Abstract 4140244: In a Murine Model of Experimental Sepsis, Cardiac-Specific Jarid2 Knockdown is Associated With Improved Myocardial Function and Survival
Bibliographic record
Abstract
Introduction: Sepsis is a life-threatening condition characterized by a dysregulated host response to infection, leading to acute heart failure, decreased contractile function, and biventricular dilation. Emerging evidence suggests that the transcriptional repressor Jarid2 may play a regulatory role in sepsis. Hypothesis: We hypothesize that cardiac-specific knockdown (KD) of Jarid2 could enhance cardiac function and improve survival in response to sepsis. Methods: We generated mice with cardiac-specific Jarid2KD using an alpha myosin heavy chain-specific Cre-LoxP system. Using an in vivo model of cecal ligation and puncture (CLP) with 12-week-old wild-type (WT) and cardiac-specific Jarid2KD mice we investigated whether Jarid2 is a potential novel target for sepsis treatment. Results: In response to 48 hours of CLP, WT mice exhibited over 60% mortality vs. WT-Sham. Survivors developed bacterial peritonitis, an increased inflammatory response (left ventricle (LV): 15-fold increase in IL-6, 3-fold increase in IL-1β and TNF-α, vs. WT-Sham), and apoptosis (LV: 2.5-fold increase in apoptotic Bax/Bcl2 ratio vs. WT-Sham). Jarid2KD showed myocardial dysfunction with a 20-35% decrease in dp/dt, echo-derived ejection fraction (EF), fractional shortening (FS)), a switch from adult α-myosin heavy chain (MHC) to fetal β-MHC, and a 40-50% reduction in LV Jarid2 mRNA and protein compared to WT-Sham. In contrast, Jarid2KD mice despite a similar decrease in LV Jarid2 expression to WT-CLP mice, demonstrated resistance to CLP-induced bacterial peritonitis with cardiac function (dp/dt, EF, FS) similar to the WT-Sham. Histological staining revealed better organization of cardiomyocytes and preservation of functional ultrastructure. Furthermore, Jairid2KD displayed a survival rate of over 90%, a reduced LV inflammatory response (LV: 2-fold increase in IL-6, no change in IL-1β and TNF-α), maintenance of α-MHC, and absence of apoptosis vs. WT-CLP. Metabolic genes such as NDUFA9, Cox4il, ND1, ND4 and PGC1b were downregulated approximately 60-75 per cent in Jarid2KD vs WT-CLP suggesting an improved ability to regulate energy usage. Improved survival was observed even 7 days post-CLP (65% in WT-CLP compared to 100% in Jarid2KD). Conclusion: Cardiac-specific JARID2KD improves survival and reduces sepsis-induced myocardial dysfunction. Thus, Jarid2 may serve as a novel therapeutic target for treating sepsis-induced myocardial dysfunction.
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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 | 0.000 | 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) | 0.000 | 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".