gilleain

> add too numbers

Did you do this on purpose to anger both Mathematicians and keen spellers?

Heh, on my watchlist - ""The Unreasonable Effectiveness of Group Theory" - https://www.youtube.com/watch?v=1XsXRUsNEC4

Yes, I was watching a video about that the other day - the 'dark proteome' or the 'ghost proteome' or similar.

A random sequence may not fold at all! I seem to remember a paper that tried this, creating a bunch of random proteins, and checking how much structure they had - I think they were helical bundles, but don't quote me.

The nice thing about stable folds, is that 'nearby' sequences in sequence space - as in, point mutations - are the same fold. If each sequence had a completely different fold, then mutation would be much more destructive. Surprisingly, however, sequences that are far apart in sequence space can also adopt the same fold (convergent evolution).

I see. I meant 'energetically accessible', but you mean more like 'affordably accessible' (in the sense that the molecular toolkit of a cell is what can 'afford' certain structures, due to chaperones available and so on).

Who knows what might be possible if you designed a cell from scratch - perhaps you could rework all the machinery to access other parts of fold space. After all, there are some weird and wonderful machines out there like the 'Vault' (https://en.wikipedia.org/wiki/Vault_(organelle)) that can fit whole proteins inside them. Possibly a different cage-like structure could help fold designed proteins into as-before unseen structures.

This is about folds, not amino acids - even if you used a larger alphabet of residues, I somehow doubt that you would get many more folds.

Thinking more about the question of protein _length_ - I'm also not convinced that longer proteins (more than say 750aa) would produce more novel folds. Larger proteins tend to be multi-domain; that is, a longer chain will fold into multiple compact domains, each one a separate fold.

I suppose there could be 'megafolds' out there in fold space, beyond 1000aa - like a 12-bladed beta propeller, or a beta-helix with alpha helices on the outside or some other wacky thing. Whether that would substantially increase the numbers of total folds, I doubt, but that is of course a guess.

(ref - https://pmc.ncbi.nlm.nih.gov/articles/PMC10251718/ for protein lengths)

I understood it as metaphor - just that evolutionarily distant sequences can adopt the same (or very similar) folds because there are only a limited number of stable, accessible folds that are possible.

They found "several thousand" novel folds? I had remembered that there were around 1000:

https://pmc.ncbi.nlm.nih.gov/articles/PMC7072414/

Oh ok, I misremembered:

"This review has focused only on small fragments of fold space with examples given for folds generated from a single secondary structure string consisting of around ten SSEs. Even in this small corner, the number of possible folds, under the current constraints, is of the order of 1000"

Ah FeMo-co! One of the cooler cofactors - iron-sulfur cluster, plus a molybdenum, and finally a bridging carbon (https://en.wikipedia.org/wiki/FeMoco)

So yes, I can understand why it took so long to calculate the energetics of the system:

"This makes measuring FeMo-co’s ground-state energy extraordinarily complex. There are more than 78,000 plausible configurations the electrons might be in"

Hate to agree, but it is true. For a while, I think, the main sequencing framework was in perl (Bioperl). Not sure what was best for structures - possibly Biojava?

It is very tempting, though - 'just' make a nice, clean API in your favourite language (eg Haskell, Ruby, ...) and everyone will flock to use it! Maybe.

DNA is one-dimensional aperiodicity, which is ... fairly common. This sentence is one-dimensionally aperiodic!

Most biological structures are amorphous in some way, rather than strictly aperiodic. There are structures (honeycombs, for example) that are extremely regular, and especially on smaller scales (like virus capsids). Other biological structures are loosely fractal (self-similar across a narrow range) - lungs, blood systems, and so on.

I don't know of any biological structures that could accurately be described as aperiodic - like a quasicrystal - but given I'm just learning about Defense-associated reverse transcriptases, it would not surprise me if there is something out there.

More than that - I think that people who are grieving may not know how they "should" be grieving. Consider that some cultures (literally) perform grief by - for example - wailing at the grave. Others may wear a particular colour of clothing, etc.

You can say to yourself "I am grieving" but still have the nagging suspicion that you are not doing it 'right' in some sense. Similarly (I think) for many emotions - how happy should I be in this moment? How excited?

On the flip side, there are people who (seemingly) over-dramatize every event - but are they pretending, or do they really feel things that keenly? I suspect that most emotion is some combination of raw/organic emotion, and the more cultural/performative/learned emotional response.

It gets complicated, is what I'm saying.

'The presenter' here being Eddie Izzard :)

Yes I thought at the start it was about how our expectations of how the law works are at odds with the reality

So the gatekeeper is the system keeping us from Justice - mostly money, but also other less tangible barriers. In theory, everyone gets a lawyer, in practice some people can afford expensive ones.

Then the end twist got me confused.

Well, the image titled 'The Shapes of Water' has 4 examples - 'Ice Ih', 'Ice VIII', 'Ice XV', and ... 'Ice IX' :)

https://en.wikipedia.org/wiki/Phases_of_ice#Known_phases - in this table, apparently discovered in 1968

That's fair (and of course, as a personal project, set any goal you like! :) ) - but I wonder if that risks setting the bar too low, so that everything is 'completed'.

I think, we're in agreement : it's your project, so you get to say what 'completed' means, but my criteria is usually writing some small amount of text about it, even if that text is "this didn't work, ho-hum".

Also it can give a feeling that it was not a waste of time - lessons learned, what you would do next time on other projects, other avenues to look into.

For years I wrote a technical blog intended just for my own reference, as the small effort required to write it up, create images and so on felt good. It was also a good point to think about what I had _actually_ done - sometimes this made me realise small mistakes or missing details.

I accept the ordering of dates is important, yes. History can be in the details, but as you say you need to comb the beach for the right stones.

I guess an interesting counterpoint to what I said is something like https://en.wikipedia.org/wiki/Phantom_time_conspiracy_theory (and similar) where a grandiose framework tries to fit inconvenient facts into a shape that is entirely invented.

Yes I was not clear, it seems. Facts are necessary but not sufficient.

There is limited time, of course - no one can learn everything, but you can pay attention to the important facts, and the connections between them.

In some ideal world you would learn every fact there is, and the connections would fall out on their own, but in the real world we have to construct theories and frameworks to organise facts.

Agreed, it interests me how much some people emphasise knowing facts - like dates in history or dictionary definitions of words.

Facts alone are like pebbles on a beach, far better (IMO) to have a few stones mortared with understanding to make a building of knowledge. A fanciful metaphor but you know ...

I've revived a project I started around 20 years ago. It is a kind of graph query description/measurement tool for protein 3D data.

The query engine itself is like a DAG of 'operators', similar to a relational DB (or more like a graph one) with scanners, filters, and matchers.

Very fun, although not at all efficient and probably overengineered for what it does :)

... but have you considered the new ballroom?

Not precisely the same:

https://en.wikipedia.org/wiki/Hydrogen_cyanide - 107 ppm (human, 10 min)

https://en.wikipedia.org/wiki/Hydrogen_sulfide - 600 ppm (human, 30 min)

https://en.wikipedia.org/wiki/Carbon_monoxide - 4000 ppm (human, 30 min)

These are "LCLo" values from the databoxes on those pages. More easily comparable numbers may be around somewhere.

Not an answer, but related, I was looking at Memgraph (graph db) query planning for Cypher, which is similar (ish) to what you are asking about:

https://memgraph.com/docs/querying/query-plan

The reason why I was looking was to do query planning for a declarative pattern-finding in atomic structures (hierarchical labelled graphs, I suppose) although I'm slowly realising just how insanely hard it might be to get it to work efficiently!

Someone's artwork _should_ be possible to (negatively) criticise. Of course, just saying "it sucks" is not constructive or helpful.

You can definitely hurt someone's feeling with unconstructive criticism of thier art. However, pointing out areas to improve should not be too painful to the artist, as they can make newer, better works.

I suppose a difficuly can arise if people get too attached to things they make (art, code, writing, whatever) and don't see any one thing as just a step on the road to even better things.

Cyclopentadiene is a great molecule - it can form 'metallocene' compounds where two cyclopentadiene (Cp) rings 'sandwich' a metal ion between them:

https://en.wikipedia.org/wiki/Metallocene

Like Cp--M--Cp where the '--' are an unusual kind of 'bond' which is somewhat like five carbon-metal bonds, although I'm sure there is a more accurate orbital description of the interaction.

Bring on the Electric Monks ...

Or by the 'Chaos Star' :)

https://en.wikipedia.org/wiki/Symbol_of_Chaos

Oh that reminds me. Could someone make an AI interface where each agent uses a different Culture ship name, and looks like the dialog from Excession?

If we are going to have a dystopia, lets make it fun, at least...

I've had reasonable results from using AI to analyse code ("convert this code into a method call graph in graphml format" or similar). Apart from hallucinating one of the edges, this worked reasonably well to throw this into yED and give me a view on the code.

An alternative that occurred to me the other day is, could a PR be broken down into separate changes? As in, break it into a) a commit renaming a variable b) another commit making the functional change c) ...

Feel like there are PR analysis tools out there already for this :)