Molecular determinants and therapeutic potential of focal ectopic activity: more than meets the Iti
Bibliographic record
Abstract
Putative molecular mechanisms of focal ectopic (triggered) activity. Inherited [e.g. catecholaminergic polymorphic ventricular tachycardia (CPVT)], acquired [atrial fibrillation (AF) or heart failure (HF)], or drug-induced cardiovascular diseases promote sarcoplasmic reticulum (SR) calcium leak, mainly via dysregulation of the ryanodine receptor type-2 (RyR2) channel or SR calcium-ATPase type-2a (SERCA2a). This SR calcium leak can give rise to calcium overload and calcium waves. Subsequent calcium-dependent activation of the sodium/calcium-exchange current (INCX) and calcium-activated chloride current [ICl(Ca)] produces a transient inward current that determines the amplitude of the delayed afterdepolarization (DAD). In parallel, direct or indirect calcium-dependent modulation of several ion channels can depolarize [INCX, late sodium current (INa, L), or transient receptor potential subfamily-M member-4 current (ITRPM4)] or hyperpolarize [basal inward-rectifier potassium current (IK1) or small-conductance calcium-activated potassium current (ISK)] the resting membrane potential (RMP). Simultaneously, calcium-dependent regulation of the peak sodium current (INa) determines cellular excitability. The balance between these processes determines whether the DADs remain subthreshold or whether the threshold for action potential (AP) generation is reached, eliciting a triggered AP that promotes ectopic firing. Meclofenamate is a TRPM4 inhibitor that reduces the depolarizing background current and decreases the likelihood of focal ectopic activity. For simplicity, only directly calcium-dependent or calcium/calmodulin-dependent protein kinase II (CaMKII)-modulated conductances are shown
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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 | 0.001 | 0.001 |
| 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 | 0.001 |
| Scholarly communication | 0.001 | 0.002 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
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".