoV-2’s target receptor — undergo endocytosis when bound by its physiological ligand, angiotensin II?

(Clarithin-mediated) endocytosis of "intended" ligands only occurs mediated by ligand-specific cargo adaptor proteins or by AP2 itself (which is a sort of "universal glue", but AP2 only binds specific motifs.)

As cargo is selected and bound
by AP2 or by cargo-specific adaptor proteins, the
clathrin coat has to be assembled.

The presence of different
cargo adaptor proteins, including the ubiquitous
protein AP2 and many accessory cargo adaptor proteins,
ensures that specific receptors are recruited to
the protein interaction network. For example, ARH is a specific adaptor for low-density lipoprotein receptors
(LDLRs), Numb binds Notch, stonin binds synaptotagmin, HRB binds SNARE proteins, and
ß-arrestin and Dishevelled bind G protein-coupled receptors (GPCRs). These accessory cargo adaptor proteins bind directly to the core AP2 adaptor appendage domains and therefore do not compete with direct cargo binding. They may be expressed by distinct cell
types to confer tissue specificity; for example, stonins are found in neurons and thereby help to recruit the calcium sensor synaptotagmin specifically into synaptic vesicles. Other tissues, such as the liver, have cargo adaptor proteins, such as ARH, that bind to LDLR to allow its incorporation into clathrin-coated vesicles. Furthermore, different accessory adaptor proteins can be expressed in different tissues, thus allowing a whole
range of proteins to be recruited into a clathrin-coated vesicle. In addition to conferring specificity, the presence of distinct cargo adaptor proteins ensures that,
when one receptor (for example, TfR) is present in high levels on the membrane, this does not block the uptake of non-cognate cargo (in this case, EGF or LDL).
Therefore, even if a receptor is present on the membrane
with low representation, it can still be endocytosed.

There is basically no such cargo adaptor protein for angiotensin II (that was identified). Nor is it clear why there should be one since ACE2 acts as a "knife" cleaving angiotensin II. Also, clathrin-coated vesicles take on the order of minutes to form (see previous ref), while the catalytic cleavage that ACE2 does almost certainly takes a lot less time; although I could not find a precise figure for the latter, it's probably on the order of milliseconds given how other reactions in that class take.
If you wonder how viruses manage to get themselves endocytosed... that's a long story, which I won't try to fully cover here, especially since it's rather poorly studied (Fields Virology 6th ed. manages to completely gloss over it), but the basic idea is that they are much bigger than a usual physiological ligand, which turns the process into a different game:

Although well-known endocytic receptors such as transferrin and LDL receptors occur in the list, the majority of virus receptors are not directly involved in the uptake of physiological ligands. By inducing clustering, viruses can generate a receptor-rich membrane microdomain that differs from the rest of the plasma membrane in protein and lipid composition (English and Hammer 2005; Lozach et al. 2011b).

I couldn't even find a detailed mechanism study for this on (any) enveloped viruses, but there is one on adenovirus (which is nonenveloped) on how it might trigger endocytosis, basically by providing its own polymerization promoters on its capsid, as summarized in a review:

Nemerow and coworkers demonstrated that the interaction between adenovirus pentons (protein complexes which together with the hexons make up the adenovirus capsid) and integrins activates phosphatidylinositol 3-kinase (PI(3)K), which in turn activates Rac and Cdc42, resulting in the polymerization of actin- and clathrin-mediated endocytosis of the virus. Activation of many different signaling pathways has since been described with the involvement of a variety of factors, including serine/threonine, tyrosine, and PI kinases; phosphatases; and a variety of small GTPases (including Arf, Rab, and Rho family members) (Greber, 2002, Pelkmans et al., 2005).

It's not really clear if all viruses come with polymerization promoters like that because even inorganic nanoparticles seem to be internalized; e.g.

Analogous to viruses, colloidal nanoparticles have been shown to be internalized through different cellular pathways in a size-dependent manner. For spherical nanoparticles, Rejman et al. related particle size and internalization pathways in the absence of specific cell receptor interactions: particles smaller than 200 nm in diameter are generally internalized by CME while particles larger than 500 nm enter cells via caveolae-mediated structures. For polystyrene particles in particular, a size of 100 nm is more efficiently internalized by CME in comparison to 50 or >200 nm. Interestingly, for gold nanoparticles, the preferred diameter for clathrin internalization is 50 nm. For both viruses and nanoparticles, the molecular and biophysical determinants driving these size-dependent entry mechanisms are still uncertain. This gap of knowledge is mainly related to the lack of a method to study virus-cell early interactions, which are highly unpredictable events that take place in a extremely narrow time-window (1–2 min).

But surely promoters would speed up the process. Furthermore, it was shown that at least for the reovirus (which is also
nonevenloped), inhibiting its usual binding to its target receptor did little to change its ability to recruit clathrin-mediated endocytosis, if the virus was otherwise pressed against the cell:

JAM-A is a critical receptor for reovirus infection. [...] Nevertheless, the number of clathrin recruitment events colocalizing with virus particles was similar in untreated cells compared to cells treated with the JAM-A neutralizing antibody. [...] these results strongly suggest that the recurrent recruitment of clathrin on immobilized viruses is JAM-A receptor independent.

Furthermore, SARS-CoV-2 doesn't actually bind to the catalytic domain of ACE2 (i.e. the part that cleaves angiotensin II) but somewhere above it, as crudely illustrated in this diagram:

Finally, regarding SARS-CoV-2 entry, the most recent research I found suggests that TMPRSS2 is the main pathway by which SARS-CoV-2 releases its payload into the cells it usually infects at plasma membrane level, with endocytosis being a secondary mechanism. (This actually explains why hydroxychloroquine [alone] works poorly in vivo in treating Covid-19.) It is a a bit unusual for coronaviruses to prefer release at the cell membrane, but not completely unheard of, e.g. Fields Virology mentions that several strains of the  mouse hepatitis virus also do this and even that:

For one strain of MHV (MHV-4), as few as three amino acid
changes in the heptad repeat region of S2 switches the virus
from plasma membrane fusion to acid pH-dependent fusion [i.e. to prefer endocytosis].

And if that's not enough, the same coronavirus can use multiple endocytic pathways, e.g. PEDV has been studied in that regard:

To clarify the specific endocytic pathways, systematic research methods were used and showed that PEDV enters cells via the clathrin- and caveolae-mediated endocytosis pathways [...]. In addition, lipid raft extraction assay showed that PEDV can also enter cells through lipid raft-mediated endocytosis  [...] but the utilization efficiency of each endocytic pathway varied depending on the different [virus] genotypes and types of cells.


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Should vaccination be based on a principle of broad and rather unspecific immunization?
In the context of Covid-19, in Denmark all ferrets/minks in farms were killed, as there is infection in humans by virus from ferret.
Thus, a  virus transferred from ferret to man proves to find the same type of target cells.  This corresponds to  Jenner's vaccination (vacca means cow) against Small pox by transferring  cowpox virus from cow to man in so  far as cow pox virus does replicate in man if to a lesser degree, not causing disease.  The diffence between infection of man by CoV from ferret/minks  seems to lie in  "attenuation". Different to cow pox (that is named different from small pox)  CoV from ferret is dangerous to man to no lesser degree.
Still,  "attenuation" may not be the working mechanism that Jenner's vaccination was based on, as target cells not being infected in man in the same way as they are in  cow  must carry different antigen. Antigens of small pox are not identical to those of cow pox.
Jenner's technique seems to be unique in its use of a different type of virus: cow pox is different from small pox. In contrast, for example, live measles vaccine is not different from live measles virus.
Whereas live measle vaccine, e.g., uses the identical antigen, Jenner's vaccination apparently did not: Cow pox isn't small pox.
Hence, a principle of identity of antigen together with attenuation (live vaccine and others) can be distinguished from vaccination (Jenner) that found some so called cross-reactivity.  Difference of target antigen equals difference of antibody and t-cell specifity.
So, instead of using attenuation as a working principle, should we look for good cross-reactivity like Jenner did when developing vaccines?
The results of the following study   seems to be  in line with presumed  principle of non-identity and   unspecific immunization ("Jenner's"):
Jacob Schön, Wei Ran et al., A modified live bat influenza A virus-based vaccine prototype provides full protection against HPAIV H5N1, May 15, 2020.
Considering that according to this finding there exists flu virus from bat that is not pathogenic in other animal species, yet valid vaccine in other species, the question may be rephrased as follows: If there is no harmful infection of a  different species/different kind of target cells found in a different species, how can such non-pathogenic virus antigen lead to immunization against disease? The finding above contradicts any principle of specifity of immunization; how to explain?
Some other reference says:
"... In contrast, viruses of the recently identified bat-borne IAV subtypes H17N10 and H18N11 encode HA and NA homologs unable to interact with sialic acid residues despite a high degree of structural homology with their conventional counterparts...",  see Ciminski/Martin Schwemmle, 2019, Bat-Borne Influenza A Viruses: An Awakening, 2019
If the mechanism of vaccination were identity of antigen and  attenuation any immunization induced by "homologs unable to interact" (with target cells) should not be of any help against infection by "conventional counterparts" (as there is no identity of antigen, thus antibodies/t cell receptor).

You're talking about completely different things, and it's not at all clear (especially after reading your self-answer) that you have any idea what you're talking about. Vaccinia and variola are two entirely separate species, while both the mink and human SARS-CoV-2 viruses are just different subtypes of the same virus. Just because Vaccinia (usually) causes a sub-lethal and eventually protective infection in humans doesn't mean anything of the sort is going on with the mink and human SARS-CoV-2 variants. Jenner was extremely lucky.

"self-answer" is pejorative for "jeopardy question and answer style share your wisdom - did I choose the wrong form, it's encouraged to answer your own question.

To MatDMO: what you're explaining contentwise suits me well That's my very question, if vaccinia virus and variola virus are or are not different in respect of immunity, and to what extent exactly. as they quite strikingly  induce  "cross-reactive" immunity!  If you only told me what exactly the difference is between variola and vaccinia is  that could be the start of a great affinity (of ours, smile).However, "Jenner was just lucky" does in fact answer my question, in the negative and according to common wisdom and perspective.

Hint: to reply to someone's comment, simply use the @username convention. I would be @MattDMo, for instance. As you type, an autocomplete box will pop up, so you don't have to type out the whole thing. The reason I'm not pinging you in this comment is because you are the original poster (OP), and so are notified of all comments in this area. In comments under answers. you would be pinged if someone @ mentions you.

@MattDMo, thank you, so this is addressing you correctly? I do not understand why my self-answer has been deleted by Chris. without comment, not by you.  I will constantly enhance my question. Currently, it's focus on "attenuation". You say Jenner was lucky, I agree (by the way, allegedly  Jenner's vaccine had been used by the Chinese much ealier) - my question refers to the possibility that modern"er" (kind of German, it's my mother tongue) vaccination relies on attenuation and just does not make use of cross-reactivity. So, no security without attenuation, Jenner did not have to  - take care

I consider this question of mine as very relevant in respect of coronavirus,.Differentiating immune cells from body cells!. It seems possible, as common cold virus is corona virus just as "corona" is, that both infectiousnous and immunity/ are just the same, i.e. common cold just like corona, vice versa vaccination against corona just like against common cold, that seems possible, thus,  and, counterintuitively, it's "only" the severeness of harm that corona does to target cells that sets it apart from the Common cold.

Changing a question completely by editing after it was answered it seen as bad practice, as this also does not respect the work of the answer. Please stop this. I will rollback the edits and lock the post.

If user is not allowed to extensively edit question after it was answered all he may do is delete the question and start anew? If he dares to? What about the consent of those have spent commenting and even answering? As I have done extensive research I feel much brighter on the subject now (I would like shift focus to "bat virus" which is a different species. Answers are correct: ferret virus is same, however bat virae are different species. "Just" let me know if this is too hot a topic for casual writing...no problem to postpone or refrain, to me).

@Chris I very much revised my question as I felt unable to delete it because - according to the rules -  it had already be answered. What are the option? I may ask the person who answered to withdraw his/her answer, then delete question? I am very keen on putting up any completely changed question, as my question  did not raise any further interest. By the way, difficult to find out if any vote count with this question would vanish too and  go away.

We cannot say if the virus in ferrets gets less or more dangerous than the one which actually circulates in humans. There are two problems with this infection:

The ferrets can build a reservoir for the virus making it possible for circulation to occur among these animals and re-introduce it into the human population. It may also be possible that the virus jumps into other animals, also enabling transmission.
It is possible that the virus mutates in the animals (it does this anyways) and changes, so acquired immunity against the original SARS-CoV-2 it will not be present or at least less effective, enabling further infections. This can also render a vaccine directed against a mutated part ineffective.

So far, these things are concerns only, but to avoid them, swift action with the killing of all Danish ferrets has been taken.
About your example with Jenner: He was simply lucky that the cow pox he used for this experiment where close enough to the small pox to generate immunity. For the SARS virus we still talk about the same virus, not a different one.

I read your answer after having edited my question, and I think it is still valid and good. Again, deleting the question would be all right by me if that's the option you opt for.

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Differences on biological classification?
Why we use the term phylum for kingdom animali but for kingdom planti ,fungi and prokaryota we use them division?                         What difference between phylum and division ?

Phylum and division are both listed under the same taxonomic ranks. The wikipedia page for phylum states that

Traditionally, in botany the term division was used instead of
  "phylum", although from 1993 the International Code of Nomenclature
  for algae, fungi, and plants accepted the designation "phylum".

What you have to keep in mind is that the scientists categorizing plants and animals worked in isolation for a long time and only recently have they come together to build a tree of life for all organisms (rather than just working separately on plants / animals / bacteria)

Is it just for a tradition ???

probably for that and legacy purposes to not confuse the people already in the field

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How are 23 chromosomes in human sperm chosen?
I'm not biologist and I have just a basic knowledge. I've been thinking for a long time about the following question: How does the body choose which 23 chromosomes should be active in human sperm and female eggs?
Thanks in advance for helping me with this!
Edit:
Each egg cell or sperm contains 23 chromosome whereas a normal cell has 46 chromosomes. So How is it that those specific 23 chromosomes are the chosen ones. Are a random collection of chromosomes selected at the end of meiosis or is it more specific than that?

What do you mean by "decides, which chromosomes to choose to be active in human sperm and female egg"? The human body has either sperm or egg, not both. Or do you mean the developing embryo?

@chris I think that this question means the OP doesn't know of diploidy and assumes that a more or less random half of the chromosomes present in a normal cell end up in a gamete.

Amir, welcome to the site! Your question is very basic, and we have trouble finding out what exactly is unclear to you. Please edit the question to explain which situation you mean exactly (when are they "chosen"? Do you know that human chromosomes are paired? etc.) I will vote to put the question on hold until you have done so, else you will get the wildest guesses as answers, and they won't be very helpful. You can also try reading http://en.wikipedia.org/wiki/Ploidy, but I admit the language will be hard for somebody who is not a native speaker of English and does not know much biology.

This should clear up some of your confusion: Wikipedia: meiosis. Meiosis is the process that halves the genetic content and produce haploid eggs and sperm.

They are not chosen, they represent an even half, a complete set of chromosomes.
The entirity of a cells genes (found on the chromosomes) is called a genome.
Somatic cells are the cells in our bodies that exclude sperm and egg. Sperm and egg are called germline cells.
The billions of somatic cells in a homo sapien have the same 46 chromosomes. 23 ( half) of them came from dad and 23 from mom. Thus we say somatic cells have two copies of each chromosome and it is abbreviated 2n. The germline cells are 1n or just n.
So your sperm has 23 chromosomes and after sexy time one of them can combine with an egg (which also has 23) to produce a cell(called a zygote) that has an entire complete genome (46). Then that zygote splits, and splits and splits.... And each time before it splits, all 46 chromosomes are copied (the copies are called sisters, or sister chromatids, respective to each other). The cells split into two new cells called  daughter cell and each daughter has an entire genome. This form of cell splitting is called mitosis.
Probably the most important event in the cell cycle is the duplication of every DNA stand. This is called a Synthesis (S) phase. This is not a component of mitosis! It's a required event that happens before mitosis. So all 46 chromosomes get copied and then during mitosis each copy (an identical copy) is attached to each other at a region called the kinetachor. A kinetachor attaches sister chromatids (each sister is a copy of each other).
At the beginning of mitosis a web forms in the cell and you can think of the strands that make the web as sliding chains that can pull stuff from the center of the cell to 1 of two perimeter locations (poles) of the cell.
The chain like web attaches to the kinetachor and it rips apart the pair of chromosomes, rips apart the sisters. So that one sister goes to one side of the cell and the other sister chromosome goes to the other side of the cell. So now at opposite sides of the cell you have a complete genome (which will become the new daughter cells).
An identical process occurs in meiosis (specifically meiosis II) which is part of the  process that forms the sperm and the egg. During meiosis however there's additional separation (separation of homologs which occurs in meiosis I) that occurs but it's really not pertinent to your question.

In biological terms, I believe the original question is asking if the separation of homologous chromosomes is random or not. Perhaps you could touch on that briefly.

Good point @canadianer

Thanks @rhill45 for your answer. I know the steps of the process, I just wondered, how are those initial 23 chromosomes chosen (@canadianer - separation of homologous chromosomes). So the answer is random as I deducted from your reply? Thanks! :)

@ememem It is random, and of course it would have to be: don't forget every person has hundreds of eggs or millions of sperm! The fact the assortment is random means every egg and sperm within a same person has a different combination of half of that person's chromosomes. If that weren't the case then brothers and sisters of same parents would be identical!

How specifically is this randomness achieved? Computers e.g. often have problems generating random numbers, how does the body achieve it?

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Do variant callers miss rare variants in reference?
Generally variant calling programs (such as GATK-UnifiedGenotyper) look for differences between reference genome and submitted sequence. However, we all know that reference genome consist rare variants in various positions. If submitted sequence has this rare form of that variant, variant call doesn't see it and doesn't report at all. However, that variant could be very precious for analysis.
So, how can I solve this problem? What should I do to not miss that rare variants even they are in reference genome?

Please don't cross-post, as you did here: http://seqanswers.com/forums/showthread.php?t=50289

Thanks for the answer. But Why shouldn't I? I want to reach people as many as possible. Actually I asked the same question on Quora. I don't think that it wrong. Seqanswers and Stackexchange are different platforms and may have different users. So, a user that is member of only single platform may miss my question. Cross-posting increase the possibility to get answer.

Cross-posting is convenient for you, but doubles/triples/etc. the work expended by the community to help you. Why should people in a community B expend time helping you when those in community A have already provided you with the answer to your question?

Actually, I'll share the answer that I found in every platform that I asked question. So, everyone in both platform will learn the answer. More people will benefit. It's better right?

Well, you'd hope that the "reference" sequence is of a healthy individual, and won't be carrying a highly detrimental allele that you care about.
Or get a bunch of control data from the 1K genome project, and compare them to the reference as well; they won't carry the rare alleles that your reference does.

If the reference sequence is associated with a disease or increased susceptibility to some phenotype, the the population you're using to compare against (with a variant) will show protection to it. So either way you're going to find an association, this will just change the sign of the coefficient.

The reference genome is a composite sequence from multiple individuals therefore scenario A should hardly occur, if at all. The unsatistying answer is that it is very unlikely that the rare variants of interest to you will be in the reference.


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How can mutation of viruses lead to loss of fit to antibodies without loss of fit to antigen of cells they infect?
Viruses are known to mutate, thereby escaping immune cells and evading vaccination. Given that there is one and the same specificity of the key to both the receptor on the infected cell causing the disease after cell entry as well as to the antibodies or immune cell receptors of the immune cells how can it be that a virus that has mutated thus escaping defense is still able to connect to cells of the body?
It should be one and the same key to one and the same lock. As it is the same key it seems logical that both locks - antibodies' and antigens' are identical, as they fit to the same key.  If mutation leads to "unfitness" in respect of antibody, how can the key still fit to the body?
In the context of mutation and vaccination this question might intuitively be answered by "different epitopes".
Is there any opinion on that at all? Textbooks seem to be not explicit at all. Is it too trivial a question? Are there are two epitopes on viruses: one for the antibody, one for the body cell? Mutation somehow deliberately restricts itself to the former?
One line of thought added: if you think of some shared (intersectional) epitope it's one and the same mutation that influences both sides, adhesion to antibody and, plus, adhesion to target receptor. Logically, it is possible that there is one mutation that is successful in both ends, i.e. results in loss of antibody fit and improves adhesion to target cell at the same time. But then, illustrating my question, it is a question of probability - as on the antibody side it is the loss of fitness which should be - at the same time - be a gain on the side of adhesion to receptor. Intuitively, this is highly unlikely, with a shared epitope.
The above speaks for different, non shared epitopes, and a multistep strategy in the evolution of virus. Is it possible and is there any authority on my assuming that it is among those virus clones that do not lose their affinity to antibody and remain under attack (as losing antibody fit, see above, means losing target fit, in probability) that selection takes place: those who do not mutate away from antibody attack evolve receptor affinity, and become "a little bit better", in speed, attain advantage in targeting against being caught antibodies. This might explain and be coherent with CoV-2 making appearance not as a variant of CoV that antibodies would not reach anymore, but much more so as a variant that has improved its target cell affinity.
So, assuming relevant mutations being selected among those strains that remain within the reach of existiting antibodies and do not mutate away from the antibody side epitope would be consistent with findings that existing vaccines and the antibodies they induce remain valid against new and upcoming strains of CoV-19. If it were found that new strains are more pathogenic, that would be coherent with that assumpton, too.
For better understanding compare this passage of the answer giben: "... which do lose their fitness against the immune system, but undergo gene reshuffling with similar viruses and again become infectious." "Lose fitness against the immune system" in strict meaning of words would mean gaining fit the to the antibody - however, the author speaks of "becoming infectious", thus refering to target cells. This made me rethink the above to the following:
If you do not assume any shared, identical epitope of body cell (lose the fit to antibody means gaining fitness against the immune system, however at the same time losing fit against the target cells that define the disease) there is some successful "moving out" of the reach of antibody which means "sucess" and that same "moving out" of the realm of target cell epitope which means "failure", losing infectivity.  At both sides it's just "into the negative", to lose a fit (however, success and failure very set apart). One has to acknowledge that both sides make sense: just losing fit to antibody is success (epitope to body receptor remains unchanged). For success of the virus on the body cell side, however, no loss will do, there must be a gain of  fit to another receptor on body cell. Why then, to illustrate my question further, should a selective stress prefer to take the hard way: gain of function towards body cell, and not easily "fall apart" from the antibody fit, thus becoming fit against the immune system?
To sum up, two alternative answers seem possible:
a. there are two separate epitopes; virus escape the antibody fit, and this suffices
b. there indeed is a shared, common epitope: it is not enough to "opt out" and exit the antibody fit but one and the same mutation - as the primise is the existence of a shared, no separate epitope - must find a new fit on the body cell receptors side.
A third answer emerges, to me:
Epitopes are separate, not shared, and mutation is a multi-step process. Then first, interestingly,  the mutation to a new fit on the body target cell side should come first, as only this sequence - not the opposite - presevers selective pressure to escape the immune system in the following second mutation.

I'll address this q and ignore the rest of the (way too long) post/theories:

Given that there is one and the same specificity of the key to both the receptor on the infected cell causing the disease after cell entry as well as to the antibodies or immune cell receptors of the immune cells how can it be that a virus that has mutated thus escaping defense is still able to connect to cells of the body?
As it is the same key it seems logical that both locks - antibodies' and antigens' are identical, as they fit to the same key. If mutation leads to "unfitness" in respect of antibody, how can the key still fit to the body?

This premise is wrong in several ways.
First, affinity is not a binary (yes/no) proposition. More technically speaking, what matters for virus binding to a receptor is avidity, which is the combination effect of affinities at multiple points in a protein, but many papers in virology nonetheless use the former term when talking about viruses binding to receptors.
You can probably already see that multiple "solutions" or "keys" are (thus) actually possible for the same "lock". For example, the SARS-CoV and SARS-CoV-2 RBD (receptor binding domains) are only about 73% similar, even though both viruses bind to the ACE2 receptor in humans, "well enough" to infect (and ultimately replicate).
Furthermore, the "lock and key" metaphor is only a very crude approximation of the more complex mechanism of viral entry.
But to single out one aspect of that, the "key" basically can "shape-shift" (undergo conformational change) so that it "looks different" during viral entry than it might otherwise look to antibodies, e.g.

The RBD in coronaviruses can be in either a standing-up state, which enables receptor binding, or a lying-down state, which does not bind to the host receptors. Cryo-EM studies have shown that, in SARS-CoV spike, the RBD is mostly in the standing-up state; however, in SARS-CoV-2 spike, the RBD is mostly in the lying-down state. Therefore, compared to SARS-CoV, although SARS-CoV-2 RBD has higher hACE2 binding affinity, it is less accessible, resulting in comparable or lower hACE2 binding affinity for SARS-CoV-2 spike. To maintain its high infectivity while keeping its RBD less accessible, SARS-CoV-2 relies on a second strategy—host protease activation. [...]  Protease activation of coronavirus spikes potentially leads to the final structural change of coronavirus S2 needed for membrane fusion; this process is irreversible and needs to be tightly regulated.

As further discussed in that paper, RBD masking/shielding is actually rather common in several other virus types (HIV, Hepatis C, Ebola etc.)
As an interesting point here showing how affinity can decrease but avidity can increase (probably in tandem with antigenic drift), a 2017 paper on H3N2 finds that:

Recent reports have suggested that current human H3N2 viruses no longer have strict specificity toward human-type receptors [using typical hemagglutination tests]. Using an influenza receptor glycan microarray with extended airway glycans, we find that H3N2 viruses have in fact maintained human-type specificity, but they have evolved preference for a subset of receptors comprising branched glycans with extended poly-N-acetyl-lactosamine (poly-LacNAc) chains, a specificity shared with the 2009 pandemic H1N1 (Cal/04) hemagglutinin. [...] Remarkably, these human-type receptors with elongated branches have the potential to increase avidity by simultaneously binding to two subunits of a single hemagglutinin trimer.

As final "food for though" as to the [in]appropriateness of the key-lock analogy, poxviruses don't seem to use any particular receptor to bind to cells, being capable of attaching to glycosaminoglycans (GAGs), which are present in all eukaryotic membranes, although various cells differ in degree of sulfation of their GAGs, which in turn changes affinity with poxviruses.

The second reason for which your premise is wrong, antibodies are not mere copies of the receptors found the on the actual cells that the virus may enter. Antibodies need to "solve" a simpler problem than the virus-cell entry; namely an antibody (if we restrict discussion to those targeting a receptor binding domain) only needs to "screw up" the RBD somehow, so the latter doesn't "fit" with the cell receptor anymore. For example, these two antibody fragments against SARS both manage that disruption, even though one only binds to the side of the RBD:

Third, there is actually a rapid evolution process of antibodies themselves known as antibody affinity maturation:

The extensive sequence diversity of antibody molecules derives from several sources: (i) combinatorial diversification, whereby two sets of light (L) chain gene segments, VL and JL, and three sets of heavy (H) chain gene segments, VH, D, and JH, rearrange to produce functional variable (V) regions; (ii) imprecise joining of these gene segments; and (iii) somatic hypermutation, by which point mutations, as well as insertions and deletions (indels), are introduced throughout the sequences encoding L and H chains. B cells expressing antibodies with improved affinity are better equipped to compete for antigen and thus receive signals that result in preferential expansion and further antibody sequence diversification via additional rounds of somatic hypermutation. Through this rapid evolutionary process of mutation and selection, antibody affinity typically improves 10- to 5,000-fold during the course of an immune response, bolstering host defense.

If the host is lucky, it might even produce antibodies that work against multiple viruses. E.g. there's a known example
of an antibody from a Covid-19 patient which also neutralizes the orignal SARS, even though this patient had
no history of infection with the latter/older virus. This is basically known as cross-reactivity of anti-bodies. However note that this antibody is not equally effective against both viruses, it needs higher concentration
to achieve the same affect against SARS-CoV than avainst SARS-CoV-2.

The antibody COVA1-16 was recently isolated from an individual
recovering from COVID-19 and cross-neutralizes SARS-CoV-2
(half-maximal inhibitory concentration [IC50], 0.13 μg/mL) and
SARS-CoV (IC50, 2.5 μg/mL) pseudovirus.

One has to distinguish the cause and the consequence: the only viruses that survive the natural selection are those that can evade the immune defenses while effectively infecting cells. A virus strain not successful at either of these tasks is less fit and likely goes extinct.
One can pose a question of what modifications in virus proteins allow it to be so specific in what it (does not) binds to. However, the answer will necessarily depend on the specific virus/strain and specific conditions (which may mean the epidemiological conditions during the time of its spread, the existing vaccines, or even the specific patient).
It is also necessary to point out that statement Viruses are known to mutate, thereby escaping immune cells and evading vaccination. is generally not true, but presents only one possible evolutionary strategy for virus survival,  characterized by  establishing a chronic infection. The typical example here is HIV. To some extent one could also use this description for influenza-like viruses, which do lose their fitness against the immune system, but undergo gene reshuffling with similar viruses and again become infectious. However one could argue that this is not a mutation, but a new virus.
Other strategies that viruses use to survive include (viewed from the point of view of population genetics rather than virology):

Hit and run approach, characteristic of cold-like viruses, which succeed to replicate before triggering the response of adaptive immune system, and thus being able to reinfect the same hosts.
Coexistence, characteristic of herpes-like viruses, which avoid extinction by being relatively low-key, i.e., not triggering substantial immune response, while establishing a lasting infection (e.g., by integrating in the host DNA).
Permanent circulation - the most well-known case is smallpox, which continued to exist in the human population for thousands of years by simply moving around the globe. This entailed no adaptation, which is why it was possible to make this virus extinct by vaccination.
No strategy - Ebola epidemies in humans are an evolutionary dead end, as the virus killing nearly all of its hosts is bound to become extinct. The reason that Ebola outbreaks still happen is because this virus exhibits a relatively harmless, flu-like, behavior in some animals and only occasionally spills to humans. Thee difference with the smallpox is mostly a quantitative one: Ebola kills its victims too fast, to spread efficiently.

References
J. Flint et al., Principles of Virology


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Is there a color changing organism that is by default translucent or otherwise "colorless"?
To illustrate a point I am trying to make in a paper I am writing it would be helpful to have an example of an organism that by default has "no color" but which can adopt the color of something in its environment (e.g., through some chameleon-like color changing ability or something like the food-derived pigments that give flamingos their pink color). I could just make up such an organism for illustrative purposes, but it would be nice if there were a non-contrived example.
By "no color"/"colorless" I'm thinking of something like translucency/transparency, but I can be flexible about the exact meaning so long as it can plausibly be construed as involving a lack of color.
Is there an animal that by default is colorless/transparent/translucent but which has the ability to take on colors present in its environment?

If you broaden the context to include all organisms then many microbes can be good candidates

@another'Homosapien' that works for me! I only specified animals because that’s what immediately sprung to mind. Any organism that doesn’t require an exhaustive description to explain its color properties semi-evocatively should work. I’ll broaden the question, thanks!

Maybe someone will have answers and I'd be curious to see examples, but I'm not sure such organisms are very realistic. Organisms typically change colors by playing on the pigments they display to the outside... But to be translucent they cannot have any pigments either outside OR inside. This organism would have to change colors based on another mechanism (like diffraction; not impossible but don't know examples), or change color by creating pigments on the fly from colorless precursors (which sounds slow), or eat colored foods (most likely mechanism to my mind but again, idk about examples).

@Oosaka when you talk about “no pigments inside” do you have in mind the way that some fish are translucent except for, e.g., certain organs? Or something a bit weirder (to me, at least) where the outside of the skin is translucent but the majority of the interior is opaque, due to something like pigmentation in an inner layer of skin or bodily fluids? I think “mostly colorless” organisms with colored organs would still work for my purposes, but an organism with, e.g., transparent skin but mostly opaque and colored interiors would not work.

@Dennis that's what I mean, to be translucent an organism has to be translucent all the way through. There is no such thing as "translucent on the outside and opaque on the inside", that's just "opaque" (I mean, if you go that way the very outer layer of our skin is translucent!). So for an organism to be translucent but change color, it needs to 1) contain pigments (because changing the pigments changes the color) and 2) not contain pigments (because pigments by definition are not translucent). If you allow isolated opaque organs that can be another workaround I guess.

Now that you say that any organism will fit just fine, there are a ton of microbes that can be good candidates. Instead of trying to list them here, I think it's better to actually have a look at some like this (instagram link; the account posts a lot of photos/videos of microbes, and the linked post shows a Rotifer with blue blobs from the algae it just ate, just mentioned that to give you some examples, not for advertisement :)


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Is Melanin a PCR Inhibitor?
I have been growing B16F10 Mouse Melanoma cells. I need to extract the genomic DNA and do PCR to amplify a specific region. However, no matter what temperature or magnesium concentration I use, I have no luck.
I obtained mouse DNA from someone who was genotyping mice. I tested the PCR oligos with that DNA, and the reaction worked, so it's not an oligo problem.
The genomic DNA had poor 260/230, about 0.6. I thought the EDTA levels may have been high, so I did an isopropanol precipitation to clean it up. This made the 260/230 ratios about 2.1. But the PCR still didn't work.
What I had noticed during the precipitation however was that the DNA pellets were gray to black. I assume this is melanin, because the cells are melanoma cells, and turn black.
Could this melanin be a problem in PCR?

Melanin is a potent inhibitor of PCR - when you use B16 cells (or any other cell line that produces melanin) you have to purify your sample from it. Unfortunately a simple Phenol-Chloroform extraction or an ethanol precipation won't do the magic, since melanin co-precipitates with the nucleic acids.
I recommend following the following paper: "CTAB–Urea Method Purifies RNA from Melanin for cDNA Microarray Analysis".
The protocol derived from the paper can also be found here.

just use a protease to break the melanin

@4DNeuron Have you ever tried this? Besides this, melanin is not a protein.

I don't have much expertise in PCR (so please do not ask me technicalities). A research has proven that melanin is a PCR inhibitor as it forms complexes with thermostable DNA polymerase and inhibits its activity, thus inhibiting PCR. See this paragraph below:

We found that both RNA and cDNA preparations derived from melanocytes contain a RT-PCR inhibitor that copurified with nucleic acids. Investigation of the candidate inhibitor melanin revealed that it potently blocks PCR at concentrations below 200 ng/ml, whereas 100 microg/ml melanin was required to inhibit reverse transcription. Melanin and thermostable DNA polymerase preferentially formed a distinct complex with reduced migration velocity as compared to pure polymerase in nondenaturating polyacrylamide gel electrophoresis. Our findings demonstrate that melanin is a potent inhibitor of thermostable DNA polymerase in vitro and that the inhibitory effect is conferred by a direct and reversible polymerase-melanin interaction.

The same paper also gives a solution to your problem as:

The inhibition of the enzyme by melanin could be reversed by diluting solutions of preformed complexes or by adding excess amounts of other proteins such as bovine serum albumin or dry milk.

Reference: http://www.ncbi.nlm.nih.gov/pubmed/10814530

Thanks, I'll take a look at the paper, and maybe try adding BSA to the PCR mix. I have no idea how concentrated the melanin is, but if it's concentrated to turn the sample black, it must be pretty high.

Yup it makes sense. I hope it'll work, else you can also try the method suggested by @chris.

There are many suggestions how to avoid melanin-caused PCR inhibition. Some we have found helpfull (like using smaller amount  of DNA sample + increasing number of cycles or adding BSA to PCR reaction), other (like trying different DNA isolation and PCR kits, purification columns etc.) are good only for profits of biotech companies. The solution is in fact very simple: using proper procedure for DNA isolation.
Rutinely we prepare DNA using high-salt lysis buffer (250 mM EDTA, pH 8,5, 1% SDS and 100 ug/ml proteaseK) and, after incubating at 50°C, single extraction step with phenol/chloroform, followed by precipitation with 1 volume of EtOH (not more, otherwise you precipitate EDTA). Under these conditions melanin remains with DNA.
For samples containing melanin we include one extraction step with phenol only before phenol/chloroform extraction. Melanin gets extracted into water/phenol interphase and falls throught phenol during centrifugation; this does not happen when you extract with phenol/chlofoform mixture. For efficient melanin extraction the high salt is important. If you need to eliminate melanin from ready-made DNA samples, add LiCl to 2M concentration and extract with phenol.


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Can Blood Types Change?
I recently heard a radio show where two callers claimed that their blood types had changed. One caller claimed that he was born O-, but recent tests said he was A+. Another caller claimed to change from AB- to AB+. Both callers claim that they had multiple tests before and after the change.
What I noticed is that both cases claim a conversion from Rh- to Rh+, or from type O to some other type. These could potentially be explained by a person carrying a gene for Rh factor or some other blood type, but failing to express the protein. Then the gene starts expressing, changing their blood type.
Of course both stories could be false, intentionally or otherwise. This is purely anecdotal evidence, and one caller claimed that her blood type change was due to extraterrestrial interference. I couldn't find any better documented cases of blood type changes after a quick search on the internet, so I thought I'd ask here.
Are there any documented cases of a change in blood type?

This is highly unlikely. The only reason which comes to my mind would be a transfer of stem cells (aka bone marrow transplant).

@Chris And I doubt that aliens are transferring stem cells.

Embryonic bone marrow transplant, maybe...? But that wouldn't work since they'd tested blood group earlier too ;)

@another'Homosapien' I would suspect that either the first test was wrong or somebody remembered something wrong.

@chris my first idea would be: "if your blood type has changed, then your body (immune system) will very soon kill you". It surely isn't easy at all...there has to be some misunderstanding here.

Possible in leukaemia.

@another'Homosapien' not in the cases when antigen is not expressed ie. if blood group changes from AB to A or B or O , or from AorB to O.

@jm97 yeah...I meant that only in cases mentioned here :P

And how are we 100% sure that hemagglutination will not happen? I also believe that there is a very high death rate, and as a result, there will be no longer human living populations with that symptoms. But what happens if the O- type changes to A+ type, I don't know. And especially how Rh- changes to Rh+, is just a mystery. @user137 Can you provide us a link where we can see if that hypothesis is true? Please check online for that radio conversation you heard. To sum up, what happens with the antigenes? It is extremely lethal to mix the blood types...

@The_Mad_Fish This was the show, I think it was the April 13th or 14th shows, but they don't let you listen to past shows without paying, so I can't link to the exact shows. But the evidence I list is the evidence they gave, purely anecdotal. Could the antigens be expressed at such low levels that hemagglutination doesn't happen?

@user137 No antigenes dont express "mildly" or "in a soft way". Their expression (if it happens, but in our case it happens 100%) is done with an almost sure result (e.g Hemagglutination).

Blood group antigens are either sugars or proteins found attached to the red blood cell membrane. ABO blood group antigens are the most clinically important antigens because they are the most immunogenic. As red blood cell antigens are inherited traits, they are usually not altered throughout the life of an individual. There have been occasional case reports of ABO blood group antigen change in malignant conditions,ABO antigen alteration associated with acute myeloid leukemia. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5242122/
https://www.ncbi.nlm.nih.gov/pubmed/15135601 ( B to O change)
https://www.ncbi.nlm.nih.gov/pubmed/22270426 (New laboratory procedures and Rh blood type changes in a pregnant woman.)
A bone marrow transplant will replace the cells which make your blood cells with cells from the donor. Over about 3-4 months (life span of a red cell), your blood will become your donors type.


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Infra/Ultra sound exposure
What risks are associated with ultrasound/infrasound listening via bone conduction?
Would you risk yourself serious physical harm doing this?
What levels for these frequencies are safe to the human body?


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Condition for a genetically modified group of cell to remain and to spread?
I was wondering: when a treatment modifies a group of gene (like in gene therapy), what makes a group of cell remains?
I mean, when a cell divide itself to create new ones, if a cell was initially genetically modified, it will lead to two modified one, right? But, I assume that we have a finite number of cells in our body, so if the process was going on like that, we would just have to modify one cell of our body. But, besides this, the other cells divide themselves too, so there might be something that makes a group of cell dominant (like the proportion, the number of neighbors of one cell...).

So, my question (cut in three) is:

What are the conditions for a group of modified cells to remain?
In what extend the modification can spread?
If it can't spread, why?

(I'm not a biologist student (I studied it in high school, so I may be able to understand the basics), but I'm interested in making a mathematical model of such a process. So if there is an answer, could you make it understandable for someone who has only the basis?)


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Limits of gene editing
I was reading some articles about CRISPR and the world of gene editing, but then a lot of questions for which I couldn't find any answer online came into my mind. Those are all about how far can we edit an organism. So here is the general question, followed by some other to narrow down a little bit this broad subject:
What are the limits of gene edition?

Can one edit the genes in its entire body? (as a human, or a multicellular organism)
What are the risks? I heard that some people who did try gene therapy ended up having some of their modified cells turned into cancer. Was is because of gene incompatibility  or because of error during the gene editing process?
Can we go as far as adding some chromosomes or changing an entire chromosome? For example, if a male human would like to change their sex, could they switch all their Y to an X?

EDIT: I decided to accept the answer from @MattDMo. However, I'm still interested in some development (clues with other technologies...)

Your question is very broad, but I'll try to address each of your points briefly.

It would be nearly impossible to edit the genes in every cell of a human being or other complex organism simply due to the number (and accessibility) of cells. A full-grown human has in the neighborhood of 30 trillion cells - 30,000,000,000,000. Cells in locations such as the brain and central nervous system are protected by the blood-brain barrier, which would keep most gene therapy vectors from accessing those cells. There are other reasons why editing each cell in the body is virtually impossible, such as vectors accumulating in the liver, but this is one of the main ones.

Cancer is indeed a risk from gene therapy in general, although DNA editing technologies like CRISPR in particular have a lower risk due to thTe circumstances surround exactly how the therapy is delivered to the nucleus of the cell where DNA resides. Other risks include potentially serious or fatal systemic inflammation due to an immune reaction to the viral vector which carries the CRISPR "machinery". Off-target effects can occur due to the wrong cells being targeted (although this risk is generally lower with CRISPR). Additionally, there is the very small but non-zero chance that the genetically-engineered vector could somehow regain its native infectious capability. Newer generations of gene therapy have significantly reduced this chance, however.

Very briefly, no. DNA is made up of "letters" (A, T, C, and G) called bases or base pairs, and typical CRISPR constructs only operate on 10-20 bases at the most — usually it's just one or a couple that are changed. A typical human chromosome has millions of base pairs encompassing hundreds to thousands of genes, so editing, adding, or removing an entire chromosome is simply out of the realm of possibility with this technology.

Thanks for your answer that was the one I was looking for. However, what are the vectors you're talking about? Retroviruses? Moreover, without using CRISPR specifically, what prevent us from just removing an entire chromosome "by hands" and then injecting a new one in one cell?

@MiKiDe As far as I know, you wouldn't want to use a retrovirus as a CRISPR vector, although they can be appropriate for other types of gene therapy. As far as removing a chromosome, you need to remember that most of the time, chromosomes are in a "relaxed" state and not tightly wound up into a single particle that could be picked up or manipulated. They need to loosen so transcription factors can get at active genes and transcribe them into mRNA. Condensed chromosomes are also extremely small, so manipulating them would just mechanically be very difficult.

Check out this and this for a brief and much more in-depth look, respectively, at how gene therapy works, including different types of vectors.


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Immune response to foreign protein
In the context of COVID-19, why is it possible to inject someone else’s antibody protein into a person without fear of stimulating an immune response. Does this indicate that, somehow, antibody conformation is universal?
Or rather ...
The immune system must differentiate between cellular and fragmentary material? It will attack any cellular material it deems ‘non-self’. But if foreign non-cellular material enters the body, such as dust, pollen etcetera we are in the realm of an allergic response. The allergic response is not absolute: only certain materials will cause a reaction.
So perhaps foreign protein, such as donor plasma products, are treated as potential allergens which, happily, do not cause an immune response; unlike midge spittle?

Educating I find that you differentiate "between cellular and fragmentary material", this brings up "MHC". People differ in their allergic reactions as they differ in their MHC?  If  any sole protein, is "no cell", it might still be about the MHC, of the "host". Not commonly  known is that antibody producing B cells take up isolated antigen without prior presentation by APCs. B cells then present on their MHC2 to   T helper cells that need presentation by APC.  Thesis: people differ in reaction because they differ in their MHCs presenting allergenes to TH1, 2 and their B cell's MHC2.

Interesting: Likewise it might be asked if T cell receptors are interchangeable between individuals - as antibody is another word for the B cell receptor turned loose from the B cells membrane.  Any T cell receptor isolated from one individuum and injected as "foreign" protein should be tolerated - it might even be taken from the horses' mouth as Behrings magic bullets were.

The complexity of the immune response requires foreign proteins to be bound first by presenting cells which happen to be like macrophages - cells that are like garbage disposals. Why some proteins are simply gobbled up and yet others are preserved and presented to the resident T cell helper population is related to the size and sequence of the protein. In other cases, even small molecules (allergens) can bind to native normal proteins and make them look abnormal.
The use of immunoglobulin (semi purified blood) was used in treating certain diseases in the past. These sera were usually developed from animals purposely infected with the disease. Though these proteins also elicited their own immune response (side effects) the kinetics of that event was days to weeks whereas the binding of the immunoglobulin to its target(the virus protein) is a first order event occurring in minutes. Clearance of that antibody antigen complex over hours to days Avoids the catastrophic exponential growth of the virus by keeping the numbers low. Eventually tho side effects WILL happen if you keep giving the serum

Activation of the immune response relies on the detection of structure features of the foreign molecule that marks it as distinct from host cells. In the case of immunoglobulin injection between a human donor and a human recipient, these immunoglobulins are naturally produced antibodies that the body makes to help you fight infections and to serve other functions for the immune system. Therefore, they do not have the structural features that can be recognized and mark them as “foreign molecules” by the immune system.
However, IVIG can cause some adverse effects such as headache, chills, etc. You can find more details in this paper.
Resources

Chaplin D. D. (2010). Overview of the immune response. The Journal of allergy and clinical immunology, 125(2 Suppl 2), S3–S23. https://doi.org/10.1016/j.jaci.2009.12.980
https://www.rheumaderm-society.org/ivig/
Guo Y, Tian X, Wang X, Xiao Z. Adverse Effects of Immunoglobulin Therapy. Front Immunol. 2018;9:1299. Published 2018 Jun 8. doi:10.3389/fimmu.2018.01299


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How to estimate oxygen consumption of an average human during different activities?
I've tried to find some resource on the internet but had little luck. I'm looking to see if there's any data on average oxygen consumption of average to well trained humans during different activities.
Specifically how much more oxygen does a human consume when panicked/under pressure in comparison to other activities such as cooking, climbing etc. Even better would be if I had a formula where I could plug in weight, height, gender and receive a percentage of how much more O2 is consumed under stress/panic vs. normal functioning. Any information would be much appreciated, please include sources where possible.
NOTE: With "panicked" I mean in the state of fearing for ones safety and being in a life threatening situation with the associated hyperventilation etc.

https://i.redd.it/expf3tuhr2g01.png panicked is a vague measure, ranging from momentarily startled to buried in an avalanche.

Yeah panicked is maybe too broad, I mean like you're in a life or death situation

may be helpful. https://onlinelibrary.wiley.com/doi/abs/10.1111/1469-8986.3860961

So “average to well trained” is the average overweight shopper to the well trained sprint cyclist?


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Any clue on what these tiny white bugs may be?
I would like to know what the bugs in the following pictures are, they are absolutely tiny, i would say 0.5mm at most, i can't get a really sharp picture, as they seem like to hang out in the dust on furniture (which messes with the focus) and to dislike strong lighting.
If this may help i'm located in North-Eastern Italy, i first noticed them last winter, in a home where i struggled with mold on walls, and i have moved since then (along with my furniture). During all of summer in the new home i haven't noticed them around, so i thought that they may have disliked the new "habitat", but recently when the climate started to get colder and moist i've been seeing some of them again. I see them in counts of approximately 10 - 20 on a surface, so i would assume that their total population in my room would reach the thousands.
Other than in dust on my furniture i see that they like particularly boxes aswell, my assumption would be that they're some kind of acari given their almost unnoticeable size, i've also seen someone talk about dust mites. I've also found some deposit of yellowish dust in strange formations that i would assume may be eggs or feces, i'll add the picture below.
I don't believe them to be harmfull, i'm just worried that they may be eating away at my furniture or damaging my electronics with their waste. I also believe to have seen tiny strings of material similar to spider webs around, that's why i believe them to be related to acari or some tipe of spider, rather than insects, although i couldn't actually count their appendices, they look almost "hairy" in a way. Also the smaller ones look whiteish-transparent while the biggest ones are beige as far as i can see.
EDIT: i have looked up and bought a macro lens that can be attached to the phohe's camera, here's the new pictures i got, although i'll have to wait to be able to take some pictures in natural lighting as these are overexposed


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Neuron repair inhibition in the CNS
Evolution provides different myelin sheathing cells (Oligodendrocyte and Schwann cells) in mammalian CNS and PNS. Damaged neurons in the CNS have little chance of recovery whereas damaged neurons in the PNS have an excellent chance of recovery. When ruptured, olidodendrocytes release Nogo that signals the damaged neuron cell body to stop any attempt at regrowing its axonal stump. Ruptured Schwann cells in the PNS do not release Nogo. Why should nature behave like this? Is it because the wiring density of the CNS is orders of magnitude greater than that of the PNS?
Or could it be because in the PNS the nerve is encased in a perineurial sheath that can readily self-repair and provide a framework for axon regeneration? There doesn't appear to be any similar sheath in the tightly packed CNS. Therefore to prevent unstructured axon regrowth, that could cause chaos in the brain, such a possibility is actively prevented?

Your question is a bit unclear. I can't understand your point about how having oligodendrocyte in CNS is detrimental.

You are misquoting me, what I said was "to the detriment of CNS neuron damage recovery" which of course is of extreme importance to many CNS injuries not the least being spinal cord injuries.

So, you are saying that having two different types of sheathing cells may be a detrimental factor in neuron repair. I still do not get your question. Please [edit] your question so that it is more clear. Comments should not be used for providing clarifications for many technical and logistic reasons.

I think you are taking a huge leap by saying "Oligodendrocytes vs Schwann cells == the reason why CNS damage recovery is more difficult than PNS recovery"... Correlation does not imply causation.

Now that’s a very interesting refutation Bryan. How would you interpret the quotations in my answer, the science seems so imperative.

I almost got it right. The consensus as of 2018 appears to be that it's a Faustian pact between providing the CNS with our unique mental powers at the cost of poor damage repair. This is not an issue in the PNS where damaged neuron repair is, in the main, impressive.
Quote (1): Principles of Neural Science 5th Ed (2013) (Eric R Kandel et al)
“ ... the regenerative capacities in the peripheral nervous system are impressive.
In contrast, in the central nervous system regeneration after injury is poor.”
“Is it the ability of peripheral axons to regenerate that is unusual, or the inability of central axons to do so? It is in fact the latter.”
“Maintaining constancy in the face of small perturbations in connectivity may therefore have the unavoidable consequence of limiting the ability of central connections to regenerate in response to injury. In this view our limited regenerative capacity is the Faustian biological bargain we have made for the possession of many precisely wired circuits that underlie our superior intellectual powers.”
Quote (2): Transl Psychiatry (2017) 7, e1214; doi:10.1038/tp.2017.170 www.nature.com/tp
“Reticulon 4 receptor (RTN4R) [aka NgR and NgR1] plays an essential role in regulating axonal regeneration and plasticity in the central nervous system ...”
Quote (3): A.R. Walmsley, D. Bourikas And A.K. Mir, 15 - Myelin Neutralization For Spinal Cord Injury And Stroke, In CNS Regeneration (Second Edition 2008)
“ ... the environment of the CNS is highly inhibitory to axonal regeneration and plasticity. In recent years, great advances have been made in our understanding of the molecular components contributing to the inhibitory environment of the CNS. The majority of these have been identified as membrane proteins present in CNS myelin, such as myelin-associated glycoprotein, Nogo-A and oligodendrocyte-myelin glycoprotein, that inhibit neurite outgrowth by binding to the multimeric Nogo-66 receptor (NgR1) complex on the neuron ...”
Quote (4): https://en.wikipedia.org/wiki/Reticulon_4_receptor
Reticulon 4 receptor (RTN4R) also known as Nogo-66 Receptor (NgR) or Nogo receptor 1 is a protein which in humans is encoded by the RTN4R gene. This gene encodes the receptor for reticulon 4, oligodendrocyte myelin glycoprotein and myelin-associated glycoprotein. This receptor mediates axonal growth inhibition and may play a role in regulating axonal regeneration and plasticity in the adult central nervous system.