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Could be, I was thinking of other routes for ME/CFS (as I’m not a big fan of the viral persistence theory) but there seems to be lots of ways that some problem or inefficiency in protein degradation could occur. That circadian rhythm seems so dependent upon these systems working reliably for...

Amazing work, well done and thanks again @Joan Crawford

The ubiquitin-proteasome system in circadian regulation Costanzo, Kara M.; Prifti, Matthew V.; Todi, Sokol V.; Mohan, Ryan D. Abstract To align sleep–wake behavior and internal physiology with the Earth’s 24-h light–dark cycle, organisms rely on circadian clocks–endogenous timekeeping systems...

On CLOCK and circadian rhythms I’ve found another review which covers this topic in more detail and will post later.

A brief summary (my interpretation , possibly over simplistic but hopefully not too off the mark…) - ULK1 is important to autophagy - KLHL20 tags ULK1 (and some other things) so they are degraded, so helping keep a brake on the process - In mouse models without KLHL20 this doesn’t happen - So...

A couple more snippets

This is one of the papers cited in the DecodeMe candidate genes and links the ubiquitin-proteasome system (UPS) and KLHL20 to autophagy termination From the discussion

Cul3-KLHL20 Ubiquitin Ligase Governs the Turnover of ULK1 and VPS34 Complexes to Control Autophagy Termination Liu, Chin-Chih; Lin, Yu-Ching; Chen, Yu-Hsuan; Chen, Chun-Ming; Pang, Liang-Yu; Chen, Hsuan-An; Wu, Pei-Rung; Lin, Mei-Yao; Jiang, Si-Tse; Tsai, Ting-Fen; Chen, Ruey-Hwa Abstract...

Another related paper https://www.s4me.info/threads/a-role-for-the-ubiquitin%E2%80%93proteasome-system-in-activity-dependent-presynaptic-silencing-2010-jiang-et-al.46986/ As above I’ve been thinking about mechanisms which may tie together things others have been talking about, some data we...

I do though like the idea @dilieil has of someone like JE having a long conversation with an LLM (although I’m not sure he would…) I don’t think it would necessarily help the LLM come up with better ideas (due to the above) but I’d be more optimistic about it helping him or others bounce ideas...

A Role for the Ubiquitin–Proteasome System in Activity-Dependent Presynaptic Silencing Jiang, Xiaoping; Litkowski, Patricia E.; Taylor, Amanda A.; Lin, Ying; Snider, B. Joy; Moulder, Krista L. Abstract Chronic changes in electrical excitability profoundly affect synaptic transmission...

To me one important underlying factor on usefulness is anchored in if the output is testable/verifiable. This is why LLMs can end up being helpful with grounded information retrieval or text summarisation, mathematics or with writing code, there can be an iterative loop there. This allows models...

I really would recommend people listen to this series. Even the long 4 hour episode, you can break it up into bits as I have been doing. There’s a lot of discussion of medical history, how we find and develop treatments for disease, how we do this even when we don’t understand disease, wider...

More episodes… The art of protein design with AI What if you could design a protein never seen in nature An interesting discussion and also some great kinks in the podcast info including this course on using AlphaFold from EMBL's European Bioinformatics Institute...

Not evidence but more of my hand waiving learning and thinking. But thought others may be interested. I came across things while thinking about and reading up on areas around the proteasome, ubiquitin and general maintenance and cleanup, with a mind on synapses and mtDNA. A bit focused on...

The proteasome: A key modulator of nervous system function, brain aging, and neurodegenerative disease Davidson, K., & Pickering, A. M. Abstract The proteasome is a large multi-subunit protease responsible for the degradation and removal of oxidized, misfolded, and polyubiquitinated proteins...

In some ways I’m similar and I think we’d all like to find a single root cause and something which can just fix us all. Maybe we will, maybe it will be quick and something off the shelf works. But maybe it will be a new target requiring new treatments to be developed. So if we can find things...

I’ve skipped some of the discussion to focus on the bit people probably care about most, DecodeME data. they have the data from 11,500 patients (smaller than full set as not everyone consented and there were some data QC issues) They have 4 main datasets, UKB, UK Sano Gold LC, NIH All Of Us and...

This is a long (over 1h) interview and I was a bit put off by Cort’s style to start but it’s actually one of the more interesting interviews I’ve heard from PrecisionLife. Which makes me hopeful for how they present and communicate any findings in their upcoming paper Points that stood out to...

I’m making some notes while listening (it’s long, over an hour) which I’ll share later but for now here’s a link to the audio of the interview Cort did with Steve https://u.pcloud.link/publink/show?code=XZnqA95ZmCdrSgozKB8OEDpE0JW960chXMuk