Mitochondrial dysfunction promotes the transition of precursor to terminally exhausted T cells through HIF-1α-mediated glycolytic reprogramming.

T cell exhaustion is a hallmark of cancer and persistent infections, marked by inhibitory receptor upregulation, diminished cytokine secretion, and impaired cytolytic activity. Terminally exhausted T cells are steadily replenished by a precursor population (Tpex), but the metabolic principles governing Tpex maintenance and the regulatory circuits that control their exhaustion remain incompletely understood. Using a combination of gene-deficient mice, single-cell transcriptomics, and metabolomic analyses, we show that mitochondrial insufficiency is a cell-intrinsic trigger that initiates the functional exhaustion of T cells. At the molecular level, we find that mitochondrial dysfunction causes redox stress, which inhibits the proteasomal degradation of hypoxia-inducible factor 1α (HIF-1α) and promotes the transcriptional and metabolic reprogramming of Tpex cells into terminally exhausted T cells. Our findings also bear clinical significance, as metabolic engineering of chimeric antigen receptor (CAR) T cells is a promising strategy to enhance the stemness and functionality of Tpex cells for cancer immunotherapy.

Prophylactic Treatment of Undernourished Mice with Cotrimoxazole Induces a Different Profile of Dysbiosis with Functional Metabolic Alterations.

Childhood malnutrition affects physiology and development. It increases infection rates, which may not present clinical signs in severe cases. The World Health Organization recommends prophylactic treatment with cotrimoxazole (SXT) and nutritional recovery to overcome this issue. This treatment is controversial, since evidence of a reduction in morbidity and mortality is not a consensus and could induce the development of antibiotic-resistant bacteria. Moreover, the impact of using this wide-spectrum antibiotic on gut microbiota in a critical period of development, and weakness is unknown. To understand how SXT prophylaxis could affect gut microbiota in undernutrition, we induced protein-energy undernutrition (PEU) in weaning C57BL/6 mice for three weeks and treated animals with SXT for two weeks. Using 16S rRNA gene sequencing, we compared the taxonomic composition and metabolic pathways of control mice, animals submitted to undernutrition (UND), treated with SXT, or undernourished and SXT treated (UND + SXT). We identified that UND mice had a significant increase in predicted pathways related to metabolic syndromes later in life. The prophylactic SXT treatment alone resulted in a significant loss in community richness and beta diversity. Furthermore, we identified the reduction of three genera in SXT treated mice, including the butyrate producers Faecalibacterium and Anaerotruncus. Both UND and double challenge (UND + SXT) resulted in a reduction of the amino acid's biosynthesis pathway related to cell growth. Our results show that the SXT prophylaxis of young mice during an undernourishment period did not re-establish the undernourished microbiota community composition similar to healthy controls but induced a distinct dysbiotic profile with functional metabolic consequences.

Observações Estruturais de Hambúrguer Adicionado de Fibra de Trigo com Diferentes Granulometrias / Structural Observations of Beef Burger containing Wheat Fiber of Different Sizes

The objective of the present study was to develop different formulations of functional beefburgers with addition of wheat fiber of different granule sizes, and to evaluate the effect of fibers on the structural and physical properties of the product. The fibers used were Fiber 200 (250 μm in length and 25 μm in thickness) and Fiber 600/30 (35 μm in length and 20 μm in thickness), and the addition followed a 2² central composite design. The fiber addition altered the physical and structural properties of the burgers. Significant differences were observed (p < 0.05) in the physical properties of the burgers due to both the variations in particle size of the wheat fiber, and the different concentrations. Comparing the observations found through microscopy with the results of shear force and cooking losses, it was concluded that there was a relationship between some properties and their respective microscopic structures. The best results were found for the treatment F2, indicating that the Fiber 200 (larger particles) allowed the maintenance of a texture close to the standard, F1 (without fiber addition), and lower cooking loss when compared to the product containing fiber of lower particle size (Fiber 600/30). The fiber mixtures in the proportions studied were not a viable alternative due to the increase in the hardness of the product.

Objetivou-se com o presente trabalho desenvolver diferentes formulações de hambúrguer funcional de carne bovina, com a adição de fibra de trigo com diferentes granulometrias e avaliar o efeito das fibras nas propriedades físicas e estruturais do produto. As fibras testadas foram denominadas de Fibra 200 (250 μm de comprimento e 25 μm de espessura) e Fibra 600/30 (35 μm de comprimento e 20 μm de espessura) e a adição seguiu um Delineamento Composto Central 2². A adição das fibras alterou as propriedades físicas e estruturais dos hambúrgueres desenvolvidos. Foram observadas diferenças significativas (p <0,05) nas propriedades físicas dos hambúrgueres, decorrentes da variação da granulometria da fibra de trigo e das concentrações testadas. Comparando as observações encontradas na microscopia com os resultados das avaliações de força de cisalhamento e perdas por cocção, conclui-se que existe relação entre algumas propriedades com as respectivas estruturas microscópicas. Os melhores resultados foram encontrados para F2, indicando que a Fibra 200 (maior granulometria) permitiu a manutenção da textura próxima do padrão F1 (sem fibra) e menores perdas por cocção, quando comparado com o produto adicionado da fibra de menor granulometria (Fibra 600/30). A mistura das fibras nas proporções testadas não se mostrou uma alternativa viável devido o aumento na dureza do produto.