Large-scale risk prediction applied to Genetic Analysis Workshop 17 mini-exome sequence data

We consider the application of Efron’s empirical Bayes classification method to risk prediction in a genome-wide association study using the Genetic Analysis Workshop 17 (GAW17) data. A major advantage of using this method is that the effect size distribution for the set of possible features is empirically estimated and that all subsequent parameter estimation and risk prediction is guided by this distribution. Here, we generalize Efron’s method to allow for some of the peculiarities of the GAW17 data. In particular, we introduce two ways to extend Efron’s model: a weighted empirical Bayes model and a joint covariance model that allows the model to properly incorporate the annotation information of single-nucleotide polymorphisms (SNPs). In the course of our analysis, we examine several aspects of the possible simulation model, including the identity of the most important genes, the differing effects of synonymous and nonsynonymous SNPs, and the relative roles of covariates and genes in conferring disease risk. Finally, we compare the three methods to each other and to other classifiers (random forest and neural network)

The Prevalence of Immunologic Injury in Renal Allograft Recipients with De Novo Proteinuria

Post-transplant proteinuria is a common complication after renal transplantation; it is associated with reduced graft and recipient survival. However, the prevalence of histological causes has been reported with considerable variation. A clinico-pathological re-evaluation of post-transplant proteinuria is necessary, especially after dismissal of the term “chronic allograft nephropathy,” which had been considered to be an important cause of proteinuria. Moreover, urinary protein can promote interstitial inflammation in native kidney, whether this occurs in renal allograft remains unknown. Factors that affect the graft outcome in patients with proteinuria also remain unclear. Here we collected 98 cases of renal allograft recipients who developed proteinuria after transplant, histological features were characterized using Banff scoring system. Cox proportional hazard regression models were used for graft survival predictors. We found that transplant glomerulopathy was the leading (40.8%) cause of post-transplant proteinuria. Immunological causes, including transplant glomerulopathy, acute rejection, and chronic rejection accounted for the majority of all pathological causes of proteinuria. Nevertheless, almost all patients that developed proteinuria had immunological lesions in the graft, especially for interstitial inflammation. Intraglomerular C3 deposition was unexpectedly correlated with the severity of proteinuria. Moreover, the severity of interstitial inflammation was an independent risk factor for graft loss, while high level of hemoglobin was a protective factor for graft survival. This study revealed a predominance of immunological parameters in renal allografts with post-transplant proteinuria. These parameters not only correlate with the severity of proteinuria, but also with the outcome of the graft

Genetic Diversity of the ORF5 Gene of Porcine Reproductive and Respiratory Syndrome Virus Isolates in Southwest China from 2007 to 2009

To gain insight into the molecular epidemiology and possible mechanisms of genetic variation of porcine reproductive and respiratory syndrome (PRRS) in Yunnan Province of China, the ORF5 gene of 32 PRRSV isolates from clinical samples collected from 2007 to 2009 were sequenced and analyzed. Nucleotide and amino acid analyses were carried out on 32 isolates and representative strains of the North American genotype, European genotype and two representative Chinese isolates. Results revealed that these isolates share 86.9–99.0% nucleotide and 87.5–98.0% amino acid identity with VR-2332 the prototypical North American PRRSV, 61.7–62.9% and 54.3–57.8% with Lelystad virus (LV) the representative strain of European genotype, 91.2–95.4% and 90.0–94.5% with CH-1a that was isolated in mainland China in 1996, 88.1–99.3% and 85.5–99.0% with JX-A1 the representative strain of High pathogenic PRRSV in China, and 86.2–99.8% and 85.5–100.0% between isolated strains of different years, respectively. Phylogenetic analysis revealed that all 32 PRRSV isolates belonged to the North American genotype and were further divided into two different subgenotypes. Subgenotype 1 comprised twenty two Yunnan isolates which divided into two branches. Subgenotype 2 comprised ten isolates which closely related to the RespPRRS vaccine and its parent strain VR-2332. The functional domains of GP5 such as the signal peptide, ectodomain, transmembrane regions and endodomain were identified and some motifs in GP5 with known functions, such as primary neutralizing epitope (PNE) and decoy epitope were also further analyzed. Our study shown the great genetic diversity of PRRSV in southwest China, rendering the guide for control and prevention of this disease

Gains in QTL Detection Using an Ultra-High Density SNP Map Based on Population Sequencing Relative to Traditional RFLP/SSR Markers

Huge efforts have been invested in the last two decades to dissect the genetic bases of complex traits including yields of many crop plants, through quantitative trait locus (QTL) analyses. However, almost all the studies were based on linkage maps constructed using low-throughput molecular markers, e.g. restriction fragment length polymorphisms (RFLPs) and simple sequence repeats (SSRs), thus are mostly of low density and not able to provide precise and complete information about the numbers and locations of the genes or QTLs controlling the traits. In this study, we constructed an ultra-high density genetic map based on high quality single nucleotide polymorphisms (SNPs) from low-coverage sequences of a recombinant inbred line (RIL) population of rice, generated using new sequencing technology. The quality of the map was assessed by validating the positions of several cloned genes including GS3 and GW5/qSW5, two major QTLs for grain length and grain width respectively, and OsC1, a qualitative trait locus for pigmentation. In all the cases the loci could be precisely resolved to the bins where the genes are located, indicating high quality and accuracy of the map. The SNP map was used to perform QTL analysis for yield and three yield-component traits, number of tillers per plant, number of grains per panicle and grain weight, using data from field trials conducted over years, in comparison to QTL mapping based on RFLPs/SSRs. The SNP map detected more QTLs especially for grain weight, with precise map locations, demonstrating advantages in detecting power and resolution relative to the RFLP/SSR map. Thus this study provided an example for ultra-high density map construction using sequencing technology. Moreover, the results obtained are helpful for understanding the genetic bases of the yield traits and for fine mapping and cloning of QTLs

Global diversity and biogeography of bacterial communities in wastewater treatment plants

Microorganisms in wastewater treatment plants (WWTPs) are essential for water purification to protect public and environmental health. However, the diversity of microorganisms and the factors that control it are poorly understood. Using a systematic global-sampling effort, we analysed the 16S ribosomal RNA gene sequences from ~1,200 activated sludge samples taken from 269 WWTPs in 23 countries on 6 continents. Our analyses revealed that the global activated sludge bacterial communities contain ~1 billion bacterial phylotypes with a Poisson lognormal diversity distribution. Despite this high diversity, activated sludge has a small, global core bacterial community (n = 28 operational taxonomic units) that is strongly linked to activated sludge performance. Meta-analyses with global datasets associate the activated sludge microbiomes most closely to freshwater populations. In contrast to macroorganism diversity, activated sludge bacterial communities show no latitudinal gradient. Furthermore, their spatial turnover is scale-dependent and appears to be largely driven by stochastic processes (dispersal and drift), although deterministic factors (temperature and organic input) are also important. Our findings enhance our mechanistic understanding of the global diversity and biogeography of activated sludge bacterial communities within a theoretical ecology framework and have important implications for microbial ecology and wastewater treatment processes

A Rice Gene of De Novo Origin Negatively Regulates Pathogen-Induced Defense Response

How defense genes originated with the evolution of their specific pathogen-responsive traits remains an important problem. It is generally known that a form of duplication can generate new genes, suggesting that a new gene usually evolves from an ancestral gene. However, we show that a new defense gene in plants may evolve by de novo origination, resulting in sophisticated disease-resistant functions in rice. Analyses of gene evolution showed that this new gene, OsDR10, had homologs only in the closest relative, Leersia genus, but not other subfamilies of the grass family; therefore, it is a rice tribe-specific gene that may have originated de novo in the tribe. We further show that this gene may evolve a highly conservative rice-specific function that contributes to the regulation difference between rice and other plant species in response to pathogen infections. Biologic analyses including gene silencing, pathologic analysis, and mutant characterization by transformation showed that the OsDR10-suppressed plants enhanced resistance to a broad spectrum of Xanthomonas oryzae pv. oryzae strains, which cause bacterial blight disease. This enhanced disease resistance was accompanied by increased accumulation of endogenous salicylic acid (SA) and suppressed accumulation of endogenous jasmonic acid (JA) as well as modified expression of a subset of defense-responsive genes functioning both upstream and downstream of SA and JA. These data and analyses provide fresh insights into the new biologic and evolutionary processes of a de novo gene recruited rapidly

MiDAS 4: A global catalogue of full-length 16S rRNA gene sequences and taxonomy for studies of bacterial communities in wastewater treatment plants

Microbial communities are responsible for biological wastewater treatment, but our knowledge of their diversity and function is still poor. Here, we sequence more than 5 million high-quality, full-length 16S rRNA gene sequences from 740 wastewater treatment plants (WWTPs) across the world and use the sequences to construct the ‘MiDAS 4’ database. MiDAS 4 is an amplicon sequence variant resolved, full-length 16S rRNA gene reference database with a comprehensive taxonomy from domain to species level for all sequences. We use an independent dataset (269 WWTPs) to show that MiDAS 4, compared to commonly used universal reference databases, provides a better coverage for WWTP bacteria and an improved rate of genus and species level classification. Taking advantage of MiDAS 4, we carry out an amplicon-based, global-scale microbial community profiling of activated sludge plants using two common sets of primers targeting regions of the 16S rRNA gene, revealing how environmental conditions and biogeography shape the activated sludge microbiota. We also identify core and conditionally rare or abundant taxa, encompassing 966 genera and 1530 species that represent approximately 80% and 50% of the accumulated read abundance, respectively. Finally, we show that for well-studied functional guilds, such as nitrifiers or polyphosphate-accumulating organisms, the same genera are prevalent worldwide, with only a few abundant species in each genus.Fil: Dueholm, Morten Kam Dahl. Aalborg University; DinamarcaFil: Nierychlo, Marta. Aalborg University; DinamarcaFil: Andersen, Kasper Skytte. Aalborg University; DinamarcaFil: Rudkjøbing, Vibeke. Aalborg University; DinamarcaFil: Knutsson, Simon. Aalborg University; DinamarcaFil: Arriaga, Sonia. Instituto Potosino de Investigación Científica y Tecnológica; MéxicoFil: Bakke, Rune. University College of Southeast Norway; NoruegaFil: Boon, Nico. University of Ghent; BélgicaFil: Bux, Faizal. Durban University of Technology; SudáfricaFil: Christensson, Magnus. Veolia Water Technologies Ab; SueciaFil: Chua, Adeline Seak May. University Malaya; MalasiaFil: Curtis, Thomas P.. University of Newcastle; Reino UnidoFil: Cytryn, Eddie. Agricultural Research Organization Of Israel; IsraelFil: Erijman, Leonardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. Universidad de Buenos Aires; ArgentinaFil: Etchebehere, Claudia. Instituto de Investigaciones Biológicas "Clemente Estable"; UruguayFil: Fatta Kassinos, Despo. University of Cyprus; ChipreFil: Frigon, Dominic. McGill University; CanadáFil: Garcia Chaves, Maria Carolina. Universidad de Antioquia; ColombiaFil: Gu, April Z.. Cornell University; Estados UnidosFil: Horn, Harald. Karlsruher Institut Für Technologie; AlemaniaFil: Jenkins, David. David Jenkins & Associates Inc; Estados UnidosFil: Kreuzinger, Norbert. Tu Wien; AustriaFil: Kumari, Sheena. Durban University of Technology; SudáfricaFil: Lanham, Ana. University of Bath; Reino UnidoFil: Law, Yingyu. Singapore Centre For Environmental Life Sciences Engineering; SingapurFil: Leiknes, TorOve. King Abdullah University of Science and Technology; Arabia SauditaFil: Morgenroth, Eberhard. Eth Zürich; SuizaFil: Muszyński, Adam. Politechnika Warszawska; PoloniaFil: Petrovski, Steve. La Trobe University; AustraliaFil: Pijuan, Maite. Catalan Institute For Water Research; EspañaFil: Pillai, Suraj Babu. Va Tech Wabag Ltd; IndiaFil: Reis, Maria A. M.. Universidade Nova de Lisboa; PortugalFil: Rong, Qi. Chinese Academy of Sciences; ChinaFil: Rossetti, Simona. Istituto Di Ricerca Sulle Acque (irsa) ; Consiglio Nazionale Delle Ricerche;Fil: Seviour, Robert. La Trobe University; AustraliaFil: Tooker, Nick. University of Massachussets; Estados UnidosFil: Vainio, Pirjo. Espoo R&D Center; FinlandiaFil: van Loosdrecht, Mark. Delft University of Technology; Países BajosFil: Vikraman, R.. VA Tech Wabag, Philippines Inc; FilipinasFil: Wanner, Jiří. University of Chemistry And Technology; República ChecaFil: Weissbrodt, David. Delft University of Technology; Países BajosFil: Wen, Xianghua. Tsinghua University; ChinaFil: Zhang, Tong. The University of Hong Kong; Hong KongFil: Nielsen, Per H.. Aalborg University; DinamarcaFil: Albertsen, Mads. Aalborg University; DinamarcaFil: Nielsen, Per Halkjær. Aalborg University; Dinamarc

Use of Praziquantel as an Adjuvant Enhances Protection and Tc-17 Responses to Killed H5N1 Virus Vaccine in Mice

BACKGROUND: H5N1 is a highly pathogenic influenza A virus, which can cause severe illness or even death in humans. Although the widely used killed vaccines are able to provide some protection against infection via neutralizing antibodies, cytotoxic T-lymphocyte responses that are thought to eradicate viral infections are lacking. METHODOLOGY/PRINCIPAL FINDINGS: Aiming to promote cytotoxic responses against H5N1 infection, we extended our previous finding that praziquantel (PZQ) can act as an adjuvant to induce IL-17-producing CD8(+) T cells (Tc17). We found that a single immunization of 57BL/6 mice with killed viral vaccine plus PZQ induced antigen-specific Tc17 cells, some of which also secreted IFN-γ. The induced Tc17 had cytolytic activities. Induction of these cells was impaired in CD8 knockout (KO) or IFN-γ KO mice, and was even lower in IL-17 KO mice. Importantly, the inoculation of killed vaccine with PZQ significantly reduced virus loads in the lung tissues and prolonged survival. Protection against H5N1 virus infection was obtained by adoptively transferring PZQ-primed wild type CD8(+) T cells and this was more effective than transfer of activated IFN-γ KO or IL-17 KO CD8(+) T cells. CONCLUSIONS/SIGNIFICANCE: Our results demonstrated that adding PZQ to killed H5N1 vaccine could promote broad Tc17-mediated cytotoxic T lymphocyte activity, resulting in improved control of highly pathogenic avian influenza virus infection

Testosterone Is Associated with Erectile Dysfunction: A Cross-Sectional Study in Chinese Men

Testosterone is essential for the regulation of erectile physiology, but the relationship between low testosterone and erectile dysfunction (ED) has not been firmly established.To examine the association between serum total, free and bio-available testosterone and ED in a population-based sample.A consecutive series of 1776 men aged 20–77 participated in the routine physical examination from September 2009 to December 2009 in Guangxi, China. ED was assessed using the five-item International Index of Erectile Function (IIEF-5) questionnaire. Total testosterone (TT), sex hormone binding globulin (SHBG) and other biochemical profiles were measured. Free testosterone (FT) and bio-available testosterone (BT) were calculated based on Vermeulen’s formula. Data were collected with regard to smoking, alcoholic drinking, physical activity and metabolic syndrome.The prevalence of ED (IIEF-5<22) was 47.6%. Men with ED were significantly older, and more prone to smoke cigarettes (≥20 cigarettes/day) or drink alcohol (≥3 drinks/week), and more likely to have elevated blood pressure (P = 0.036) or hyperglycemia (P<0.001) compared with those without ED. The significant increase in SHBG with age was parallel to its increase with increasing severity of ED (P<0.001). The obscure increase in TT across the ED status was detected without significance (P = 0.418), but TT was positively associated with ED after adjustment for age [odds ratio (OR)  = 1.02, 95% CI (confidence internal): 1.00–1.04]. FT and BT were inversely associated with ED (OR = 0.14, 95%CI: 0.06–0.33; OR = 0.92 (95%CI: 0.89–0.96, respectively) in the univariate analysis, and this inverse association appeared to be independent of smoking status, alcoholic drinking, physical activity, hyper-triglyceridemia and hyperglycemia.FT and BT are inversely related to worsening ED, whereas the positive association between TT and ED is most likely due to the increase in SHBG