SUN1 Accumulation mediates nuclear alteration, a novel hallmark driving Pulmonary hypertension.
Bibliographic record
Abstract
Rationale: Pulmonary hypertension (PH) is a deadly disease with multifactorial pathology. Due to limited treatment options, unravelling novel drug able signaling axis to be modulated as a therapeutic strategy is of utmost interest. The nuclear compartment is a key organelle driving numerous biological processes. It is therefore important that the nuclear structural integrity is maintained to ensure its optimal functioning. The nuclear structural integrity could be compromised or altered as a result of cellular stress, or mechanosensing. This has been a concept in various pathological conditions but not yet elucidated in the context of PH. Thus, the aim of this study is to decipher nuclear alterations associated with PH and the molecular signature involved. Methods: We employed confocal microscopy, western blotting, qPCR, Pharmacology and siRNA technologies to unravel nuclear alteration and dysregulation of nucleoproteins in PAH patients. We replicated thesame using Hypoxia induction and actin polymerization with Jasplakinolide. In addition, we used RNA-seq to unravel the signaling pathways involved. To investigate the translational potential of our findings, in vivo (Sugen-hypoxia and Monocrotaline-induced rat models) and Ex-vivo (human PCLS) were used. Results: Results: Our results show that SUN1 accumulation is associated with PAH with same seen upon PASMC-Hypoxia induction, Jasplakinolide treatment and rat models of PH. siSUN1 cells subjected to RNA-seq show dysregulation of Hippo signaling pathway and reversal of PH-like signatures. Interestingly, pharmacological inhibition of Hippo pathway attenuated hemodynamic alterations in both models and ablated SUN1-Hippo axis in vitro, Ex-vivo and In vivo.
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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 | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.006 | 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".