The function of the mammalian brain relies upon the specification and spatial positioning of diversely specialized cell types. Yet, the molecular identities of the cell types and their positions ...within individual anatomical structures remain incompletely known. To construct a comprehensive atlas of cell types in each brain structure, we paired high-throughput single-nucleus RNA sequencing with Slide-seq
-a recently developed spatial transcriptomics method with near-cellular resolution-across the entire mouse brain. Integration of these datasets revealed the cell type composition of each neuroanatomical structure. Cell type diversity was found to be remarkably high in the midbrain, hindbrain and hypothalamus, with most clusters requiring a combination of at least three discrete gene expression markers to uniquely define them. Using these data, we developed a framework for genetically accessing each cell type, comprehensively characterized neuropeptide and neurotransmitter signalling, elucidated region-specific specializations in activity-regulated gene expression and ascertained the heritability enrichment of neurological and psychiatric phenotypes. These data, available as an online resource ( www.BrainCellData.org ), should find diverse applications across neuroscience, including the construction of new genetic tools and the prioritization of specific cell types and circuits in the study of brain diseases.
The recent success of immune checkpoint blockade in melanoma and lung adenocarcinoma has galvanized the field of immuno-oncology as well as revealed the limitations of current treatments, as the ...majority of patients do not respond to immunotherapy. Development of accurate preclinical models to quickly identify novel and effective therapeutic combinations are critical to address this unmet clinical need. Pancreatic ductal adenocarcinoma (PDA) is a canonical example of an immune checkpoint blockade resistant tumor with only 2% of patients responding to immunotherapy. The genetically engineered Kras
;Trp53
;Pdx-1 Cre (KPC) mouse model of PDA recapitulates human disease and is a valuable tool for assessing therapies for immunotherapy resistant in the preclinical setting, but time to tumor onset is highly variable. Surgical orthotopic tumor implantation models of PDA maintain the immunobiological hallmarks of the KPC tissue-specific tumor microenvironment (TME) but require a time-intensive procedure and introduce aberrant inflammation. Here, we use an ultrasound-guided orthotopic tumor implantation model (UG-OTIM) to non-invasively inject KPC-derived PDA cell lines directly into the mouse pancreas. UG-OTIM tumors grow in the endogenous tissue site, faithfully recapitulate histological features of the PDA TME, and reach enrollment-sized tumors for preclinical studies by four weeks after injection with minimal seeding on the peritoneal wall. The UG-OTIM system described here is a rapid and reproducible tumor model that may allow for high throughput analysis of novel therapeutic combinations in the murine PDA TME.
The National Weather Service (NWS) Office of Water Prediction (OWP), in conjunction with the National Center for Atmospheric Research and the NWS National Centers for Environmental Prediction (NCEP) ...implemented version 2.1 of the National Water Model (NWM) into operations in April of 2021. As with the initial version implemented in 2016, NWM v2.1 is an hourly cycling analysis and forecast system that provides streamflow guidance for millions of river reaches and other hydrologic information on high‐resolution grids. The NWM provides complementary hydrologic guidance at current NWS river forecast locations and significantly expands guidance coverage and water budget information in underserved locations. It produces a full range of hydrologic fields, which can be leveraged by a broad cross section of stakeholders ranging from the emergency responder and water resource communities, to transportation, energy, recreation and agriculture interests, to other water‐oriented applications in the government, academic and private sectors. Version 2.1 of the NWM represents the fifth major version upgrade and more than doubles simulation skill with respect to hourly streamflow correlation, Nash Sutcliffe Efficiency, and bias reduction, over its original inception in 2016. This paper will discuss the driving factors underpinning the creation of the NWM, provide a brief overview of the model configuration and performance, and discuss future efforts to improve NWM components and services.
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