Amyotrophic Lateral Sclerosis Mutant VAPB Causes a Nuclear Envelope Defect
Why this work is in the frame
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Bibliographic record
Abstract
A proline to serine mutation (P56S) in vesicle-associated membrane protein-associated protein B and C (VAPB) causes an autosomal dominant form of amyotrophic lateral sclerosis (ALS). We show that the mutation also causes a nuclear envelope defect. Transport of nucleoporins (Nups) and emerin (EMD) to the nuclear envelope is blocked, resulting in their sequestration in dilated cytoplasmic membranes. Simultaneous overexpression of the FFAT motif (two phenylalanine residues in an acidic track) antagonizes the effect of mutant VAPB and restores transport to the nuclear envelope. VAPB function is required for transport to the nuclear envelope, with knockdown of endogenous VAPB recapitulating this phenotype. Moreover, we identified the compartment into which the Nups and EMD were sequestered as the endoplasmic reticulum (ER)-Golgi intermediate compartment (ERGIC), with nuclear envelope membrane proteins transiting to the ERGIC before VAPB-dependent retrograde transport to the nuclear envelope.
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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 | 0.000 | 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) | 0.000 | 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