ZEB1-AS1 as a TRPML1 Inhibitor to Cause Lysosome Dysfunction and Cardiac Damage in Aged Mice
Why this work is in the frame
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Bibliographic record
Abstract
The prevalence of cardiovascular diseases (CVDs) has increased markedly as the world population has aged. Long non-coding RNAs (lncRNAs) have been reported as novel regulators in diverse pathophysiological conditions. Here, we performed RNA sequencing (RNA-seq) and observed that the lncRNA Zeb1os1 (zinc finger E-box binding homeobox 1, opposite strand 1), which is known as ZEB1-AS1 (zinc finger E-box binding homeobox 1 antisense 1) in humans, was upregulated in the aged mice hearts, senescent cardiomyocytes, and human blood from elderly individuals. The human blood ZEB1-AS1 level was positively relevant to human age but negatively relevant to peak E to peak A (E/A). Silencing Zeb1os1 ameliorated diastolic dysfunction and cardiac senescence in aged mice. On the other hand, Zeb1os1 overexpression triggered cardiac dysfunction resembling that observed in aged mice. Mechanistically, we provide compelling evidence that Zeb1os1 interacts with the transient receptor potential mucolipin 1 (TRPML1) for ubiquitination (UB)-mediated degradation. This process inhibits lysosomal Ca 2+ efflux, impairing lysosome function. In addition, the functional domain of Zeb1os1, which contains the key nucleotides responsible for the pro-senescence property of full-length Zeb1os1 in cardiomyocytes. Together, these data suggest that Zeb1os1 is a potential target for ameliorating lysosomal dysfunction and aging-related cardiac impairment.
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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 | 0.000 |
| 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 it