Abstract 17994: Rad Gtpase Depletion is a Novel Positive Inotrope Without Pathological Signaling
Bibliographic record
Abstract
Rationale: The small GTPase Rad is a negative regulator of voltage-dependent L-type calcium channel (LTCC) current (ICaL); however, the effects of Rad ablation on cardiomyocyte function and calcium homeostasis are unknown. Increased ICa,L may have dual effects , inducing transcriptional regulation in addition to positive inotropism. Alternatively, Rad as a member of the LTCC complex may restrict effects to contractile function only. Objective: This study tests the hypothesis that Rad-depletion causes positive inotropic effects without inducing pathological transcriptional signaling. Methods and Results: Ventricular myocytes from adult Rad-/- mice were isolated and evaluated for ICa,L and action potentials by patch clamp recordings, as well as calcium transients, and sarcomere shortening. Maximum ICaL is elevated in Rad-/-, decay kinetics are faster, and ICa,L activated at lower voltages thus mimicking effects of beta-adrenergic receptor (β-AR) stimulation. Diastolic and systolic calcium are elevated in Rad-/-, and sarcomere shortening is enhanced, particularly at lower pacing frequencies. Consequentially frequency-dependence of calcium transients is reduced in Rad-/-, and the frequency dependence of relaxation is also significantly blunted. In isolated ex vivo working hearts similar results were obtained, chiefly, contractility (+dP/dt) was elevated at baseline and was less responsive to acute β-AR stimulation. In single cells, at lower infra-physiological frequencies, non-stimulated CaMKII-sensitive calcium release is observed. Remarkably, Rad-/- hearts did not show pathological hypertrophic growth despite elevated levels of diastolic calcium. Conclusions: This study demonstrates that the depletion of Rad GTPase parallels β-AR agonism, remarkably without stimulating pathological cardiac hypertrophy. Thus, Rad GTPase is a novel potential therapeutic target for calcium homeostasis-driven positive inotropic support of 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) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 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".