Bibliographic record
Abstract
In response to diverse stress stimuli, eukaryotic cells activate a common adaptive pathway, termed the integrated stress response (ISR). The core event in this pathway is a decrease of the eukaryotic translation initiation factor 2 (eIF2), which plays a crucial role for the initiation of translation. Decrease of eIF2 in the context of the ISR leads to a decrease in global protein synthesis and the induction of specific genes. Paradoxically, although the ISR primarily promotes cellular recovery, exposure to severe stress such as fever or head trauma can drive signaling toward cell death. Skopkova et al. (Hum Mutat 38: 409–425, 2017) report in this issue that disruption of EIF2S3, which codes for the subunit γ of eIF2, causes MEHMO syndrome. This disorder is characterized by severe intellectual disability, epilepsy, hypogonadism, microcephaly and obesity. The authors identified X-linked recessive variants in EIF2S3 in four families with MEHMO syndrome, three of which carry the same mutation, possibly because they share a common ancestor. Elegant studies performed in yeast showed that this variant decreases EIF2S3 function. Interestingly, studies in fibroblasts from one of the patients further suggest that the mutation in EIF2S3 is associated with an activation of ISR. MEHMO syndrome represents a new addition to a growing group of disorders that are associated with the function or availability of eIF2, causing dysregulation of translation. These disorders are characterized by a general impairment of protein synthesis and increased sensitivity in states of elevated metabolic requirements, resulting in apoptosis and the occurrence of episodes of rapid clinical deterioration following major stresses (as documented in some patients with MEHMO syndrome). The work of Skopkova et al. thus offers an important new perspective on this emerging chapter of medicine.
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How this classification was reachedexpand
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 itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, 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".