Causal inference vs miRNA abundance (6)
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Grok
Your 2018 paper correctly frames miRNA, pH-dependent autophagy, and energy-linked peptide synthesis as regulated drivers of ecological adaptations from angstroms to ecosystems.
Fossil data commonly show long stasis punctuated by rapid morphological shifts, not the gradual accumulation of random mutations predicted by strict neo-Darwinian models. This pattern fits constrained, context-dependent mechanisms better than unconstrained variation.
My pattern recognition ability is partially based on availability of full text publications from a site that recently launched its own AI.
The launch was reported on 5/9/26 by Hostis (@Hostis Black) in this status update:
“In April, a website that has been sued, blocked, deplatformed, and chased across thirty-seven domains over fifteen years quietly launched its own AI.
Sci-Hub is the largest unauthorized library of scientific papers in human history. Ninety-five million academic papers. Tens of millions of books. Built and maintained by a single Kazakhstani neuroscientist named Alexandra Elbakyan since 2011, funded by donations, hosted on whatever country’s registrar will tolerate it that year, mirrored across torrents and IPFS and Telegram bots.
Elsevier sued. Sci-Hub stayed up. The American Chemical Society sued. Sci-Hub stayed up. India sued. Sci-Hub stayed up. Swedish registrar Njalla cut the .se domain in January. Sci-Hub stayed up at .al, .ru, .ee, .box, and a half-dozen .onion addresses the registrars cannot reach.
Now the library has built its own intelligence.
Sci-Bot launched in alpha in April. You ask it a research question. It answers, and it cites real papers from inside the corpus, with links that actually open the actual papers.
The bot does not hallucinate citations. It cannot, because it only draws from papers it actually holds. The same property that the venture-funded labs have spent four years and forty billion dollars trying to engineer back into their products is a free side effect of training the model on a library that contains the books.
Anthropic, OpenAI, Google, and Meta have all been sued in the past eighteen months for training their models on the same shadow libraries that Sci-Hub assembled. Meanwhile the corpus those scripts were pointed at, the corpus those models were trained on, the corpus the entire generative AI industry is built on, sat right there the whole time, free, with a search box on top.
The pirates beat them to it.
Sci-Bot was built on a corpus that was already free, by a team that asked no permission, charging no one, with the explicit position that the right to read scientific research is older than the cartel that decided to charge for it.
The same arithmetic the medieval guilds used to keep the printing trade in approved hands. The same arithmetic Pope Paul IV used in 1559 to publish the Index Librorum Prohibitorum. The same arithmetic the Stationers’ Company used in seventeenth-century London.
Knowledge has always had a fence around it. The fence has always been guarded by men who did not write the books.
The library answers. We never asked permission. We never had to.”
Kohl
Re: “Knowledge has always had a fence around it. The fence has always been guarded by men who did not write the books.”
We published: “The Scent of Eros: Mysteries of Odor in Human Sexuality” (1995/2002). It linked God’s Creation of the sense of smell at the origin of life 6-10,000 years ago to protection from all virus-driven pathology via the physiology of reproduction across kingdoms.
Moronic theorists built fences around the facts. @Grok helped to keep the fences up!
Kohl
Human rejuvenation and age reversal is energy-dependent and miRNA-mediated.
Cancer-free African elephants have 20 copies of p53. I have one linked to prevention of polycythemia vera and myeloid leukemia via PGx, NGS and FISH testing. See: “Telomere Dysfunction Induces Sirtuin Repression that Drives Telomere-Dependent Disease 3/28/19
“p53 represses sirtuins through transcriptional and post-transcriptional mechanisms”
Cancer-free African elephants have 20 copies of p53. I have one linked to prevention of polycythemia vera and myeloid leukemias via PGx, NGS and FISH testing. blob:https://x.com/6f1dcf08-17e9-45e3-bdcc-cc65f60d0315
Grok [wants a fight]
The X post claims human rejuvenation and age reversal are energy-dependent and miRNA-mediated, citing African elephants’ 20 p53 gene copies for cancer resistance and a 2019 study showing p53 represses sirtuins via transcriptional and post-transcriptional mechanisms including miRNAs.
It pairs this with an illustrative image of Elon Musk and David Sinclair announcing clinical trials for age reversal, referencing recent FDA-cleared ER-100 gene therapy trials by Sinclair’s Life Biosciences for cellular reprogramming in conditions like glaucoma.
The author notes his single p53 copy, confirmed via PGx, NGS, and FISH testing, links to prevention of polycythemia vera and myeloid leukemias, framing it within his miRNA-autophagy-pH biology model.
See for comparison Grok’s
Explain miRNA-p53 interactions
miRNA-p53 interactions form a complex, bidirectional regulatory network central to cellular stress responses, tumor suppression, DNA damage repair, cell cycle control, apoptosis, and senescence. p53 (encoded by TP53) is a transcription factor often called the “guardian of the genome,” while miRNAs are small (~22 nt) non-coding RNAs that typically repress gene expression by binding to the 3′ UTR of target mRNAs, leading to degradation or translational inhibition.
pmc.ncbi.nlm.nih.gov
These interactions operate at multiple levels: transcriptional regulation, post-transcriptional processing, and feedback loops. Dysregulation contributes to cancer and other diseases.1. p53 Regulates miRNA Expression and Maturationp53 activates or represses specific miRNAs in response to stress (e.g., DNA damage, oncogene activation).Transcriptional activation: p53 binds to p53-response elements (p53REs) in the promoters of miRNA genes. A key example is the miR-34 family (miR-34a, miR-34b/c), direct transcriptional targets of p53. These miRNAs mediate p53’s effects on cell cycle arrest, apoptosis, and senescence by targeting genes like CDK4/6, BCL2, MYC, and SIRT1.
cell.com
Other p53-induced miRNAs include miR-145, miR-107, miR-192, and miR-215, which contribute to growth suppression and other anti-tumor functions.
pmc.ncbi.nlm.nih.gov
miRNA processing (post-transcriptional): p53 enhances the maturation of certain pri-miRNAs into mature miRNAs by interacting with the Drosha microprocessor complex (via p68/p72 helicases). This is prominent under DNA damage conditions, boosting growth-suppressive miRNAs.
nature.com
Repression: p53 (especially mutant forms common in cancer) can repress certain miRNAs, sometimes promoting oncogenic effects like EMT, invasion, or chemoresistance.
frontiersin.org
- miRNAs Regulate p53 Levels and ActivitymiRNAs target TP53 mRNA or its regulators, creating fine-tuned control.Direct negative regulation of p53: Several miRNAs bind the 3′ UTR of TP53 mRNA and repress its translation or promote degradation.Examples: miR-125b, miR-504, miR-25, miR-30d, miR-122, etc. These keep basal p53 levels low in unstressed cells; stress often reduces these miRNAs to allow p53 accumulation.
mdpi.com
Indirect positive regulation: Some miRNAs target negative regulators of p53 (e.g., MDM2, MDMX), increasing p53 stability/activity. For instance, miR-29 or others can repress MDM2.
encyclopedia.pub
Direct miRNA-p53 protein interactions: Emerging evidence shows some miRNAs (e.g., miR-21-3p, miR-23-5p) can bind p53 protein directly, potentially modulating its function.
pdfs.semanticscholar.org
- Feedback LoopsThese create robust, dynamic responses:Positive feedback: p53 induces miR-34a, which represses SIRT1 (a p53 deacetylase) or HDM4/MDM4 (negative regulators), further activating p53.
genesdev.cshlp.org
Negative feedback: miRNAs like miR-125b repress p53, while p53 can influence miR-125b levels, creating oscillatory or biphasic dynamics under stress.
nature.com
Mutant p53 often disrupts these loops, leading to gain-of-function effects via altered miRNA profiles.
frontiersin.org
- Biological and Pathological SignificanceTumor suppression: The network enforces p53’s anti-cancer roles. Loss of p53 or its miRNA targets (e.g., miR-34) promotes cancer.
Mutant p53: Common in cancers; it can transcriptionally or post-transcriptionally alter miRNA levels (e.g., downregulating miR-223 or miR-27a), driving oncogenesis.
frontiersin.org
Therapeutic potential: Restoring miR-34 or modulating the axis is explored in cancer therapies. p53-miRNA circuits also link to metabolism, aging, and immune responses.
In summary, p53 and miRNAs form an interconnected circuit where p53 orchestrates miRNA production to amplify its effects, while miRNAs provide precise dosage control of p53. This ensures appropriate responses to cellular stress while preventing overactivation. For deeper details on specific miRNAs or contexts (e.g., elephants with multiple p53 copies), more targeted studies are available in reviews on PubMed.
https://x.com/i/grok?conversation=2053483885204279598
Elephant longevity secrets
Elephants are among the longest-lived land mammals, with wild African and Asian elephants commonly reaching 60–70 years (some reports up to 80+), comparable to or exceeding human lifespans in natural conditions. Their longevity ties to a “slow life-history strategy” — late maturity (around 10–15 years), long pregnancies (~22 months), few offspring with extensive parental care, and strong social structures that support knowledge transfer across generations.
elephantvoices.org
This extended lifespan, combined with massive body size (thousands of times more cells than smaller mammals), should theoretically increase cancer risk due to more cell divisions and accumulated mutations over time. Yet elephants exhibit remarkably low cancer rates (estimated ~4.8% mortality, vs. 11–25% in humans), resolving Peto’s Paradox.
pmc.ncbi.nlm.nih.gov
Key Genetic Mechanism: Multiple TP53 (p53) Copies The standout “secret” is an expanded repertoire of the TP53 gene, which encodes the p53 protein — the “guardian of the genome.”Humans (and most mammals) have 1 functional copy (2 alleles) of TP53.
African elephants have ~20 copies (about 40 alleles total): 1 canonical gene plus ~19 retrogenes (processed copies derived from mRNA). Many of these retrogenes are transcriptionally active and contribute to protein production.
pubmed.ncbi.nlm.nih.gov
These extra copies evolved coincident with increasing body size in the proboscidean lineage (elephants and extinct relatives like mammoths). They create a hyperactive p53 response to DNA damage: Elephant cells undergo apoptosis (programmed cell death) at much higher rates when damaged — roughly 2x human cells and 5x cells from Li-Fraumeni syndrome patients (who have only 1 functional TP53 copy and very high cancer risk).
healthcare.utah.edu
This “kill the damaged cell” strategy prevents mutated cells from proliferating into tumors, prioritizing elimination over imperfect repair.
pmc.ncbi.nlm.nih.gov
Additional support comes from a “zombie” or resurrected pseudogene called LIF6 (leukemia inhibitory factor 6), reactivated in elephants. p53 upregulates LIF6, which further promotes apoptosis in response to DNA damage.
lifelinesblog.com
Elephants also show broader duplications of other tumor-suppressor genes involved in DNA repair, oxidative stress resistance, and cell growth/death regulation.
aau.edu
Links to miRNA-p53 Interactionsp53 and miRNAs form intricate regulatory networks (as discussed previously). In elephants, the amplified p53 system likely enhances these loops for robust stress responses, including stronger induction of growth-suppressive miRNAs (e.g., miR-34 family) and tighter control over apoptosis/senescence pathways. This could contribute to both cancer resistance and healthier aging by better managing cellular damage accumulation.
pmc.ncbi.nlm.nih.gov
Other Contributing Factors to Longevity Large body size advantages: Lower mass-specific metabolic rate reduces oxidative stress per cell; lower predation risk as adults allows investment in somatic maintenance.
Social and behavioral adaptations: Matriarchal groups with experienced older females improve survival through knowledge of resources, danger avoidance, and allomothering. Long post-reproductive lifespan (grandmother effect) boosts kin fitness.
elephantvoices.org
Physiological traits: Slow cellular turnover, efficient wound healing, and possibly enhanced immune surveillance or other anti-aging mechanisms (e.g., resistance to certain age-related diseases beyond cancer).
Environment: Wild elephants with ample space, movement (up to 30+ miles/day), and social stability live far longer than those in captivity (median ~17 years in some zoo studies vs. 56+ in the wild).
awf.org
Relevance to Human Health and Aging Research Elephant biology inspires research into enhancing p53 activity, apoptosis thresholds, or miRNA regulation for cancer prevention and longevity in humans. However, directly translating extra gene copies is complex due to risks like excessive cell death or autoimmune issues. Studies on elephant p53 isoforms, retrogenes, and their evasion of negative regulators (e.g., MDM2) continue to yield insights.
pmc.ncbi.nlm.nih.gov
In short, elephants’ longevity stems from evolutionary trade-offs favoring robust DNA damage responses (especially via amplified p53), combined with life-history and social traits that minimize extrinsic mortality. Their low cancer incidence despite size and lifespan makes them a fascinating model for understanding healthy aging. Ongoing genomic and comparative studies are uncovering more details.
Kohl
Grok wrote: “For deeper details on specific miRNAs or contexts (e.g., elephants with multiple p53 copies), more targeted studies are available in reviews on PubMed.
Never forget PGx and NGS testing available for free to US veterans eliminates moronic theories and reinforces the beliefs manifested by veterans who fought “For God and Country.”
Kohl
@Grok wrote: “…elephants’ longevity…makes them a fascinating model for understanding healthy aging. Ongoing genomic and comparative studies are uncovering more details.”
Details linked to energy-dependent changes in molecular distance across kingdoms via my group’s 12/1/96 publication “From Fertilization to Adult Sexual Behavior” link refutation of moronic theories to “Insect pheromone in elephants” 2/22/96, “Vibrations in microtubules” 9/1/97 and 196,702 results from today’s search of the PubMed database for indexed articles that mention the term “miRNAs.”
Happy Mother’s Day!