Androgen Regulated Genes in Human Prostate Xenografts in Mice: Relation to BPH and Prostate Cancer

Benign prostatic hyperplasia (BPH) and prostate carcinoma (CaP) are linked to aging and the presence of androgens, suggesting that androgen regulated genes play a major role in these common diseases. Androgen regulation of prostate growth and development depends on the presence of intact epithelial-stromal interactions. Further, the prostatic stroma is implicated in BPH. This suggests that epithelial cell lines are inadequate to identify androgen regulated genes that could contribute to BPH and CaP and which could serve as potential clinical biomarkers. In this study, we used a human prostate xenograft model to define a profile of genes regulated in vivo by androgens, with an emphasis on identifying candidate biomarkers. Benign transition zone (TZ) human prostate tissue from radical prostatectomies was grafted to the sub-renal capsule site of intact or castrated male immunodeficient mice, followed by the removal or addition of androgens, respectively. Microarray analysis of RNA from these tissues was used to identify genes that were; 1) highly expressed in prostate, 2) had significant expression changes in response to androgens, and, 3) encode extracellular proteins. A total of 95 genes meeting these criteria were selected for analysis and validation of expression in patient prostate tissues using quantitative real-time PCR. Expression levels of these genes were measured in pooled RNAs from human prostate tissues with varying severity of BPH pathologic changes and CaP of varying Gleason score. A number of androgen regulated genes were identified. Additionally, a subset of these genes were over-expressed in RNA from clinical BPH tissues, and the levels of many were found to correlate with disease status. Our results demonstrate the feasibility, and some of the problems, of using a mouse xenograft model to characterize the androgen regulated expression profiles of intact human prostate tissues

Effects of frozen soil on soil temperature, spring infiltration, and runoff: results from the PILPS 2(d) experiment at Valdai, Russia

Permission to place copies of these works on this server has been provided by the American Meteorological Society (AMS). The AMS does not guarantee that the copies provided here are accurate copies of the published work. © Copyright 2003 American Meteorological Society (AMS). Permission to use figures, tables, and brief excerpts from this work in scientific and educational works is hereby granted provided that the source is acknowledged. Any use of material in this work that is determined to be “fair use” under Section 107 of the U.S. Copyright Act or that satisfies the conditions specified in Section 108 of the U.S. Copyright Act (17 USC §108, as revised by P.L. 94-553) does not require the AMS’s permission. Republication, systematic reproduction, posting in electronic form on servers, or other uses of this material, except as exempted by the above statement, requires written permission or a license from the AMS. Additional details are provided in the AMS Copyright Policy, available on the AMS Web site located at (http://www.ametsoc.org/AMS) or from the AMS at 617-227-2425 or [email protected] Project for Intercomparison of Land-Surface Parameterization Schemes phase 2(d) experiment at Valdai, Russia, offers a unique opportunity to evaluate land surface schemes, especially snow and frozen soil parameterizations. Here, the ability of the 21 schemes that participated in the experiment to correctly simulate the thermal and hydrological properties of the soil on several different timescales was examined. Using observed vertical profiles of soil temperature and soil moisture, the impact of frozen soil schemes in the land surface models on the soil temperature and soil moisture simulations was evaluated. It was found that when soil-water freezing is explicitly included in a model, it improves the simulation of soil temperature and its variability at seasonal and interannual scales. Although change of thermal conductivity of the soil also affects soil temperature simulation, this effect is rather weak. The impact of frozen soil on soil moisture is inconclusive in this experiment due to the particular climate at Valdai, where the top 1 m of soil is very close to saturation during winter and the range for soil moisture changes at the time of snowmelt is very limited. The results also imply that inclusion of explicit snow processes in the models would contribute to substantially improved simulations. More sophisticated snow models based on snow physics tend to produce better snow simulations, especially of snow ablation. Hysteresis of snow-cover fraction as a function of snow depth is observed at the catchment but not in any of the models

The representation of snow in land surface schemes: results from PILPS 2(d)

Permission to place copies of these works on this server has been provided by the American Meteorological Society (AMS). The AMS does not guarantee that the copies provided here are accurate copies of the published work. © Copyright 2001 American Meteorological Society (AMS). Permission to use figures, tables, and brief excerpts from this work in scientific and educational works is hereby granted provided that the source is acknowledged. Any use of material in this work that is determined to be “fair use” under Section 107 of the U.S. Copyright Act or that satisfies the conditions specified in Section 108 of the U.S. Copyright Act (17 USC §108, as revised by P.L. 94-553) does not require the AMS’s permission. Republication, systematic reproduction, posting in electronic form on servers, or other uses of this material, except as exempted by the above statement, requires written permission or a license from the AMS. Additional details are provided in the AMS Copyright Policy, available on the AMS Web site located at (http://www.ametsoc.org/AMS) or from the AMS at 617-227-2425 or [email protected] land surface schemes (LSSs) performed simulations forced by 18 yr of observed meteorological data from a grassland catchment at Valdai, Russia, as part of the Project for the Intercomparison of Land-Surface Parameterization Schemes (PILPS) Phase 2(d). In this paper the authors examine the simulation of snow. In comparison with observations, the models are able to capture the broad features of the snow regime on both an intra- and interannual basis. However, weaknesses in the simulations exist, and early season ablation events are a significant source of model scatter. Over the 18-yr simulation, systematic differences between the models’ snow simulations are evident and reveal specific aspects of snow model parameterization and design as being responsible. Vapor exchange at the snow surface varies widely among the models, ranging from a large net loss to a small net source for the snow season. Snow albedo, fractional snow cover, and their interplay have a large effect on energy available for ablation, with differences among models most evident at low snow depths. The incorporation of the snowpack within an LSS structure affects the method by which snow accesses, as well as utilizes, available energy for ablation. The sensitivity of some models to longwave radiation, the dominant winter radiative flux, is partly due to a stability-induced feedback and the differing abilities of models to exchange turbulent energy with the atmosphere. Results presented in this paper suggest where weaknesses in macroscale snow modeling lie and where both theoretical and observational work should be focused to address these weaknesses

Effects of Frozen Soil on Soil Temperature, Spring Infiltration, and Runoff: Results from the PILPS 2(d) Experiment at Valdai, Russia

The Project for Intercomparison of Land-Surface Parameterization Schemes phase 2(d) experiment at Valdai, Russia, offers a unique opportunity to evaluate land surface schemes, especially snow and frozen soil parameterizations. Here, the ability of the 21 schemes that participated in the experiment to correctly simulate the thermal and hydrological properties of the soil on several different timescales was examined. Using observed vertical profiles of soil temperature and soil moisture, the impact of frozen soil schemes in the land surface models on the soil temperature and soil moisture simulations was evaluated. It was found that when soil-water freezing is explicitly included in a model, it improves the simulation of soil temperature and its variability at seasonal and interannual scales. Although change of thermal conductivity of the soil also affects soil temperature simulation, this effect is rather weak. The impact of frozen soil on soil moisture is inconclusive in this experiment due to the particular climate at Valdai, where the top 1 m of soil is very close to saturation during winter and the range for soil moisture changes at the time of snowmelt is very limited. The results also imply that inclusion of explicit snow processes in the models would contribute to substantially improved simulations. More sophisticated snow models based on snow physics tend to produce better snow simulations, especially of snow ablation. Hysteresis of snow-cover fraction as a function of snow depth is observed at the catchment but not in any of the models

Geospatial Resolution of Human and Bacterial Diversity with City-Scale Metagenomics

The panoply of microorganisms and other species present in our environment influence human health and disease, especially in cities, but have not been profiled with metagenomics at a city-wide scale. We sequenced DNA from surfaces across the entire New York City (NYC) subway system, the Gowanus Canal, and public parks. Nearly half of the DNA (48%) does not match any known organism; identified organisms spanned 1,688 bacterial, viral, archaeal, and eukaryotic taxa, which were enriched for harmless genera associated with skin (e.g., Acinetobacter). Predicted ancestry of human DNA left on subway surfaces can recapitulate U.S. Census demographic data, and bacterial signatures can reveal a station’s history, such as marine-associated bacteria in a hurricane-flooded station. Some evidence of pathogens was found (Bacillus anthracis), but a lack of reported cases in NYC suggests that the pathogens represent a normal, urban microbiome. This baseline metagenomic map of NYC could help long-term disease surveillance, bioterrorism threat mitigation, and health management in the built environment of citie

Elucidating the Role of the Complement Control Protein in Monkeypox Pathogenicity

Monkeypox virus (MPXV) causes a smallpox-like disease in humans. Clinical and epidemiological studies provide evidence of pathogenicity differences between two geographically distinct monkeypox virus clades: the West African and Congo Basin. Genomic analysis of strains from both clades identified a ∼10 kbp deletion in the less virulent West African isolates sequenced to date. One absent open reading frame encodes the monkeypox virus homologue of the complement control protein (CCP). This modulatory protein prevents the initiation of both the classical and alternative pathways of complement activation. In monkeypox virus, CCP, also known as MOPICE, is a ∼24 kDa secretory protein with sequence homology to this superfamily of proteins. Here we investigate CCP expression and its role in monkeypox virulence and pathogenesis. CCP was incorporated into the West African strain and removed from the Congo Basin strain by homologous recombination. CCP expression phenotypes were confirmed for both wild type and recombinant monkeypox viruses and CCP activity was confirmed using a C4b binding assay. To characterize the disease, prairie dogs were intranasally infected and disease progression was monitored for 30 days. Removal of CCP from the Congo Basin strain reduced monkeypox disease morbidity and mortality, but did not significantly decrease viral load. The inclusion of CCP in the West African strain produced changes in disease manifestation, but had no apparent effect on disease-associated mortality. This study identifies CCP as an important immuno-modulatory protein in monkeypox pathogenesis but not solely responsible for the increased virulence seen within the Congo Basin clade of monkeypox virus

Patterns and rates of exonic de novo mutations in autism spectrum disorders

Autism spectrum disorders (ASD) are believed to have genetic and environmental origins, yet in only a modest fraction of individuals can specific causes be identified1,2. To identify further genetic risk factors, we assess the role of de novo mutations in ASD by sequencing the exomes of ASD cases and their parents (n= 175 trios). Fewer than half of the cases (46.3%) carry a missense or nonsense de novo variant and the overall rate of mutation is only modestly higher than the expected rate. In contrast, there is significantly enriched connectivity among the proteins encoded by genes harboring de novo missense or nonsense mutations, and excess connectivity to prior ASD genes of major effect, suggesting a subset of observed events are relevant to ASD risk. The small increase in rate of de novo events, when taken together with the connections among the proteins themselves and to ASD, are consistent with an important but limited role for de novo point mutations, similar to that documented for de novo copy number variants. Genetic models incorporating these data suggest that the majority of observed de novo events are unconnected to ASD, those that do confer risk are distributed across many genes and are incompletely penetrant (i.e., not necessarily causal). Our results support polygenic models in which spontaneous coding mutations in any of a large number of genes increases risk by 5 to 20-fold. Despite the challenge posed by such models, results from de novo events and a large parallel case-control study provide strong evidence in favor of CHD8 and KATNAL2 as genuine autism risk factors

Gene Expression Profiling of a Mouse Model of Pancreatic Islet Dysmorphogenesis

In the past decade, several transcription factors critical for pancreas organogenesis have been identified. Despite this success, many of the factors necessary for proper islet morphogenesis and function remain uncharacterized. Previous studies have shown that transgenic over-expression of the transcription factor Hnf6 specifically in the pancreatic endocrine cell lineage resulted in disruptions in islet morphogenesis, including dysfunctional endocrine cell sorting, increased individual islet size, increased number of peripheral endocrine cell types, and failure of islets to migrate away from the ductal epithelium. The mechanisms whereby maintained Hnf6 causes defects in islet morphogenesis have yet to be elucidated.We exploited the dysmorphic islets in Hnf6 transgenic animals as a tool to identify factors important for islet morphogenesis. Genome-wide microarray analysis was used to identify differences in the gene expression profiles of late gestation and early postnatal total pancreas tissue from wild type and Hnf6 transgenic animals. Here we report the identification of genes with an altered expression in Hnf6 transgenic animals and highlight factors with potential importance in islet morphogenesis. Importantly, gene products involved in cell adhesion, cell migration, ECM remodeling and proliferation were found to be altered in Hnf6 transgenic pancreata, revealing specific candidates that can now be analyzed directly for their role in these processes during islet development.This study provides a unique dataset that can act as a starting point for other investigators to explore the role of the identified genes in pancreatogenesis, islet morphogenesis and mature beta cell function

Transcriptional recapitulation and subversion of embryonic colon development by mouse colon tumor models and human colon cancer

Colon tumors from four independent mouse models and 100 human colorectal cancers all exhibited striking recapitulation of embryonic colon gene expression from embryonic days 13.5-18.5