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Also might be worth saying the eQTL data specifically points to increased expression in brain cortex and pancreas, not really much on anywhere else. So where NLRP3 is concerned could point to microglia.

Not necessarily! It depends on how much we can trust the eQTL data, and from what I've gathered it may not be all that reliable.

According to OMIM loss of function of ZNFX1 leads to hyperinflammation and immunodeficiency. I remember reading a paper which I can't find at the moment which suggested these people usually die in childhood of severe viral infections of various kinds, or even without evidence of a virus seem to...

This is harsh. Doing a 2D scatterplot of the two features after normalisation should look pretty much exactly the same as the PCA that's currently there (the entire figure might be rotated slightly but the relative positions of the datapoints should be identical). It's not misleading, it's just...

- Their cohorts seem well matched, though their ME cohort has significantly lower white cell counts (p 0.005) and neutrophils (p 0.01) than the controls. I haven't seen that described in ME before? I think they saw some differences in leukocyte numbers in Beentjes' UK biobank study but not with...

Nice work! @DMissa It looks like a nice study! As has been pointed out I think the biggest limitation is the lack of accounting for BMI. I know they've been passaged many times but they seem to be remembering something through all those passages, maybe some kind of insulin resistance phenotype...

TASL stands for TLR Adaptor Interacting With Endolysosomal SLC15A4. SLC15A4 is one of the 14 genes found in precisionLife's MECFS ukbiobank study. TLR7/8/9 , SLC15A4 and TASL are in a TLR/interferon signalling axis: proposed mechanism from this paper:

But this would be the most extreme possible scenario and I dont think is what is being suggested here. You could have subsets of neurons fire more without them having to die. It does sound like a bad situation doesn't it... but I agree with you, I dont think it has to be that, or a generalised...

There must be a neural correlate for subjective experiences. To me your second sentence provides an example of that, assuming reduced excitability of motor cortex always correlates with the subjective feeling of fatigue. If it doesn't, then there must be other neurons elsewhere that do. So am...

Must there be? Wouldn't a simpler explanation be that all those things you described (Eg meeting for half an hour, going to lunch) amount to a routine that works like a rube-goldberg machine - A ball bounces off a spring, then gets whacked by a mallet and goes down a slide - and the timing of...

This surely can't be right because pwME are all experiencing fatigue and the direct experience of that must be encoded by neurons in the brain. If there is a common experience of any kind between individuals there must be a pattern hypothetically observable by the activity of neurons in the...

What we were taught at UCL as an undergraduate was that the CLOCK system is slightly out of sync with the day night cycle and if you put a human (or mouse) in total darkness or lightness it will shift - backwards or forwards by some magnitude depending on the person. The day night cycle...

Why are all these things named the way they are? I have some recollection that butyrylcholinesterases can have a broad affinity for longer chained molecules not necessarily just of the butyrylated variety. I googled this the other day about the butyrophilins and I think it said they were named...

You said there were no signs of neural damage and I don't think that's necessarily the case. Doesn't have to be microglia that was a bit of a throwaway comment. The rationale was that it provides a link for how maybe both stroke and excitotoxicity could cause fatigue - while also providing a...

I'm not sure, but I'm not suggesting there would be big chunks of damage like you'd surely see with stroke. It would be a mosaic of neurons or even just parts of neurons, maybe just the dendrites. Still enough perhaps to prime or activate microglia in some way. Would that be visible on the kind...

I guess the two levers I'm imagining that could lead to that would be exertion leading to an increase in neuron firing rates in some circuits in a given time period, or exertion leading to an increase in the fragility of the neurons via some indirect method (hormonal?)

I think we shouldn't exclude the possibility that there is damage occurring, a few reasons why: 1) As has been alluded to ME/CFS like fatigue is also seen in CNS injury: Yes, and also post stroke fatigue. 2) I wasn't keen on the idea of there being mitochondrial dysfunction before but I think...

I think that would give you the best chance, that's my feeling about the way it works on a practical level too. The more rest the better. The problem is the neurons don't stop firing and life is random and tricky and you can just relapse anyway. That's just my experience, but the model would fit...

I think it's maybe not quite that. One thing I believe that stops a positive feedback loop from happening is the global scaling of the firing rate of a neuron, and in this model that is happening: Neuron B loses its input from Neuron A so it globally upscales its firing rate to compensate - its...

How about something like this as a model for how fragile synapses could produce ME/CFS like disease dynamics: - Using here a hypothetical set up of two neurons that could explain the dynamics of PEM, and how you to get locked into a disease state that could be escapable in some...