GSK3 inhibition ameliorates the abnormal contractility of Newfoundland ACM patient iPSC-cardiomyocytes
Bibliographic record
Abstract
Arrhythmogenic Cardiomyopathy (ACM) is clinically characterized by ventricular arrhythmias causing sudden cardiac death and fibrofatty replacement of the myocardium leading to heart failure. One form of ACM is highly prevalent in the Canadian Province of Newfoundland and Labrador (NL) and has earned the moniker, The Newfoundland Curse. This ACM in NL patients is often caused by a fully penetrant heterozygous missense pathogenic variant in the TMEM43 gene (TMEM43 c.1073C>T; TMEM43 p.S358L). Although the causative variant has been identified, little is known about the function of the TMEM43 protein in cardiomyocytes, how the TMEM43 p.S358L mutation contributes to the development of arrhythmias, or why the disease is more severe in males than females. To explore the role of TMEM43 in cardiomyocyte function, we generated induced pluripotent stem cells (iPSCs) from 2 severely affected male Newfoundland ACM (TMEM43 p.S358L) patients. CRISPR-Cas9 was used to genetically repair the heterozygous TMEM43 variant in ACM patient iPSCs or for TMEM43 gene knockout. ACM patient iPSC-cardiomyocytes with the TMEM43 p.S358L variant display pro-arrhythmogenic phenotypes in vitro with significantly elevated contraction rates and altered calcium handling, although no obvious gross abnormalities were observed across several major intracellular organelles. GSK3 inhibition significantly increased protein expression of b-catenin as well as Lamin A/C and ameliorated the pro-arrhythmic tendencies of ACM patient iPSC-CMs.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".