Wolffjeppesen8790

Planar cell polarity (PCP) and neural tube defects (NTDs) are linked, with a subset of NTD patients found to harbour mutations in PCP genes, but there is limited data on whether these mutations disrupt PCP signaling in vivo. The core PCP gene Van Gogh (Vang), Vangl1/2 in mammals, is the most specific for PCP. We thus addressed potential causality of NTD-associated Vangl1/2 mutations, from either mouse or human patients, in Drosophila allowing intricate analysis of the PCP pathway. Introducing the respective mammalian mutations into Drosophila Vang revealed defective phenotypic and functional behaviors, with changes to Vang localization, post-translational modification, and mechanistic function, such as its ability to interact with PCP effectors. Our findings provide mechanistic insight into how different mammalian mutations contribute to developmental disorders and strengthen the link between PCP and NTD. Importantly, analyses of the human mutations revealed that each is a causative factor for the associated NTD. © 2020, Humphries et al.Glycosyltransferases (GTs) are prevalent across the tree of life and regulate nearly all aspects of cellular functions. The evolutionary basis for their complex and diverse modes of catalytic functions remain enigmatic. Here, based on deep mining of over half million GT-A fold sequences, we define a minimal core component shared among functionally diverse enzymes. We find that variations in the common core and emergence of hypervariable loops extending from the core contributed to GT-A diversity. We provide a phylogenetic framework relating diverse GT-A fold families for the first time and show that inverting and retaining mechanisms emerged multiple times independently during evolution. Using evolutionary information encoded in primary sequences, we trained a machine learning classifier to predict donor specificity with nearly 90% accuracy and deployed it for the annotation of understudied GTs. Our studies provide an evolutionary framework for investigating complex relationships connecting GT-A fold sequence, structure, function and regulation. © 2020, Taujale et al.The choroid, which provides vascular supply to the outer retina, demonstrates progressive degeneration in aging and age-related macular degeneration (AMD). However mechanisms that maintain or compromise choroidal homeostasis are obscure. We discovered that the ablation of choroidal macrophages via CSF1R blockade was associated with choroidal vascular atrophy and retinal pigment epithelial (RPE) changes including structural disruption, downregulation of visual cycle genes, and altered angiogenic factor expression. Suspending CSF1R blockade following ablation enabled spontaneous macrophage regeneration, which fully restored original macrophage distributions and morphologies. Macrophage regeneration was accompanied by arrested vascular degeneration and ameliorated pathological RPE alterations. These findings suggest that choroidal macrophages play a previously unappreciated trophic role in maintaining choroidal vasculature and RPE cells, implicating insufficiency in choroidal macrophage function as a factor in aging- and AMD-associated pathology. Modulating macrophage function may constitute a strategy for the therapeutic preservation of the choroid and RPE in age-related retinal disorders.Although heterogeneity is recognized within the murine satellite cell pool, a comprehensive understanding of distinct subpopulations and their functional relevance in human satellite cells is lacking. We used a combination of single cell RNA sequencing and flow cytometry to identify, distinguish, and physically separate novel subpopulations of human PAX7+ satellite cells (Hu-MuSCs) from normal muscles. We found that, although relatively homogeneous compared to activated satellite cells and committed progenitors, the Hu-MuSC pool contains clusters of transcriptionally distinct cells with consistency across human individuals. New surface marker combinations were enriched in transcriptional subclusters, including a subpopulation of Hu-MuSCs marked by CXCR4/CD29/CD56/CAV1 (CAV1+). In vitro, CAV1+ Hu-MuSCs are morphologically distinct, and characterized by resistance to activation compared to CAV1- Hu-MuSCs. In vivo, CAV1+ Hu-MuSCs demonstrated increased engraftment after transplantation. Our findings provide a comprehensive transcriptional view of normal Hu-MuSCs and describe new heterogeneity, enabling separation of functionally distinct human satellite cell subpopulations. © 2020, Barruet et al.Optimal mechanical ventilatory support is a vital component of intraoperative anesthesia care, lung protection, and minimizing postoperative pulmonary sequela. Although concepts surrounding ventilation can be multifaceted and ambiguous, a pragmatic approach coupled with contemporary evidence and skilled assessments will facilitate ideal intraoperative management. Effective mechanical ventilation is dependent on obtaining the best pulmonary mechanics, including compliance, resistance, and gas exchange. Optimally titrated positive end-expiratory pressure is the foundation for ideal pulmonary mechanics, preventing ventilator-induced lung injury, and minimizing postoperative pulmonary complications. A knowledgeable application of pressure support ventilation can offer additional advantages during general anesthesia and emergence, providing synchronized ventilation and augmenting the patient's own respiratory efforts. These concepts, coupled with clinical expertise, will offer insight into the methods, tools, and techniques available to modern anesthetists. Copyright © by the American Association of Nurse Anesthetists.The worldwide obesity epidemic has led to an increase in the number of bariatric procedures for treatment. Currently, the most commonly performed bariatric surgical operation in the United States is the laparoscopic sleeve gastrectomy (LSG). The risk of postoperative nausea and vomiting (PONV) is exceptionally high following the LSG as much as 65%. Anesthesia providers should be mindful of this elevated risk and stay up to date on evidence-based techniques that help to mitigate the incidence of PONV related to this specific procedure. The purposes of this clinical review are to increase provider awareness of the PONV risk following LSG and to examine methods for improving PONV outcomes for this population. RGDyK chemical structure Copyright © by the American Association of Nurse Anesthetists.