Heavy metals and metalloids such as cadmium [Cd(II)] and arsenic [As(III)] are widespread environmental toxicants responsible for multiple adverse health effects in humans. However, the molecular mechanisms underlying metal-induced cytotoxicity and carcinogenesis, as well as the detoxification and tolerance pathways, are incompletely understood. Here, we use global fitness profiling by barcode sequencing to quantitatively survey the Schizosaccharomyces pombe haploid deletome for genes that confer tolerance of cadmium or arsenic. We identified 106 genes required for cadmium resistance and 110 genes required for arsenic resistance, with a highly significant overlap of 36 genes. A subset of these 36 genes account for almost all proteins required for incorporating sulfur into the cysteine-rich glutathione and phytochelatin peptides that chelate cadmium and arsenic. A requirement for Mms19 is explained by its role in directing iron–sulfur cluster assembly into sulfite reductase as opposed to promoting DNA repair, as DNA damage response genes were not enriched among those required for cadmium or arsenic tolerance. Ubiquinone, siroheme, and pyridoxal 5′-phosphate biosynthesis were also identified as critical for Cd/As tolerance. Arsenic-specific pathways included prefoldin-mediated assembly of unfolded proteins and protein targeting to the peroxisome, whereas cadmium-specific pathways included plasma membrane and vacuolar transporters, as well as Spt–Ada–Gcn5-acetyltransferase (SAGA) transcriptional coactivator that controls expression of key genes required for cadmium tolerance. Notable differences are apparent with corresponding screens in the budding yeast Saccharomyces cerevisiae, underscoring the utility of analyzing toxic metal defense mechanisms in both organisms.

Pancreatic β cells are central to glycemic regulation through insulin production. Studies show autophagy as an essential process in β cell function and fate. Autophagy is a catabolic cellular process that regulates cell homeostasis by recycling surplus or damaged cell components. Impaired autophagy results in β cell loss of function and apoptosis and, as a result, diabetes initiation and progress. It has been shown that in response to endoplasmic reticulum stress, inflammation, and high metabolic demands, autophagy affects β cell function, insulin synthesis, and secretion. This review highlights recent evidence regarding how autophagy can affect β cells’ fate in the pathogenesis of diabetes. Furthermore, we discuss the role of important intrinsic and extrinsic autophagy modulators, which can lead to β cell failure.

Systemic steroid exposure, while useful for the treatment of acute flares in inflammatory bowel disease (IBD), is associated with an array of side effects that are particularly significant in children. Technical advancements have enabled locoregional intraarterial steroid delivery directly into specific segments of the gastrointestinal tract, thereby maximizing tissue concentration while limiting systemic exposure. We investigated the feasibility of intraarterial steroid administration into the bowel in a cohort of nine pediatric patients who had IBD. This treatment approach provided symptom relief in all patients, with sustained relief (>2 weeks) in seven out of nine; no serious adverse effects occurred in any patient. In addition, we identified patterns of vascular morphologic changes indicative of a vasculopathy within the mesenteric circulation of inflamed segments of the bowel in pediatric patients with Crohn’s disease, which correlated with disease activity. An analysis of publicly available transcriptomic studies identified vasculitis-associated molecular pathways activated in the endothelial cells of patients with active Crohn’s disease, suggesting a possible shared transcriptional program between vasculitis and IBD. Intraarterial corticosteroid treatment is safe and has the potential to be widely accepted as a locoregional approach for therapy delivery directly into the bowel; however, this approach still warrants further consideration as a short-term “bridge” between therapy transitions for symptomatic IBD patients with refractory disease, as part of a broader steroid-minimizing treatment strategy.