GPx1 deficiency confers increased susceptibility to ferroptosis in macrophages from individuals with active Crohn's disease.

Intestinal cell death is a defining feature of Crohn's disease (CD), a major form of inflammatory bowel disease. The focus on this aspect of enteric inflammation has mainly been on epithelial cells, while other cell types such as stromal and myeloid cells have received less attention. Hypothesising that decreased macrophage viability in an oxidative environment could be a contributing factor to the pathophysiology of CD, we found that monocyte-derived macrophages from individuals with active CD (but not those in clinical disease remission) have increased sensitivity to cell death induced by HO.

Discovery of Potent and Orally Bioavailable Pyrimidine Amide cGAS Inhibitors via Structure-Guided Hybridization.

Using a high-throughput screening (HTS) approach, a new GTP-site binding pyridine-carboxylate series of cGAS inhibitors was discovered. The biochemical potency of this new pyridine carboxylate series was improved 166-fold from the original hit to double-digit nanomolar levels using structure-based design insights, but the series was found to suffer from low permeability and low bioavailability. A structure-based hybridization of the metal-binding motifs of the pyridine carboxylate series and our previously disclosed tetrahydrocarboline GTP-site ligand identified pyrimidine amide compound .

Post-traumatic stress disorder in the Australian Defence Force: estimating prevalence from defence electronic health system records.

Objective: To estimate the prevalence of post-traumatic stress disorder (PTSD) in serving members of the Australian Defence Force (ADF) in the year 2015-2016.

Methods: The electronic health records of serving members of the ADF were screened for the term PTSD over a 12-month period. A 10% sample of these records were examined alongside a randomised matched sample of records.

Integrative scRNA Analysis of Human Colonic Epithelium Indicates Four Tuft Cell Subtypes.

This study integrated and analyzed human single-cell RNA sequencing data from four publicly available datasets to enhance cellular resolution, unveiling a complex landscape of tuft cell heterogeneity within the human colon. Four tuft subtypes (TC1-TC4) emerged as defined by unique gene expression profiles, indicating potentially novel biological function. Tuft cell 1 (TC1) was characterized by an antimicrobial peptide signature; TC2 had an increased transcription machinery gene expression profile consistent with a progenitor-like cell; TC3 expressed genes related to ganglion (neuronal) development; and TC4 expressed genes related to tight junctions.

Evidence for dual roles of histone H3 lysine 4 in antagonizing Polycomb group function and promoting target gene expression.

Tight control over cell identity gene expression is necessary for proper adult form and function. The opposing activities of Polycomb and trithorax complexes determine the on/off state of cell identity genes such as the Hox factors. Polycomb group complexes repress target genes, whereas trithorax group complexes are required for their expression.