An Update on ME/CFS Research with Ronald W. Davis, PhD

[M Paine]

Well a good start would be to test for the receptor the AU group found defective TRPM3. Even to confirm or move on. If it is realted and make sense.
Has anybody heard Ron's comments on this paper?
https://www.ncbi.nlm.nih.gov/m/pubmed/27727448/

That's an interesting idea, but I'm not sure that it's that simple. The TRPM3 gene is not ubiquitously expressed in tissues. It's most prevalent in Kidney, Brain, Ovary, Testis, Prostate, Adrenal, and Thyroid. There are many more cells which express them, but many as well which don't. As an example, skeletal muscle does not account for much TRPM3 expression, however I would expect skeletal muscle to strongly exhibit the dysfunction which Ron's group is looking at.

In addition, it's still possible for the metabolic dysfunction to be a secondary, or downstream consequence of some failure somewhere else in the body. For example, the down-regulation of metabolism could be immune regulated via cytokine activity.

I don't know which cell line Ron's group is using for their testing, skeletal muscle or white blood cells would be my guess? @Rose49?

Expression of TRPM3 in tissues:

 

[Seven7]

I don't mind donating whatever is needed. Muscle, lymph tissue just let me know!

 

[M Paine]

Great, I hear that they need testicle samples asap!

 

[nandixon]

I don't know which cell line Ron's group is using for their testing, skeletal muscle or white blood cells would be my guess?

They're using PBMCs (peripheral blood mononuclear cells).

 

[BruceInOz]

Well, for about a year my maths skills have been seriously affected, so I wouldn't be any use!

But the point is, does trying to solve a maths problem invoke PEM? I imagine whether you could actually solve it ir not would be irrelevant.

However, I would have thought since people have very different mathematical training and abilities, using maths as a stressor sounds like a dumb idea. Would a former maths teacher and someone that hated maths at school and did poorly at it both be provoked into PEM by the same maths problem?

 

[RogerBlack]

But the point is, does trying to solve a maths problem invoke PEM? I imagine whether you could actually solve it ir not would be irrelevant.

However, I would have thought since people have very different mathematical training and abilities, using maths as a stressor sounds like a dumb idea. Would a former maths teacher and someone that hated maths at school and did poorly at it both be provoked into PEM by the same maths problem?

By the same difficulty for them - perhaps.
I know at least for me that lying down reading complex stuff and trying to understand it in detail, 'pushing through' beyond what I can easily do - does trigger PEM, including muscle pain.

 

[Seven7]

Great, I hear that they need testicle samples asap!

That is the one thing I do not have

 

[Wolfiness]

Retrain your brain to control body function x is psychobiobabble.

Ok, but can anyone explain to me why my involuntary movements i.e. myoclonic movements and tonic-clonic convulsions are less tiring than I would expect the same movements made deliberately to be?

I note that in me remission is usually accompanied by hypomania, which I assume overrides Naviaux's dauer state. Could even split-second involuntary movements somehow do the same?

 

[ash0787]

I don't quite get what you mean because its written in too technical of terms but I have gotten PEM after shivering while asleep because our central heating system doesn't work at the same time as the water heater and on one night it was particularly cold in my room.

 

[wastwater]

Heres a bit on FOX proteins I still think they maybe important in this somehow http://humgenomics.biomedcentral.com/articles/10.1186/1479-7364-4-5-345

 

[Jesse2233]

Does anyone know why intravenous pyruvate can't be used on a maintenance basis to regularly correct the serum defect Dr Davis mentioned?

Is it because the pathways would eventual adjust and it would become non-effective?

There are several studies that show intravenous pyruvate has been used for different purposes, so it's theoretically possible

https://www.ncbi.nlm.nih.gov/m/pubmed/8181295/

https://www.ncbi.nlm.nih.gov/m/pubmed/10600844/

https://www.researchgate.net/figure...of-Pyruvate-Decreases-Laconic-Signals-More-in

 

[trishrhymes]

Does anyone know why intravenous pyruvate can't be used on a maintenance basis to regularly correct the serum defect Dr Davis mentioned?

My limited understanding suggests that it is the step after production of pyruvate that is the problem. I think we can get as far as producing pyruvate, but we can't turn it into Acetyl CoA to start the mitochondrial energy production cycle. Doubtless others with better biochemical knowledge will enlighten us further.

 

[Jesse2233]

My limited understanding suggests that it is the step after production of pyruvate that is the problem. I think we can get as far as producing pyruvate, but we can't turn it into Acetyl CoA to start the mitochondrial energy production cycle. Doubtless others with better biochemical knowledge will enlighten us further.

I see, but didn't he mention that adding pyruvate to the serum made the cells normal under stress?

 

[ash0787]

it was said in this thread that its because it wont dissolve properly, you could make some way for a decent amount of it to dissolve when you are adding it into a test tube etc where there is thousands of cells but trying to put it into a form which can be used effectively in a needle against billions ? of cells its a different situation entirely. We used to do experiments to see how much of something can be dissolved, eventually it just starts to crystalize and settle out at the bottom, it could also have been when making Jam, its a case of trying to dissolve large amounts of sugar.

 

[Amused]

But it needs to be published. If not it might as well not exist.

I think their policy for publishing data is on the OMF website. The Naviaux data is on there, and was put on very quickly.

 

[aimossy]

Ok, but can anyone explain to me why my involuntary movements i.e. myoclonic movements and tonic-clonic convulsions are less tiring than I would expect the same movements made deliberately to be?

I note that in me remission is usually accompanied by hypomania, which I assume overrides Naviaux's dauer state. Could even split-second involuntary movements somehow do the same?

That is interesting. Only thing I can think of is that seizures can do things to neuro transmitters.

 

[Simon]

(Ron Davis's) nanoneedle biosensor technology used in this study

Obviously this study has huge potential. First, there's developing a model for this illlness at the cellular level, getting white blood cells to show stress-based changes mirroring PEM experienced in patients. Then there's the finding that the problem is in the serum not the cells (wow) - and the work underway to find out what in the serum is the problem Because the study is so important, I'd love to know a bit more about what the change in impedance actually means in terms of what's happening to cells.Here's what I found out - more answers very welcome.

Basic impedance approaches go back decades, measuring the impedance of the broth that bacteria are cultured in: metabolising bacteria chuck out metabolites that tend to be charged molecules that conduct better than water, so impedance (electrical resistance) falls.

This still from the video (transcript, thanks!) shows the technology used here is nanoneedle biosensors, which is a Stanford Genome Technology center nanobiotechnology project.

It was apparently developed by bioengineer Rahim Esfandyarpour, with Ron Davis as the senior author on the 2013 paper announcing it. Here's what I understand of it:

Nanoneedle: basically a tiny rod with 2 electrodes that measures impedance. Cells and medium/serum accumulate on the nanoneedle (not sure how many, small number I think) and it's the impedance of that mix that's measured.

Biosensor: normally this means it's 'tuned' to detect impedance from a particular molecule which could even be an antibody. Here it might be a a specific metabolite or metabolites. OR maybe they've chose to measure impedance more generally.

Here's a bit more on the mechanism from another 2013 paper

Cells captured on the surface of the nanoneedle tip results in a decrease in the impedance across the sensing electrodes. The basic mechanisms behind the electrical response of cells in solution under an applied alternating electrical field stems from modulation of the relative permittivity at the interface.

Unfortunately that doesn't mean a whole lot to me! Answers welcome.

I'd also be interested to know they cells are 'stressed' as it's the all-important step distinguishing mecfs cells from healthy ones (or healthy cells in mecfs serum from healthies).

I sent an email a few days ago to Janet and Ron asking for more info (thanks for providing that, @Rose49). I'm know they are both very busy but will post here if I hear anything back.

 

[BurnA]

I'd also be interested to know they cells are 'stressed'

Simon, Ron answered this question in one of videos, going back a few months, the one with the really bad audio quality taken at a conference.

Something to do with turning on the pumps, by adding salt I think, but will stand corrected if anyone has better info.

 

[Neunistiva]

@BurnA Was it IACFS Conference video published on Facebook?

Edit: Found it https://www.facebook.com/OpenMedicineFoundation/videos/956825444421877/
Dr. Davis starts speaking around 36:00

 

[Barry53]

The basic mechanisms behind the electrical response of cells in solution under an applied alternating electrical field stems from modulation of the relative permittivity at the interface.

Unfortunately that doesn't mean a whole lot to me! Answers welcome.

Referring to permittivity suggests capacitance, which is about storing electrical charge across a dielectric material. I do not have all the answers by any means, but some pointers.

A rough analogy to a capacitor is a taut stretchy diaphragm across the inside of a water or hydraulic pipe, where the fluid flow represents electrical current. Once fully stretched the pipe is effectively blocked. When not stretched at all there is negligible obstruction. So in effect constant flow (akin to direct current) is completely obstructed. For to-and-fro flow (akin to alternating current) there is less obstruction, how much depending on things like alternation frequency, the dielectric's charge-holding capability, etc (how rapidly the flow changes direction, how big/stretchy/strong the diaphragm is, etc). High frequency means very low obstruction, the membrane being hardly stretched at all (negligible charge build-up on dielectric); low frequency results in high obstruction. The obstructive effect is known as electrical reactance, and is distinct from electrical resistance. Reactance also applies to inductance, but is not relevant here by the look of it.

Electrical impedance is the combination of electrical resistance and electrical reactance. So it looks as if Dr. Davis is using a.c. electrical signals to assess the true impedance characteristics of cells, taking not just resistive but also capacitive effects into account. Really exciting stuff going on here!