asthma and reduced exacerbations, hospital admissions or unscheduled healthcare visits and exposure to systemic corticosteroids and probably reduces adverse events compared with FABA as required alone. FABA/ICS as required is as effective as regular ICS and reduced asthma-related hospital admissions or unscheduled healthcare visits, and average exposure to ICS, and is unlikely associated with increased adverse events.This study aimed to assess immune activation in tissues by measuring glucose metabolism with 18F-fluorodeoxyglucose (FDG) and investigate the associations of various peripheral markers of disease progression with initiation and interruption of combination antiretroviral therapy in SIV-infected rhesus macaques (Macaca mulatta). Mixed-effect linear models revealed a significant inverse association of peripheral blood CD4+ T cell counts (p less then 0.01) and a direct association of plasma viral load (p less then 0.01) with the FDG uptake in the spleen, bone marrow, and most clusters of lymph nodes. In contrast, no significant associations were found for the liver and the bowel FDG uptake. We also found no association of the fraction of proliferating peripheral blood T and B lymphocytes with FDG uptake in any analyzed tissues. The bowel FDG uptake of uninfected animals was heterogeneous and reached levels as high as those seen in the bowel or the clusters of lymph nodes or the spleen of high viremic SIV-infected animals, suggesting that factors beyond SIV-induced immune activation dominate the gut FDG uptake.Biliary tract cancer ranks among the most lethal human malignancies, representing an unmet clinical need. Its abysmal prognosis is tied to an increasing incidence and a fundamental lack of mechanistic knowledge regarding the molecular basis of the disease. Here, we show that the Pdx1-positive extrahepatic biliary epithelium is highly susceptible towards transformation by activated Pik3caH1047R, but refractory to oncogenic KrasG12D. Using genome-wide transposon screens and genetic loss-of-function experiments, we discover context-dependent genetic interactions that drive extrahepatic cholangiocarcinoma (ECC) and show that PI3K-signaling output strength and repression of the tumor-suppressor p27Kip1 are critical context-specific determinants of tumor formation. This contrasts the pancreas, where oncogenic Kras in concert with Trp53-loss are key cancer-drivers. Notably, inactivation of p27Kip1 permits KrasG12D-driven ECC development. These studies provide a mechanistic link between PI3K-signaling, tissue-specific tumor suppressor barriers, and ECC pathogenesis, and present a novel genetic model of autochthonous ECC and genes driving this highly lethal tumor-subtype.The production of ammonia through the Haber-Bosch process is regarded as one of the most important inventions of the 20th century. Despite significant efforts in optimizing the process, it still consumes 1 to 2% of the worldwide annual energy for the high working temperatures and pressures. The design of a catalyst with a high activity at milder conditions represents another challenge for this reaction. Herein, we combine density functional theory and microkinetic modeling to illustrate a strategy to facilitate low-temperature and -pressure ammonia synthesis through modified energy-scaling relationships using a confined dual site. Our results suggest that an ammonia synthesis rate two to three orders of magnitude higher than the commercial Ru catalyst can be achieved under the same reaction conditions with the introduction of confinement. Such strategies will open pathways for the development of catalysts for the Haber-Bosch process that can operate at milder conditions and present more economically viable alternatives to current industrial solutions.This article provides county-level estimates of the cumulative prevalence of four levels of Child Protective Services (CPS) contact using administrative data from the 20 most populous counties in the United States. Rates of CPS investigation are extremely high in almost every county. Racial and ethnic inequality in case outcomes is large in some counties. The total median investigation rate was 41.3%; the risk for Black, Hispanic, and White children exceeded 20% in all counties. Risks of having a CPS investigation were highest for Black children (43.2 to 72.0%). Black children also experienced high rates of later-stage CPS contact, with rates often above 20% for confirmed maltreatment, 10% for foster care placement, and 2% for termination of parental rights (TPR). The only other children who experienced such extreme rates of later-stage CPS interventions were American Indian/Alaska Native children in Middlesex, MA; Hispanic children in Bexar, TX; and all children except Asian/Pacific Islander children in Maricopa, AZ. The latter has uniquely high rates of late-stage CPS interventions. In some jurisdictions, such as New York, NY, (0.2%) and Cook, IL (0.2%), very few children experienced TPR. These results show that early CPS interventions are ubiquitous in large counties but with marked variation in how CPS systems respond to these investigations.RNA viruses exist as genetically heterogeneous populations due to high mutation rates, and many of these mutations reduce fitness and/or replication speed. Selleck Crenigacestat However, it is unknown whether mutations can increase replication speed of a virus already well adapted to replication in cultured cells. By sequentially passaging coxsackievirus B3 in cultured cells and collecting the very earliest progeny, we selected for increased replication speed. We found that a single mutation in a viral capsid protein, VP1-F106L, was sufficient for the fast-replication phenotype. Characterization of this mutant revealed quicker genome release during entry compared to wild-type virus, highlighting a previously unappreciated infection barrier. However, this mutation also reduced capsid stability in vitro and reduced replication and pathogenesis in mice. These results reveal a tradeoff between overall replication speed and fitness. Importantly, this approach-selecting for the earliest viral progeny-could be applied to a variety of viral systems and has the potential to reveal unanticipated inefficiencies in viral replication cycles.