ROLE OF THE CYSTIC FIBROSIS TRANSMEMBRANE REGULATOR (CFTR) CHLORIDE CHANNEL IN MACROPHAGE LYSOSOME ACIDIFICATION
Bibliographic record
Abstract
Background: Lysosome acidification is the result of proton pumping by thevacuolar-type ATPase (V-ATPase). Because the V-ATPase is electrogenic, a substantial lysosomal membrane potential can develop if left uncompensated by counterions. An increasing membrane potential will oppose further proton pumping, limiting the acidification. It has generally been assumed that a parallel anion influx accompanies proton pumping to enable acidification. Indeed, defective anion channel function in cystic fibrosis (CF) has been suggested as the mechanism underlying attenuated lysosomal acidification and impaired microbial killing in the lung (Di A, et al., 2006, Nature Cell Biol. 8, 933-944). Chronic lung inflammation and infection represent the major source of morbidity and mortality in CF, and understanding the mechanism underlying the disease will therefore have far-reaching therapeutic implications. As such, it is important to accurately evaluate the reported role of CFTR in lysosome acidification. Methods: To assess the individual contribution of counterions to acidification, we carried out cytosolic and lysosomal ion substitution experiments in intact cells while monitoring lysosomal pH by ratiometric imaging. Results: Replacement of cytosolic Cl^- with impermeant anions did not alter the rate or extent of proton pumping. In contrast, permeant luminalcations were required for normal acidification. Because cations are the main counterion for lysosomal proton uptake, defects in the lysosomal pH are not anticipated in CF cells. Accordingly, the lysosomes of CFTR-deficient alveolar macrophages were found to acidify normally. Conclusion: We conclude that cations are the primary counterions responsible for lysosomal acidification and that defects in lysosomal anion conductance cannot explain the impaired microbicidal capacity of CF phagocytes.
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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 | 0.001 | 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 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 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".