Abstract 13350: Cardiac-specific Deletion of GSK-3α and GSK-3β Leads to Fatal Dilated Cardiomyopathy With Mitotic Catastrophe
Bibliographic record
Abstract
In mammals, glycogen synthase kinase-3 (GSK-3) exists as two homologs, GSK-3α and GSK-3β, encoded by independent genes which share similar kinase domains but differ substantially in their N and C termini. Previously we have shown that cardiomyocyte specific deletion of 2 functional GSK-3α or 2 functional GSK-3β alleles has a negligible role in normal homeostasis of myocardial biology. In contrast, herein we describe the creation of mice that are specifically targeted to lack 3 or 4 GSK-3 alleles. Mice lacking any 3 of the alleles live longer than 120 days but develop cardiac hypertrophy and display impaired cardiac function assessed by hemodynamics. Mice lacking all four alleles (double knockout, DKO) develop profound dilated cardiomyopathy and heart failure, leading to death. Pathologically, the hearts of DKOs show giant myocardial nuclei, multi-nucleation, metabolic abnormalities including excess glycogen deposition, degeneration and cell death; and fibrotic remodeling. Microarray and functional pathway analysis demonstrate that these disturbances arise from marked disorders of the cell cycle. Western blot and immunofluorescence confocal microscopy show dysregulated expression of major cell cycle/checkpoint markers, apoptotic proteins and DNA damage markers. These findings indicate that the cardiomyocyte undergoes cell cycle initiation, but this is followed by mitotic catastrophy, DNA damage and apoptosis. This study confirms that GSK-3 is a central regulator of the cell cycle in the heart.
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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) | 0.001 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.006 | 0.002 |
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".