Robert D Phair

• PhD
• Principal Investigator at Integrative Bioinformatics Inc.

Textbooks depict the innate immune response as ending with the onset of the adaptive immune response. Recognizing that the "end" of the innate immune response is not well-defined in my question, what is your molecular hypothesis for the turning off of innate immune pathways during the handoff of responsibility to adaptive immunity?

Details: We know that each of the following molecular mechanisms is capable of inhibiting type I interferon signaling: 1) SOCS1/3 suppression of cytokine signaling, 2) ZBED2 competition for ISREs, 3) phosphatases such as SHP1 that can reverse JAK-mediated phosphorylations, and 4) other mechanisms more recently suggested, such as IL-10 and IL-6 or TGFb.

But what do you see as the likely chain of cause and effect that turns off innate immune signaling at the "appropriate" time?

Comments and questions are welcome.

Many mitochondrial proteins are encoded by the nuclear genome. Do different cell types supply the same set of proteins to their mitochondria? Or do different cell types fine-tune mitochondrial function to suit their own physiological function?

A year ago I asked if the cytosolic pH (pHcyto) was equal to the pH in the mitochondrial intermembrane space (pHims). One person responded, and we agreed that the outer mitochondrial membrane is no barrier to the movement of protons so pHcyto = pHims. But two people do not make a scientific consensus.

In recent decades it has become clear that the outer mitochondrial membrane has a vital role in programmed cell death, but this does not address its normal physiological role.

Questions for discussion:

Does a red blood cell have the minimum machinery to support attachment, entry, replication, and export of a +strand RNA virus like SARS-CoV-2?

Can you cite a reference?

Thank you.

As far as I know, the "reference" genome in a genome browser is usually the genome of a single sequenced individual.

I have often wondered if there is a special track in genome browsers consisting of the major allele at every position for that population (EAS, EUR, SAS, etc). It's true this track would change as more and more individuals are sequenced, but wouldn't such a track be widely useful?

When speaking of Mitchell's chemiosmotic hypothesis, it's common to consider the proton gradient as measured from the mitochondrial intermembrane space to the mitochondrial matrix. But textbooks say the outer mitochondrial membrane is freely permeable to molecules smaller than ~5kDa. Does this mean that the pH of the mitochondrial intermembrane space is equal to the cytosolic pH?

Metz et al. (International Immunol 2014, and earlier papers) have reported that IDO2 is expressed mainly in APCs, liver, kidney, brain, and placenta. Metz and Prendergast and their colleagues are making a strong case for IDO2's role in immunomodulation, and I'm wondering what is known about the function of IDO2 in neurons and glia. In other words, is it known what role IDO2 plays in parenchymal cells of the organs and tissues where it is expressed? I'm sure this question is sometimes confounded by the presence of IDO1 and TDO, but I'd like to know who, if anyone, is working on this aspect of IDO2 biology. Thanks.

We often discuss the importance of the mitochondrial adenine nucleotide exchanger; indeed, many suggest it is rate limiting for oxidative phosphorylation. But its function has no effect on total mitochondrial nucleotide content.

What is your view of the control of total mitochondrial adenine nucleotide content (ATP + ADP + AMP)? Are isolated mitochondria capable of purine biosynthesis?

If mitochondria can only exchange one mitochondrial ATP for one cytosolic ADP, then there is nothing a mitochondrion can do to increase or decrease the sum of mitochondrial ATP+ADP+AMP. This seems paradoxical. Where does a mitochondrion get its initial allocation of adenine nucleotides?