A gradient of force generation at rest differentiates cardiomyopathy outcomes with variants of actin located at the same residue
Bibliographic record
Abstract
The calcium sensitivity hypothesis helps explain the development of different forms of cardiomyopathy: increased sensitivity to calcium in cardiac sarcomeres leads to hypertrophic cardiomyopathy (HCM) and decreased sensitivity results in dilated cardiomyopathy (DCM). This hypothesis has driven the development of next generation drugs targeting sarcomere proteins to correct the amount of force generated as a result of changes in calcium sensitivity (e.g. mavacamten decreases cardiac myosin activity to treat HCM). Characterization of variants of cardiac actin (ACTC) found in patients with HCM or DCM has generally supported the calcium sensitivity hypothesis. Of interest are two different substitution mutations at R312 on ACTC: R312H leads to DCM, while R312C was found in patients with HCM. To determine how changes in the same codon on the same gene lead to different disease phenotypes, we characterized recombinant R312H- and R312C-ACTC variant proteins. Both variants exhibited the same change in calcium sensitivity, suggesting that a factor other than calcium sensitivity is responsible for disease differentiation. We observed a gradient of increased residual myosin activity with R312-ACTC variant proteins under relaxing conditions which may trigger different disease development. Our findings suggest that factors other than calcium sensitivity may contribute to cardiomyopathy development and should be considered when planning treatments.
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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 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 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) | 0.000 | 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".