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Epithelial barriers are programmed for defense and repair but are also the site of long-term structural remodeling and disease. In general, this paradigm features epithelial stem cells (ESCs) that are called on to regenerate damaged tissues but can also be reprogrammed for detrimental remodeling. Here we identified a Wfdc21-dependent monocyte-derived dendritic cell (moDC) population that functioned as an early sentinel niche for basal ESC reprogramming in mouse models of epithelial injury after respiratory viral infection. Niche function depended on moDC delivery of ligand GPNMB to the basal ESC receptor CD44 so that properly timed antibody blockade of ligand or receptor provided long-lasting correction of reprogramming and broad disease phenotypes. These same control points worked directly in mouse and human basal ESC organoids. Together, the findings identify a mechanism to explain and modify what is otherwise a stereotyped but sometimes detrimental response to epithelial injury., Introduction Epithelial barriers maintain a fundamental responsibility to respond to injuries from the full range of environmental toxins and infectious agents. This role depends critically on carefully controlled growth and [...]

Globally, the majority of people living with HIV are women or girls, but they have been a minority of participants in clinical trials and observational studies of HIV. Despite this underrepresentation, differences in the pathogenesis of HIV have been observed between men and women, with contributions from both gender- and sex-based factors. These include differences in the risk of HIV acquisition, in viral load set point and immune activation in responses to viremia, and differences in HIV reservoir maintenance. These differences obligate adequate study in both males and females in order to optimize treatments, but also provide a powerful leverage point for delineating the mechanisms of HIV pathogenesis. The shifts in exposure to sex steroid hormones across a lifespan introduce additional complexity, which again can be used to focus on either genetic or hormonal influences as the driver of an outcome. In this Review, we discuss consistent and reproducible differences by sex across the spectrum of HIV, from acquisition through pathogenesis, treatment, and cure, and explore potential mechanisms and gaps in knowledge., Overview The HIV pandemic has claimed more than 40 million lives and has been a galvanizing force in research into the prevention, pathogenesis, and treatment of infectious diseases. It has [...]

Introduction Phenotypic plasticity is a hallmark of cancer (1-3). In advanced prostate cancer, up to 15%-20% of patients develop resistance to androgen receptor-directed (AR-directed) therapies through conversion from an androgen-driven [...], Notch signaling can have either an oncogenic or tumor-suppressive function in cancer depending on the cancer type and cellular context. While Notch can be oncogenic in early prostate cancer, we identified significant downregulation of the Notch pathway during prostate cancer progression from adenocarcinoma to neuroendocrine (NE) prostate cancer, where it functions as a tumor suppressor. Activation of Notch in NE and Rb1/Trp53-deficient prostate cancer models led to phenotypic conversion toward a more indolent, non-NE state with glandular features and expression of luminal lineage markers. This was accompanied by upregulation of MHC and type I IFN and immune cell infiltration. Overall, these data support Notch signaling as a suppressor of NE differentiation in advanced prostate cancer and provide insights into how Notch signaling influences lineage plasticity and the tumor microenvironment (TME).