Abstract W P218: Interleukin 21 receptor: A Major Modulator of Infarct Volume
Bibliographic record
Abstract
Using the permanent middle cerebral artery occlusion (MCAO) model of stroke, we have demonstrated that different inbred mouse strains show profound differences in infarct volume, indicating that infarction is under strong genetic control. To identify natural genetic determinants modulating infarction, we employed quantitative trait locus (QTL) linkage analysis and a genome-wide association study of cerebral infarct volume. We identified a locus on distal chromosome 7 that contributes over 50% of the variation in infarct volume, as well as other loci of smaller effect. Using interval-specific ancestral haplotype analysis, we fine-mapped the chromosome 7 locus to only 12 candidate genes. To identify the gene(s) underlying this locus, we determined the strain-specific transcript levels of all 12 genes in relevant tissues that included P1 and adult brain cortex, and embryonic macrophages, the latter due to their importance in the development of the cerebrovascular system. One gene, interleukin 21 receptor (Il21r), showed a 7-fold expression difference between strains and harbors a coding SNP difference that segregates with infarct volume. To determine whether Il21r is a major modulator of infarction, we examined Il21r in mice for their cerebrovascular anatomy as well as the cerebral infarct volume after MCAO. While Il21r-/- mice show a moderate reduction in collateral vessel connections compared to wild-type littermate mice cerebral infarct volume in Il21r-/- mice is increased 3-fold. This suggests that Il21r has effects on both cerebrovascular anatomy and innate neuroprotection. To examine the latter, we performed an ex vivo study of brain slices under in vitro oxygen deprivation. In this system devoid of any potential circulatory effects, but retaining appropriate tissue architecture, Il21r-/- brain slices showed an increase in oxygen-deprivation induced cell death, showing that Il21r is also involved in cerebrovascular-independent neuroprotection. Biochemical studies of the brain slices show that Il21R regulates ischemia-induced apoptosis. The identification of Il21R as a cerebrovascular-independent modulator of infarct volume provides a fundamental advance in the understanding of genetic modulation of ischemic stroke.
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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 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 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 | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.005 | 0.002 |
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".