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This paper: Axonal transcription factors signal retrogradely in lesioned peripheral nerve - Ben-Yaakov et al 2012 describes a signaling axis involving the phosphorylation of the transcription factor STAT3 at the site of nerve injury (sciatic nerve crush), which is then transported retrograde...

I made a few comments about this kind of idea on this thread, but I wanted to explore the idea a little more and see what others thought - you can perhaps tell me if it's unlikely then why. The reasoning is the delay often reported with PEM lines up quite well with the timings associated with...

Very exciting to see this paper out, thank you @Jonathan Edwards Would you expect though, that many clones at a lowish level - as opposed to very low levels - would show up as a decreased repertoire diversity overall. The Dibble/Ponting study @Hutan referenced did not see differences in...

My understanding was, that could be misremembered, that in neurons you can get mRNA packaged up into riboproteins that can be shuttled along microtubules to the ends of the neurons. In this way you would have a little bit of an ability to quickly respond to signals locally with regulation at the...

Ah I see! Either way any transcriptional change in the neuron must take a while to affect the protein composition at its terminals. @Snow Leopard or others do you know how long a change in neuron excitability might take to appear after a signaling event? Could it be done almost instantly by...

If you had a transcriptional change in a DRG cell for instance, as a result of some (immune) signalling in the DRG itself, how long would it take to move mRNA along microtubules in the axon to be presumably translated in the nerve endings in the tissues. A PEM delay type length of time?

Though i suppose it could be synapses behaving poorly in the brain that directly affects the events at peripheral neuron tissue junctions which is where the substance of the pathology is happening.

What compartments can you definitively rule out? Blood... others?

What are the reasonable tissues to look at? if we're thinking neurons generally then we've got muscle NMJ and sensory neurons, para/sympathetic ganglia, dorsal root ganglia, CNS, lymphoid tissue, some other tissue like adipose tissue? If we're thinking thinking peripheral synapses then the only...

Here is how it looks with simulated random data. From 72k features in each of three groups consisting of 5 individuals sure enough you get here ~3.6k (3575) positive hits with anovas and a PCA that look very similar to theirs on the significant fragments. Note that doing the PCA on all the...

I think you're right, but it's not just the PCA it's also the fact they don't multiple test correct and find basically exactly the number of positive results you'd expect by chance. It's cool there are genes that could make sense, but as it stands I don't feel I can trust any of it. However, if...

Yeah exactly, it looks like it's a negative finding to me. If they've done 73239 tests which is how it seems, they have a huge multiple testing problem and it seems like they probably haven't multiple test corrected? By chance, with this many tests you would expect 0.05x73239 = 3661 false...

But why would the number of what they call amyloid deposits and what you think must be nerve cells increase in the day after their exercise challenge.

Probably not trivial but I wonder if there's a solution involving digesting the tissue like you'd do for scRNA-seq, staining and sorting out the population(s) of interest

I wonder how Rob Wuest is doing with his muscle staining. There was the question of whether he was inadvertently staining acetylcholinergic neurons. There's the nerve gas acetylcholinesterase connection with GWS. There's sets of genes from precisionLife and heal2 pertaining to synaptic function...

Were these model systems completely divorced from RA patients? Or was antibody taken from the patients to apply to the model system? That would still be measuring a parameter directly linked to the disease which possibly we wouldn't be able to do with ME.

I'm always on the cusp of a sore throat at any one time, it comes and goes like the weather. With cognitive activity it tends to stack if i do a lot over a period like multiple days, and seems to increase the odds of that sore throat seesawing into a full flu feeling and into PEM. A relative of...

I take your point about the cytokines, but I still wonder how you get fatigue from eg flu. You have an infection in a peripheral tissue and it has to let the brain know somehow. So even if it's not a cytokine, your choices are most likely either some endocrine signal through the blood, still via...

There was some talk on the Zhang et al HEAL2 thread about whether epigenetics could be relevant in ME. I don't know that epigenetics has really been looked at in ME but they look at it here in this paper using ATAC-seq on n=7 patient CD8 T memory cells. I noticed from this volcano pot that the...

This is very interesting I know next to nothing about this kind of thing or the methods they use. Do we think fatigue during illness eg flu works in a similar kind of way? I understand cytokines like IL-6 IL-1beta act on the CNS to invoke fever, is a similar mechanism involved in illness...