Screen for Chemical Modulators of the Laminin‐induced Clustering of Dystroglycan Reveals Novel Inhibitors of Aquaporin‐4 Polarized Distribution in Astrocytes
Bibliographic record
Abstract
Aquaporin‐4 (AQP4) is the principal water channel in the brain and is mainly concentrated at perivascular astrocyte endfeet. This distribution of AQP4 is of major importance because it renders the channel capable of regulating water fluxes between the brain and the bloodstream and therefore plays a role in the water homeostasis. Evidence points to a role of the dystrophin‐associated protein (DAP) complex in the localization of AQP4 at astrocyte endfeet, via dystroglycan (DG) interaction with perivascular laminin. Interestingly, lack of AQP4 concentration at these endfeet in the dystrophin null mouse has been associated with a delayed onset of brain edema. It is therefore of particular importance to identify molecules that modulate the perivascular localization of AQP4. Here, we carried out a high‐throughput screen, using a chemical library of 3,594 small molecules, to identify modulators of the laminin‐induced co‐clustering of the DAP complex and AQP4 in primary astrocyte cultures. Of the 6 inhibitory molecules identified, one induced the reduction of the clustering by promoting the metalloproteinase‐mediated shedding of DG. These findings demonstrate the robustness of our in vitro model that provides a powerful tool for high‐throughput screening and allows us to identify and validate new compounds capable of disrupting the laminin‐induced co‐clustering of the DAP complex with AQP4. Grant Funding Source : Canadian Institutes of Health Research (CIHR), Muscular Dystrophy Canada (MDC)
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| 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) | 0.003 | 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".