By sequencing the gut microbiome of infants from nonindustrialized populations and comparing them with counterparts from industrialized nations, a team of researchers from Stanford University has found all infants begin life with similar gut microbiota compositions, but population-specific differences begin to appear soon after birth. While infant microbiome assembly has been intensely studied in infants from industrialized nations, little research has been performed to study this process in nonindustralized populations. To address this shortfall, the scientists deeply sequenced infant stool samples from the Hadza hunter-gatherers of Tanzania and analyzed them in a global meta-analysis. As reported in this week's Science, they find that microbiomes develop along lifestyle-associated trajectories, with more than 20 percent of genomes detected in the Hadza infant gut representing novel species. Notably, industrialized infants, even ones who breastfeed, have microbiomes characterized by a lack of the lactic acid bacteria Bifidobacterium infantis and gene cassettes involved in human milk utilization. "The population-specific differences in infant microbiome composition and function underscore the importance of studying microbiomes from people outside of wealthy, industrialized nations," the study's authors write.
The epigenetic reactivation of developmental transcription factors drives the progression of pulmonary hypertension, according to a new study appearing in Science Translational Medicine this week, pointing to a potential new strategy for treating the condition. Pulmonary arterial hypertension (PAH) occurs when pulmonary hypertension develops in pulmonary arterioles. It is a fatal disease and current treatments are unable to restore vascular structure. In this week's study, a group led by investigators from the Max Planck Institute for Heart and Lung Research integrated RNA sequencing and chromatin immunoprecipitation sequencing data from PAH pulmonary artery fibroblasts to reveal de-repression of transcriptional signatures for lung morphogenesis. By silencing associated transcription factors, as well as a regulator of developmental transcription factor expression, the researchers were able to reverse established PAH in three rodent models in vivo, as well as reduce vascular remodeling in precision-cut tissue slices from human PAH lungs ex vivo. The work suggests that controlling the epigenetic dysregulation of developmental transcription factors may be beneficial in the treatment of PAH.
The single-cell multiomics profiling of chimeric antigen receptor T cell therapy (CAR T) infusion products is published in Science Advances this week, offering insights that may help address relapses in acute lymphoblastic leukemia (ALL) patients who receive such treatments. While CAR T is highly effective in treating ALL, a large number of patients who initially respond to the therapy experience CD19-positive relapse within a year. To better understand whether this outcome is due to the characteristics of CAR T cells in infusion products, a group led by Yale University scientists combined single-cell RNA sequencing and comeasurement of a panel of surface proteins to examine the single-cell activation landscape in 12 pediatric ALL patients. They find substantial heterogeneity in the antigen-specific activation states, among which a deficiency of T helper 2 function was associated with CD19-positive relapse compared with durable responders. Proteomic data revealed that the frequency of early memory T cells, rather than activation or coinhibitory signatures, could distinguish the relapse. The researchers corroborated these findings via independent functional profiling of 49 patients and built an integrative model to predict patient response. "Our data thus illuminate potential strategies to improve the response duration to CAR T therapy by precisely strengthening specific CAR T functionality and restoring early memory phenotype," the study's authors conclude.