Meta-analysis identifies multiple loci associated with kidney function-related traits in east Asian populations.

Chronic kidney disease (CKD), impairment of kidney function, is a serious public health problem, and the assessment of genetic factors influencing kidney function has substantial clinical relevance. Here, we report a meta-analysis of genome-wide association studies for kidney function-related traits, including 71,149 east Asian individuals from 18 studies in 11 population-, hospital- or family-based cohorts, conducted as part of the Asian Genetic Epidemiology Network (AGEN). Our meta-analysis identified 17 loci newly associated with kidney function-related traits, including the concentrations of blood urea nitrogen, uric acid and serum creatinine and estimated glomerular filtration rate based on serum creatinine levels (eGFRcrea) (P < 5.0 × 10(-8)). We further examined these loci with in silico replication in individuals of European ancestry from the KidneyGen, CKDGen and GUGC consortia, including a combined total of ∼110,347 individuals. We identify pleiotropic associations among these loci with kidney function-related traits and risk of CKD. These findings provide new insights into the genetics of kidney function.

Ajustes de quadrado médio do erro em ensaios de competição de cultivares de milho pelo método de Papadakis

O objetivo deste trabalho foi avaliar as diferentes formas de calcular o índice de produtividade, usado como covariável pelo método de Papadakis, e verificar se este método é eficiente para aumentar a precisão experimental nos ensaios de competição de cultivares de milho (Zea mays L.) com grande número de tratamentos. Em relação ao rendimento de grãos, procedeu-se a verificação das pressuposições do modelo matemático, a análise da variância no delineamento de blocos ao acaso e a análise de covariância no delineamento inteiramente casualizado, usando como covariável o índice de produtividade estimado por cinco formas (método de Papadakis). A comparação da análise convencional (blocos ao acaso) com a análise pelo método de Papadakis foi realizada com base nas estimativas do quadrado médio do erro, coeficiente de variação, diferença mínima significativa pelo teste de Tukey, número de grupos formados pelo teste de Scott-Knott e o índice de diferenciação de Fasoulas. O método de Papadakis melhorou a precisão experimental entre 10,5% e 48,1% em relação às diferentes formas de estimação da covariável índice de produtividade, mostrando que a vizinhança mais próxima (unidade experimental de referência e as quatro laterais) é a forma mais eficiente na redução do erro experimental.

Automatic filtering and substantiation of drug safety signals

Drug safety issues pose serious health threats to the population and constitute a major cause of mortality worldwide. Due to the prominent implications to both public health and the pharmaceutical industry, it is of great importance to unravel the molecular mechanisms by which an adverse drug reaction can be potentially elicited. These mechanisms can be investigated by placing the pharmaco-epidemiologically detected adverse drug reaction in an information-rich context and by exploiting all currently available biomedical knowledge to substantiate it. We present a computational framework for the biological annotation of potential adverse drug reactions. First, the proposed framework investigates previous evidences on the drug-event association in the context of biomedical literature (signal filtering). Then, it seeks to provide a biological explanation (signal substantiation) by exploring mechanistic connections that might explain why a drug produces a specific adverse reaction. The mechanistic connections include the activity of the drug, related compounds and drug metabolites on protein targets, the association of protein targets to clinical events, and the annotation of proteins (both protein targets and proteins associated with clinical events) to biological pathways. Hence, the workflows for signal filtering and substantiation integrate modules for literature and database mining, in silico drug-target profiling, and analyses based on gene-disease networks and biological pathways. Application examples of these workflows carried out on selected cases of drug safety signals are discussed. The methodology and workflows presented offer a novel approach to explore the molecular mechanisms underlying adverse drug reactions

The EU-ADR Web Platform: delivering advanced pharmacovigilance tools

PURPOSE: Pharmacovigilance methods have advanced greatly during the last decades, making post-market drug assessment an essential drug evaluation component. These methods mainly rely on the use of spontaneous reporting systems and health information databases to collect expertise from huge amounts of real-world reports. The EU-ADR Web Platform was built to further facilitate accessing, monitoring and exploring these data, enabling an in-depth analysis of adverse drug reactions risks.METHODS: The EU-ADR Web Platform exploits the wealth of data collected within a large-scale European initiative, the EU-ADR project. Millions of electronic health records, provided by national health agencies, are mined for specific drug events, which are correlated with literature, protein and pathway data, resulting in a rich drug-event dataset. Next, advanced distributed computing methods are tailored to coordinate the execution of data-mining and statistical analysis tasks. This permits obtaining a ranked drug-event list, removing spurious entries and highlighting relationships with high risk potential.RESULTS: The EU-ADR Web Platform is an open workspace for the integrated analysis of pharmacovigilance datasets. Using this software, researchers can access a variety of tools provided by distinct partners in a single centralized environment. Besides performing standalone drug-event assessments, they can also control the pipeline for an improved batch analysis of custom datasets. Drug-event pairs can be substantiated and statistically analysed within the platform's innovative working environment.CONCLUSIONS: A pioneering workspace that helps in explaining the biological path of adverse drug reactions was developed within the EU-ADR project consortium. This tool, targeted at the pharmacovigilance community, is available online at https://bioinformatics.ua.pt/euadr/. Copyright © 2012 John Wiley & Sons, Ltd.

Logging versus fire : how does disturbance type influence the abundance of Pinus strobus regeneration?

Abstract

Reduction of ARNT in myeloid cells causes immune suppression and delayed wound healing.

Aryl hydrocarbon receptor nuclear translocator (ARNT) is a transcription factor that binds to partners to mediate responses to environmental signals. To investigate its role in the innate immune system, floxed ARNT mice were bred with lysozyme M-Cre recombinase animals to generate lysozyme M-ARNT (LAR) mice with reduced ARNT expression. Myeloid cells of LAR mice had altered mRNA expression and delayed wound healing. Interestingly, when the animals were rendered diabetic, the difference in wound healing between the LAR mice and their littermate controls was no longer present, suggesting that decreased myeloid cell ARNT function may be an important factor in impaired wound healing in diabetes. Deferoxamine (DFO) improves wound healing by increasing hypoxia-inducible factors, which require ARNT for function. DFO was not effective in wounds of LAR mice, again suggesting that myeloid cells are important for normal wound healing and for the full benefit of DFO. These findings suggest that myeloid ARNT is important for immune function and wound healing. Increasing ARNT and, more specifically, myeloid ARNT may be a therapeutic strategy to improve wound healing.

TWEAK, via its receptor Fn14, is a novel regulator of mesenchymal progenitor cells and skeletal muscle regeneration.

Inflammation participates in tissue repair through multiple mechanisms including directly regulating the cell fate of resident progenitor cells critical for successful regeneration. Upon surveying target cell types of the TNF ligand TWEAK, we observed that TWEAK binds to all progenitor cells of the mesenchymal lineage and induces NF-kappaB activation and the expression of pro-survival, pro-proliferative and homing receptor genes in the mesenchymal stem cells, suggesting that this pro-inflammatory cytokine may play an important role in controlling progenitor cell biology. We explored this potential using both the established C2C12 cell line and primary mouse muscle myoblasts, and demonstrated that TWEAK promoted their proliferation and inhibited their terminal differentiation. By generating mice deficient in the TWEAK receptor Fn14, we further showed that Fn14-deficient primary myoblasts displayed significantly reduced proliferative capacity and altered myotube formation. Following cardiotoxin injection, a known trigger for satellite cell-driven skeletal muscle regeneration, Fn14-deficient mice exhibited reduced inflammatory response and delayed muscle fiber regeneration compared with wild-type mice. These results indicate that the TWEAK/Fn14 pathway is a novel regulator of skeletal muscle precursor cells and illustrate an important mechanism by which inflammatory cytokines influence tissue regeneration and repair. Coupled with our recent demonstration that TWEAK potentiates liver progenitor cell proliferation, the expression of Fn14 on all mesenchymal lineage progenitor cells supports a broad involvement of this pathway in other tissue injury and disease settings.

Conflictivitat comunicativa en episodis d'emergència: aproximació a la cobertura informativa i la gestió institucional de l'esfondrament d'un túnel del metro al barri del Carmel de Barcelona

En aquesta investigació s’estudien els processos de producció de la informacióper part dels mitjans de comunicació i la gestió comunicativa institucional en episodis d’emergència. En concret, s’analitzen les negociacions entre els actors, les fonts informatives i el respecte deontològic en la divulgacióde les notícies. Per tal de conèixer específicament aquesta conflictivitat,s’ha escollit per a l’estudi de cas l’esfondrament d’un túnel del metro albarri del Carmel de Barcelona el gener de 2005. Per a realitzar aquesta investigació,s’ha utilitzat una perspectiva teòrica multidisciplinària. S’han pres en consideració els postulats teòrics de la sociologia, a partir del diàleg queestableixen diferents autors (Beck, Giddens, Lash i Luhmann) entre el conceptede modernitat i el nou paradigma que Beck (1998) denomina la societat del risc. També s’han tingut en compte els camps de la teoria i la sociologia de la comunicació i, més específicament, el marc teòric del periodisme i de les relacions públiques.

Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure.

Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 × 10(-8) to P = 2.3 × 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP.

Leguminosas arbóreas introduzidas em pastagem

O objetivo deste trabalho foi analisar, por meio de métodos de análise de variância multivariada, o comportamento de 16 espécies de leguminosas arbóreas, introduzidas em pastagem estabelecida de Brachiaria decumbens, a partir de mudas pequenas e em presença de animais, em quatro épocas do ano, em Seropédica, RJ. Nove variáveis relacionadas ao comprimento e ao número de brotos das mudas, antes e após o pastejo dos animais, foram utilizadas nas avaliações. As diferenças estatísticas entre as médias da variável canônica principal, pelo teste de Scott-Knott, indicaram a formação de quatro agrupamentos, tendo-se destacado o grupo formado pelos tratamentos Mimosa tenuiflora nas 3ª e 4ª avaliações. Diferenças entre as médias dos tratamentos, para cada variável, calculadas por meio de intervalos de confiança de Bonferroni, mostraram que o maior comprimento e o maior número de brotos na muda, após o pastejo, foram encontrados na M. tenuiflora. Esta leguminosa é indicada para ser introduzida, com maior probabilidade de sucesso, nas pastagens de B. decumbens na região, sem a proteção das mudas e em presença de gado.

GWAS of 126,559 individuals identifies genetic variants associated with educational attainment.

A genome-wide association study (GWAS) of educational attainment was conducted in a discovery sample of 101,069 individuals and a replication sample of 25,490. Three independent single-nucleotide polymorphisms (SNPs) are genome-wide significant (rs9320913, rs11584700, rs4851266), and all three replicate. Estimated effects sizes are small (coefficient of determination R(2) ≈ 0.02%), approximately 1 month of schooling per allele. A linear polygenic score from all measured SNPs accounts for ≈2% of the variance in both educational attainment and cognitive function. Genes in the region of the loci have previously been associated with health, cognitive, and central nervous system phenotypes, and bioinformatics analyses suggest the involvement of the anterior caudate nucleus. These findings provide promising candidate SNPs for follow-up work, and our effect size estimates can anchor power analyses in social-science genetics.

Caracterização morfoagronômica e coeficientes de trilha de caracteres componentes da produção em mandioca

Os objetivos deste trabalho foram caracterizar agronomicamente cem clones de mandioca (Manihot esculenta Crantz) e calcular os coeficientes de trilha entre a produção de raízes tuberosas e cinco componentes da produção, de modo a auxiliar na seleção de clones superiores. O experimento foi conduzido em área experimental da Universidade Federal de Lavras, em 2005 e 2006. Cem clones de mandioca foram avaliados em delineamento látice quadrado 10x10. A unidade experimental foi constituída por quatro plantas espaçadas de 1,0x0,6 m. As análises estatísticas foram realizadas considerando-se as oito características individualmente, utilizando-se o teste de Scott-Knott para agrupamento das médias. Os clones 87 e 88 mostraram-se promissores tanto para serem utilizados em cruzamentos quanto para fixação como novas cultivares em virtude do excelente desempenho nas características comprimento, número e produção de raízes tuberosas por planta. A análise de trilha mostrou que o número de raízes por planta e o peso total da parte aérea podem ser utilizados como critérios na seleção indireta para produção de raízes tuberosas em mandioca.

No interactions between previously associated 2-hour glucose gene variants and physical activity or BMI on 2-hour glucose levels.

Gene-lifestyle interactions have been suggested to contribute to the development of type 2 diabetes. Glucose levels 2 h after a standard 75-g glucose challenge are used to diagnose diabetes and are associated with both genetic and lifestyle factors. However, whether these factors interact to determine 2-h glucose levels is unknown. We meta-analyzed single nucleotide polymorphism (SNP) × BMI and SNP × physical activity (PA) interaction regression models for five SNPs previously associated with 2-h glucose levels from up to 22 studies comprising 54,884 individuals without diabetes. PA levels were dichotomized, with individuals below the first quintile classified as inactive (20%) and the remainder as active (80%). BMI was considered a continuous trait. Inactive individuals had higher 2-h glucose levels than active individuals (β = 0.22 mmol/L [95% CI 0.13-0.31], P = 1.63 × 10(-6)). All SNPs were associated with 2-h glucose (β = 0.06-0.12 mmol/allele, P ≤ 1.53 × 10(-7)), but no significant interactions were found with PA (P > 0.18) or BMI (P ≥ 0.04). In this large study of gene-lifestyle interaction, we observed no interactions between genetic and lifestyle factors, both of which were associated with 2-h glucose. It is perhaps unlikely that top loci from genome-wide association studies will exhibit strong subgroup-specific effects, and may not, therefore, make the best candidates for the study of interactions.

Divergência genética entre cinco cultivares de mamoneira

O objetivo deste trabalho foi avaliar a divergência genética entre cultivares de mamoneira (Ricinus communis L.), a partir dos caracteres adaptativos, dos componentes de produção e do rendimento. O experimento em delineamento em blocos ao acaso, com cinco tratamentos e cinco repetições, foi implantado em Latossolo Amarelo em Cruz das Almas, BA. Os dados foram submetidos à análise de variância, ordenados pelo teste de Scott-Knott, a 5% de probabilidade e, com base na análise multivariada, realizou-se análise de agrupamento e análise dos componentes principais para determinação da divergência genética. Houve formação de três grupos, ou seja, constatou-se a existência de divergência genética entre os genótipos. A cultivar mais divergente foi Mirante 10, e não é recomendada para hibridação em virtude do baixo desempenho apresentado. Há expectativa de combinações promissoras entre Sipeal 28 x BRS 188 Paraguaçu, Sipeal 28 x BRS 149 Nordestina, EBDA MPA 17 x BRS 188 Paraguaçu e EBDA MPA 17 x BRS 149 Nordestina, em virtude da maior dissimilaridade apresentada e do melhor desempenho médio desses genótipos.