Restoring the trafficking of pathological mutants of the kidney anion exchanger 1
Bibliographic record
Abstract
The kidney anion exchanger 1 (kAE1) regulates physiological pH by facilitating Cl − /HCO 3 − exchange. It is expressed as a dimer on the basolateral membrane of the α‐intercalated cells in the collecting duct, responsible for fine‐tuning of HCO 3 − reabsorption. Mutations in kAE1 can lead to distal renal tubular acidosis (dRTA), characterized by inability to acidify urine pH < 5.5, nephrocalcinosis, hypokalemia, bicarbonaturia and eventually failure to thrive. Often, lack of Cl − /HCO 3 − exchange is due to inappropriate localization of kAE1, not complete abolishment of function. We seek to rescue trafficking mutants of kAE1 using chemicals (DMSO, glycerol), 30°C, and inhibitors/potentiators of chaperones that prevent/aid mutant trafficking. The mutants studied are two recessive mutants, C479→W and G701→D; and a dominant mutant, R589→H. DMSO improved trafficking of G701D kAE1 (GD): Increase in the complex glycosylated form of GD was seen on western blot. Surface detection via immunofluorescence and flow cytometry showed a modest increase in GD at the plasma membrane (PM). A functional assay monitoring the Cl − /HCO 3 − exchange in cells expressing GD showed significant increase in activity upon treatment. Our data demonstrate that some dRTA mutants can be functionally rescued at the PM, raising the hope that dRTA can be treated by correcting the molecular defects in these patients. Alberta Innovates Health Solutions, Canadian Foundation for Innovation, CIHR, The Kidney Foundation of Canada, Women & Children's Health Research Institute
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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) | 0.000 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".