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There is a video of a talk by Michael Maes on the Australian ME group's (eMErge) site. Early on in the talk, he quotes two European government bodies whose policy was (I don't know when) exactly what you describe.

I'm assuming your "below 15% of the RDA" means below 15% of the normal reference range for plasma vit B3. You're right there could be a limitation in niacin transport, but some is clearly getting in. And fortunately, NAD+ is not consumed in energy production, just cyclically converted from NAD+...

Good critical question. When I first encountered the 5 mutations in IDO2, I was looking at genes one by one, manually. I started with all the mitochondrial proteins in the electron transport chain, then moved on to central energy metabolism. IDO2 was the 86th gene I looked at in the SIPS study...

We are already measuring cell serotonin in our mixed population of PBMCs, but it's likely that only the dendritic cells are in the trap, so it may be hard to make the required measurements without first isolating the cell types we think are in the trap. Since the kynurenine pathway (KP) is not...

Yes, depending on which isoform of TPH (the first enzyme in the Trp-to-serotonin pathway) is expressed in serotonergic neurons. One isoform is, itself, substrate inhibited so high intracellular Trp could cause low serotonin synthesis. The other (I'm guessing this is the one in serotonergic...

The IDO metabolic trap cannot occur in any cell type where TDO2 is is expressed. The TDO2 gene product does not undergo substrate inhibition, so TDO2 is a backup for substrate-inhibited IDO1. If we or anyone else finds that TDO is expressed in midbrain serotonergic neurons, then the IDO...

Good question. For the moment, we are relying on the high probability that any normal control has a 40% chance of being at least heterozygous for a broken copy of IDO2. Since our controls are sometimes unaffected relatives, our chance of getting heterozygotes is probably even greater. If the...

If you have seen single cell RNAseq data for cell types where only IDO1 is expressed and not IDO2 or TDO, please point them out to me. One place to look is the Broad Institute at MIT where they are accumulating scRNAseq data on gene expression and have built a public portal to access the data...

In biological terms, what happens is that (after the point of no return) IDO1 is now inhibited by its own substrate, Trp. Importantly this can only happen in cells where the kynurenine pathway is the major degradation route for Trp and where TDO2 is not expressed. It becomes irreversible because...

Alex, I agree with you that bistability is a natural way to think about CFS. And having grown up in non-linear systems theory in the 1960s before I became a physiologist in the 1970s, I too have been thinking about bistability in nonlinear biological systems for a long time. For CFS, I had the...

I've thought a good deal about this. Ron has too. One way is to simply consume too much Trp. The gut, the BBB and the neurons all use the same LAT1 transporter to transport Trp. In cells it has a uM Km on the way in and a mM Km on the way out. You will know many athletes who fell victim to CFS...

@Simon M Thanks for thinking about the metabolic trap so carefully. JaimeS sent me your questions, and as I read through them and some of the other thoughtful comments in this thread, I simply felt compelled to join s4me and be part of your conversation. Obviously doing so takes me away from the...

This is a nice summary. The only error is mine, not Simon's. My error was that I said there were, on average, 1.7 damaged copies out of 2. What the SIPS patients actually have is, on average, 1.7 (predicted) damaging mutations, and every patient has at least one. Since there are at least 5...