Abstract 1880: Molecular Basis of Inward-Rectifier Potassium Current Upregulation in Human Atrial Fibrillation: Contrasting Mechanisms for I <sub>K1</sub> versus Constitutive I <sub>KACh</sub>
Bibliographic record
Abstract
Introduction: Upregulation of Kir-based inward rectifiers I K1 and constitutively active acetylcholine-regulated current (I KACh,c ) is a prominent contributor to atrial fibrillation (AF) maintenance. This study assessed occurrence and molecular basis of altered I K1 and I KACh,c in man. Methods: Left atrial samples from mitral valve repair patients (n = 21 AF; n = 20 SR) were studied. Patch-clamp was applied to record currents. Immunoblots and confocal microscopy were used to study protein content and localization. Quantitative real-time PCR was performed to study microRNA and mRNA levels. Results: I K1 and I KACh,c densities were greater in cells from AF than SR patients (at −120 mV: 3.5 ± 2.6 vs. 2.1 ± 1.1 pA/pF for I K1 and 1.3 ± 0.8 vs. 0.4 ± 0.3 pA/pF for I KACh,c ). Kir2.1 protein (underlying I K1 ) was increased by AF (Fig. ) but Kir2.3 was unchanged. Kir2.1 mRNA was increased and Kir2.3 mRNA reduced. Kir3.1 and Kir3.4 (underlying I KACh,c ) protein was unaffected. The inhibitory regulatory G-protein G αi-3 was downregulated, potentially explaining increased free G αγ and I KACh,c . No change in other regulatory proteins (RGS4, calmodulin) or subcellular channel and regulatory proteins localization occurred with AF. Kir2.1 protein expression is known to be downregulated by the microRNA miR-1: miR-1 expression was reduced by AF (Fig. ). Conclusions: Both inward rectifier currents I K1 and I KACh,c are increased in human AF. I K1 changes are caused by increased protein expression through transcriptional and post-transcriptional modifications related to miR-1 downregulation, whereas the increase in I KACh,c is functional, possibly mediated by decreased inhibitory G-protein expression.
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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) | 0.000 | 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 | 0.000 |
| 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".