230Plakophilin 2 haploinsufficiency linked to arrhythmogenic cardiomyopathy is associated with sodium current abnormalities and glycogen synthase kinase 3 beta activation
Bibliographic record
Abstract
Funding Acknowledgements: This work was supported by Russian Science Foundation grant number 14-15-00745-П. Background: Nav1.5 is the most abundant cardiac voltage-gated sodium channel responsible for initiation of action potential. Nav1.5 is reported to predominantly localize within macromolecular complexes of intercalated disc interacting with large number of proteins. Reduction of sodium current was described as a possible cause of arrhythmias during early stages of arrhythmogenic right ventricular cardiomyopathy (ARVC), the disease affecting intercalated disc structure. Recent studies revealed the putative role of glycogen synthase kinase 3 beta (GSK3B) in the regulation of sodium current and ARVC development. Purpose: The aim of this study was to investigate sodium current abnormalities in patient-specific iPSC-derived cardiomyocytes carrying PKP2 double mutation and test different approaches for restoration the Nav1.5 function. Methods: iPSCs from patient carried two mutations in plakophilin 2 gene (PKP2, NM_004572.3: c.354delT, p.Lys859Arg) were generated and differentiated into cardiomyocytes (iPSC-CMs) using small molecule Wnt modulation protocol followed by metabolic selection. Gene expression was measured using qPCR. Intracellular level of Nav1.5 was evaluated by immunocytochemistry. Sodium currents were recorded using standard patch clamp technique (whole-cell configuration). For expression of PKP2 constructs iPSC-CMs were transduced with corresponding lentiviral particles and selected for blasticidin resistance. GSK3B inhibitors were applied for 24 h before patch clamp measurements.
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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 | 0.007 | 0.002 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.002 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.001 |
| 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 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".