John Hemming's Web Log

Prompt: ""of the diseases of aging which are assocated with changes to RNA splicing" Diseases of Aging Associated with Changes to RNA Splicing Many major age-related diseases have documented links to altered RNA splicing—both via age-related drift in the spliceosome and via disease-specific mutations in splicing factors or cis-elements. Below are key examples by system (not exhaustive, but covering major, well-supported cases). 1. Neurodegenerative Diseases Alzheimer’s disease (AD) What’s altered? Alternative splicing of tau (MAPT) , shifting 3R/4R isoform balance. Splicing of APP , PSEN2 , and various synaptic genes. Mechanism: Mis-spliced tau isoforms are more aggregation-prone and disturb microtubules; age-related decline in spliceosome components (e.g. SRSF and hnRNP proteins) pushes splicing patterns in a pro-pathology direction. Frontotemporal dementia (FTD) and other tauopathies What’s altered? ...

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principal mitochondrial K+ uniport is associated with respiratory complex I is an interesting preprint that has been withdrawn "due to disagreement with UCSF over data rights.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...