Impact of injury mediators on CNS glia
Bibliographic record
Abstract
Multiple Sclerosis (MS) is an inflammatory disorder of the central nervous system (CNS). It is characterized by the infiltration of immune cells into the brain, leading to myelin destruction and the demise of oligodendrocytes (OLs), the myelinating cells of the CNS. The mechanisms of tissue destruction are still being elucidated. We have looked at the effects of two putative injury mediators on resident CNS glia. Firstly, we investigated the functional consequences of signaling via death receptors Fas, DR4 and DR5 and their ligands Fas ligand (FasL) and tumor necrosis factor related apoptosis inducing factor (TRAIL) in astrocytes isolated from fetal CNS and in OLs from human adult brain. We find astrocytes express these receptors but are resistant to apoptosis upon their ligation due to the expression of FLICE inhibitory protein (FLIP). Receptor expression is however not silent as distinct signaling pathways are activated as a result of receptor ligation. In OLs, we find receptor expression can be induced upon upregulation of the stress induced protein p53, at which point OLs become susceptible to FasL and TRAIL killing. In situ in MS lesions displaying oligodendrogliopathy, we demonstrate that a high proportion of OLs are immunopositive for p53, suggesting p53 may play a role in OL demise. Secondly, we investigated the effects of the excitatory amino acid glutamate, acting through ionotropic glutamate receptors, on human adult OLs. Based on animal models, excitotoxicity has been proposed to play a role in OL destruction in MS. We find human OLs are in fact resistant to excitotoxicity mediated by AMPA or kainate receptors and this is in sharp contrast to their rodent counterparts. We propose this resistance is due to the lack of expression of glutamate receptors on human OLs both in vitro and in situ. These results indicate that glutamate is not directly responsible for the killing of otherwise healthy OLs in MS. These studies demonstrate
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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 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.002 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.002 | 0.001 |
| Insufficient payload (model declined to judge) | 0.158 | 0.051 |
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".