Conformational disruption of PI3Kδ regulation by immunodeficiency mutations in <i>PIK3CD</i> and <i>PIK3R1</i>
Bibliographic record
Abstract
Significance Activated PI3K Delta Syndrome (APDS) is a primary immunodeficiency disease caused by activating mutations in phosphoinositide 3-kinases (PI3Kδ). Activating mutations in either the p110δ catalytic or the p85α regulatory subunit of PI3Kδ result in APDS. Mutations in p85α leading to APDS are surprising, as other p85α-activating mutations are oncogenic when bound to the PI3Kα isoform. Using hydrogen–deuterium exchange mass spectrometry, we determined the molecular mechanisms by which APDS mutations in p110δ or p85α activate PI3Kδ and reveal why the p85α APDS2 mutant primarily activates PI3Kδ. All APDS mutants are potently inhibited by the PI3Kδ-specific inhibitor idelalisib. Together, the biophysical and biochemical data reveal insights into PI3Kδ regulation and provide a possible therapeutic strategy for treating patients with APDS.
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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".