Preascitic Sodium Retention in Cirrhosis: A Role for Disregulated Proteolysis by Proprotein Convertases?
Bibliographic record
Abstract
ABSTRACT Loss of effective arterial blood volume, secondary hyperaldosteronism, adrenergic activation and nonosmotic hypersecretion of vasopressin induce sodium and water retention in cirrhotic patients with ascites. The mechanisms of sodium retention that precede ascites formation remain elusive. In patients who are at the preascites stage of cirrhosis, no sign of reduced effective volaemia is found; nonetheless, tubular sodium retention is already present. Maturation and full functionality of epithelial sodium channels (ENaC) in distal segments of the nephron and, therefore, final control of sodium excretion are dependent on regulated proteolysis by proprotein convertases. Evidence of abnormal or incomplete maturation of ENaCs in preascitic cirrhosis exists, but the complex mechanisms of regulated proteolysis leading to ENaC maturation through sequential action of serine endopeptidases (i.e., furin, site‐1 protease, prostasin, plasmin) have never been studied in liver cirrhosis. Also, the mechanisms of cirrhosis‐associated immune dysfunction, which are characterised by systemic sterile inflammation and release of proinflammatory cytokines that profoundly influence renal function, remain largely unknown. Release of proinflammatory cytokines and functions of respective receptors are controlled through regulated proteolysis by cell membrane metallopeptidases (mainly ADAM‐10 and ‐17). Once again, little is known in preascitic cirrhosis about potential disregulated proteolysis of proinflammatory cytokines that may trigger systemic inflammation and renal dysfunction. We advance a new hypothesis that (a) may link proprotein convertases to disregulated proteolysis of tubular sodium channels, renin‐angiotensin system receptors and inflammatory mediators, and that (b) may shed light on the mechanisms of sodium retention before any systemic neurohormonal activation in liver cirrhosis.
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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 | 0.001 |
| 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 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".