LIST OF QUESTIONS TO FEED DEEP RESEARCH (ideally w/agents)

#1

why isnt cCREs or CpGs in SRSF1 a top longevity gene in humans?

why aren’t protein repair genes super-associated wtih longevity in humans
what about proteasome genes? beta7 is implicated but others not as much

what cell junction proteins/membrane stability ones are associated with longevity in NMRs. do they have really tight cell membrane barriers/boundaries

what robert ghrist/chad giusti simplicial complexes (or PPN network motifs) might be most important for longevity in NMRs. is persistence homology higher in PPN network motifs of long-lived organisms like NMRs? [or in more educated people who maintain function better with age even if they do not age more slowly]

longevity motifs are PROTEIN-PROTEIN interanction networks NOT individual genes, and USUALLY ones that target genes NOT USUALLY ASSOCIATED with each other (not so high clustering coefficients)

ok which genes most important in transthyrein amyloidosis (or preventing it)

ok what are the genes that protect proteins from oxidative damage (or repair them). esp ones that repair the first 3 steps of damage from glucose
Um Ok, genes for proteasomes like beta7 repeat?

well NMR ribosomes translate more slowly, what genes cause this

why are most longevity related gene SNPs with highest effect size not always the most central in gene regulatory networks?
what about STIFFNESS sensing proteins like YAP are those central to NMR longevity

do NMRs have better spliceosome enzymes and whihc ones
what are most impt spliceosome genes
what are the most important genes in epitranscriptome regulation (yogesh saletore)

what were the central longeviyt genes that Stuart Maudsley studied? GCN1??

“half the methylation cpg sites are actually hydroxymethylation” - can you analyze this

#2

whya re encode cCREs a big deal? what about layered H3K27Ac (OVER OTHER HISTONE MODIFICATIONS) in UCSC gene browser

What are the chromatin-regulation/chromatin control/histone acetylation/histone methylation genes differentially expressed between bowhead whales, NMRs, and supercentenarians?

Is entropy/erosion of histone acetylation/methylation landscape with age DIFFERENT for acetylation marks different from H327a3? (also how is this different between bowhead whales, NMRs, supercentenarians, and cockatoos)

What are the cCRE sites differentially expressed between bowhead whales, NMRs, and supercentenarians?

What are the genes most associated with changing how ratio of long-transcript to small-transcript ratio mRNAs changes with age, and how are they different between bowhead whales, NMRs, and supercentenarians

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What genes/histone acetylation marks/epitranscriptome marks/polyadenylation marks are most upstream of cellular sensitivity to “repair genes” to “growth genes”

What genes/histone acetylation marks/epitranscriptome marks/polyadenylation marks are most upstream of cellular sensitivity to maintaining cell membrane potential with age [or cell’s ability to do mechanotransduction OR maintaining H3K27ac distribution OR reducing H3K27ac increases in entropy with age, OR maintaining a cell’s resistance against increases in transcript entropy with age, particularly cryptic splice sites or alternative splicing variants that should not exist, except that happen in older people]

does aging result in an increase in alternative splicing diversity (or combinatorial explosion thereof)

How do dynamical systems/limit cycles/“decay coefficients in PDEs” explain why there is a huge difference in “bad outcome” between acute stress and chronic stress for an organism maintaining homeostasis and resiliently adapting to all possitlbe perturbations LONG TERM?

#3

Stress-selection: “stress sharing” is this why michael levin and martin nowak group selection believe that …

#4

whya re encode cCREs a big deal? what about layered H3K27Ac (OVER OTHER HISTONE MODIFICATIONS) in UCSC gene browser

OK but why cCREs and not trans regualtory elements in ENCODE

[cf Denis Odinokov] Does excess sequencing of dead/frozen tissue in spatial transcriptomics distort the reading of some mRNA strands b/c some mRNA strands in some regions of the cell decay way more quickly than others?

#5

CELL SIZE WITH AGE: THINK OF SKOTHEIM LAB [why does cytosolic to nuclear ratio change with aging and how does this affect ability of mRNA and proteins to get where they need to go?] Is this change different between long neurons and other cells?

What are the special organelles neurons use for translating mRNA [granules…] AND HOW does this idiosyncracy explain how short stubby spines decline way more than larger spines in the neuron with aging and can psilocybin rescue these deficits or not?

If you had the perfect (super-rare or expensive) dataset (with INTERVENTION and control) to be preserved for later, what dataset woud you have, and what near-term “spatial transcriptomics”/“ALL THE OMICS” techniques would you use to grab it all.

What happens if we excessively use fibroblast and endothelial cells and not enough of other cell types [especially in the most commonly used organiss] and how does this distort the field of spatial transcriptomics applied to the most high-information/most specialized/most differentiated cell types?

What cell types require the highest degree of transcription factors for full transcriptional control?

MOSAICISM WITH AGING: ok so jan vijg said that loss of cellular identity from mosaicism is the least recersible thing in his 2007 book “aging of the genome”. How well has his 2007 hypothesis held up?

#6

What celltype in ANY ORGANISM (eg falcon, hummingbird) has the most exquisite level of sensitivity to detect the most minute perturbation in the environment to a change in differences in {light, temperature, motion, etc…}

What are the biggest “control knobs/sensitivity amplifiers” to amplify any gene like a 40copy addgene/benchling plasmid in the human excitatory L5 pyramidal cell? [not just immunoglobulin genes in B cells]. What are the opamps vs “precise control knobs” of the cell

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What celltype is best at precisely delivering protein/PSD95 cargo with highest degree of sensitivity/spatial resolution?

#7

A lot of the above is cell control stuff

how does the cell sense curvature and torsion and tortuosity?

it’s not… molecular events like nonenzymatic post-translational modifications to proteins (and how this affects chemical biology of the cell) Yet. Maybe michael levin (high level) or even the gero.ai guys has primed me to care a little less about this stuff than I used to

WHAT TISSUE BIOBANKS (or super-rare tissue) would you use new sensing technology (like precigenetics OR the latest optical pooling or molecular barcoding/braincode/expansion microscopy methods or the strongest future SEMs/AFMs/confocal microscopes on - eg the last boyden lab methods) on. [and how to preserve the tissue so you that you can use it

what is dif between Olink and somalogic aptamer technology for proteomic age gaps

What are the antifragility/pro-hormesis motifs (or self-healing materials) in dynamical systems like brusselators, ring oscillators, and Eugene M. Izhikevich’s seminal work "Simple Model of Spiking Neurons?

Can the cell (from deep inside/center/on the organelles) do the PDEs to tell small differences in vmem from small differences in HOW the membrane ion channels are arranged (or their ratios)

atavistic gene expression for aging cells: WELL isn’t atavistic gene expression ALSo what happens if you do iPSC reprogramming and make the cell express more developmental genes?

#8

leo pio lopez says increased levels of vmem heterogeneity/degradation of bioelectric spatial organization: how does this happen? how much of this is bc of increased stiffness in the cell/reducd ability of the cell to precisely target curvature/tortuosity b/c the cytoskeleton/vimetin/microtubules dont know where to precisely go anymore [this is also loss of goal-directedness once the neuron stops developing and the organism doesn’t care for reproducing anymore]

regeneration achieved thru reactivating dev by providing cells with embryonic information: ok well doesnt this also break down their cell compartmentalization? cells depolarize when you induce epigenetic reprogramming

#9

Aging is associated with increases in entropy/“erosions in highly peaked values” of H3K27ac, protein localization, splicing isoforms, long-transcript to short-transcript, transcriptomic noise, and CpG site spread (DMEs vs VMEs), and cell polarity

Ok so where do increases of entropy happen first? And in which of these cases are the increases in entropy least reversible with cell reprogramming/maintaining cell differentiation/etc?