This is one in a number of papers exploring how biological phase separation/condensation may have provided favourable microenvironments for early life development.
Some other work on phase separation as a means for primordial evolution and biochemistry includes a paper from Christine Keating in 2012 (WAY WAY ahead of the curve) [1], elegant work by Frank Jülicher [2], and more recently a nice paper from Keating and Phil Bevilacqua [3].
These papers (IMO) tie rather nicely into some theoretical predictions on self-organization from Jeremy England [4].
[1] Keating, C.D. (2012). Aqueous phase separation as a possible route to compartmentalization of biological molecules. Acc. Chem. Res. 45, 2114–2124.
[2] Zwicker, D., Seyboldt, R., Weber, C.A., Hyman, A.A., and Jülicher, F. (2016). Growth and division of active droplets provides a model for protocells. Nat. Phys. 13, 408.
[3] Poudyal, R.R., Pir Cakmak, F., Keating, C.D., and Bevilacqua, P.C. (2018). Physical Principles and Extant Biology Reveal Roles for RNA-Containing Membraneless Compartments in Origins of Life Chemistry. Biochemistry 57, 2509–2519.
[4] England, J.L. (2013). Statistical physics of self-replication. J. Chem. Phys. 139, 121923.
So it seems like there are two timescales for what 'transient' means in the paper.
1) There are different levels/numbers of i-motifs identified depending on the cell cycle position (highest at G1/S boundary, although this is only comparing cells synchronized to G1, G1/S and early S so maybe more at different points?), suggesting these structures don't just stably form and then just sit happily around for the entire lifetime of the cell.
2) In vitro these motifs are less stable than (say) G-quadruplexes so presumably there is a suggestion they may be transient over short timescales, but this is not actually examined in the paper. No idea how you'd actually test this without inherently perturbing the equilibrium being examined in vivo. Even if you could avoid fixing the cells antibodies would be out of the question because of the inherent linkage (if you bind the i-motif with a 500 pM Kd [high affinity] you're gonna HUGELY stabilize that conformation).
"What excited us most is that we could see the green spots – the i-motifs – appearing and disappearing over time, so we know that they are forming, dissolving and forming again,”
anyone know what technique they used during this observation? It sounds.. not fixed?
what matters most in my opinion is whether this is a spontaneous DNA conformation or whether this is a transient conformation DNA assumes while transcription machinery is preparing to read nearby bases. (if the former, kinda interesting; if the latter, much less interesting)
Right - yeah; I don't know, I had the same thought when I read the commentary (I read the paper first). Nothing in the papers suggests the ability to monitor formation/loss in realtime I don't think? My guess is this is an interpretation of the data from the fact that you see lower levels in G1, higher levels in G1/S and lower levels in early S - i.e. they must be 'transient' because the levels go up and down again.
Seeing this happen in real cells in realtime would be – I would have thought – technically almost impossible. We're at the cusp of viewing the formation/loss of clusters of RNA POL or mediator clusters with the most advanced super-res (see Ibrahim Cissé's work) but these are comparatively massive protein clusters, so the idea of being able to view DNA structural transitions at [effectively] single-molecule resolution where that transition involves a few nucleotides in a non-perturbative way seems like a reach.
Seems like the obvious next step is to break 'em with synonymous mutations and ask if there's any detectable phenotype.
"No idea how you'd actually test this without inherently perturbing the equilibrium being examined in vivo. Even if you could avoid fixing the cells antibodies would be out of the question because of the inherent linkage (if you bind the i-motif with a 500 pM Kd [high affinity] you're gonna HUGELY stabilize that conformation)."
I mean, I trust the reviewers/editors of Nature but I don't understand how this is not a serious confound!
But this is literally the entire point of the this paper. The sentence you just pasted was the the previous state of the art, this paper makes the point that they have now imaged them in cells (using i-motif specific antibodies).
'in vitro' can mean 'in cells in a dish'. I think the previous state of the art was 'unsure if these exist in living cells' (could be wrong, but id be surprised if they did this exp in vivo). edit based on your comment above you probably have the paper and are in a better position to comment on this. I defer to op.
Yeah agreed (what in vitro means to different people is a whole other conversation :-P), but that sentence makes it pretty clear that by in vitro they mean not in cells (because it says, "and not inside cells"). Agreed, of course, that this doesn't necessarily mean it happens in cells in an organism (though in the authors' defense they do examine three different cell lines).
Edit: For clarity - all the in cell work is cultured cell lines and not cells taken from an animal model or in situ imaging.
Literally my only point was that 'this might not matter for biology because we've not even seen it in cells' is no longer true. It still might not matter for biology though!
Then, with all due respect (and perhaps I misunderstood), perhaps you should consider a greater degree of open mindedness?
If the fact that you disagrees with the first clause in an argument is enough for you to conclude the rest of the discussion is unable to make you change your opinion, I'd argue that is a much more significant barrier to open dialogue.
"With all due respect" so often precedes a mark of disrespect that it's already a small example of the kind of rhetoric that gets people's backs up before you even get to your point. I don't think it's generally deliberate, but it's a pretty good sign of talking at someone instead of genuinely trying to get closer to a common understanding. If I notice those words about to come out, I try to step back and remind myself we're both human -- prone to being wrong about practically everything. My career is all about being wrong dozens of times a day sometimes, about really obvious stuff once it's pointed out by the helpful little computer. Do I really know the bigger picture so well I can just lay down the law to this disagreeable fellow human?
I don't even expect either of our beliefs to change much here, but conversations do add up to something over the decades. And some people are much better at this than others. I know, your side of the culture war compared to them, oh Lord. I don't know if Dunning-Kruger applies to open-mindedness -- are there studies?
Ha! - point extremely well taken, in much the same vein as "I'm not racist, BUT...".
I did feel awkward writing it - in this case it was actually meant sincerely. I really wasn't sure if I'd misunderstood. It seemed too ironic in a discussion on open minded-ness to basically say "I immediately stopped listening after I heard something I didn't like" (although maybe this is a reasonable approach? I'd strongly argue it's not, but that's certainly a discussion we can have). I'll do my best to catch myself in the future. I should say that I did read your comment as a touch condescending, just FYI.
WRT to Dunning-Kruger for open-mindedness (which is a very interesting idea) some quick searches didn't reveal anything obvious, but I may be using the wrong keywords - social psychology isn't exactly my strong suit! Sort of intuitively you'd think a similar kind of relationship might exist ("Of course I'm open minded, but I _know_ that X is X and Y is Y, but those are truths not debatable ideas!") - although maybe now I'm conflating open mindedness with the ability to think critically...
> I did read your comment as a touch condescending, just FYI.
Sigh, yeah, I need to watch that. Good of you to let me know.
My take on the not-listening thing -- of course I'm not Aron -- is that if you've heard a faction hector you a lot, and you don't think they're listening to you except maybe to match some of your words into their standard bingo cards, then it's natural to tune someone out the moment they say one of that faction's shibboleths. From this POV, telling the speaker how their rhetoric failed is actually reaching out to them a little. That's not the POV I aspire to: I try to consider more words that piss me off than I really feel like, because I meta-want to be less biased. Sometimes I do, and sometimes they even get through.
Re: social psychology, I'm just starting on Haidt's The Righteous Mind in hopes of learning some basics.
(Since many more people might read this, I guess I want to make it completely clear that I didn't say what brand of words piss me off.)
>My take on the not-listening thing -- of course I'm not Aron -- is that if you've heard a faction hector you a lot, and you don't think they're listening to you except maybe to match some of your words into their standard bingo cards, then it's natural to tune someone out the moment they say one of that faction's shibboleths.
Ah - this is very good point, thanks for following up on this!
As mentioned in the memo, gendered interests are predicted by exposure to prenatal testosterone – higher levels are associated with a preference for mechanically interesting things and occupations in adulthood. Lower levels are associated with a preference for people-oriented activities and occupations. This is why STEM (science, technology, engineering and mathematics) fields tend to be dominated by men.
And why we see fields like law being dominated by women, right?
EDIT: I, and I suspect most other scientists wouldn't disagree that there are [edit - had this as aren't previously, woops!] physiological differences between men and women, but as I read the memo, that was not what was being argued. What was being argued was that those differences were the reason for the gender imbalance in tech (i.e. women are predisposition to be less interested/capable in STEM fields), in other words, the effect size associated with biological sex is larger (and indeed must be significantly larger) than any/all combined societal/'nurture' effects.
This is anecdotal. But a testament on how difficult this problem is.
I have two nieces and 1 nephew, all of which I've tried to encourage into programming. I have tried to get my nieces interested in programming with great difficulty but my nephew has taken to it almost instantly and effortlessly.
This is also anecdotal. I'm a female working as a technical lead. When trying to describe what I do to non-tech-worker female friends that ask, I often find that they get a look of slight confusion and state things such as "wait, that actually sounds like an interesting job!". It's as if their entire experience of computers, maths and tech is boring, so they think working with them must be as well.
I think how girls get introduced into STEM subjects has to change. I also think it would be worthwhile continuing to encourage adult females to give things like programming a go as well, even if they've tried in the past and didn't like it. Most of the barriers to interest seem to be how the subjects are talked about, as opposed to the subjects themselves.
We do see people-focused fields like psychology dominated by women. Perhaps law is somewhere in the middle.
The memo didn't say biology was "larger than any/all combined societal/'nurture' effects". In the memo there is a section with this title:
> Possible non-bias causes of the gender gap in tech
Note "possible". No one knows the exact combination of causes of the gap, it likely has many factors. The memo is saying there may be non-bias factors too, and that Google is blind to those, so it's pointing those out. That's not the same as saying non-bias factors are larger than everything else.
> We do see people-focused fields like psychology dominated by women. Perhaps law is somewhere in the middle.
Law is a broad area. I'd expect the combination of interests and skills that lead to one becoming, say, a corporate tax lawyer are quite different from those that lead to becoming, say, a public defender, or a patent attorney, or a real estate lawyer.
It would be interesting to see what the gender distribution is for these various areas of law.
This is oddly poignant to me. I just (literally a few hours ago) submitted my PhD thesis on (broadly) the biophysics of emergent phenomena. People don't usually read theses cover to cover, with good reason, but I included one short paragraph in the preface to be the true "take home" message:
We wish to understand mechanism through the elucidation of design principles, yet evolution does not select for principles, it selects for fitness, an epistatic and emergent property. If similar outcomes can be achieved in different but equivalently fit ways, then given the stochastic nature of evolution this is almost guaranteed to happen. We have specific examples where every statement in the preceding paragraph is true [ed: a collection of proposed mechanisms]. We do not need one person to be right or wrong; our nascent understanding of complex biological systems is that the space of information-processing solutions is astronomical. Think of the diversity observed in structural biology - the repertoire of tertiary structures is enormous. There are countless examples of nearly identical functions being performed by proteins with radically different structure.
This divergence, this variety in structure and function, is what makes evolution robust. It is an inherent bet-hedging mechanism woven into the fabric of statistical physics. On the contrary, the desire to categories and abstract complexity into distinct groups is an inherently human endeavour. Much as we may wish and as convenient as it would be, Nature does not have a plan.
The thesis won't be publicly available for a while because there is fair amount of (currently) unpublished data that is associated with various collaborations.
+1 as well, very very interested. If you could post some resources that an interested reader could educate themselves with in the meantime, it would be deeply appreciated. Maybe a sample of the bibliography from your thesis?
So for some context, my work is not directly about evolution, but about how amino acid sequence determines function in the context of unfolded/disordered proteins.
That said, here are several at least semi-relevant papers that have influenced my thinking on a bunch of things (no particular order).
[1] Wheeler, L.C., Lim, S.A., Marqusee, S., and Harms, M.J. (2016). The thermostability and specificity of ancient proteins. Curr. Opin. Struct. Biol. 38, 37–43. (Probably paywalled but available on the Harms' lab website - https://harmslab.uoregon.edu/publications/. Mike's work on thinking about the biophysics of evolution is in general super cool. Similarly work by Adrian Serohijos is really interesting, although I am in general less familiar with it http://www.serohijoslab.org/publications.html)
[2] Tikhonov, M. (2016). Community-level cohesion without cooperation. Elife 5. (Open Access, really cool, and publishing a single-author original paper in a top journal in this day-and-age is incredibly impressive).
[3] Riback, J.A., Katanski, C.D., Kear-Scott, J.L., Pilipenko, E.V., Rojek, A.E., Sosnick, T.R., and Drummond, D.A. (2017). Stress-Triggered Phase Separation Is an Adaptive, Evolutionarily Tuned Response. Cell 168, 1028–1040.e19. (Paywalled, but IMO a HUGELY important study for thinking about 'aggregation' in the context of cellular fitness)
[4] Chakrabortee, S., Byers, J.S., Jones, S., Garcia, D.M., Bhullar, B., Chang, A., She, R., Lee, L., Fremin, B., Lindquist, S., et al. (2016). Intrinsically Disordered Proteins Drive Emergence and Inheritance of Biological Traits. Cell 167, 369–381.e12. (Paywalled, but potentially one of the most important discoveries in cellular adaptation in decades. More work to be done though!)
[5] Halabi, N., Rivoire, O., Leibler, S., and Ranganathan, R. (2009). Protein sectors: evolutionary units of three-dimensional structure. Cell 138, 774–786. (Paywalled, but super important for thinking about the relationship between local structural coupling and evolutionary behaviour. In general, everything Rama puts out is just gold.)
You've submitted this. I hope the spelling and grammatical errors aren't a problem for the readers. First of which is a missing 'the' in the first sentence. Later 'categories' instead of categorise.
Still, it seems interesting and I wish you all the best. I hope you are awarded your PhD.
Thank you - categories vs. categorise is a great spot!!! Where are the spelling mistakes? I don't see the missing 'the' in the first sentence? Mechanism here is in the abstract, if that's what you're referring to? That said, I've also not slept a lot in the last week...
FWIW, this is the submission to my committee, so I'm now spending the next few weeks meticulously going through to tighten up the grammar, catch typos etc., before it gets officially submitted in June.
I had to pause on that spot too because it felt stilted when reading over it, though after reading it again I got what you were talking about and it read fine.
Not at all - there's some additional text that provides set-up for the idea of mechanism. Re-reading it now cold, I read it exactly as you (and others) did as well. And I (embarrassingly) am relatively confident I wouldn't have caught the categories/categorise error, huge thank you!
Haha, man first time I opened my thesis, all fresh from the press, on a random page I saw an error. PhD students don't have editors haha, only professors who probably don't read back to back.
It is unprovable, because you can always posit a plan that matches the actual outcome from what was actually a random process. What the evidence does do is to weaken the claim that there is evidence for a plan.
The plan is clearly to do anything to live and reproduce...You can see the innate struggle against increasing entropy in most living things, even as death is certain, because certainty is death.
This isn't proof of a plan, life does anything to live and reproduce because life without those qualities would not be sustainable. Those traits could be accidental though. The plan also isn't consistent when you step back, everything from planets to the universe do not seem to be following this plan.
Nature produce plans - nature produced you and you have plans...And if you have plans it's not too much of a stretch to say other living things have plans too, and their degree of planning varies depending on their level consciousness, memory and intelligence. The detail of planning is a continuum between non-life, virus, microbes, plants, animals, and humans. The intention in planning, however, is mostly constant.
Or both nature and me produce no plans, our actions are the result of some set of variables that have led to this point. This isn't proof.
And you're still focusing on too narrow of a spectrum, you can't even be sure that life must follow these rules just that it has in the one example we have.
Too true - in this life it's good to be not too sure of anything because often we are wrong about everything. In the end it doesn't really matter to our everyday lives if you or I believe one way or the other...
Believe is the key word here. This is impossible or nearly impossible to prove, so you can believe whatever idea you want. It just isn't science.
My personal beliefs are similar but I do expand it to the cosmic stage. I can't answer "why is there something rather than nothing?" But as soon as something exists, either through luck or some plan it does everything it can to ensure it doesn't go back to nothing.
Nature has a plan, it's called extinction. What is it over 90% of things which ever evolved have gone extinct. That's nature's plan to make things which are very, very, very likely to go extinct. Some may say that's it's a sieve, but if it's a sieve then why is the universe not filled with intelligent life, it's not a sieve, it's a death sentence. We're all made to die, eventually forever. Into the deep, dark night. All of us.
Great to see this in the NYT. I'm working with Thomas (who, in addition to being a truly exceptional scientists is a really great guy) on understanding the underlying biophysics of how these disordered proteins facilitate stress protection.
Many of these proteins are intrinsically disordered proteins (IDPs), meaning they don't actually have a set 3D structure, but instead existing in a kind of 'cloud' (ensemble) of interconverting conformations. A consequence of this is that there is no 'one' representative structure, due to this conformational heterogeneity.
People used to (very reasonably) assume that 'disordered' just meant totally random, so the thought was these disordered proteins behaved like a random polymer. However, just like in folded proteins, the amino acid sequence of these IDPs has a major impact on the way these clouds of conformations behave. Happy to discuss more here or 'offline' (see my profile for contact info) - this is basically my whole PhD, so, you know, I can go more in depth...
Yes (that's the fun part!) - I should have specified that I was just interested in getting an atomistic model of one of these tardigrade proteins to play around with in an MD simulation.
The sequences have only recently been found, and the interesting proteins don't share much homology.
Check out http://kumamushi.org for a lot if technical detail in the genome. jfarlow in comments below points to one of the interesting proteins that apparently provides dna protection.
FitBit's customer service with me has been nothing but exceptional from start to finish, and is the reason I have bought several for family members.
I would hope that FitBit would recognize the loyalty they create based on this quality of service could be magnified by grandfathering Pebble's various services and by maintaining them, while helping Pebble users to transition at their convenience. This would allow Pebble users to continue to have functioning Pebble watches, with the likelihood of sticking with FitBit once the watch does finally break.
> It is because of the close collaboration with the Fitbit team that the Pebble user experience will continue. Fitbit will maintain services so that Pebble devices continue to work as normal. Pebble functionality and service may be reduced in the future.
Short chain fatty acids can be things like acetic acid, propionic acid, butyric acid. The fermentation process takes in fiber and puts out these guys, so while fiber isn't an SCFA polymer, I don't think this statement is inaccurate (i.e. I don't have the metabolic pathways off hand but these could be direct breakdown products given the shortness of the carbon chains - acetic acid almost certainly is.)
The main path for glucose involves splitting it in two 3 carbon molecules, mainly pyruvate https://en.wikipedia.org/wiki/Glycolysis From this it's easy to make acetic acid (2 carbons), like the acetic acid in vinegar. And , I guess it's also not very difficult to make propionic acid (3 carbons).
I can accept that they say that fiber or glucose is "break down" to acetic acid, propionic acid, but I think it's misleading. (And the usual definition of fatty acid starts at 4 carbons https://en.wikipedia.org/wiki/Fatty_acid )
I think they're using it colloquially: you can "break down" trees in to paper, even though the paper technically requires reassembly and further processing from the most deconstructed tree step.
But it is a phrase that the average layperson would take as "simpler things made from the raw ingredients by the processors", rather than a direct deconstruction pathway.
It's a common problem when technical language collides with a common term or phrase, because most articles will mean the common one and send pendants in to a fit.
I think this is the crux of the issue. If one ascribed to the prion hypothesis, than ketogenic metabolism would almost certainly have to be related to higher probability of prion formation, and more survivable conditions in vivo.
Another common way some AAs are metabolised is by hydrogenation is red blood cells. So I think this eats up a hydrogen ion at the very least, leading to greater intra-cellular oxidisation and a messed up blood plasma pH, increasing the occurrence of abnormal enzymatic reactions. The metabolites you mentioned are present in much larger quantities on low carbs, due to increased synthesis and use of proteins for energy, including for the brain...
Oh and at least a few of those metabolites sometimes ultimately metabolise to acetone, especially if normal metabolism disrupted by wonky pH balance.
Anion gap in soft tissue cells may also explain 'twitches': spontaneous muscular activation due to soft tissue cell hyper-natremia (unbalanced towards sodium).
Crazily, excess acetone restoration is one theory that explains spontaneous human combustion (acetone is quite volatile and flammable)...
Same here actually. I haven't logged into my reddit account in like two years now. Also don't have any cookies from reddit so I dunno. The site does show me logged out of everything else so I think it's either broken or something else.
For a nice primer on what biological phase separation is, see this (non-paywalled) general audience article from earlier this year in Nature (https://www.nature.com/articles/d41586-018-03070-2).
Some other work on phase separation as a means for primordial evolution and biochemistry includes a paper from Christine Keating in 2012 (WAY WAY ahead of the curve) [1], elegant work by Frank Jülicher [2], and more recently a nice paper from Keating and Phil Bevilacqua [3].
These papers (IMO) tie rather nicely into some theoretical predictions on self-organization from Jeremy England [4].
[1] Keating, C.D. (2012). Aqueous phase separation as a possible route to compartmentalization of biological molecules. Acc. Chem. Res. 45, 2114–2124.
[2] Zwicker, D., Seyboldt, R., Weber, C.A., Hyman, A.A., and Jülicher, F. (2016). Growth and division of active droplets provides a model for protocells. Nat. Phys. 13, 408.
[3] Poudyal, R.R., Pir Cakmak, F., Keating, C.D., and Bevilacqua, P.C. (2018). Physical Principles and Extant Biology Reveal Roles for RNA-Containing Membraneless Compartments in Origins of Life Chemistry. Biochemistry 57, 2509–2519.
[4] England, J.L. (2013). Statistical physics of self-replication. J. Chem. Phys. 139, 121923.