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Good question I'm afraid I'm too ignorant to know! I don't think it's talking rubbish - it can only be talking rubbish if someone is pretending to know something they don't.

For that particular idea, it wouldn't be that you would feel PEM in different places over time. It would be that signals from eg just used muscles would take a while to reach the neuron nuclei and cause a transcriptional response, but once it did the whole neuron could be eg sensitised at once...

Talked about an idea in this thread - Could nerve damage or retrograde microtubule based transport in axons explain the delay associated with PEM? about whether the time delay associated with PEM could be linked to the amount of time it takes from nerve injury/an event at nerve terminals to the...

There is a lab working on CCPG1 in the context of autophagy apparently in the same building as Chris Ponting's lab: https://institute-genetics-cancer.ed.ac.uk/research/research-groups-a-z/wilkinson-group/autophagy-in-tissue-homeostasis-cancer

Noting a potential commonality between CCPG1 and ARFGEF2 in the trafficking of GABA receptors.

Interesting, in that study neuroligins and neurexins appear to be down in various CNS cells which express batteries of inteferon stimulated genes. That would suggest an inhibition of stable connections between synapses. That would match the direction of the loss of function NLGN I believe seen...

I'm sure we've talked about this before but I forget - Is anything known about the basic biology of why IFN type 1/2 causes fatigue? I seem to recall that it not just causes fatigue acutely but can also lead to an enduring fatigue that last long after IFN therapy ends. Possibly by interacting...

True and of course their black box analysis makes it harder to trust, but a point in favour is the replication in long covid. I believe they are doing this analysis in decode data too so we can wait and see what they find there. In my opinion it is still evidence we should factor in and not stop...

I don't think you're wrong but in my opinion you're being too cautious. We don't know anything for sure, but I think there is enough here to take as a guide that the immune and especially nervous systems may be involved, especially if you add to that both precisionLife and zhang's WGS data you...

Thank you those are good arguments. A rebuttal I could imagine being made to the argument about half of all adults having herpes virus in their nervous system would be - where the reservoir is and how much of it there is could make a difference (eg in brain stem or hypothalamus). 'is a neuron...

That's fair. I'm using a lot of the single cell type annotations from proteinatlas.org as a bit of a guide, and then some of the descriptions of the genes. ARFGEF2 for example supposedly has a role in GABA receptor recycling from endosome to membrane, which would suggest a neuronal function to...

So it seems like loss of function of the proteins in this complex would if anything lead to an excessive downscaling or loss of integrity of the synapse. It's a bit complicated though because I think the loss of some Homer proteins would actually have the opposite effect, and the same can be...

I don't know if it's been discussed much in this thread what the impact of the loss of function of these genes, especially the HOMER-SHANK-DLGAP complex would have on the function of the synapse. I think there's also a plausible link to the proteasome genes that also come up in this paper...

A couple more thoughts and open questions - cell type most clearly implicated is the neuron - Which type of neurons are affected and where? Peripheral ones or Central ones, acetycholinergic ones or glutamatergic ones? Or any type anywhere. GWI might suggest acetylcholinergic, and the...

One thing I'm trying to get my head around is to what extent the 'immunological' and 'neurological' parts of the genetics story are compartmentalised. For example is there a inteferon response happening within the neurons (or glia) themselves or would something like that be happening elsewhere...

A question I have is if there is any way to infer whether we are looking at one common pathological process or more from the GWAS data. A related question is if the risk from each risk variant stacks additively. If you have all 8 for instance would you just combine the increased risk from each...

Vesicle trafficking at the region around the endosome once again, just like RABGAP1L. The eQTL data would suggest that the effect of both would be to reduce recycling of endosome contents back to the plasma membrane / reduced exocytosis. ARFGEF2 acts to promote recycling from endosome to...

phosphatidylcholine is probably the most replicated metabolomics finding other than triglycerides if I recall correctly, so that's interesting to see

ZNFX1 is a decodeME candidate with eQTL data supporting its levels are increased in ME/CFS.

Abstract Inherited deficiency of zinc finger NFX1-type containing 1 (ZNFX1), a dsRNA virus sensor, is associated with severe familial immunodeficiency, multisystem inflammatory disease, increased susceptibility to viruses, and early mortality. However, limited treatments for patients with...