Bibliographic record
Abstract
Interest in potential implications of necroptosis (Fig. 1 )—i.e., a recently uncovered programmed cell death pathway—in neurodegenerative diseases has been growing over the recent years 1 , 2 . However, very few studies addressed its role in amyotrophic lateral sclerosis (ALS). Dominguez et al. 3 recently brought some negative findings on this topic: (i) the genetic inactivation of receptor-interacting protein kinase (RIPK)1 did not protect against motor neuron degeneration in the superoxide dismutase (SOD)1 model of ALS and (ii) phosphorylated (p)-RIPK1 did not accumulate in the spinal cords of ALS compared to non-ALS patients. These findings raise doubts about the implication of necroptosis in the pathophysiology of ALS. In contrast, other studies detected robust activation of RIPK1, RIPK3, and mixed lineage kinases domain-like (MLKL) proteins in preclinical as well as clinical studies of ALS 4 , 5 , 6 , 7 . The discrepancies between these studies 4 , 5 and others 3 , 8 might be explained by (i) the use of western blotting in whole-tissue extracts 4 , 5 , 8 versus in situ immunolabelling targeting motor neurons 7 , (ii) the removal of circulating blood cells—a rich source of necroptotic markers 9 —in some studies but not in others, (iii) the various time frame of tissue sampling, which matches or not the transient expression of necroptotic markers 10 , or (iv) technical limitations in the availability and specificity of in vivo tools of detection of necroptotic markers 3 , 4 , 5 , 7 , 8 . Fig. 1: Schematic overview of necroptotic cell death. Necroptosis is triggered by inflammatory mediators, including TNF-α and FasL. Upon the recruitment of adapter proteins, the phosphorylation of RIPK1 is induced. The necrosome is composed of interaction and activation (i.e. phosphorylation) of RIPK1, RIPK3, and MLKL. Necroptosis of the cell is induced by mitochondrial fission through interaction of MLKL with mitochondrial phosphatase PGAM5 and Drp1 recruitment. Phosphorylated MLKL also triggers cell death through the disruption of the plasma membrane integrity 1 , 2 . Other mechanisms by which MLKL induces cell death remains to be elucidated. Pharmacological or genetic modulations ( ⊥ ) of necroptosis signaling can target RIPK1, RIPK3, MLKL, as well as their phosphorylated forms 12 , 13 , 14 . Drp1 dynamin-related protein 1, FADD Fas-associated protein with Death Domain, Fas-L Fas-ligand, MLKL mixed lineage kinases domain-like, p phosphorylated, PGAM5 phosphoglycerate mutase family member 5, RIPK receptor-interacting protein kinases, TNFα tumor necrosis factor α, TNFR1 tumor necrosis factor receptor 1, TRADD tumor necrosis factor receptor type 1-associated death. Full size image
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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 | 0.005 | 0.004 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.004 | 0.001 |
| Bibliometrics | 0.003 | 0.004 |
| Science and technology studies | 0.001 | 0.003 |
| Scholarly communication | 0.006 | 0.011 |
| Open science | 0.002 | 0.003 |
| Research integrity | 0.008 | 0.007 |
| Insufficient payload (model declined to judge) | 0.006 | 0.003 |
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".