Abstract 4144814: A novel small molecule synthesized based on a snail hibernation model induces hibernation in mouse fibroblasts and perfused hearts
Bibliographic record
Abstract
Animals during hibernation suffer no ischemic consequences from their very much decrease heart/respiration rates, otherwise incompatible with life, but humans lost the ability to hibernate (presumably when their ancestors gained independence from the weather) and are highly vulnerable to ischemia. In a snail hibernation model, we isolated a brain metabolite only present in the plasma and brain of hibernating snails, and we characterized it with HPLC/MS. We found it is an activator of PHLPP1, a critical phosphatase in the conserved AMPK/mTOR signaling networks implicated in hibernation and fuel sensing (O 2 , glucose, amino acids). We synthesized it chemically and named it Snail Neurometabolite Activator of PHLPP1 (SNAP). We hypothesized that SNAP may induce hibernation in snails as well as mouse cells and organs that normally do not exhibit hibernation. We utilized in vivo, in vitro and ex vivo models, using Alberta snails, mouse-derived fibroblasts and ischemia and reperfusion (IR) injury model with Langendorff-perfused mouse hearts, to assess the effects of SNAP on snail hibernation, as well as the fuel deprivation-induced stress resistance in mouse-derived cells and hearts. SNAP injections in snails induced reversible hibernation indistinguishable from physiologic. SNAP specifically dephosphorylates the PHLPP1 targets p-S6K and p-AKT (downstream of mTOR and AMPK respectively) in fibroblasts cultured in hypoxic and low-glucose conditions for 3 days, significantly suppressed O 2 consumption, apoptosis, and cell-cycle progression, but enhanced autophagy formation. Upon discontinuation of SNAP and return to normal culture conditions, the SNAP-treated cells had preserved metabolism and re-entered the cell cycle at much higher rates compared to the vehicle, suggesting protection from ischemia and reperfusion (IR) injury and entrance in a reversible hibernation-like state. Furthermore, SNAP conferred cardioprotective effects during IR injury by preserving LV pressure, max and min dp/dt and re-entering normal function much earlier at reperfusion compared to the vehicle. SNAP offers protection from IR injury, inducing a hibernation-like state in mice cells and hearts, with wide implications for heart attack/stroke, preservation of donated organs for transplantation or even ultra-long space travel.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".