New research update video with Prof. Ron Davis, March 29th 2021

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Easily distracted etc today but I think I sort of get it, you modified the yeasts to make them not be able to do IDO2, and disabled other biomechanics for 'debugging' purpose...they gotta rely on IDO1. They get stuck at high concentration of substrate and they can't lower it for reasons I forgot ( is it like an equilibrium thing ? ) What I didn't understand immediately is how would adding other drugs help, unless they are gonna demethylate IDO1 or IDO2 ( I remembered though the whole point of this trap hypothesis is it doesn't require the persistent viral origin theory of me/cfs ) .

So that means that the potential drug must be doing something to restructure the enzyme to make it work properly in those conditions where it would normally be 'substrate inhibited' ? or is it doing something somewhere else to lower the substrate level ? either reacting with it or facilitating other chemical processes ? but I thought all those other processes were disabled in the yeast, its a little hard to understand.

Could this metabolic trap thing have applications beyond the problem of me/cfs or simply beyond the question of 'is our problem caused by tryptophan / kynurenine levels ' was the concept really never conceived of before ? I'm curious whether the slowed down yeast would respond at all to the drug which your son Whitney was taking ? does it really act at the core pathogenesis or is it just helping in some other way by saving energy, suppressing neuroinflammation or something ? interesting times we are in thankyou Dr Davis & co.
 

Alvin2

The good news is patients don't die the bad news..
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Learner1

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Dont want to derail, but does niacin feedback mean we shouldnt take it? I have been since becoming ill. It seems to help, at least for a little bit after ingestion. Nad+ didnt work for me really. For some reason.

Also too ill to read the update atm but I’m glad people are feeling positive About it. Thanks for the update Ben and ron/dafoes
You might want to post this in one of the NAD threads or start a niacin thread.
 
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Maybe someone else shares this experience as well. As previously mentioned, I tried Niacin already. It was a high dose. For a few days, I might have felt a little improvement, but no remission. And after 5 days or so, I got significantly worse. I had GI issues, my extremities felt extremely cold. I was freezing and had tremors that came in waves. 10 seconds tremor, 20 seconds relaxing, and so on. On top of that, tachycardia and low blood pressure etc.
I took 500 mg of niacin for 4 days. I had to stop because i felt a very noticeable aggravation. I was stable for more than a year.
I have a question; Does someone know the effects of quinolones on IDO1/2?
 

mitoMAN

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Hi guys,

Here is a new research update from Prof. Ron Davis.

Huge thanks again to Ashley Haugen for her hard work doing this, also to Ron and Janet.


@Janet Dafoe
@Whit
Dear @Ben H and @Janet Dafoe I was wondering if you have investigated into WHY Ativan helps so many people and if it might be the TSPO binding affinity (as Ativan helps much more then most other benzodiazepines without TSPO affinity)?

I know that Ron posted about the modulation of T-Cells and ATP output while Ativan is in play.
But has there be a mechanism linked yet?
 

Marylib

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@joshua.leisk - here is a transcript/summary of a talk in case you and Aline are interested. Some one had asked in another thread.

Here is a rough transcript I did for patients that cannot watch or listen to the video:




-Intro from Ron. Ron's sole focus is ME/CFS.

-Working on treatments/cure.

-Metabolic Trap idea. This is where critical enzyme gets trapped in it's function.

-Difficult to test in human cells, testing in bakers yeast. Have great technology for this.

-Have taken bakers yeast + put in critical gene that gets trapped (function gets trapped) + that is IDO1 gene.

-IDO1 converts tryptophan (in diet) to kynurenine.

- Kynurenine v. important-regulates immune system, can suppress inflammation etc.

- Placing gene into yeast can control it, but it makes the same protein that is made in humans.

- Many human genes will work in yeast and vice versa.

- Yeast doesn't really have this level of pathway so kynurenine can be used to make NAD.

- NAD is chemical compound that is extensively used in metabolism of organisms, human + yeast.

- In humans NAD used in ~400 chemical reactions, really essential.

- Required for production of energy in mitochondria.

- What they have done is make kynurenine in yeast with this enzyme + require it to make NAD.

- Yeast has multiple ways to make NAD so have removed all genes involved in the production of NAD.

- So ONLY way yeast can make NAD is to have this pathway on.

- If they trigger the metabolic trap, will shut down the enzymatic activity of ido1 then it can't kynurenine, and it can't make NAD. If can't make NAD, won't grow.

-One problem is don't want yeast to consume tryptophan by any other pathway.

-Looked into yeast, all genes have been sequenced + understand their function, found several genes that consume tryptophan for other purposes.

-Have removed these genes.

-This new developed yeast is now suitable for a test.

-Grew on low tryptophan, cells grew fine.

-If raise tryptophan concentration, high level of tryptophan can inhibit enzyme.

-This is very strange.

-Here is an enzyme (IDO1) that converts tryptophan to kynurenine. Would guess that if raised tryptophan would simply make more kynurenine.

-Not true-the high tryptophan inhibits the enzyme and can't make kynurenine.

-If it can't make kynurenine can't grow-so if raise concentration of tryptophan gets to point where it stops growing.

-As long as you leave tryptophan in at a high level, can't grow.

-If you then wash out the high level of tryptophan + put in low level of tryptophan, starts growing again.

-OR if leave high level of tryptophan but give yeast kynurenine (required for NAD) starts growing again even in presence of high tryptophan and absence of activity of enzyme.

-Why are they doing all this? One is to test the Metabolic Trap-something you can do in a test tube-does it work in a cell?

-This experiment shows it CAN work in a cell. It's yeast, but can still work in a cell.

- This is a possibility what is happening in humans.

-There is another reason to do this. Now have system where can shut down the enzyme in metabolic trap + the only way cell can grow is to get rid of tryptophan.

-Human cells not quite the same, it's not growth, it's making kynurenine which is critical factor.

-If this true in human cells, only way to make kynurenine would be to get rid of the tryptophan. The only way to get rid of tryptophan is to convert it to kynurenine.

-That's why it's called a trap, you get into it, you can't get out.

-However if they can find compound-that will 'block the block'-the inhibition that tryptophan has over the enzyme/IDO1 this then will reactivate IDO1, IDO1 will consume the tryptophan and cells will produce kynurenine.

-That's the stage are at at the moment with yeast.

-Fairly simple to do with yeast. Put in high tryptophan + can add drug(s) at different concentrations + look for growth.

- Have a robot that can do all of this, can do 96 at a time + have 3 robots, can do this with different concentrations of drugs.

-Can set up + leave to do experiments. Robot can do lots of experiments! Is being set up now.

-Unfortunately it's an old robot, needs some repairs + is in the process of repair.

-Getting help + are going to get fixed. So is just about ready to start doing drug screens.

-Have all FDA-approved drugs in their freezer. Have already screened all those drugs for their effect on yeast + know concentration that has some effect.

- Ron excited about this, has no idea what the probability is but is optimistic. Lots of things to try at lots of different concentrations.

-Also, if it works out + don't find any FDA-approved drugs, will start screening herbal extracts.

-Wants to have something patients can take + a new compound would take updated approval + take years to do. Doesn't want to do that.

-Optimistic can find something. If metabolic trap is real they have something can treat it with.

-Next thing is move to human cells. In process of doing that.

-Ron says thank you.
@ Ben H
Here is a rough transcript I did for patients that cannot watch or listen to the video:




-Intro from Ron. Ron's sole focus is ME/CFS.

-Working on treatments/cure.

-Metabolic Trap idea. This is where critical enzyme gets trapped in it's function.

-Difficult to test in human cells, testing in bakers yeast. Have great technology for this.

-Have taken bakers yeast + put in critical gene that gets trapped (function gets trapped) + that is IDO1 gene.

-IDO1 converts tryptophan (in diet) to kynurenine.

- Kynurenine v. important-regulates immune system, can suppress inflammation etc.

- Placing gene into yeast can control it, but it makes the same protein that is made in humans.

- Many human genes will work in yeast and vice versa.

- Yeast doesn't really have this level of pathway so kynurenine can be used to make NAD.

- NAD is chemical compound that is extensively used in metabolism of organisms, human + yeast.

- In humans NAD used in ~400 chemical reactions, really essential.

- Required for production of energy in mitochondria.

- What they have done is make kynurenine in yeast with this enzyme + require it to make NAD.

- Yeast has multiple ways to make NAD so have removed all genes involved in the production of NAD.

- So ONLY way yeast can make NAD is to have this pathway on.

- If they trigger the metabolic trap, will shut down the enzymatic activity of ido1 then it can't kynurenine, and it can't make NAD. If can't make NAD, won't grow.

-One problem is don't want yeast to consume tryptophan by any other pathway.

-Looked into yeast, all genes have been sequenced + understand their function, found several genes that consume tryptophan for other purposes.

-Have removed these genes.

-This new developed yeast is now suitable for a test.

-Grew on low tryptophan, cells grew fine.

-If raise tryptophan concentration, high level of tryptophan can inhibit enzyme.

-This is very strange.

-Here is an enzyme (IDO1) that converts tryptophan to kynurenine. Would guess that if raised tryptophan would simply make more kynurenine.

-Not true-the high tryptophan inhibits the enzyme and can't make kynurenine.

-If it can't make kynurenine can't grow-so if raise concentration of tryptophan gets to point where it stops growing.

-As long as you leave tryptophan in at a high level, can't grow.

-If you then wash out the high level of tryptophan + put in low level of tryptophan, starts growing again.

-OR if leave high level of tryptophan but give yeast kynurenine (required for NAD) starts growing again even in presence of high tryptophan and absence of activity of enzyme.

-Why are they doing all this? One is to test the Metabolic Trap-something you can do in a test tube-does it work in a cell?

-This experiment shows it CAN work in a cell. It's yeast, but can still work in a cell.

- This is a possibility what is happening in humans.

-There is another reason to do this. Now have system where can shut down the enzyme in metabolic trap + the only way cell can grow is to get rid of tryptophan.

-Human cells not quite the same, it's not growth, it's making kynurenine which is critical factor.

-If this true in human cells, only way to make kynurenine would be to get rid of the tryptophan. The only way to get rid of tryptophan is to convert it to kynurenine.

-That's why it's called a trap, you get into it, you can't get out.

-However if they can find compound-that will 'block the block'-the inhibition that tryptophan has over the enzyme/IDO1 this then will reactivate IDO1, IDO1 will consume the tryptophan and cells will produce kynurenine.

-That's the stage are at at the moment with yeast.

-Fairly simple to do with yeast. Put in high tryptophan + can add drug(s) at different concentrations + look for growth.

- Have a robot that can do all of this, can do 96 at a time + have 3 robots, can do this with different concentrations of drugs.

-Can set up + leave to do experiments. Robot can do lots of experiments! Is being set up now.

-Unfortunately it's an old robot, needs some repairs + is in the process of repair.

-Getting help + are going to get fixed. So is just about ready to start doing drug screens.

-Have all FDA-approved drugs in their freezer. Have already screened all those drugs for their effect on yeast + know concentration that has some effect.

- Ron excited about this, has no idea what the probability is but is optimistic. Lots of things to try at lots of different concentrations.

-Also, if it works out + don't find any FDA-approved drugs, will start screening herbal extracts.

-Wants to have something patients can take + a new compound would take updated approval + take years to do. Doesn't want to do that.

-Optimistic can find something. If metabolic trap is real they have something can treat it with.

-Next thing is move to human cells. In process of doing that.

-Ron says thank you.
 

max_yazhbin

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It’s the way that gene works. It’s called substrate Inhibition. When the substrate, tryptophan, gets too high, it stops working
If Ron or his team hasn't already looked into James Sethna, Cornell University, “Sloppy models, Differential geometry, and How Science Works”, or Chris Rackauckas, Massachusetts Institute of Technology, "Scientific Machine Learning," these people's software and insights might help narrow the search space for testing the metabolic models. With Julia, there could be a 10,000x speedup in some computations since they don't just use standard stochastic gradient descent. My background is in chemical engineering, software engineering, and nonlinear dynamics and chaos. I think there could be much more done in terms of computation to see if this metabolic trap idea is false, obviously nature is the ultimate source of reality with experimentation being how scientists probe it.
 

max_yazhbin

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@Janet Dafoe wondering if you saw this video:
, they discuss kyneurinine and tryptophan around the middle of the video

The naturopaths have some interesting ideas and have been at ME/CFS for decades. Sources of relevant physicians include those at the Institute of Functional Medicine and the Kalish Institute. I also like Richard Lord's book: https://b-ok.cc/book/5255411/b85ea8
 

Marylib

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@Janet Dafoe wondering if you saw this video:
, they discuss kyneurinine and tryptophan around the middle of the video

The naturopaths have some interesting ideas and have been at ME/CFS for decades. Sources of relevant physicians include those at the Institute of Functional Medicine and the Kalish Institute. I also like Richard Lord's book: https://b-ok.cc/book/5255411/b85ea8
I know you are quite ill @max_yazhbin, and while I haven't yet watched the video you posted and I don't know what you have access to in terms of naturopathic physicians, if you have the money, etc. (I don't have the money or access I need at the moment) but nutritional IV's from a naturopathic physician in Oregon, US, temporarily reverse my symptoms. Forgive me if I am repeating myself in several places on this forum. It's a huge forum and the moderators do an excellent job trying to keep track of things. I give them permission to move or delete my posts as they feel best. I need to dig out the paper copy I have that lists the ingredients and dosages of those IV nutrients. Please remind me if you are interested in seeing what was in those IV bags.
 

Marylib

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@max_yazhbin I should also add that when I first became non-healthy, an integrative style MD tested my serum for all kinds of things and the amino acid profile was .. alarming. He said he had never seen every single amino acid that low except in a corpse while he was studying med school back in Germany.

I orginally saw him for out-of-control candida. He put me on oral supplementation, a keto-style diet, big whammy meds for the candida and the numbers improved. I also had what he called an anti-viral IV only once, which helped too. Unfortunately I don't know what was in that IV bag. At that time, I could still exercise freely and regularly, but could not sleep.

He tried to put me on trazodone for the sleep but it wasn't a mini-dose so I discontinued. I didn't know about mini-doses at that time, nor was I familiar with any drug or medication so the side-effects put me off. This was in the late or mid 1990's. He's a great doc and still in practice in West Los Angeles or Ojai, California. I don't know your location or your situation at the moment, but send me a message if you wish.
 

lenora

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Yes, Marylib, trazodone seems to be recommended so often for our problems. I don't think sleep clinics ever send anyone away except with a prescription for trazodone (unless, as I've said before, it's a CPAP machine).

I've yet to find anything that helps with sleep. There are nights, when I'll do OK, but most others are spent as per this night....up and at 'em from midnight or so. I have many prescriptions, but know they'll only work if I use one per mo.,, and I consider that fortunate. There is something very wrong with our sleep/brain barrier....too many of us suffer from the same problem to have it be anything else.

I also agree that the Moderators do a wonderful job and, like you, I've given them permission to move my comments to a place that's most suitable for them. I try, but frankly the Thread idea just hasn't engaged my brain. It's good to find a good naturopath....lucky you. Yours, Lenora.