Microbiota-derived isovalerate ameliorates sex-specific gut barrier dysfunction in malnutrition.

August 18, 2026| Source: Proceedings of the National Academy of Sciences of the United States of America

Malnutrition increases intestinal permeability and the risk of sepsis, yet mechanisms underlying malnutrition-induced gut barrier dysfunction are poorly defined. Here, we aimed to determine how the gut microbiome and microbiota-derived metabolites influence intestinal barrier function in the malnourished host. We induced malnutrition in specific pathogen-free (SPF) and germ-free (GF) mice using a low-protein, low-fat diet. Colonic permeability was quantified in Ussing chambers and invasive bacteria were cultured from liver and spleen. Targeted metabolomics identified microbial metabolites depleted in malnutrition. Candidate metabolites were screened in human-derived colonoid monolayers and administered to malnourished mice to determine whether gut barrier dysfunction can be rescued. Malnutrition thinned the colonic mucus layer, increased gut barrier permeability, and facilitated bacterial translocation in male, but not female, SPF mice. Malnourished GF mice exhibited normal barrier function. In the malnourished intestine, a subset of microbial short-chain fatty acids, the branched-chain fatty acids (BCFAs), was depleted in SPF mice of both sexes. Treating human-derived colonoid monolayers with BCFAs, especially isovalerate, increased transepithelial electrical resistance and altered the expression of genes associated with epithelial junction complexes. In malnourished male SPF mice, either enemas with isovalerate or gavages with its branched-chain amino acid fermentation substrate, leucine, restored the localization of the integral membrane protein claudin-8 within the colonic crypt and reduced barrier permeability. Together, these findings identify BCFAs, including isovalerate, as microbiota-derived regulators of intestinal junction complexes and barrier integrity. We propose the branched-chain amino acid leucine as a microbiota-directed precision nutrition therapy that could target intestinal barrier dysfunction in malnutrition.

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Extensive glacier loss in the coterminous United States.

Glaciers populate the mountain ranges of the western conterminous United States and despite their importance to alpine hydrology, their area and volume change have never been comprehensively evaluated. Our study shows that since the mid-twentieth century about one-quarter of the glaciers have disappeared and the overall area and volume are reduced by one-third. The pattern of glacier shrinkage suggests most glaciers in the conterminous United States are largely maintained by local topographic in

Physical/TechOctober 20, 2026

Reaction-based cryo-EM resolves the continuous conformational spectrum of CTP synthase catalysis.

Capturing enzymes under native turnover conditions remains a grand challenge in structural biology. Here, we develop a reaction-based cryo-electron microscopy (cryo-EM) strategy that directly samples Drosophila melanogaster cytidine triphosphate synthase (CTPS) from actively catalyzing mixtures containing only natural substrates and allosteric effectors. By integrating reaction-based sampling with three-dimensional variability analysis, we resolve a continuous conformational spectrum of CTPS dur

Physical/TechOctober 20, 2026

GTP orchestrates CTP synthase via an allosteric effector-cycling mechanism.

Cytidine triphosphate (CTP), a fundamental building block of RNA, plays vital roles in diverse biological processes. CTP synthase (CTPS) is the only known enzyme for de novo synthesis of CTP. Efficient CTPS catalysis requires guanosine triphosphate (GTP) in a dose-dependent, nonconsumptive manner; however, the precise mechanism by which GTP drives CTP formation remains unclear. Here, we integrate a series of cryo-EM structures of Drosophila melanogaster CTPS captured from actively catalyzing sam

Physical/TechOctober 20, 2026

Antiferromagnetism and tightly bound Cooper pairs induced by kinetic frustration.

Antiferromagnetism and superconductivity are often viewed as competing orders in correlated electron systems. Here, we demonstrate that kinetic frustration in hole motion facilitates their coexistence within the square-lattice repulsive Hubbard model. Combining exact analytical solutions on tailored geometries with large-scale numerical simulations, we reveal a robust pairing mechanism: Holes on opposite sublattices behave as if they carry opposite effective charges due to spin singlet formation

Physical/TechOctober 20, 2026

Coordinated transformations of the labyrinth and occiput during the dinosaur-bird transition.

Evolutionary shape changes of the vertebrate semicircular canals (SCCs) are often ascribed to evolutionary transitions in locomotion, including the origin of flight during the dinosaur-bird transition. However, the potential for transformations of braincase architecture to influence SCC shape independent of sensory-functional adaptation has generally been overlooked. We evaluate the influence of both factors using a large dataset of 146 living and recently extinct crown birds, including taxa rep