John Hemming's Web Log

I put a couple of prompts into Gemini and the following came out as answers: Impact of RNA Splicing on Endothelial Function in CVD User Query To what extent are protein changes as a result of RNA splicing changes that cause endothelial problems part of cardiovascular disease? AI Analysis Protein changes resulting from aberrant RNA splicing in endothelial cells are not merely bystanders but are increasingly recognized as active drivers of cardiovascular disease (CVD). To answer your question directly: these changes contribute to CVD to a significant extent by creating "molecular switches" that can flip a healthy endothelial cell into a diseased state without necessarily changing the total amount of the gene being expressed. This process often explains why a patient might have "normal" levels of a protein but impaired function. The following s...

The principal mitochondrial K+ uniport is associated with respiratory complex I is an interesting preprint that has been withdrawn "due to disagreement with UCSF over data rights. This withdrawal decision is not related to the validity of the data presented in this study, and these authors understand that this work cannot be cited as reference for the project until the disagreement is resolved." It remains, however, interesting. The reason I find it interesting is that there is clear evidence that there is a link between the delta pH between the mitochondrial matrix and Intermembrane Space and the mitochondrial membrane potential. This was evidenced in experiments which varied one and saw the proton motive force (which is the total of the two adjusted for the same units) remain essentially constant. Furthermore it seems that where Potassium Ion transport changes with age we can also see a reduction in the membrane potential, but an increase in delta pH. This is signif...

These are two lists of reviews looking at mainly acetyl-CoA, but also other acyl-CoAs. They were selected by a search using chatGPT for the first one and Claude for the second one. Some are behind a paywall. My plan is to read through these and draw out conclusions I will separate out the ones which are behind a paywall. Acetyl-CoA: a central metabolite and second messenger (Cell Metab, 2015) Acetyl-CoA and the regulation of metabolism (Trends Biochem Sci, 2015) Spatiotemporal control of acetyl-CoA metabolism in chromatin regulation (Trends Biochem Sci, 2018) Compartmentalised acyl-CoA metabolism and roles in chromatin regulation (Molecular Metabolism, 2020) Should we consider subcellular compartmentalization of metabolism? (Trends Cell Biol, 2019) The multiple facets of acetyl-CoA metabolism: Energetics, biosynthesis, regulation, acylation and inborn errors (Mol Genet Metab, 2023) Molecular targets and small molecules modulating acetyl-CoA metabolism (ACS Pharmacol Transl...

I recently read a paper Ribonucleotide incorporation into mitochondrial DNA drives inflammation which I found very interesting. The reason I found it interesting is perhaps summarised in the first paragraph of the discussion section which I will quote: We demonstrate that increased incorporation of rNTPs into mtDNA during replication leads to the release of mtDNA fragments from mitochondria and proinflammatory signalling. Our results therefore highlight the challenge that the high molar excess of rNTPs relative to dNTPs poses to cells. Although RNase H2 removes incorporated rNMPs from nuclear DNA as part of the ribonucleotide excision repair pathway, this repair mechanism is not present in mitochondria, which are therefore prone to accumulating rNMPs in their genome. Similar to the effect of rNMPs on nuclear DNA replication27,40, due to the inherent reactivity of the 2′-OH group of the ribose ring or collisions with the replication fork, misincorporated rNMPs may cause DNA strand br...

People who study NCD (Non Communicable Diseases) and particularly those that focus on the diseases of aging (which I think include many of the NCDs, but not all of them) have a concept of someone having a biological age as well as a chronological age. This guides things like how frail someone is, how well their cognition works, whether they are at the risk of cancer or diabetes or indeed how they look. Human beings are quite good at judging each other's general health by appearance. That is because the various NCDs tend to correlate with how well the body maintains the skin and when someone is frail it is quite easy to see this by how they move around. Regular readers of my blog will know that I think this is because the genome stops functioning properly as people get older. In essence cells stop producing the right proteins. I provide full details of this hypothesis on this web page https://citrate.science/2025poster/poster2025.html . Various approaches have been used to cal...

I tend to ask chatGPT for a summary of the transcript of videos so that I don't have to spend the time watching them. I have done this for the ALS Scientific Advisory Council from about a month ago which follows (the critique is of chatGPT - my critique is that they don't talk about mitochondria, the closest they come to epigenetics is DNA methylation): International Alliance of ALS/MND Associations Scientific Advisory Council Webinar – Transcript Summary Opening & Housekeeping Jessica Mabe (Programs Coordinator, International Alliance) welcomed attendees and introduced the webinar, noting caption availability (via Zoom chat or QR code) and thanking sponsor Mitsubishi Tanabe Pharma . The Scientific Advisory Council Chair & Moderator: Dr Nicholas Cole (Head of Research, MND Association, UK) Panelists: Dr Kuldip Dave – Vice President of Research, ALS Association (USA) Dr Nadia Sethi – Co‑chair, NE...

I think it is useful to try to identify: a) The most heavily energy using neurons b) The balance in those cells between OxPhos (which produces Reactive Oxygen Species - ROS) and Glycolysis I will be using various LLMs to search for information relating to this and will be spending time checking the responses for hallucinations, but I may not at the time of you reading this page finished validating everything. I will also be concentrating on validating the analysis for dopaminergic and motor neurons because those are the neurons which cause PD and ALS/MND. In principle the rank is not really valid. Although this table is produced using a ranking that is not going to be reliable, it is still useful. What I am trying to get from this is to identify the cells which would be vulnerable to rapid deterioration through ROS. The first step is those with a high energy usage. This, however, I would expect to vary from time to time and any actual accurate calculation for one human being ...