Hedechilders3072

The identification of functional regions in the noncoding human genome is difficult but critical in order to gain understanding of the role noncoding variation plays in gene regulation in human health and disease. C16 We describe here a co-localization approach that aims to identify constrained sequences that co-localize with tissue- or cell-type-specific regulatory regions, and we show that the resulting score is particularly well suited for the identification of rare regulatory variants. For 127 tissues and cell types in the ENCODE/Roadmap Epigenomics Project, we provide catalogs of putative tissue- or cell-type-specific regulatory regions under sequence constraint. We use the newly developed co-localization score for brain tissues to score de novo mutations in whole genomes from 1,902 individuals affected with autism spectrum disorder (ASD) and their unaffected siblings in the Simons Simplex Collection. We show that noncoding de novo mutations near genes co-expressed in midfetal brain with high confidence ASD risk genes, and near FMRP gene targets are more likely to be in co-localized regions if they occur in ASD probands versus in their unaffected siblings. We also observed a similar enrichment for mutations near lincRNAs, previously shown to co-express with ASD risk genes. Additionally, we provide strong evidence that prioritized de novo mutations in autism probands point to a small set of well-known ASD genes, the disruption of which produces relevant mouse phenotypes such as abnormal social investigation and abnormal discrimination/associative learning, unlike the de novo mutations in unaffected siblings. The genome-wide co-localization results are available online. Escherichia coli broadly colonize the intestinal tract of humans and produce a variety of small molecule signals. However, many of these small molecules remain unknown. Here, we describe a family of widely distributed bacterial metabolites termed the "indolokines." In E. coli, the indolokines are upregulated in response to a redox stressor via aspC and tyrB transaminases. Although indolokine 1 represents a previously unreported metabolite, four of the indolokines (2-5) were previously shown to be derived from indole-3-carbonyl nitrile (ICN) in the plant pathogen defense response. We show that the indolokines are produced in a convergent evolutionary manner relative to plants, enhance E. coli persister cell formation, outperform ICN protection in an Arabidopsis thaliana-Pseudomonas syringae infection model, trigger a hallmark plant innate immune response, and activate distinct immunological responses in primary human tissues. Our molecular studies link a family of cellular stress-induced metabolites to defensive responses across bacteria, plants, and humans. Over the past five decades, thanatology has come to include the study of how individual cells in our bodies die appropriately and inappropriately in response to physiological and pathological stimuli. Morphological and biochemical criteria have been painstakingly established to create clarity around definitions of distinct types of cell death and mechanisms for their activation. Among these, ferroptosis has emerged as a unique, oxidative stress-induced cell death pathway with implications for diseases as diverse as traumatic brain injury, hemorrhagic stroke, Alzheimer's disease, cancer, renal ischemia, and heat stress in plants. In this review, I highlight some of the formative studies that fostered its recognition in the nervous system and describe how chemical biological tools have been essential in defining events necessary for its execution. Finally, I discuss emerging opportunities for antiferroptotic agents as therapeutic agents in neurological diseases. Interferon-induced transmembrane protein 3 (IFITM3) is a key interferon effector that broadly prevents infection by diverse viruses. link2 However, the cellular factors that control IFITM3 homeostasis and antiviral activity have not been fully elucidated. Using site-specific photo-crosslinking and quantitative proteomic analysis, here we present the identification and functional characterization of VCP/p97 AAA-ATPase as a primary interaction partner of IFITM3. We show that IFITM3 ubiquitination at lysine 24 is crucial for VCP binding, trafficking, turnover, and engagement with incoming virus particles. Consistently, pharmacological inhibition of VCP/p97 ATPase activity leads to defective IFITM3 lysosomal sorting, turnover, and co-trafficking with virus particles. Our results showcase the utility of site-specific protein photo-crosslinking in mammalian cells and reveal VCP/p97 as a key cellular factor involved in IFITM3 trafficking and homeostasis. The etiology of aortic aneurysms is poorly understood, but it is associated with atherosclerosis, hypercholesterolemia, and abnormal transforming growth factor β (TGF-β) signaling in smooth muscle. Here, we investigated the interactions between these different factors in aortic aneurysm development and identified a key role for smooth muscle cell (SMC) reprogramming into a mesenchymal stem cell (MSC)-like state. SMC-specific ablation of TGF-β signaling in Apoe-/- mice on a hypercholesterolemic diet led to development of aortic aneurysms exhibiting all the features of human disease, which was associated with transdifferentiation of a subset of contractile SMCs into an MSC-like intermediate state that generated osteoblasts, chondrocytes, adipocytes, and macrophages. This combination of medial SMC loss with marked increases in non-SMC aortic cell mass induced exuberant growth and dilation of the aorta, calcification and ossification of the aortic wall, and inflammation, resulting in aneurysm development. The respiratory system, which includes the trachea, airways, and distal alveoli, is a complex multi-cellular organ that intimately links with the cardiovascular system to accomplish gas exchange. In this review and as members of the NIH/NHLBI-supported Progenitor Cell Translational Consortium, we discuss key aspects of lung repair and regeneration. We focus on the cellular compositions within functional niches, cell-cell signaling in homeostatic health, the responses to injury, and new methods to study lung repair and regeneration. We also provide future directions for an improved understanding of the cell biology of the respiratory system, as well as new therapeutic avenues. CIRM has created a unique funding process and structure aimed to make a meaningful impact on translating science into the clinic. By sharing some of the lessons learned by CIRM, we hope to provide insights into concrete improvements that have made a difference in our efforts. Gene correction presents one of few options for a cure for all patients with cystic fibrosis. This commentary discusses new applications of CRISPR-based gene editing technology with increased efficiency and specificity to correct the cystic fibrosis transmembrane regulator (CFTR) function in patient-specific primary epithelial cells. Asymmetric partitioning of damaged proteins is thought to play a key role in preserving stem cell function with age. In this issue of Cell Stem Cell, Morrow et al. (2020) show that vimentin recruits proteasome machinery to aggresomes to control NSC proteostasis during quiescence exit. The existence of an endocrine progenitor in the adult mouse pancreas has been controversial. Recently in Cell, Wang et al. (2020) use the cell-surface marker Procr to define a population of cells within the adult islet of Langerhans that is capable of generating all endocrine cells and is amenable to in vitro expansion. In this issue of Cell Stem Cell, Fumagalli et al. (2020) employ intravital microscopy of colorectal cancer organoid xenografts to investigate the cell of origin of metastases. While tumor-initiating cells are Lgr5+, most disseminated cancer cells are Lgr5- and seed liver metastases in which Lgr5+ cells then appear, showing that bidirectional plasticity of phenotypic states drives metastasis. Gastruloids are embryo-like structures that display key features of post-implantation embryonic development, yet whether they fully recapitulate in vivo embryogenesis remains unsolved. Recently in Nature, van den Brink et al. (2020) performed high-resolution gene expression analysis to identify significant similarities between mouse gastruloids and embryos in positional lineage segregation and somite formation. This Perspective explores the application of machine learning toward improved diagnosis and treatment. We outline a vision for how machine learning can transform three broad areas of biomedicine clinical diagnostics, precision treatments, and health monitoring, where the goal is to maintain health through a range of diseases and the normal aging process. For each area, early instances of successful machine learning applications are discussed, as well as opportunities and challenges for machine learning. When these challenges are met, machine learning promises a future of rigorous, outcomes-based medicine with detection, diagnosis, and treatment strategies that are continuously adapted to individual and environmental differences. Structures of 70 unique G protein-coupled receptors (GPCRs) have been determined, with over 370 structures in total bound to different ligands and the receptors in various conformational states. Structure-based drug design has been applied to an increasing number of GPCR targets over the past decade and now a few of these drug candidates have entered clinical trials. Given the length of time required for a drug to reach the market, there are no documented examples of licensed drugs being developed with the aid of a structure, but this is likely to change as current efforts come to fruition. The discovery of the strikingly rapid and robust antidepressant effects of r/s-ketamine for the treatment of antidepressant-resistant symptoms of depression has led to new insights into the biology of antidepressants and the FDA approval of its s-isomer, Esketamine (Spravato), the first mechanistically new treatment for depression in over 60 years. To view this Bench to Bedside, open or download the PDF. Autoimmune diseases are a result of the immune system being misdirected toward its host and have major and increasing unmet clinical needs. In general, present therapies are broadly acting and non-disease specific; consequently, they are associated with numerous side effects. Precise and early intervention strategies are urgently needed. link3 We highlight the challenges, progress, and prospects in achieving these goals. Ervebo is the first licensed vaccine for prevention of Ebola virus disease. The vaccine, originally developed by the Public Health Agency of Canada, is delivered in a single 1 mL dose and has been delivered to >200,000 people in an ongoing 2018-2020 outbreak of disease. To view this Bench to Bedside, open or download the PDF. Cell therapies present an entirely new paradigm in drug development. Within this class, immune cell therapies are among the most advanced, having already demonstrated definitive evidence of clinical benefits in cancer and infectious disease. Numerous features distinguish these "living therapies" from traditional medicines, including their ability to expand and contract in proportion to need and to mediate therapeutic benefits for months or years following a single application. Continued advances in fundamental immunology, genetic engineering, gene editing, and synthetic biology exponentially expand opportunities to enhance the sophistication of immune cell therapies, increasing potency and safety and broadening their potential for treatment of disease. This perspective will summarize the current status of immune cell therapies for cancer, infectious disease, and autoimmunity, and discuss advances in cellular engineering to overcome barriers to progress.