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Why does vaccine development take so long?
The main principle behind a vaccine is to take a deactivated virus, "show" it to the immune system so it can "learn" how it looks like, so if and when the real virus does attack us, our immune system is already prepared for it. Vaccines have been developed using this idea even in the 1880's.
If that's the case, why does it take so much time and effort to develop a vaccine, for example, against covid-19? (and why are there several variants with different measures of reliability?) Is it only about balancing how strongly we damage the original pathogen, too much damage and our body might not learn the correct identifiers, and to little damage and it might still be active enough to cause the disease?

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I'm confused. In what way do you find the development of a COVID-19 vaccine slow?  From what I've read, it's by far the fastest developed vaccine in history — it's been less than a year.  Isn't that incredibly fast?  Doesn't it usually take 10-20 years?

@gerrit That would raise the question as to why it usually takes ten to twenty years. A year seems slow to me too, because to me as a layman it seems such a simple thing to 1. find a medium that the live virus multiplies in, and 2. find a way  to soak that live virus in a chemical that binds to its genetic material so that it cannot get reproduced by the cellular machinery. Especially since these two steps have already been done with many other viruses, and covid is just SARS, so a known threat for at least ten years or however long it's been since the (first) SARS outbreak.

@MatthewChristopherBartsh : I'd answer your raised question with this: https://xkcd.com/1217/

Roni Saiba's answer does a good job of explaining what goes into current vaccine development and why it takes so much effort, but I want to directly address the question of why we can't just grow some virus, kill it with UV and have a protective vaccine.
The answer is that not all immune responses to viral antigens are helpful in fighting infections of that virus. In some cases it can be harmful; antibodies to dengue virus of one serotype will attach to viral particles of another serotype but aren't able to inactivate them. The attachment of antibodies to active viruses makes their absorption by cells more efficient, and infections where this antibody-dependent enhancement occurs are more severe than first-time dengue infections.
Some viruses have evolved mechanisms to capitalize on this. The reason we need to get a new flu shot every year is that influenza viruses present a "knob" at the end of their glycoprotein that can change its structure and still retain function. This part is much more 'visible' to the immune system than parts of the virus that can't tolerate changes, so the immune response to this variable part outcompetes and prevents an immune response that would provide long-lasting protection. Conserved stalk-targeting vaccines are being intensely investigated for this reason. SARS-CoV-2 may have a immune-faking mechanism as well: the "spike" glycoproteins responsible for binding the ACE2 receptor and entering the cell convert to their post-binding form prematurely part of the time. Antibodies that bind the "post-fusion" form of the protein don't inactivate the virus, and this form sticks out more so may serve to compete for immune attention with the pre-fusion form that would provide protection if bound by antibodies.
In this last example, we can see that a vaccine made of killed SARS-CoV-2 virus particles would be useless if all of the spike proteins had converted to the post-fusion state. The mRNA vaccines therefore don't encode the natural spike protein, but a mutated version which can't convert to the post fusion state as easily:

S-2P is stabilized in its prefusion conformation by two consecutive proline substitutions at amino acid positions 986 and 987

In conclusion, viruses and the immune system are very complicated. Simple vaccines work for some viruses, and don't work for others. When they don't work, the reason is always different, but hopefully I've communicated some general understanding of the background issues.
EDITS:
This doesn't relate to the rest of my answer but I want to respond to Ilmari Karonen's and there is not enough room in a comment.
Looking at the timeline for SARS-CoV-2 vaccine development gives a very misleading impression of how long it takes generally. This is because ~90% of the development work was already done before COVID-19 was ever identified, in the 18 years since the SARS-CoV-1 outbreak started in 2002. Vaccines against SARS were developed and tested up to phase I trials, but couldn't proceed further since the virus was eliminated. I discussed this in a previous answer to a similar question, but to expand/reformat, here's some of what we knew and had available on March 17th 2020, when the "covid vaccine timeline" begins:

Identified the receptor as ACE2, and knew that antibodies targeting the receptor binding domain (RBD) of the spike protein neutralize the virus. Protocols to test that these were also true of SARS-CoV-2 were already developed and validated. Without this there would have been a lot more trial-and-error experimentation and false starts with vaccine candidates that looked promising but didn't pan out in testing.
Animal models. There is no naturally-occurring model organism for COVID-19. This is a subtle point because other animals can be infected with the virus, and some develop morbidities because of it. However, these are different enough from what we see in humans that something that protects against the reactions we see in the animal can't be assumed to protect against the reactions that cause problems in humans. For SARS, researchers developed transgenic mice that used the human version of ACE2, and showed that the disease they got from SARS were analogous to the disease humans got. This took several years, and the colony was still available when the virus causing the outbreak in Wuhan was identified as SARS-like and researchers started looking for animal models. As an aside, in an interview on This Week in Virology that I can't find right now, one of the maintainers of that colony said they were months or weeks away from shutting it down and euthanizing all the transgenic mice when the pandemic began, so if funding had been just a bit tighter we probably would not be having this particular conversation now.
How to stabilize the pre-fusion form of coronavirus spike proteins had been determined from work on SARS and MERS vaccines.

In addition to these, a large amount of miscellaneous knowledge about coronavirus functions and the immune reactions to them had been accumulated, and this sped up development, and increased confidence in results, which allows vaccine candidate production and testing to proceed more aggressively.
Historically, vaccine development has taken years or decades of research after the need has been identified. Testing is still longer in many cases, but the current case is very unusual.

So, to sum it up, is it that some viruses are simple enough that the strategy of "breeding them in a petri dish, heating them up and we have a vaccine" strategy works (this is why there are some 130+ year old vaccine manufacturing methods which still work), but other viruses are more complicated to defend against, so more special solutions have to be developed?

It's not really a matter of simplicity or complexity. Smallpox is one of the most complex viruses to infect humans (186,000 base pair genome vs. 13,000 for flu) but it's defeated by innoculation with an attenuated strain. Yellow fever is closely related to dengue, but a very effective YFV vaccine was developed in 1938, while DENV still can't be vaccinated against with 2020 technology. It's kind of random. Our immune systems have a lot of tricks, and different viruses have different strategies to defeat them, and they are better and worse at evading different parts of the immune system.

Very interesting, well-written, and informative, and I would love to upvote it, but I can't: IMHO it doesn't answer the question. It hints at an answer, but it is mainly only implying that it's too hard for us to understand, and we should just trust and respect and thank the researchers that came up with a vaccine, and stop asking why it took so long. To really the answer the question, you would need to explain/prove how/that the effective inactivated vaccines such as from Sinopharm and Sinovac required so much time to be developed and used (and even now many people have not been vaccinated).

You completely ignore Sinopharm when you talk of "killing it with UV", apart from the fact that talk of killing a virus is not appropriate since it isn't alive as such. You can only alter it so that it can no longer get itself reproduced. "Neutered" would make as much sense as "killed". You don't explain how all this complexity that you teach in a very readable way (thanks for a great read) prevents a trial and error approach from succeeding. Specifics were lacking. The specifics of the development of Sinovac should have been covered and how it related to the post fusion form and so on, IMHO.

You keep saying "sometime this" or "sometimes that", when to explain how vaccine development always has taken a long time (including the covid vaccines, IMHO) you need to be saying something like "always...". "SARS-CoV-2 may have a immune-faking mechanism as well", you say. Isn't this known? Again, something that only may be the case does not explain why the first covid vaccine took (rather than "may have taken") so long to be developed. To change the subject: "couldn't proceed further since the virus was eliminated" ignores the beliefs about what is ethical that prevented CHIM being used.

CoronaVac is indeed a blind spot of this answer, but I haven't since found enough useful info to justify updating it again. I didn't give a concise, definitive answer to the question because I don't believe one exists. The topic is indeed very complicated. Readers don't need to blindly accept the conclusions of experts, but if they want to understand 'why' questions about vaccine development, it will require substantial time investment; much more than a SE question or a review article in a journal can provide. My goal was to provide a broad view that could serve as a starting point.

Please "@" me when you reply to me. I really feel fobbed off by the answer, and by your most recent comment although, of  course, feelings don't trump reality. You don't mention in your answer anything about CHIM being rarely allowed for supposed ethical reasons. Surely if CHIM (human challenge) was freely used (within reasonable ethical constraints such as informed consent) vaccines would be developed faster, and therefore a reason they are not developed faster is that CHIM only rarely is allowed to be used? Correct me if I'm wrong: clinical trials are a time-consuming part of development.

@MatthewChristopherBartsh I am sorry I made you feel fobbed off. I think you would be better served asking about these points in a separate question. I did not address CHIM because I am not familiar with the acronym and did not find anything that seemed relevant when I looked it up. I've since skimmed some reviews and it seems to be used on well-characterized diseases that have resisted past vaccination campaigns. I don't think it could speed up vaccine development for a new disease.

There's no need to apologize. If it was sincere (I really can't tell), accepted. Maybe I misjudged you. I wasn't saying you were fobbing me off, just that that's how it looked to me. My complaint was equally towards you and everyone who voted your answer up to the top. It calls to mind (for me) that Biblical scene where God says to Job, “Have you visited the storehouses of the snow or seen the storehouses of hail?"
Could you give me some links to what you found when you looked it up (that did not seem relevant) and also to some of those reviews you refer to? ("some" means at least one :))

@MatthewChristopherBartsh here is the chim report I looked at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5627502/

"Potential benefits
Accelerating or streamlining vaccines/treatment relevant to
the national health burden." That's a quote from the well-written paper that you linked to.  "They provide an efficient framework for selecting vaccine and drug candidates for further development and can be carried out on a much smaller number of volunteers, and much more rapidly than Phase IIb-III studies. Protection against specific microbial strains can be evaluated in a controlled setting, and biomarkers to resistance and protection against infection can be efficiently assessed." How is that not relevant?

While the existing answers are great and cover a lot of the difficulties in vaccine development, I feel that they fail to address (or at least sufficiently emphasize) the fundamental misconception at the core of the question:

If that's the case, why does it take so much time and effort to develop a vaccine, for example, against covid-19?

The answer to that question is simple: developing a vaccine does not take much time.  What takes a lot of time is testing the vaccine and making sure that it does not have any unforeseen side effects.
For example, let's take a look at the Pfizer/BioNTech COVID-19 vaccine, since it's been in the news lately.  To save time and research effort, I googled for "pfizer covid vaccine timeline" and found this article from Financial Review, whose timeline I will further summarise below:

March 17, 2020: Plans to develop the vaccine are announced.
April 29, 2020 (six weeks later): First tests on human volunteers begin.  At this point the vaccine development is essentially done, and the vaccine has presumably also already passed initial tests using in vitro cell cultures and animal test subjects to ensure that it at least seems to be doing something and doesn't have any obviously bad side effects.  (The first human trials are done with four different variants of the vaccine, because the developers obviously want to minimize the risk of having to start over from scratch in case one specific variant turns out to be ineffective or dangerous.)
July 1, 2020 (two months later): Preliminary results from the first human tests are announced.  One particularly promising candidate vaccine out of the four initial variants is chosen for further testing.
December 2, 2020 (five months later): The UK is the first country to approve the vaccine for use through a "rolling review" system, which allows a novel vaccine to be temporarily approved for emergency use in an epidemic even while it still undergoes further testing.  Requests for similar emergency use authorizations are currently under review in other countries, including the US and Canada.

So, basically, even under this extremely accelerated emergency testing and approval regime (which squeezed into months what would normally take years), the actual development of the vaccine took less than 20% of the total time from initial planning to approval.  All the rest is just testing, testing and more testing.
Now, the other answers have already covered pretty well the reasons why all this testing is needed, but let me anyway give a quick summary for completeness:

Vaccines intended for humans need to be tested in humans, because that's the only way to be sure that they work and are safe to use for humans.  Cell cultures and animal models can never give a fully accurate picture of how the vaccine will interact with the complete immune system in a real human body.

Because all human bodies are different, any new vaccine (or other medical treatment) needs to be tested with as many different people as possible, with as many different ages, ethnic backgrounds, pre-existing conditions, etc. as possible, to make sure that there are no harmful side effects that only show up in a small subset of the population.

Also, when testing a vaccine, one of the most important things that need to be confirmed is that it actually prevents the disease.  But since it would be grossly unethical to deliberately expose test subjects to a dangerous infection, the only way to test that is to vaccinate a lot of volunteer test subjects and wait for some of them to get naturally exposed to the disease (and then compare the vaccinated test subjects with an unvaccinated control group).  This waiting takes time, and since (for most diseases) most of the test subjects will never get exposed and infected anyway, it means that a lot more subjects are needed.

Because human testing in inherently risky (but necessary), nobody wants to take the unnecessary risk of administering a completely untested vaccine to a large number of people.  But a large number of people still need to be tested to confirm that the vaccine is safe for everyone.  Because of this, testing is invariably carried out in multiple phases: first with just a small number of volunteers, then (if no severe issues show up in the initial tests) with a slightly larger group, and then with an even larger group, and so on.  But since each new phase can only be started after sufficient data has been collected from the previous phase, this multiplies the already long duration of the testing by several times.

FWIW, most of the same issues apply to all new medical treatments, not just to vaccines.  New drug development and testing is also notoriously slow and expensive for pretty much the same reasons — and even then there are plenty of cases where major side effects were only discovered when the drug was already on the market.
One issue that does specifically affect vaccines is that they're preventative treatments that must be administered to a large fraction of the healthy population, not just to already infected people.  (Even only vaccinating specific groups at high risk isn't generally sufficient to provide herd immunity.)  This means that their safety needs to be tested to a significantly higher standard (since many more people will be receiving the vaccine) and that, as noted above, determining their efficacy requires a must larger pool of test subjects (since not all subjects will be exposed to the disease).
Anyway, the upshot of all this is that if it weren't for all this testing and re-testing, we could've had a COVID-19 vaccine in April, or maybe earlier.  (Moderna started their vaccine development already in January, and their first human trials in March.)  But even in the face of a global pandemic, the testing is still necessary to make sure that the vaccines that eventually do get approved and widely used will in fact do what they're supposed to do, and that any side effects they may have don't turn out to be worse than the infections they prevent.

BTW, this need for extensive human testing to confirm the safety and effectiveness of a vaccine even after it has been developed is not just the reason why even one company will often develop multiple initial vaccine candidates in parallel, but also one of the main reasons (besides simply capitalism) why there are so many different competing vaccines being developed by different companies.  Basically, even the companies that were late to start their vaccine development and testing could, for a long time, still hope to be the first ones to market if testing happened to turn up serious issues with their competitors' vaccines.
Of course, other reasons exist too: the second, third, fourth etc. companies to get their vaccine approved can also expect to win a decent share of the market, especially if their vaccine happens to be cheaper, more effective and/or easier to store and transport than the alternatives.  Also, many countries may prefer to use a locally developed and produced vaccine if one is available in order to limit their dependence on foreign suppliers.

That's a really great summary, and good points! Indeed, I can imagine that if it wasn't a vaccine, but a treatment to administer to the already ill, then in case of a very deadly illness people would be more eager to undergo the treatment no matter how risky it is, if the alternative would be a high chance of dying of the disease they already have.

Some trials do involve deliberate exposure, if the outcome of treatment after early detection is good. My mom did a trial for a malaria vaccine where they literally had malaria-carrying mosquitoes bite her (the mosquitoes were in a cup covered with cloth, the cloth side was held against the skin until a certain number of bites were observed). The participants had 2x daily observation and blood draw for (I think) a week or so and obviously the treatment was immediately to hand in case anyone actually developed malaria.

I'm against calling it "Pfizer's vaccine" when the people who actually developed it work at BioNtech.

@smcs Fair enough, changed.

While the list of withdrawn drugs is great, I believe we should distinguish between cases when a drug was the safest available at the time of introduction, and was withdrawn later as a safer alternative appeared, and cases when a drug genuinely turned out to be worse than its indication.

There's also the fact that the only way to be absolutely sure what the long term effects are is to wait long term. Right now, we can be pretty sure that there aren't problems that show up on a six month delay. And that is strong evidence that none show up on a one year delay, but we can't be absolutely sure. And we can be pretty sure that the vaccine gives immunity for several months, but we can't be completely sure that it gives immunity for a year.

While it is true that deactivated (e.g. heat killed viruses) are used in some cases, the Pfizer, Moderna vaccines are in fact mRNA vaccines. The figure below from the Oxford website details the processes involved in vaccine their DNA based vaccine development. This Moderna page has a video detailing their approach as well. Pfizer also has a nice video explaining the process of mRNA vaccine development.
As you can see, it is not an easy process. A prerequisite of both their solutions is the knowledge of the SARS-CoV-2 genome sequence (in this case the genome is a single stranded RNA). This requires some time to get done and once the data is available, one has to wait for others to verify it to some extent. Interestingly, the Moderna video says that they had a human ready vaccine in 42 days.
The differences in efficiency can stem from multiple factors:

What vector is used to deliver the vaccine
How the mRNA is tweaked to produce Spike glycoprotein
Physiology of the individuals receiving the vaccine

and many other factors which are beyond the scope of a single answer and can be proprietary knowledge of the manufacturers.
Another significant addition to the 'time' factor is the clinical trials. Pfizer and Moderna require two doses spaced over 3-4 weeks for their phase-I trials. Since these vaccines are being rapidly developed, and you are amidst a global pandemic, you get only 1 chance at a clinical trial (and subsequent profits) and you have to make it count. Various national regulatory authorities also need to keep the health of their citizens in mind. Thus there is immense pressure to get these trials done right and the global consensus in this case seems to be taking a slightly long duration of clinical testing.
Regarding the last question, no, none of the Oxford, Pfizer or Moderna vaccines care about damage done to the original pathogen because there is no pathogen being delivered.

@Chris I cite from Mulligan et al., "who were randomized to receive 2 doses—separated by 21 days—of 10 μg, 30 μg or 100 μg of BNT162b1." I wanted to convey this as two doses in my answer.

"the promising Covid-19 vaccines are in fact mRNA vaccines. The figure below from the Oxford website details the processes involved in vaccine development" Isn't the Oxford/AstraZeneca vaccine in particular not an mRNA vaccine but inactivated virus?

@AndreKR what I understood from the Oxford website is the delivery vector is a weakened adenovirus i.e. has the disease causing genes removed from its genome. These viral particles are then packed with spike glycoprotein sequence in the hopes that human cells will express these on cell surface leading to immune response. On the other hand Pfizer and Moderna use lipid nanoparticles for their delivery.

Not sure this answers the actual question that was asked. The premise of the question is essentially: "Injecting a deactivated virus ought to be quick and easy. Why then hasn't a COVID-19 vaccine been developed quickly and easily?". You've stated that most vaccines in development have been mRNA vaccines. But that doesn't address why there hasn't been a quick and easy vaccine based on the first approach. I believe this is what the OP wants to know.

@JBentley I had not thought of the question that way. In principle mRNA vaccine development is faster than validating the protocol for deactivating a virus (i.e. delete replication related proteins from the genome) in a reproducible manner. Then is the issue of mass producing these viral particles and remember their replication related genes have been removed, so you need to to some clever transgenics. On the other hand, as soon as you know the genome sequence for a viral surface protein, mRNA vaccines can be developed and their delivery is less complicated.

Should also be noted that the mRNA route is considerably faster (if it works) than the deactivated virus one.  I imagine there are (or were) groups following that method as well.

For an mRNA vaccine, it's necessary to know which viral protein will confer immunity, which isn't trivial. For SARS-2 this was accelerated by 20 years of SARS-1 research but in the general case would probably take more time than validating inactivation protocols.

Does the diagram in this answer show an mRNA vaccine?

@user253751 I will change my answer to reflect Pfizer and Moderna are using mRNA vaccines and not Oxford as i understand. User timeskull is more knowledgeable on the subject and they will likely have the right answer.

"the global consensus in this case seems to be taking a slightly long duration of clinical testing." NO, you simply don't understand! The amount of time that's been taken for efficacy trials is INCREDIBLY short - it usually takes YEARS to develop a new vaccine!

@MattDMo The AstraZeneca (“Oxford”) vaccine AZD1222 is definitely not an mRNA vaccine (see e.g. https://www.nature.com/articles/d41586-020-03441-8).

@MattDMo The oxford vaccine is not an mRNA vaccine. I did not get any notification that you had forced edits on my answer. I thought that the owner of a post needs to accept edits. PLEASE do not force edit answers.

@RoniSaiba The entire Stack Exchange system is based around collaborative community edits. Please see this help center article to learn more about it. I apologize that edited in some incorrect information to your answer, but I did fix several other issues as well. I've been an active member of this community for 8 1/2 years, since it was in beta, and have done a lot of work to accrue enough reputation to have the privileges that I do, including not needing to have edits approved. I'll continue making edits when I feel they need to be made.

@AndreKR In this context, "inactivated virus" means the virus being vaccinated against (the covid virus) is inactivated. The Astra-Zeneca vaccine is a hollowed out (so to speak - its genes are "dead") adenovirus (in a sense, "inactivated", but that doesn't count here), stuffed with a bit of artificial DNA that codes for the covid "spike" (a misnomer, since it's now known to be a soft, flexible, club shaped projection) protein (or part of it). It is also not an an mRNA vaccine, because it uses artificial DNA to achieve the same result: making the cell machinery produce "spike proteins".


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Why is the spinal cord shortened in some vertebrates (cauda equina) but not in others?
Hodos, 2009, mentions that the "spinal cord tail" that humans have is not present in most vertebrates. This page mentions cauda equina is not present early on in human embryonic development, but forms later on because vertebral column gets longer. Hodos mentions anglerfish (Lophius piscatorius) also have a "spinal cord tail". What does it look like across other species, like, wolves, gorillas, tigers, crocodiles, dolphins, elephants? Mainly, instead of going species specific, is there any pattern to why some species develop a cauda equina while others do not?
Edit: I can add that according to Uehara, teleosts in general have a spinal cord that extends along the entire vertebral canal, while tetraodontiform fishes have a shortened spinal cord with a cauda equina. This corroborates Hodos claim that most vertebrates have a spinal cord runs the entire length of the vertebral column (teleosts account for 50% of all vertebrates, so... ) Have looked up that dogs have a cauda equina. But, have not been able to understand exactly why some species develop a cauda equina while others do not.
Edit: more context, from Uehara, 2015, "the spinal cord in the majority of the teleosts, the urodelan amphibians, and the reptilian sauropsids and birds extends through the entire vertebral canal, but in the anuran amphibians and mammals is significantly shorter than the vertebral canal."
Edit: more references giving good overview of phylogeny and shortening of spinal cord, but, not really a definitive cause. Nieuwenhuys, 1964 and 1998, and Kuhlenbeck, 1975.
References
Hodos W. (2009) Evolution of the Spinal Cord. In: Binder M.D., Hirokawa N., Windhorst U. (eds) Encyclopedia of Neuroscience. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-29678-2_3171
Uehara, M., Hosaka, Y. Z., Doi, H., & Sakai, H. (2015). The shortened spinal cord in tetraodontiform fishes. Journal of morphology, 276(3), 290–300. https://doi.org/10.1002/jmor.20338
Nieuwenhuys, R. (1964). [Progress in Brain Research] Organization of the Spinal Cord Volume 11 || Comparative Anatomy of the Spinal Cord. , (), 1–57. doi:10.1016/s0079-6123(08)64043-1
Nieuwenhuys, R., ten Donkelaar, H. J., & Nicholson, C. (1998). The Meaning of It All. In The Central Nervous System of Vertebrates (pp. 2135–2195). Springer Berlin Heidelberg. https://doi.org/10.1007/978-3-642-18262-4_24
Kuhlenbeck, H. (1975). The Central Nervous System of Vertebrates, Vol. 4 (Spinal Cord and Deuterencephalon) || VIII. The Spinal Cord. , (), 1–287. doi:10.1159/000395633

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Unknown larvae in grey cocoon
Location: Germany
While cleaning the windows today, I realized some dirt falling off the top of the window frame. By looking further, it seemed to be some kind of cocoon. (The first picture is very bad, I'm sorry)

Those cocoons were about 2-3cm long. There was a total of 6 cocoons.
Two were damaged by falling down.

The last picture shows the inner part of the second picture I think. The larvae(?) was about 0.8cm to 1cm long.
Not sure if it matters, but the window is an attic window, located at the third floor.
Do you have any idea, what kind of larvae it is?

This is a neophyte that has been recorded in Europe since 1979:
Sceliphron curvatum, in German also known as orientalische Mörtelwespe. Unusually large considering what else is buzzing around, but mostly harmless.
The nests, or rather individual larvae cells, are made of mud and while there are about thirty species in the genus, only Sceliphron curvatum is found in Germany - there‘s no other wasp or other insect in Germany that builds similar nest cells, especially the size is a good indicator. Your description of nest location in a window frame is typical, curtain folds or (vertical) nooks in furniture, e.g. shelves are also welcome. Our specimen picked a hiding spot behind a few books a few years ago.
Because of their size, there are usually some articles about them in the low-news summer media lull, describing baffled citizens and their “discovery”. A few less sensational descriptions, photos and further information can be found here (sorry, in German).
Nice find!

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How to attract Cyanobacteria?
I would like to attract cyanobacteria in one spot on an object (e.g. cloth,) instead of having it swim in the media. my current method is to pour it on the object in a beaker and wait for some of them to become attached (very pour attachment yield).
Now, I am thinking of making the object emit light. Do you think that the bacteria will swim all the way to the cloth because there are attracted to light?
is there a better method to help the bacteria get attached to the cloth?

Do you have more details about the experimental setup and constraints? E.g. is your goal to deplete cyanobacteria from a sample? Or to observe the diversity of cyanobacteria in a sample? How pure must the product be (is it a problem if you attract other bugs than cyanobacteria as well)? Can you modify the cyanobacteria, if it's a laboratory strain? And so on... we need as much detail as you can provide to give you an accurate answer!

It might work, many cyanobacteria are reported to be phototaxic. https://www.pnas.org/content/115/52/E12378

We're looking for longer, self-contained answers. It's important to refer to external resources, but your answer will be better received if you can summarize the key points from a source that are relevant to the question asked so that your answer itself is informative beyond just a link.


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Why would hawk moths evolve long tongues for Darwin's Star Orchid when there are other flowers around?
Why would hawk moth evolve long tongues for Darwin's Star Orchid when there are other flowers around? Also isn't it counter productive for some flower to evolve a long nectar tube as this would shift the pollinators to other plants?
This coevolution makes sense if the only source of food for the moth is this star orchid and the only pollinator for the flower is the hawk moth. But if we consider other species to also exist in the picture, this coevolution seems counterproductive to me. For example most flower evolve mechanisms to attract pollinators as their is competition for pollinators as well.

I think the key terms are niche and co-evolution;

Why would hawk moths evolve long tongues for Darwin's Star Orchid when
there are other flowers around [?]

Because the moths have grown a long proboscis as an adaptation to a certain niche. As you say, not much other species can feast on the flower's nectar, so it makes perfect sense to narrow your niche by elongating your proboscis, and reap the benefits of this little visited flower.
A niche is

[T]he range of environmental conditions in which a species can exist.

As the University of South Africa explains:

One important part of the idea of the niche is that it is controlled
by how the species exploits resources in its environment.  If there
are two species living together and exploiting the same resources,
then one will usually be worse than the other at doing this –
eventually, that species will disappear because the other species will
outcompete it. However, species can live together because they
exploit different resources or because they exploit the same resources
in different ways.  These species then have different niches, even
though they occur in the same place.

Then how would the flower benefit? Now I'm going a bit more into a hypothetical explanation, but flowers need cross-pollination to reproduce and genetic mixing. If a plant species can bind a certain pollinating species to itself, it can make sure that that pollinating species only forages on that particular species of plant. Hence, that plant species can ascertain that the pollinating species carries only the right pollen and therefore make sure the transferred pollen is from the same plant species. This is beneficial, as pollen from other species won't pollinate them.
It's all a matter of co-evolution, in this case of two mutualistic species, nicely and succinctly explained by the University of California, Berkeley:

The term coevolution is used to describe cases where two (or more) species reciprocally affect each other's evolution. So for example, an evolutionary change in the morphology of a plant, might affect the morphology of an herbivore that eats the plant, which in turn might affect the evolution of the plant, which might affect the evolution of the herbivore...and so on.
Coevolution is likely to happen when different species have close
ecological interactions with one another. These ecological
relationships include:

Predator/prey and parasite/host
Competitive species
Mutualistic species

The hawk moth Xanthopan morganii praedicta pollinates the Madagascar star orchid (Angraecum sesquipedale) with its long proboscis. source: Encyclopedia Briattanica

This hypothesis of binding a certain species increasing the chances of cross-pollination is really convincing!

Two other hypotheses might be that nectar and pollen come from different parts of a flower, so flowers designed in ways that make it harder to reach nectar may be better at transferring pollen, and that some pollinators are more effective than others due to their foraging habits or body structure, so visits from some pollinators are preferred over others. These are just generic, I don't know if either applies in this case.


text:
Why do trees prefer their sunlight a bit diffused?

I don't know what "a bit diffused" here means.

Do other plants also "prefer their sunlight a bit diffused"?

     Mount Pinatubo was the most powerful volcanic eruption in nearly one hundred years. Within two hours of
the main blast, sulfuric ash had reached twenty-two miles into the sky. By the time it was done, Pinatubo
had discharged more than 20 million tons of sulfur dioxide into the stratosphere. What effect did that have
on the environment?
      As it turned out, the stratospheric haze of sulfur dioxide acted like a layer of sunscreen, reducing the
amount of solar radiation reaching the earth. For the next two years, as the haze was settling out, the earth
cooled off by an average of nearly 1 degree Fahrenheit, or .5 degrees Celsius. A single volcanic eruption
practically reversed, albeit temporarily, the cumulative global warming of the previous hundred years.
     Pinatubo created some other positive externalities too. Forests around the world grew more vigorously
because trees prefer their sunlight a bit diffused. And all that sulfur dioxide in the stratosphere created
some of the prettiest sunsets that people had ever seen.

Dubner, Levitt. SuperFreakonomics: Global Cooling, Patriotic Prostitutes, and Why Suicide Bombers Should Buy Life Insurance (2009). p 176.

I strongly doubt this is true, and I wouldn't get my biology info from Levitt and Dubner. Do they provide a reference? (SuperFreakonomics is, by the way, generally considered a big step down from Freakonomics in quality.)

Who asked the trees what they preferred ?

The studies are very complex and varied. There is evidence that strong omnidirectional light can get through to the understory of dense foliage more effectively.
Here is a Dutch study for crops in dutch greenhouses using light-diffusing rooves which maintain the quantity of light while making it omnidirectional. They report higher growth from diffuse light. https://www.researchgate.net/publication/40803021_The_Effect_of_Diffuse_Light_on_Crops
Studies of tree rings after volcanic eruptions have also found an overall higher growth for the periods following 5 major eruptions.
quotes: Under the presence of clouds, some studies have reported increases in both photosynthetic carbon gain (due to light levels closer to optimal) and water use efficiency, with less impact of photoinhibition due to excessive sunlight (Germino and Smith 2000; Gu et al. 2002)
This research suggests higher growth from direct sunlight in open forests and higher growth in dense, shaded forest under cloudy condition (research)


text:
Why do GPCRs pass exactly 7 times through the cell membrane?
7-transmembrane domain receptors or GPCRs are one of the most common receptors in biology.
They can be found in eukaryotic cells.
What is the significance of the number 7 here: why does it pass exactly 7 times through the cell membrane? What is so good about having it pass 7 times through it?
I can't find literature which goes deeper into this issue.

The Goldilocks effect? The magic number? There is no obvious functional reason, the structure works, but we don't know that some other would not have so any argument is circular and futile. The thing that interests experimental scientists, and can be answered by experiments, is how the binding of a hormone to the receptor transmits a signal into the cell. The details may be complex, but science seldom his simple answers, and you should be wary of people would provide them.


text:
How can predicting protein folding speed up drug discovery?
I'm asking this as a layperson without much knowledge in biology, so please correct me if my understanding is wrong.
Recently DeepMind's AlphaFold managed to predict protein structure from acid amino sequence with stunning accuracy. We are being told that this could "pave ways toward advances in drug discovery."
But I fail to see how it can happen. From my understanding the combination of protein structure is infinite, and if we tweak a protein structure that works good to fight against a virus, it will either work better or worse, but the key point is we don't know until we try. So essentially this is still a hit-and-miss thing, depending purely on dumb luck.
So how can the fast, accurate prediction of protein folding help in drug discovery?

Why is this question downvoted?

Firstly protein structures are not infinite. Most proteins adopt specific structure.
Drugs carry out their function by binding to its target protein. Structure prediction helps drug discovery process in two ways -

it allows identification of pockets in target proteins (where drugs can bind) whose structures are not yet solved using experimental methods
it allows in silico experimentation i.e. you can take a large number of molecules and simulate whether they will bind to a specific location in your target

I would suggest going through these reviews to get a better overview of the importance of fast and accurate structure determination in drug discovery :

Verinde and Hol, 1994, Structure
Montfort and Workman, 2017, Essays in Biochemistry

Simulation of Ligand-Receptor binding usually involves the retrieval of X-ray crystallography of the desired protein (Receptor) from bioinformatic databases. The X-ray data of the protein contains important features of the protein, one of which is Protein conformation (Folding status). Gathering X-ray crystallography data of a specific  new polypeptide is an extremely hard, time consuming process which requires advanced techniques and accurate purification of the protein from biological systems. Therefore if an algorithm can predict the folding of a protein correctly (at least to some extents) , other algorithms can benefit from this independence from experimental results. Fast, simultaneous docking surveys (Virtual Screening) would be available with a lot more ease eventually leading to designing new medications only by computer simulations (Which requires extremely less financial budget compared to testing each candidate molecule one by one on animals)


text:
Why do organisms not just have more genes to account for the possible gene products generated from alternative splicing?
Alternative splicing can generate many gene products from single genes, by combinatorial inclusion / exclusion of introns / gene segments. What is the evolutionary advantage of having a complex processing system that allows for alternative splicing, rather than just having more genes in the genome that directly encode the numerous protein products that an alternatively spliced gene could provide?

Your thinking about evolution is basically flawed. You can ask why a particular development might be advantageous to an organism in particular circumstances, but evolution isn't directed, so asking why some other mechanism didn't evolve to achieve the same thing is invalid. Nature has more than one way of killing cats, and eukaryotes make use of duplicated genes. It might help you to think about how alternative splicing is used in a eukaryotic context.

Does this answer your question? Why do some bad traits evolve, and good ones don't?

@mgkrebbs — The question is poor, but it is not a duplicate of the one you cite. It has nothing to do with good or bad traits as far as I am concerned, so I cannot vote to close it on that account. If I have time next week I will suggest ways of thinking about the questions it actually provokes.

A few factors to consider will be as follows:

This paper shows that compared to prokaryotes, eukaryotic genomes are resilient to the increase in genomic material. They show that the energetic cost of genome maintenance is under less selection pressure in eukartoyes compared to prokaryotes. Thus, multiple genes coding for multiple splice variants may be possible in certain cases.
Gene expression is a tightly regulated process and requires production of multiple repressors, activators etc. Having multiple genes for each splice variant will require transcriptional silencing of all but one / few variants (many tissue types express a specific splice variant). You can imagine that for a large number of genes for their splice variants, regulation is going to be difficult.
Introns have also been hypothesized to confer a degree of resistance to deleterious mutations as there may be no change in the protein ever if the intronic regions get mutated.
Research also indicates that introns are responsible for inhibiting formation of RNA - DNA hybrids during transcription.

In summary, although having multiple genes coding for multiple splice variants is possible at the genomic level, their regulation will be difficult. Moreover, introns have been proven to be beneficial for genome integrity.

Energy cost arguments are really unconvincing. Think about polyploidy. I think (and have written several times) that you really have to guard against self-fulfilllment arguments on molecular evolution questions. It is like this so it must be better than (what) so any argument I can think of justifies it.

@David I have changed my first point and included a reference for the same.

The question asks about evolution, and makes a basic mistake of thinking that there is a goal that the organism is trying to evolve to, and that it has some sort of choice as to how to get there. All one can actually say in cases like this is what the particular advantages are for an organism that "chances" on this new possibility, and whether there are any mechanistic reasons why it might evolve rapidly — perhaps more rapidly than other mechanisms. Don't fall into traps set by poorly thought out questions.


text:
Can the mutation rate vary for individuals of the same species, growing in similar environments?
Suppose we consider several populations who originally inherited their genome from the same ancestor, and that we put for a few thousands generations in similar environments.
Could the mutation rate vary between the different populations or within the same population, but between different time points?

Yes.

between individuals: https://academic.oup.com/mbe/article/34/2/419/2528250
between individuals: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4617969/
hypermutation (transient): https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1087688/


text:
Do all anabolic reactions involve condensation?
I know that condensation is one example of an anabolic reaction (building macromolecules from monomers), but do all anabolic reactions involve condensation? Or is there an example of an anabolic reaction which isn't also a condensation reaction?
Could anyone elaborate on this please?

Assuming that all valencies of the reactants are satisfied, an anabolic reaction will always involve condensation as some bonds will be broken when a new bond between the reactants is formed.

We (or at least the school of biochemists with which I associate myself) do not talk about individual reactions as anabolic or catabolic, but use these terms for the overall  metabolic pathways. The classification of enzymes by the International Union of Biochemistry is solely by their chemistry — see https://www.qmul.ac.uk/sbcs/iubmb/enzyme/rules.html. Individual reactions in an anabolic pathway will differ chemically.


text:
Why can't C1r cleave C4 proteins?
I am researching the complement system, and have ran into something I'm not really sure about. In the past, the C1r2s2 complex was thought to be an 8-like structure tucked inside C1q's collagenous strands. However, this article says that the serine proteases actually protrude away from the core. Originally, it is said the C1s SP cleaves the C4 and C2 proteins because the C1r proteins are hidden in the core. If this new structure is true, however, then the C1s and C1r proteins are close to each other outside the C1q core. If this is the case, what is preventing C4 from being cleaved by C1r instead of C1s? Their serine protease domains should be largely identical.

I have found an answer. The serine proteases on complement proteins actually have very limited enzyme substrate specificity. C1r only has two natural substrates, zymogen C1r and C1s, whereas C1s can only cleave C4, C2 and a few non-complement proteins. This was proven by superimposing the structure of serpins (serine protease inhibitors) with C1r and C1s. This analysis revealed that the access to these substrate-binding sub-sites is severely restricted, compared with digestive serine proteases such as trypsin. The trypsin or chymotrypsin-like pockets were only the primary specificity pockets. The strong preference displayed for Gln residues at P2 and Ile residues at P1 matched those found in physiological substrates of C1r, zymogen C1r and C1s. An example on how these specificity filters work can be seen when we substitute the Gln at P2 with Asn or Gly. To only allow Gln residues, polar or charged molecules will be placed where Gln’s residue’s polar head will be, and hydrophobic residues where the carbon chain will be.  When Asn is substituted for Gln, the shorter carbon chain will cause the polar head to overlap with the hydrophobic residues of C1r, which is highly detrimental for binding. Substituting this with Gly will eliminate the interaction altogether, so it will not be as detrimental, but the stability resulting from the Gln-C1r interaction will be lost.
More information in this article here.

You mean substrate specificity. And to say that an enzyme cannot cleave a substrate because of substrate specificity is saying nothing at all. Just delete your question.

@David I've tried to, but it is not allowing me. So, I'll just try to make my answer a bit better so it can help others.


text:
What are the considerations for studying population genetics of bacterial pan-genomes?
I am beginning to work in the field of human gut microbiome, and wondering how (and if) the concepts of population genetics could be applied there.

Considering the competition between the species seems straightforward, although ecological models are probably more appropriate in this case.
Considering the pan-genome of single species however seems next to impossible, as it cannot be divided into independent alleles. One could probably define a number of alleles as the number of copies of a particular gene in the community. However, as it confers fitness on the whole community, it is not clear how to define selection. The notion of genetic drift also seems vague.

I will appreciate clarifications and references to relevant literature.
Update
To clarify the question:

The question is rather theoretical, motivated more by my previous work than by what I am about to do in the field of metagenomics. The latter will be analysis of shotgun sequencing data, where the focus is on identifying new species and comparing the species composition in many patients. I doubt that we will have any data permitting to study the intra-species evolution within a single patient. However, understanding how bacteria evolve to be a particular strain in a particular patient could be a plus: if members of a bacterial community with different genomes live as a group, we can't meaningfully say that some of them are more fit or less fit.
My past experience with population genetics is in the field of HIV, which for most purposes can be treated as a diploid hermaphrodite (each virion carries two copies of the genome, and the genomes are shuffled when a cell is co-infected with several virions). Thus, many basic population genetics concepts are easily applied, although the speed of evolution and the need for constant adaptation add other difficulties (motivating such approaches as fitness edge).
Finally, as was pointed in the comments, the problem is not specific to bacteria - altruism does take place in many communities, and should raise the same kinds of issues as I mentioned previously. I admit that I am not familiar with the necessary theoretical frameworks, and this can be considered a part of the question. I would guess however that most such frameworks do not account for direct gene exchange.

Update 2
A relatively recent article by Eduardo Rocha (2018) discusses the shortcomings of the neutral model (as the principal null model for modern genomics) when applied to procaryotes. This has clarified a lot for me, and I give below a short list of their points:

Mutations in bacteria cannot be treated as neutral.
Polymorphism concept is poorly defined for genomes of varying length, which requires new mathematical framework.
Promiscuity of bacteria, freely recombing and exchanging genes via the horisontal gene transfer makes it difficult to define species and apply many concepts of the traditional population genetics.
Difficulties in separating demographics and genetics (essentially, one needs a combined genetico-ecological approach).

Update 3
Inclusive fitness theory / kin theory (also here) probably fits into this context.

can you clarify why you can't divide the pangenome into different alleles? with present technology the recovery/abundance analysis of metagenome-assembled genomes using parametric (e.g. MetaBAT) or proximity-ligation techniques (e.g. Hi-C) is quite possible, if more intensive than low-pass shotgun sequencing. e.g. https://www.nature.com/articles/s41564-019-0625-0 (full disclosure: i work for a Hi-C company)

@MaximilianPress do you mean that you can assign genomes on a single cell basis? This doesn't make these bacteria independent. E.g., a gene possessed by one of the bacteria may benefit its neighbors of the same species more than itself - how do you define selection in this case? Perhaps, you know a lot more than I about this question, and could expand it in an answer?

I will try to answer the question, but i think i still need to know why you think "Considering the pan-genome of single species however seems next to impossible, as it cannot be divided into independent alleles." I don't really know what you mean by this. If you actually laid out the data you are thinking of using and a couple of details about your proposed methodology, then that would likely help. For example: you are probably sequencing, but with what? Nanopore, Illumina? Are you just doing 16S and OTU counts? How deeply? How are you representing the data as "alleles"?

Also.... when you write "a gene possessed by one of the bacteria may benefit its neighbors of the same species more than itself - how do you define selection in this case?" How is this any different from altruism in any other population genetic context (i.e. usually ignored)? Editing your question to explain some of these implicit assumptions might make it clearer.

There is actually quite a growing field of study examining the community dynamics and "succession" of bacterial communities in people's guts. I'm not sure if this would inform your particular study in the way you're looking for, but it might be interesting to peruse. I'm away from my office right now and can't think of a specific source off the top of my head. If you think it might be useful, I can maybe add an answer that points out some starting points

@theforestecologist Thank you for chiming in. I certainly would appreciate your answer. Moreover, as I have no background in ecology, I could use some direction here.

It is possible to perform gene-level population genetics analyses on microbiome-derived bacterial species.1,2 † However, the biology of bacteria and the nature of metagenomic sequencing data make such analyses difficult and intractable to many of the well-worked tools of population genetics. Here are some of the things you should keep in mind as you build a conceptual framework for understanding the field:
Bacterial genomes are flexible
The term "allele" connotes gene variants, and the underlying assumption of analyses involving alleles is that each (diploid) individual in a population has one or two alleles of a given gene.  When considering a bacterial population, specifically all the cells that constitute a species, some genes will not be present in all cells. For this reason, "allele" is not frequently used in discussions of complex bacterial communities.  For well-studied species like E. coli and K. pneumoniae with many complete strain genomes, plotting the number of genes found across genomes gives a characteristic U-shaped distribution.3  For a given species, this suggests that many genes are present in most strains, and many genes are present in only one or two strains.  The simple thing to do is to constrain your analysis to the gene set that you observe to appear in all ‡ individuals in a population (the core genome, to use a pangenomics term), but this likely excludes genes that are important for niche-specific fitness like virulence factors, antibiotic resistance genes, carbohydrate degradation operons, etc.  Recently, this problem has been addressed computationally by representing pangenomes as weighted graphs with genomic features at nodes 4 and by building composite reference genomes from strain genomes data encoded as reference graphs.3 #
Metagenomes are messy (but getting cleaner!)
Horizontal gene transfer is likely a frequent occurrence in microbiomes,5 confounding analyses that rely on strict inheritance. Since microbiome sequencing is often short-read, the problem of horizontal gene transfer is exacerbated by the difficulty in reliably assembling transferred genes with specific metagenome-assembled genomes.  As noted by Maximillian Press, there are several ways to address this issue. At the bench, proximity ligation sequencing can supplement traditional metagenomic assembly-by-alignment using the ground truth of physical closeness.5,6 Likewise, single-cell isolation combined with multiplexed whole-genome amplification greatly reduces complexity of assembly.7  At the computer, sequence composition (i.e. kmer content) and coverage profiles can be leveraged to associate metagenomic contigs in bins,8,9 which are like pseudo-genomes.§ If you're lucky enough to have long-read sequencing data, many of the problems associated with assembly of short reads are no longer an issue,10 with the added bonus that SMRT and nanopore sequencing produce methylation data -- unique methylation profiles can be used to infer which contigs likely belong to the same genome or to associate extragenomic contigs (e.g. plasmids) with their hosts.11,12  All of this to say that getting complete genomes from microbiome sequencing is non-trivial, but there are many techniques and tools at your disposal.
Microbiome data is relative
Much of population genetics deals in counted data -- $n$ individuals with allele $a$, $m$ individuals with allele $b$, and so on. Concerning microbiomes, the absolute abundances of individual microbes are not recoverable from sequencing alone. Microbiome data is therefore said to be compositional.  Like RNA-seq, gene or organism abundances derived from metagenomic sequencing are relative, and, importantly, many of the assumptions underlying the statistical analyses applied to absolute counts do not hold for compositional data.13,14  Thankfully, statisical tools for population-level analysis of microbiomes have been developed,15,16 though their widespread adoption has been slow.
Microbiome members are often interdependent
As hinted at in the question update, bacteria display a type of community altruism, where an individual cell with a specific gene can influence the fitness of neighboring cells that lack the gene.  For an example, see my answer to Will all bacteria become resistant against all antibiotics in the long term? concerning secreted β-lactamases.
Therefore, spatial association is an added factor when considering population dynamics of a genetically heterogeneous bacterial species.  Some methods that address cell-cell spatial proximity in microbiomes include sequencing of cryofractured fragments 17 and probe-based spectral imaging.18 Even if microbes are not spatially associated, different microbes may play complementary roles in the iterative metabolism of large carbohydrates into small metabolites.19,20
Surely, this discussion is incomplete, though I hope my answer has given you the footing you need to continue your own exploration to find the appropriate resources for your research.  For a more in-depth discussion of the points I've addressed here, see What Is Metagenomics Teaching Us, and What Is Missed?,21 particularly the sections titled Strain-Level Analyses and Ecoevolutionary Modeling.

† I recommend keeping up with the publications of Ran Blekhman, Peer Bork, and Katie Pollard.
‡ Core genome membership seldom requires that 100% of individuals represented by that genome contain the gene in question, and setting such a strict cutoff would likely exclude truly essential genes that were not found associated with a given strain due to gaps.  In practice, core genome cutoff thresholds are on the order of 90%.
# The senior author for reference 3 made a great explanatory Twitter thread.
§ Contigs and Bins and MAGs, oh my! As with any field, metagenomics has field-specific jargon. Coursera seems to have a good lecture that includes these concepts and how they relate to eachother.

References

Garud NR, Pollard KS. Population Genetics in the Human Microbiome. Trends Genet. 2020 Jan;36(1):53-67. doi: 10.1016/j.tig.2019.10.010.
Priya S, Blekhman R. Population dynamics of the human gut microbiome: change is the only constant. Genome Biol. 2019 Jul 31;20(1):150.
Colquhoun RM et al. Nucleotide-resolution bacterial pan-genomics with reference graphs. bioRxiv 2020.11.12.380378.
Gautreau G et al. PPanGGOLiN: Depicting microbial diversity via a partitioned pangenome graph. PLoS Comput Biol. 2020;16(3):e1007732.
Kent AG et al. Widespread transfer of mobile antibiotic resistance genes within individual gut microbiomes revealed through bacterial Hi-C. Nat Commun. 2020 Sep 1;11(1):4379.
Stalder T et al. Linking the resistome and plasmidome to the microbiome. ISME J. 2019 Oct;13(10):2437-2446.
Chijiiwa R et al. Single-cell genomics of uncultured bacteria reveals dietary fiber responders in the mouse gut microbiota. Microbiome 8, 5 (2020).
Alneberg J et al. Binning metagenomic contigs by coverage and composition. Nat Methods. 2014 Nov;11(11):1144-6.
Kang DD et al. MetaBAT, an efficient tool for accurately reconstructing single genomes from complex microbial communities. PeerJ. 2015 Aug 27;3:e1165.
Kolmogorov M et al. metaFlye: scalable long-read metagenome assembly using repeat graphs. Nat Methods 17, 1103–1110 (2020).
Beaulaurier J et al. Metagenomic binning and association of plasmids with bacterial host genomes using DNA methylation. Nat Biotechnol. 2018;36(1):61-69.
Tourancheau A et al. Discovering and exploiting multiple types of DNA methylation from individual bacteria and microbiome using nanopore sequencing. bioRxiv. 2020.02.18.954636.
Tsilimigras MC and Fodor AA. Compositional data analysis of the microbiome: fundamentals, tools, and challenges. Ann Epidemiol. 2016 May;26(5):330-5.
Gloor GB et al. Microbiome Datasets Are Compositional: And This Is Not Optional. Front Microbiol. 2017 Nov 15;8:2224.
Shi P et al. Regression analysis for microbiome compositional data. Ann. Appl. Stat. 10 (2016), no. 2, 1019--1040.
Kurtz ZD et al. Sparse and compositionally robust inference of microbial ecological networks. PLoS Comput Biol. 2015 May 7;11(5):e1004226.
Sheth RU et al. Spatial metagenomic characterization of microbial biogeography in the gut. Nat Biotechnol. 2019 Aug;37(8):877-883.
Shi H et al. Highly multiplexed spatial mapping of microbial communities. Nature. 2020 Dec.
Kundu P et al. Species-wide Metabolic Interaction Network for Understanding Natural Lignocellulose Digestion in Termite Gut Microbiota. Sci Rep 9, 16329 (2019).
Selber-Hnatiw S et al. Metabolic networks of the human gut microbiota. Microbiology. 2020 Feb;166(2):96-119.
New F, Brito IL. What Is Metagenomics Teaching Us, and What Is Missed? Annual Review of Microbiology. 2020 74:1, 117-135.

Thank you for clearly restating the points that were somewhat confused in my question. I appreciate very much the reference list - it would have taken me hours of work to pin down all of these (I had seen only Garud&Pollard article).

This is a great reference list.

I will answer this as best as I am able, the updates are helpful for providing context. I'll also note that there are several questions packed in here, which makes it a bit more laborious to answer. I am going to try to answer the following questions:

How can I infer selection on microbiota within single hosts (patients)?
How can I resolve genomes of related organisms from a complex mixture?
How can I do population genetics in the presence of horizontal gene transfer (HGT)?

Question 1
I think that there are some assumptions here that rest on methodological tractability that are, as far as I can tell, not accurate. For example: "...if members of a bacterial community with different genomes live as a group, we can't meaningfully say that some of them are more fit or less fit."
This seems to be the crux of the issue. I would argue that if you are willing to take time-courses from the same patient, it is not at all difficult to measure changes in abundance. Causal inference of e.g. selection is a somewhat harder problem, but one that has been treated exhaustively elsewhere.
If you are willing to postulate that you can deconvolute lineages from a single sample, and measure multiple samples from the same patient, then you can try to measure selection over time. Some steps of this are hard (e.g. if lineages are closely related), but those are merely technical problems that can be solved.
There are also methods that try to infer bacterial growth rates from a single sample, but they're a bit more complicated.
Question 2
Resolution of complex mixed populations into genomes is a well-studied problem. THere are a number of approaches to do this (all of which require relatively high investment and sequence assembly probably):

Long-read single-molecule sequencing: simply use Nanopore or high-coverage PacBio reads to directly ascertain the genome. Expensive (especially for complex samples) but perfectly possible. If you use Nanopore you may not even need to assemble!
Assembly binning: Statistical approaches such as MetaBAT2 attempt to deconvolute metagenomic assemblies based on sequence composition and contig coverage. Limited by the resolution of your assembly- if a contig is collapsed in the assembly, you can't put it in two places (as in the case of very closely related genomes).
Proximity-ligation binning: similar to assembly binning, but using complementary single-cell information to place contigs into the same bin. Some additional refs. More accurate and higher-resolution, but involves an additional data type/expense. Full disclosure: I work for a company that provides this as a service and sells kits to do it.

All of these methods, in principle, could be applied to a subset of samples (e.g. beginning and end) and reference genomes could be imputed to the other samples, where you can just measure them by low-coverage shotgun.
Question 3
This is a big one, I would suggest simply googling it to learn more than I could hope to tell you about population genetic theory in the presence of HGT.
The shorter version is that detectable HGT is not super common at the time scales that you are likely to be dealing with. Most HGT ends quickly with the transferred DNA getting digested for energy or selected out as genomic junk.
Nonetheless there is a clear case that selection of lineages can be driven by HGT events, especially under very strong challenges like antibiotics.
I would argue that if you can measure abundance of a lineage and assign HGTs to genomes in specific samples (readily possible with proximity ligation at least), there is no barrier to doing population genetics and measuring selection. It's just another kind of mutation that happens to have a high rate and to occur in parallel. People measure the selective advantage of e.g. antibiotic resistance all the time.
You may be using heuristics and ad hoc methods for some steps, but genomics is just heuristics and ad hoc methods anyways.

Thank you for this answer - I will certainly return to it more than once, as I immerse myself deeper into the field. Your insights about our ability to access single genomes are particularly valuable. I am not sure why we are locked in a particular sequencing approach (I have recently joined the team) - I will raise the question with my colleagues, when I have a chance.

@Vadim glad that it is helpful. As for the approach, my expectation is that it is 1) cost limited (plain low coverage Illumina is quite cheap these days, the other techs are likely at least $500 sample, minimum), 2) familiarity with the approaches. Bringing expensive new technologies into the lab can be a hard sell when you have infrastructure in place for a cheap approach that is perfectly good for answering most questions. For example, low-coverage Illumina is probably just fine for the  interspecific measurements!


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How correlated is the chirality of different molecules?
In astrobiology, a proposed way of testing whether life found on another world is alien or originates from Earth is to determine the chirality of its molecules. This is of course only useful when the biochemistry is similar enough that one may suspect contamination.
But this test has a weakness. While different chirality can confirm alien origin, similar chirality does not exclude alien origin.
To mend this, a plausible idea is to cross check the chirality of a wide range of compounds. A false positive suggesting Earth origin would then have an exponentially smaller chance to match every single compound tested.
...or so I hope.
The issue is that I fear various chiral compounds do not have statistically independent default chirality. For instance, common biochemical pathways may produce one compound from another, leading the chirality of the first molecule to directly determine the chirality of the second.
I'm looking for a high level perspective: Does the chirality of a single compound more or less determine the chirality of all other compounds in an entire biochemistry, or are there a great number of compounds that have an arbitrary default chirality compared to others?

If the chirality is not conserved along the biochemical pathways, then the test outlined in the first paragraph is not valid. Although, concievably one could design other tests, comparing various compounds and chains.

Hypothetically if an alien species were found , and if they contained similar biochemical polymers (DNA with A,T,C,G , Protein with 20 Amino acids etc) then we MAY be able to conclude that they share an origin with us. (Just similar chirality does not necessitates the theory of same origin)

Does the chirality of a single compound more or less determine the chirality of all other compounds in an entire biochemistry?

Yes. As Chiral molecules are almost always produced/purified from chiral medium (containing other chiral molecules and/or chiral physical attributes e.g. polarized light).
Therefore (Assuming that the reaction is enantioselective and you want pure chemical with a specific stereochemistry) the configuration of the chiral center of a new molecule does depend on the reagent chirality. Still this relation is not constant and differs from one reaction to another. For instance textbook SN2 reaction leads to inversion of configuration while Williamson ether synthesis reaction maintains the chirality.
A non-racemic mixture of a chiral compound is resulted from previous non-racemic mixture and so on. therefore the stereochemistry of the first non-racemic mixture determined the S/R , L/R ,(-/+) chirality of the entire life per se whose identity may never be fully understood.

Biologic reactions preserve chirality whereas non-biologic reactions generally do not (although there are examples of rxns where chirality is preserved )
I think this strategy would work for comparing  biomolecules with multiple chiral centers. For example, from an IUPAC perspective, D-glucose is (2R,3S,4R,5R)-2,3,4,5,6-Pentahydroxyhexanal and simply among aldoses  & ketals , finding a single biomolecule (not just carbohydrates,) with multiple chiral centers where a single carbon involves a different chiralty than one used by life on earth, would highly suggest that non-earth originated life was responsible.


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How do the High-Energy Electrons During Chemiosmosis Come from Water?
On Pg. 199 of Campbell, this is stated.

Both* work by way of chemiosmosis, but in chloro- plasts, the high-energy electrons dropped down the transport chain come from water, while in mitochondria, they are extracted from organic molecules (which are thus oxidized).

*Both refers to the to chemiosmosis in mitochondria and in chloroplasts (during photosynthesis).
My question is, how do the high-energy electrons in the transport chain for chemiosmosis come from water? Aren’t these high-energy electrons derived from light harvesting done by the light-harvesting complexes?

The light harvesting complexes use light energy to "lift" electrons to a higher energy state from which they can be used to reduce organic molecules (by way of an electron transport chain and NADPH), leaving a "hole" or cation behind in the LHC and thereby oxidizing it. If these complexes were not re-reduced by something, they would become non-functional after absorption of a single photon. So, they are re-reduced by removing electrons from water to generate molecular oxygen, which happens in photosystem II. So the photosystems I and II act as a series of "pumps" that make otherwise thermodynamically "uphill" (unfavorable) electron transfer from water to NADPH spontaneous, but they do not act as a net source of electrons--water does.


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In plant species' description, does the leaf length include the lamina and petiole, or only the lamina?
The description (partially pasted below) of Ramosmania rodriguesii in Verdcourt (1996) states that the leaves are up to 30 cm long. Does this length include both the lamina and petiole, or only the lamina?

Reference (source of above paragraph):
Verdcourt, B. (1996). Ramosmania rodriguesii Rubiaceae. Curtis's Botanical Magazine, 13(4), 204-209.

https://www.google.com/search?q=leaf+length+and+width&sxsrf=ALeKk03Q4CwiJUDmkRdlbh6NScJPyAzRYA:1607256593282&source=lnms&tbm=isch&sa=X&ved=2ahUKEwi5qriyqbntAhUS8uAKHbMNBbMQ_AUoAXoECBsQAw&biw=1572&bih=838#imgrc=2vp2ZJXmVhBuaM

According to "Plant Identification Terminology: An Illustrated Glossary" (Harris & Harris, 2001) [my emphases added]:

A leaf is "an expanded, usually photosynthetic organ of a plant."

A lamina is the "expanded portion" of a leaf.

A petiole is a "leaf stalk" and a stalk is "the supporting structure of an organ, usually narrower in diameter than the organ."

I know you know the definitions here, but I'm using this as evidence that the petiole is often considered separate from the leaf itself.
I do not know of a flora, key, or guide that uses the petiole as part of the measurement.
Since Kew's Plants of the World Online lists this species as having 30 cm long leaves (and assuming they do not include the petiole as is common practice), I would assume your source likewise is not including the petiole.
Disclaimer: I have never seen Ramosmania rodriguesii, so I can't comment from personal experience/knowledge of this specific species. However, if typical measurement practices have been employed, I assume the petiole is excluded in leaf length measurements.

No it doesn't these days. That description of the leaf excludes the petiole length. 38 including both.

Hey FYI, your link doesn't work. Please fix and also consider both quoting from and formally citing the source to avoid issues of broken links. Thanks!


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Speed of protein conformational change?
Although the speed may vary a lot based on factors like protein size/scale of conformational change/type of changes (small block change/arm movement,etc), are there examples of experimental results of time scale of such processes? (Only a single conformational change is considered i.e. the time delay between the begain and the end of a single conformational change event of a single protein (or subunit to be more precise?) )

This paper uses "ultrafast 2D-IR vibrational echo chemical-exchange spectroscopy" to track switching between different protein conformations and finds that they take place on the order of 50 pico-seconds ($ 1 \times 10^{-12} $ seconds). Another paper finds something similar but notes that full equilibriation can take on the order or nanoseconds:

Although the main conformational change of the backbone is completed after only 20 ps, the subsequent equilibration in the new region of conformational space continues for times >16 ns.


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To a population with no immunity, why is smallpox or measles more deadly compared to COVID-19?
Specifically, this is not a question asking how easily a virus spread in a
population (airborne, asymptomatic spread, etc), but regarding the
mechanism or the "havoc" it wreaks once inside a person's body.
Edit: The question is based on the assumption that, once a human body can readily recognize the virus signature and starts flooding the blood with anti bodies, the virus won't be a problem.

Today, We have no prior immunity to COVID; 400 years ago, Americans
had no prior immunity to smallpox either.
Both virus can be effectively combatted once the body has immunity
(recognization and anitbody production).
Yet, smallpox is so much more lethal and its damage horrifying.

I would suggest not asking multiple questions at once as it runs a risk of getting flagged as too broad. In each point you have made some assertions - please add references for the same. e.g. for point 2 add references for the paper/book/article which details which cell types are affected by covid/measles etc. For the third point you have your own hunch - have you done any research for the same? If yes, add references; if no, mention that. Finally please complete the tour from your profile to understand what qualifies as a good question/answer.

I think this is an interesting question, and I've been struggling to put together a good answer to it for a while. Unfortunately, everything I came up with just boils down to "some viruses are more deadly because they kill more cells faster" which is pretty circular. A detailed understanding at the subcellular level of what happens during virus infections doesn't exist.
It's instructive here to look at the evolutionary pressures on human-infecting viruses. SARS-1 was about 10x as deadly as SARS-2, but it was contained quickly, while SARS-2 is on track to infect a substantial portion of all humans on the planet. SARS-2 is more successful because of, not in spite of, its lower lethality. Because many infections are asymptomatic, the infection can't easily be contained. If we look at things this way, the asymptomatic infections are the ones that go "according to plan" for the virus, and the severe cases and deaths are unwanted collateral damage. Severe cases of COVID are associated with the presence of viral RNA in the blood. But SARS-2 primarily enters new hosts through droplets expelled from infected hosts' respiratory systems. Any viral activity outside of the respiratory system cannot produce these droplets, and is therefore "wasted effort". This is similar to polio, which causes no symptoms when it transmits successfully by replicating in intestinal cells, but causes paralysis when it gets stuck in the dead end of its host's nervous system.
So, if viruses are most successful when they cause no disease, shouldn't they all quickly evolve into harmless versions? They don't because the "sweet spot" of asymptomatic transmission is the unstable result of an immune response that is just effective enough. If a virus fights the immune system either too hard or not hard enough, the infection will end too fast to spread effectively; due to the death of the host or the virus, respectively. Similarly, if a virus is too "aggressive" in entering cells it will damage tissues that don't lead to transmission or new infections, but if it is not aggressive enough it will not be enter those tissues it needs to make, e.g. respiratory droplets carrying new virus in the case of SARS. Since a lethal disease still results in some transmission but complete suppression by the immune system doesn't, it's more evolutionarily favorable for viruses to err on the size of causing worse disease.
Edits for changes in the question:
I think the differences between covid-19 and smallpox are a bit misleading. The big differences between the two diseases is that, while the human populations most affected by smallpox were naive to the virus, the virus was not naive to them. Smallpox is believed to have been infecting humans since at least the 3rd century BCE. It had a lot of time to evolve tricks to defeat the human immune system. And as a dsDNA virus with a 186,000 base pair genome, it had plenty of space to store those tricks. For comparison, SARS-CoV-2 has a 30 kb RNA genome, and poliovirus has a 7.5 kb RNA genome. However, Herpesviruses have been infecting humans since before humans were human, have large genomes, but only cause disease when the immune system is suppressed or nonfunctional. In those cases, however, it is quite effective at spreading throughout the host and can kill. So we see that herpesviruses also rely on the immune system of the host to stay in their sweet spot, they just have a different strategy than smallpox. Since smallpox has been exterminated and herpesvirus is in nearly every human on earth, we can say the mild strategy is the unequivocal winner, at least for now.

This is true. There were mysterious burst of horrible disease burst into the scene and just killed droves in short period of time from the well-known Athens, Justinian to less well known ones as late as the (1800s?). These disease don't last long. And modern version of the disease we are dealing with today like Cholera are less lethal as well. There is this tendency to converge to the sweet spot. This "meta" is indeed very interesting, thank you for mentioning it. However, my question is really about the details  inside one individual, not the meta.

Yes, unfortunately, how viruses interact with cells and the immune system is mostly only known in broad strokes.

actually, if you want to focus on a comparison between covid and smallpox, there are a few things we can say. I'll edit them in.

I have some somewhat-informed hunches. My original question before edit focused on "attacking of the adaptive immune system", and the depth the attack goes, do you just infect front line workers and presenters? or do you attack the antibody factory?. Also I don't believe in "killing body cells" is the cause of death, more like "causing disorder". Septic shock for example, it pretty much immune system overreacting and killing the host instead of what baterias are doing.

It might have something to do with what particular cells a virus can attack.  E.g. just abou everyone gets cold viruses, yet they seem to only attack the respiratory system, and mostly cause a week or so of mild discomfort.  HIV attacks the immune system, and can proliferate there for years before causing accute symptoms.  A lot seems to depend on the specific method a virus uses to enter cells.  The COVID virus latches on to specific receptor molecules, the much more deadly Ebola virus uses a "non-specific engulfing process called macropinocytosis".  (Not enough room for links :-()

@jamesqf that kind of information is exactly what I was hoping for. thank you for listing terms I can google with. That engulfing thing is absolutely fascinating by the way! by some odd chance you think we can have our own pet virus in our cells like mitochondria! with enough time we may be able to have our pet virus clone anti bacteria phages and release them into blood stream


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Why we need a plasmid for r-DNA technology
Recently I was studying Biotechnology. When I went through the texts, I had a doubt: both plasmids and gene of interest are made of DNA stretches and bacteria directly absorb plasmids in a test tube (where reactions take place). Why is the gene of interest not directly put in the test tube instead of recombinant DNA Technology (using Edited plasmids), so that it gets absorbed by bacteria?

A plasmid has a site necessary for replication of genetic material know as the origin of replication (ori) since gene of interest (GOI) is just a segment of DNA it only posseses the sequence of interest and lacks an ori site, due to this it will not be able to replicate by itself. Replication of GOI is important for product formation in r-DNA technology (mostly protien) as when the host cells divides the GOI is duplicated and is transferred to both daughter cells. This way the number of recombinant cells will increase hence producing more of the final product.

Please add some references to your answer and maybe add some descriptions to the technical terms you have used.

Welcome to Biology.SE! This looks like the start of a good answer (note that plasmids also add stability and selectability), but answers are much more likely to receive a favorable response if you include supporting references (primary literature is best). Without that support, your answer is indistinguishable from opinion. This is a good example of how to format references. ——— Thank you for taking the [tour], but please also consult the [help] pages for additional advice on [Answer] effectively on this site. Thank you!


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What is a "membrane holding potential"?
What is a membrane holding potential? I have come across this term but haven't been able to find a definition.
From "Voltage-gated sodium channels as therapeutic targets in epilepsy and other neurological disorders", legend to Figure 4:

Voltage-dependent and frequency-dependent inhibition of voltage-gated Na+ channels by Na+ channel blockers (A) Inhibition of Na+ currents by phenytoin is dependent on membrane holding potential. The top traces show currents evoked by depolarisation to 0 mV, with control (a standard physiological saline solution) and with 50 M phenytoin. In each of the four pairs of current traces, the larger trace is the control. The traces on the left were elicited from a holding potential of 130 mV, whereas the traces on the right were from a holding potential of 65 mV. The control current at 65 mV is smaller, due to greater inactivation induced by the more depolarised holding potential. Moreover, phenytoin is a much more effective blocker at the more depolarised holding potential. This is more evident in the bottom traces, in which the amplitudes have been scaled so that the control currents are the same size. (B) Phenytoin block builds up during repetitive channel activation. The graph shows normalised current amplitudes of whole-cell Na+ currents over the course of depolarising pulses to 0 mV, from a holding potential of 85 mV, applied at 2 Hz. Red dots indicate discrete measurements. Dashed line indicates a baseline to monitor decline in amplitude. (C) Voltage-dependent and frequency-dependent inhibition of Na+ channels by phenytoin and other antiepileptic or local anaesthetic drugs with a similar mode of action (green diamond) are qualitatively explained by a modulated receptor model. In this model, the drug binds with higher affinity to inactivated channel states than to resting channel states. Biophysical and molecular data suggest that the modulated receptor site is within the inner vestibule of the ion-conducting pore.

The membrane holding potential is the voltage level set by the experimenter in a voltage-clamp recording.


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Do you know what this black spider-like insect is?

I have encountered these insects before, but I always assumed them to be spiders even though I always noticed they have 6 legs, as an exception. But slowly with time I ended up observing them more. One day I almost stepped on one of them, but thankfully didn't crush it and that was the day I realized they may not be spiders at all, Because I felt like I had stepped on a thorn or something. These insects are 6 legged and that rules them out as spiders but can't be sure. They don't seem to have distinguishable spinneret. If they don't belong to spider species then it is possible that the spider-like appearance is mostly a camouflage and a single spike on their back would be a defensive measure. They don't seem to behave aggressive like spiders.
I live in a rural area, State of Odisha, India

Related: https://biology.stackexchange.com/questions/87848/what-bug-is-this-manchester-uk/87853

that sort of makes sense, I need to observe and research those more....

They normally have 8 legs. You can see it is missing its second-to-front left leg.

thanks to autotomy


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Spontaneous generation of fruit flies
I live in the South of England. It is currently winter.
Whenever I buy bananas, even one, if I leave the discarded banana peel in my kitchen, within hours or even minutes, there is a cloud of little flies to be seen in the vicinity.
Given that this doesn't happen with other fruit such as apples, I hypothesise that these flies spontaneously generate in the presence of opened bananas and/or their peel.
Notes
Bananas are not native to the British Isles and are imported from hot countries.
I can go months or even years without purchasing a banana and yet, when I do, these flies appear almost immediately. They also disappear almost immediately when I dispose of the fruit and its peel.
The flies do not appear until I unpeel the banana.
Question
How can I disprove my hypothesis of spontaneous generation?
Note: A secondary hypothesis is that fruit fly eggs are distributed all around the world (including in my kitchen) and simply waiting for a banana to appear. This seems less likely but more difficult to disprove. If this is so, how do the flies have time to mate and lay the next generation of eggs in my kitchen when the banana detritus is disposed of almost immediately.

Francesco Redi performed this experiment 350 years ago: https://courses.lumenlearning.com/microbiology/chapter/spontaneous-generation .  Further work by Louis Pasteur and John Tyndall ~150 years ago definitively convinced the science community that spontaneous generation does not occur -- a belief which is in no way controversial to this day.

@theforestecologist: But that rather begs the question: where DO the fruit flies come from?

Regarding spontaneous generation:
Francesco Redi performed an experiment 350 years ago disproving spontaneous generation of insects (see here).

 Source: Lumen Learning
Further work by Louis Pasteur and John Tyndall ~150 years ago definitively convinced the science community that spontaneous generation does not occur -- a belief which is in no way controversial to this day.
Regarding fruit flies:
Fruit flies lay their eggs in fruit. According Orkin, the eggs will hatch into larvae in ~30 hours when in an optimal temperature (75-80 oF).
Produce is typically refrigerated during shipment and storage to prolong shelf-life. This means that the hatching process is halted until the fruit nears your home (or on the grocer's shelf if they are not managing their temperatures or unboxing procedures effectively). Assuming your grocer is taking good care of their fruit (i.e., keeping it cool), then you are likely only starting (or restarting) the egg-hatching timeline after you bring the fruit home. Result: you find fruit flies in your home that you didn't see in the store.

Ripening bananas, by the way, produce their own heat. So even if ambient temperatures are cooler than optimal for fruit flies, the heat from the ripening bananas might push the temp within optimal conditions. This is especially true if bananas are in any form of storage container (e.g., their shipping box). This is why a good grocer opens their banana boxes upon arrival -- it extends shelf-life and prolongs/prohibits fly development. (This also means that if the grocer doesn't unbox their bananas or leaves them in dense piles in poorly refrigerated display shelves, the 30-hour timer started before you brought them home).

So if Redi had performed his experiment with bananas instead of meat, he would have found that spontaneous generation occurred :-)

@jamesqf actually, if he'd just let it sit long enough, bananas would've grown out of the meat.