Modulating α‐actinin‐4 dynamics in podocytes
Bibliographic record
Abstract
Podocytes are epithelial cells that line the outer aspect of renal blood vessels and provide a platform for the kidney's filtering apparatus, the slit diaphragm. Mutations in alpha-actinin-4, an actin bundling protein highly expressed in podocytes, result in increased affinity for actin and cause a familial form of focal segmental glomerulosclerosis. We hypothesized that such gain-of-affinity mutations would override alpha-actinin-4's sensitivity to regulatory factors such as calcium (acting via two EF-hand motifs), and phosphoinositides. We generated calcium- (mutEF) and phosphoinositide- (mutPI) insensitive variants of alpha-actinin-4, comparing their properties to a disease-associated mutant (K256E) and to the wildtype (wt) protein. alpha-Actinin-4(mutPI) displayed increased affinity for actin, while the affinity of alpha-actinin-4(mutEF) was unchanged. Addition of calcium to actin sedimentation assays caused a decrease in the association of alpha-actinin-4(wt) with filamentous actin, while phosphoinositides generally increased this association. Similar to alpha-actinin-4(K256E), alpha-actinin-4(mutPI) was mislocalized in cultured podocytes, being preferentially associated with filamentous actin and focal adhesions. Fluorescence recovery after photobleaching experiments revealed a rapid turnover of alpha-actinin-4(wt) and alpha-actinin-4(mutEF) along stress fibers and focal adhesions, while the turnover of alpha-actinin-4(K256E) and alpha-actinin-4(mutPI) was dramatically reduced at these subcellular locales. Equibiaxial mechanical stimulation of podocytes, a mimic of intraglomerular forces, reduced podocyte surface area by 50%; this decrease was more severe (70%) in the presence of high-affinity mutants of alpha-actinin-4. These data suggest that dynamic regulation of alpha-actinin-4/actin interactions may be necessary for maintaining podocyte structure in response to glomerular hydrostatic forces.
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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".