Bibliographic record
Abstract
Background: Abdominal aortic aneurysm (AAA) is an age-related disease characterized by progressive degradation of elastic lamellae, defective collagen architecture and medial smooth muscle cell loss. We previously demonstrated that knocking out the serine protease granzyme B (GZMB) reduces incidence and severity of AAA in mice; however, while GZMB is known for its role in apoptosis, it also accumulates extracellularly during inflammation and can cleave extracellular matrix (ECM) components such as decorin and fibrillin-1. We hypothesized that GZMB contributes to AAA development through the degradation of vascular ECM and that the inhibition of extracellular GZMB would reduce the incidence and severity of AAA progression.Methods: Human aneurysmal samples were obtained and apolipoprotein E(apoE)-knockout (KO), GZMB/apoE-double knockout (GDKO) and perforin/apoE-DKO (PDKO) mice were implanted with osmotic minipumps releasing angiotensin II for 28 days to induce AAA formation. Additional apoE-KO mice were injected with the GZMB inhibitor, serpin A3N (SA3N, 4-120 μg/kg) or anti-GZMB neutralizing antibody (1 mg/kg) prior to pump implantation. Tissues were assessed for aneurysm pathology, inflammation and ECM composition. Collagen content was analysed by second harmonic generation and transmission electron microscopy.Results: Human aneurysmal tissues showed elevated levels of GZMB immunopositivity compared to controls. A significant reduction in AAA incidence and severity was observed in GDKO mice compared to apoE-KO, whereas perforin deficiency was not protective against AAA. A dose-dependent reduction in the frequency of aortic rupture was observed in mice that received SA3N or anti-GZMB antibody treatment. Pre-incubation with SA3N prevented decorin cleavage by GZMB in vitro. Reduced GZMB and a corresponding reduction in loss of adventitial decorin were observed in SA3N and anti-GZMB-treated mice while collagen density was increased. Adventitial collagen from SA3N-treated mice exhibited significantly higher fibre density and reduced fibril size irregularity.Conclusions: GZMB promotes destruction of the elastic lamellae via degradation of fibrillin-1 and destabilization of elastic microfibrils while GZMB-mediated degradation of decorin contributes to loss of adventitial collagen organization and density. The extracellular inhibition of GZMB prevented decorin loss and enabled a beneficial remodelling of adventitial collagen in response to medial injury, leading to higher vessel tensile strength and increased resistance to aortic rupture.
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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) | 0.001 | 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 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".