Precipitation Sensitivity to Surface Heat Fluxes over North America in Reanalysis and Model Data

A new methodology for assessing the impact of surface heat fluxes on precipitation is applied to data from the North American Regional Reanalysis (NARR) and to output from the Geophysical Fluid Dynamics Laboratory’s Atmospheric Model 2.1 (AM2.1). The method assesses the sensitivity of afternoon convective rainfall frequency and intensity to the late-morning partitioning of latent and sensible heating, quantified in terms of evaporative fraction (EF). Over North America, both NARR and AM2.1 indicate sensitivity of convective rainfall triggering to EF but no appreciable influence of EF on convective rainfall amounts. Functional relationships between the triggering feedback strength (TFS) metric and mean EF demonstrate the occurrence of stronger coupling for mean EF in the range of 0.6 to 0.8. To leading order, AM2.1 exhibits spatial distributions and seasonality of the EF impact on triggering resembling those seen in NARR: rainfall probability increases with higher EF over the eastern United States and Mexico and peaks in Northern Hemisphere summer. Over those regions, the impact of EF variability on afternoon rainfall triggering in summer can explain up to 50% of seasonal rainfall variability. However, the AM2.1 metrics also exhibit some features not present in NARR, for example, strong coupling extending northwestward from the central Great Plains into Canada. Sources of disagreement may include model hydroclimatic biases that affect the mean patterns and variability of surface flux partitioning, with EF variability typically much lower in NARR. Finally, the authors also discuss the consistency of their results with other assessments of land–precipitation coupling obtained from different methodologies

Land-atmosphere feedbacks exacerbate concurrent soil drought and atmospheric aridity.

Compound extremes such as cooccurring soil drought (low soil moisture) and atmospheric aridity (high vapor pressure deficit) can be disastrous for natural and societal systems. Soil drought and atmospheric aridity are 2 main physiological stressors driving widespread vegetation mortality and reduced terrestrial carbon uptake. Here, we empirically demonstrate that strong negative coupling between soil moisture and vapor pressure deficit occurs globally, indicating high probability of cooccurring soil drought and atmospheric aridity. Using the Global Land Atmosphere Coupling Experiment (GLACE)-CMIP5 experiment, we further show that concurrent soil drought and atmospheric aridity are greatly exacerbated by land-atmosphere feedbacks. The feedback of soil drought on the atmosphere is largely responsible for enabling atmospheric aridity extremes. In addition, the soil moisture-precipitation feedback acts to amplify precipitation and soil moisture deficits in most regions. CMIP5 models further show that the frequency of concurrent soil drought and atmospheric aridity enhanced by land-atmosphere feedbacks is projected to increase in the 21st century. Importantly, land-atmosphere feedbacks will greatly increase the intensity of both soil drought and atmospheric aridity beyond that expected from changes in mean climate alone

Intranasal administration of acetylcholinesterase inhibitors

This short review outlines the rationale, challenges, and opportunities for intranasal acetylcholinesterases, in particular galantamine. An in vitro screening model facilitated the development of a therapeutically viable formulation. In vivo testing confirmed achievement of therapeutically relevant drug levels that matched or exceeded those for oral dosing, with a dramatic reduction in undesired emetic responses. Intranasal drug delivery is an effective option for the treatment of Alzheimer's disease and other central nervous system disorders

Process-Oriented Evaluation of Climate and Weather Forecasting Models

Realistic climate and weather prediction models are necessary to produce confidence in projections of future climate over many decades and predictions for days to seasons. These models must be physically justified and validated for multiple weather and climate processes. A key opportunity to accelerate model improvement is greater incorporation of process-oriented diagnostics (PODs) into standard packages that can be applied during the model development process, allowing the application of diagnostics to be repeatable across multiple model versions and used as a benchmark for model improvement. A POD characterizes a specific physical process or emergent behavior that is related to the ability to simulate an observed phenomenon. This paper describes the outcomes of activities by the Model Diagnostics Task Force (MDTF) under the NOAA Climate Program Office (CPO) Modeling, Analysis, Predictions and Projections (MAPP) program to promote development of PODs and their application to climate and weather prediction models. MDTF and modeling center perspectives on the need for expanded process-oriented diagnosis of models are presented. Multiple PODs developed by the MDTF are summarized, and an open-source software framework developed by the MDTF to aid application of PODs to centers’ model development is presented in the context of other relevant community activities. The paper closes by discussing paths forward for the MDTF effort and for community process-oriented diagnosis

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment

Comprehensive Research Synopsis and Systematic Meta-Analyses in Parkinson's Disease Genetics: The PDGene Database

More than 800 published genetic association studies have implicated dozens of potential risk loci in Parkinson's disease (PD). To facilitate the interpretation of these findings, we have created a dedicated online resource, PDGene, that comprehensively collects and meta-analyzes all published studies in the field. A systematic literature screen of ∼27,000 articles yielded 828 eligible articles from which relevant data were extracted. In addition, individual-level data from three publicly available genome-wide association studies (GWAS) were obtained and subjected to genotype imputation and analysis. Overall, we performed meta-analyses on more than seven million polymorphisms originating either from GWAS datasets and/or from smaller scale PD association studies. Meta-analyses on 147 SNPs were supplemented by unpublished GWAS data from up to 16,452 PD cases and 48,810 controls. Eleven loci showed genome-wide significant (P<5×10−8) association with disease risk: BST1, CCDC62/HIP1R, DGKQ/GAK, GBA, LRRK2, MAPT, MCCC1/LAMP3, PARK16, SNCA, STK39, and SYT11/RAB25. In addition, we identified novel evidence for genome-wide significant association with a polymorphism in ITGA8 (rs7077361, OR 0.88, P = 1.3×10−8). All meta-analysis results are freely available on a dedicated online database (www.pdgene.org), which is cross-linked with a customized track on the UCSC Genome Browser. Our study provides an exhaustive and up-to-date summary of the status of PD genetics research that can be readily scaled to include the results of future large-scale genetics projects, including next-generation sequencing studies