Conformational disruption of PI3Kδ regulation by immunodeficiency mutations in <i>PIK3CD</i> and <i>PIK3R1</i>
Why this work is in the frame
A frame that forgets how it found something cannot be audited. These are the routes that admitted this work.
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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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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 | 0.001 | 0.002 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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 it