Impaired stretch modulation in potentially lethal cardiac sodium channel mutants
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Bibliographic record
Abstract
The presence of two slowly inactivating mutants of the cardiac sodium channel (hNa(V)1.5), R1623Q and R1626P, associate with sporadic Long-QT3 (LQT3) syndrome, and may contribute to ventricular tachyarrhythmias and/or lethal ventricular disturbances. Cardiac mechanoelectric feedback is considered a factor in such sporadic arrhythmias. Since stretch and shear forces modulate hNa(V)1.5 gating, detailed electrophysiological study of LQT-Na(V)1.5 mutant channel alpha subunit(s) might provide insights. We compared recombinant R1623Q and WT currents in control vs. stretched membrane of cell-attached patches of Xenopus oocytes. Macroscopic current was monitored before, during, and after stretch induced by pipette suction. In either mutant Na(+) channel, peak current at small depolarizations could be more than doubled by stretch. As in WT, R1623Q showed reversible and stretch intensity dependent acceleration of current onset and decay at all voltages, with kinetic coupling between these two processes retained during stretch. These two Na(V)1.5 channel alpha subunits differed in the absolute extent of kinetic acceleration for a given stretch intensity; over a range of intensities, R1623Q inactivation speed increased significantly less than did WT. The LQT3 mutant R1626P also retained its kinetic coupling during stretch. Whereas WT stretch-difference currents (I(Na)(V,t) without stretch minus I(Na)(V,t) with stretch) were mostly inhibitory (equivalent to outward current), they were substantially (R1623Q) or entirely (R1626P) excitatory for the LQT3 mutants. If stretch-modulated Na(V)1.5 current (i.e., brief excitation followed by accelerated current decay) routinely contributes to cardiac mechanoelectric feedback, then during hemodynamic load variations, the abnormal stretch-modulated components of R1623Q and R1626P current could be pro-arrhythmic.
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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 | 0.000 | 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 | 0.001 |
| 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 it