Long Non Coding RNAs and pain

[Yann04]

Wasn't there a mouse model for ME/CFS? Or is it not valid?

All the ME/CFS mouse models I’ve seen were basically forcing mice to overexert and then studying them as exhausted after overexerting.

I really don’t think that’s equivalent to ME, maybe closer to overtraining syndrome.

 

[Kitty]

I really don’t think that’s equivalent to ME

Absolutely. We didn't get ME/CFS by being forced to run about till we were knackered—if that happened, football would be a very different game!

 

[V.R.T.]

All the ME/CFS mouse models I’ve seen were basically forcing mice to overexert and then studying them as exhausted after overexerting.

I really don’t think that’s equivalent to ME, maybe closer to overtraining syndrome.

There was also the IgG mouse model studies from den Dunnen and Putrino/Iwasaki where they gave the mice serum or plasma (my scientific knowledge is failing me here!) and the mice had what they claimed were ME
/LC like symptoms.

 

[Yann04]

Yes — that was interesting — and apparently replicated?

If it actually gets properly shown, I think it would be an interesting way to have an ME mouse model. Though even if the blood of pwME / LC induces symptoms that control blood doesn’t, it is another question if that actually gives the mice ME/LC and is valid as a model.

 

[Utsikt]

Ron Davis claims to have ME/CFS models in bacteria, zebrafish and mice/rats. A team in Utah, apparently. They are using them to screen all FDA-drugs++.

 

[V.R.T.]

Yes — that was interesting — and apparently replicated?

If it actually gets properly shown, I think it would be an interesting way to have an ME mouse model. Though even if the blood of pwME / LC induces symptoms that control blood doesn’t, it is another question if that actually gives the mice ME/LC and is valid as a model.

That's why I was fascinated by the muscle on a chip abstract that was doing the rounds a little while back. Similar thing but with lab grown muscle tissue or something similar rather than mice.

 

[V.R.T.]

Ron Davis claims to have ME/CFS models in bacteria, zebrafish and mice/rats. A team in Utah, apparently. They are using them to screen all FDA-drugs++.

Surely that is a model of the itaconate shunt, which is obviously a valid theory but has never been proven in ME, so even if the model is accurate to humans it may be of no use.

 

[Utsikt]

Surely that is a model of the itaconate shunt, which is obviously a valid theory but has never been proven in ME, so even if the model is accurate to humans it may be of no use.

Idk what it is, but that’s a fair guess. No model is valid before we know the mechanism(s) of ME.

 

[Jonathan Edwards]

Wasn't there a mouse model for ME/CFS? Or is it not valid?

No it wasn't in any way validated.

How did they get "unhealthy" rats for their experiments?

They already knew what the gene defect was in humans and knocked it out in rats. So the model was not to prove a mechanism but to see how a known mechanism operates. There was a very interesting finding. With one gene defect the people with no pain scratched the back of their neck down to raw tissue. Only the back of the neck. The mice with the knockout did exactly the same - just scratched the skin off the back of their neck. That shows how powerful a model can be at pointing to questions we did not even know had an answer.

 

[forestglip]

Not sure if this is relevant, but this review was published about a week ago:

S4ME: Unlocking the secrets of the immunopeptidome: MHC molecules, ncRNA peptides, and vesicles in immune response, 2025, Balakrishnan et al

1.2 Emerging insights: ncRNA-derived peptides and extracellular vesicles

ncRNA-derived peptides are a novel class of peptides originating from previously considered non-coding RNAs, including long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), which were initially believed to have no role in protein production. However, emerging evidence suggests that some ncRNAs possess internal ribosome entry sites (IRES) that facilitate their translation into small, functional peptides. MHC molecules can present these peptides, which are now considered part of the immunopeptidome and thus can influence immune recognition and response. This groundbreaking discovery challenges conventional views and opens new avenues for understanding immune responses. Importantly, not all ncRNA-derived peptides come from truly “non-coding” regions, as some may result from previously unannotated or cryptic open reading frames (ORFs) (7).

 

[Creekside]

Would these LNCRNA genes be a factor only in certain cells? Might they might exist in all cells, being part of the DNA, but their effects might only show up in astrocytes, for example, and maybe only if there was an epigenetic change in those cells, or only if a virus had altered something in the cells? In that case, I suppose it could still be detected via gene scanning and statistical processing, but worse than a needle in a haystack search, since it might need to search for a needle of a certain length and a bit of yellow silk thread and a greenish grain of sand in each stack.

 

[Jonathan Edwards]

Would these LNCRNA genes be a factor only in certain cells?

That seems to be often the case. They are 'expressed' (i.e. make RNAs) very specifically in certain cells.

I suppose it could still be detected via gene scanning and statistical processing

Only if you could sample the cells and you cannot sample nervous tissue without destroying it. (Not sure what you mean by gene scanning. The genes in terms of DNA are of course in all cells but they may be quite normal, only the expression different.)

 

[poetinsf]

Idk what it is, but that’s a fair guess. No model is valid before we know the mechanism(s) of ME.

Not sure if I'd agree. Model is valid as long as it can predict. Nobody really knows of how quantum mechanics work, but it's still valid. The underlying mechanism can be further investigated afterwards if the model is proven correct. Perhaps that's unlikely in something as complex as human body. But you still can posit a model and then test it without first knowing the mechanism.

edit: grammatic

 

[Utsikt]

Not sure if I'd agree. Model is valid as long as it can predict.

It would have to predict something meaningful for ME/CFS, though. And that’s where the current models struggle.

But yes, I agree with the correction.

Although a model can give the correct prediction based on the wrong reasoning.

If you predict that apples fall to the ground because the sun rays pushes it down, you would get a correct prediction for the behaviour of the apple. But the reasoning would be incorrect.

 

[Jonathan Edwards]

Nobody really knows of how quantum mechanics work, but it's still valid.

But QM isn't a model of something else in the sense that an animal model is. It doesn't even 'work'. It doesn't have a 'mechanism'. In fact it posits no mechanism for the indivisible quantum level.

It is purely a set of mathematical rules that turn out to predict in the context it was derived in. So I think that is pretty firmly non-sequitur!

But you still can posit a model and then test it without first knowing the mechanism.

But if a model does not correspond to what you are wanting it to model then what does 'testing it' achieve. I agree that if you manipulate the model to see if it behaves the same way as the human disease and you find it doesn't then you can chuck the model out. But that means it wasn't much use anyway. If you can mimic further features of the illness with it maybe it suggests you are on the right track but you still don't know that. And I don't know of many animal models that do that.

I used to be on the lecture circuit as the animal model expert for arthritis but after about five years, having realised that none of the models were any use for working out disease mechanisms I turned to more productive work.

 

[poetinsf]

It would have to predict something meaningful for ME/CFS, though.

Yes, definitely. The ATG13 theory for example predicts that rapamycin will improve the symptoms since it reduces ATG13. They don't know yet if the theory is true; they are only guessing based on their study.

 

[poetinsf]

But QM isn't a model of something else in the sense that an animal model is.

I'm not sure how you mean. Everything is model -- model is how our brain understands its environment. There is no "something else"; the model is it.

It is purely a set of mathematical rules that turn out to predict in the context it was derived in.

That sure doesn't stop people from questioning what QM means in reality and how it really works.

But if a model does not correspond to what you are wanting it to model then what does 'testing it' achieve.

That would prove that the model, or the proposed understanding, is wrong, right? Then we move on to heliocentric theory from geocentric one, so to speak.

I agree that if you manipulate the model to see if it behaves the same way as the human disease and you find it doesn't then you can chuck the model out. But that means it wasn't much use anyway.

I guess we were talking about slightly different things. I was speaking in general, not something specific like animal model. I'll have to take your word for it if you are saying studying human diseases on animal isn't much of use. I'm simply saying a model predicts, and then you can accept/reject by testing the prediction, or at least the probability that the model is true/false, without having to know the underlying mechanisms.

 

[EndME]

People with this gene defect supposedly do not feel pain at all, at least from what I've understood. As far as I can see, to a larger exten,t people with ME/CFS feel pain in the same way as the general population. If they cut their finger, this hurts as it does for most people, burning their hands on the stove gives the feeling most are familiar with and so does stumping their toe or hitting their head against something. There however seem to be problems with pain related to certain areas, possibly more muscle pain, more headaches, sore lymph nodes and the like.

Hypothetically can that provide an indication in which cells disordered expressions might be more likely or less likely to be occuring, or what the knock-on effects of these are more likely to be?