Bibliographic record
Abstract
The intestinal epithelium serves as a vital barrier, selectively absorbing nutrients while restricting commensal and pathogenic microbes from invading deeper tissues and causing aberrant inflammation. This epithelial barrier must continuously withstand the harsh conditions of the intestine, and numerous mechanisms have evolved to ensure its integrity. Of these mechanisms, innate immune signalling is a significant pathway in maintaining homeostasis. Immune signalling is often thought of as the activation of immune cells during sickness; however, the functions of these pathways are far more widespread than this. In its most basic form, innate immunity is simply the ability of a cell to detect signals of damage or danger. These damage or danger signals may be derived from the host, as in the case of dying cells, or from microbial organisms, including both pathogens and commensals. Activation of innate immune signalling is responsible for reinforcing the intestinal barrier by regulating proteins that create the biochemical and physical barriers of the intestine. While there has been much progress in understanding the role innate immune signalling plays in regulating the intestinal epithelium, the regulation of intestinal stem cells (ISCs) is less characterized. ISCs are a crucial component of this barrier, as they divide rapidly to replace shed and dying cells continually. Although we know microbes likely play an essential role in regulating ISC function, the mechanisms underlying this regulation remain poorly characterized. To this end, the work presented in this thesis demonstrates a functional role for innate immune signalling in ISCs. ADP-Heptose (ADP-Hep), a metabolite produced by Gram-negative bacteria as an intermediate of lipopolysaccharide biosynthesis, is detected in the host cytosol by the kinase ALPK1, which engages TIFA-dependent innate immune responses. In the intestinal epithelium, ALPK1 and TIFA were mainly expressed by the ISC pool, where they controlled the replacement of homeostatic ISCs by new revival stem cells (revSCs) following injury. Mechanistically, ADP-Hep triggered pro-inflammatory NF-κB signalling and TNF-dependent ISC apoptosis, which initiated a TGF-β- and YAP-dependent revSC program. Single-cell transcriptomics and lineage-tracing experiments identified Paneth cells as a cell of origin for revSC induction in response to ADP-Hep. In vivo, revSC emergence following irradiation or dextran sodium sulphate-induced injury was blunted in Tifa-/- mice. Together, our work reveals that ALPK1-TIFA signalling contributes to ISC turnover in response to bacterial detection in the intestine.
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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) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
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".