Pore-forming pyocin S5 utilizes the FptA ferripyochelin receptor to kill Pseudomonas aeruginosa.

Pyocins are toxic proteins produced by some strains of Pseudomonas aeruginosa that are lethal for related strains of the same species. Some soluble pyocins (S2, S3 and S4) were previously shown to use the pyoverdine siderophore receptors to enter the cell. The P. aeruginosa PAO1 pore-forming pyocin S5 encoding gene (PAO985) was cloned into the expression vector pET15b, and the affinity-purified protein product tested for its killing activity against different P. aeruginosa strains. The results, however, did not show any correlation with a specific ferripyoverdine receptor. To further identify the S5 receptor, transposon mutants were generated. Pooled mutants were exposed to pyocin S5 and the resistant colonies growing in the killing zone were selected. The majority of S5-resistant mutants had an insertion in the fptA gene encoding the receptor for the siderophore pyochelin. Complementation of an fptA transposon mutant with the P. aeruginosa fptA gene in trans restored the sensitivity to S5. In order to define the receptor-binding domain of pyocin S5, two hybrid pyocins were constructed containing different regions from pyocin S5 fused to the C-terminal translocation and DNase killing domains of pyocin S2. Only the protein containing amino acid residues 151 to 300 from S5 showed toxicity, indicating that the pyocin S5 receptor-binding domain is not at the N-terminus of the protein as in other S-type pyocins. Pyocin S5 was, however, unable to kill Burkholderia cenocepacia strains producing a ferripyochelin FptA receptor, nor was the B. cenocepacia fptA gene able to restore the sensitivity of the resistant fptA mutant P. aeruginosa strain.

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.

Financiamento dos Sistema de Saude

Este Relatório sobre a Saúde no Mundo foi produzido sob a direcção geral de Carissa Etienne, Assistente do Director-Geral, Sistemas e Serviços de Saúde e Anarfi Asamoa-Baah, Director Geral Adjunto. Os redactores principais froam David B Evans, Riku Elovainio e Gary Humphreys; com contribuições de Daniel Chisholm, Joseph Kutzin, Sarah Russell, Priyanka Saksena e Ke Xu. Contribuições sob a forma de caixas de texto e análises foram fornecidos por: Ole Doetinchem, Adelio Fernandes Antunes, Justine Hsu, Chandika K. Indikadahena, Jeremy Lauer, Nathalie van de Maele, Belgacem Sabri, Hossein Salehi, Xenia Scheil-Adlung (ILO) and Karin Stenberg. Sugestões e comentários foram recebidos dos Directores Regionais, Assistentes do Director-Geral e respectivas equipas. Análises, dados e revisões da organização do texto, vários rascunhos ou secções específicas foram fornecidos por (em adição às pessoas jáacima mencionadas): Dele Abegunde, Michael Adelhardt, Hector Arreola, Guitelle Baghdadi-Sabeti, Dina Balabanova, Dorjsuren Bayarsaikhan, Peter Berman, Melanie Bertram, Michael Borowitz, Reinhard Busse, Alexandra Cameron, Guy Carrin, Andrew Cassels, Eleonora Cavagnero, John Connell, David de Ferranti, Don de Savigny, Varatharajan Durairaj, Tamás Evetovits, Josep Figueras, Emma Fitzpatrick, Julio Frenk, Daniela Fuhr, Ramiro Guerrero, Patricia Hernandez Pena, Hans V Hogerzeil, Kathleen Holloway, Melitta Jakab, Elke Jakubowski, Christopher James, Mira Johri, Matthew Jowett, Joses Kirigia, Felicia Knaul, Richard Laing, Nora Markova, Awad Mataria, Inke Mathauer, Don Matheson, Anne Mills, Eduardo Missoni, Laurent Musango, Helena Nygren-Krug, Ariel Pablos-Mendez, Anne-Marie Perucic, Claudia Pescetto, Jean Perrot, Alexander Preker, Magdalena Rathe, Dag Rekve, Ritu Sadana, Rocio Saenz, Thomas Shakespeare, Ian Smith, Peter C Smith, Alaka Singh, Ruben Suarez Berenguela, Tessa Tan-Torres Edejer, Richard Scheffler, Viroj Tangcharoensathien, Fabrizio Tediosi, Sarah Thomson, Ewout van Ginneken, Cornelis van Mosseveld e Julia Watson. A redacção do Relatório foi informada por muitos indivíduos de várias instituições que forneceram documentos de suporte; estes documentos de suporte podem ser encontrados em: http://www.who.int/healthsystems/topics/financing/healthreport/whr_background/en Michael Reid editou as cópias do Relatório, Gaël Kernen produziu as figuras e Evelyn Omukubi forneceu o valioso apoio secretarial e administrativo. O desenho e paginação foi feito por Sophie Guetaneh Aguettant e Cristina Ortiz. Ilustração por Edel Tripp (http://edeltripp.daportfolio.com). A tradução foi realizada por Jorge Cabral e Aurélio Floriano e revista por Aurélio Floriano e Paulo Ferrinho, do Instituto de Higiene e Medicina Tropical, da Universidade Nova de Lisboa - Lisboa, Portugal. A publicação foi produzida com o apoio da Comunidade dos Países de Língua Portuguesa (CPLP), sob autorização do Director Geral da Organização Mundial da Saúde (OMS). As informações contidas neste Relatório não podem, de forma alguma, ser tomadas como a expressão das posições da CPLP

A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance.

Recent genome-wide association studies have described many loci implicated in type 2 diabetes (T2D) pathophysiology and β-cell dysfunction but have contributed little to the understanding of the genetic basis of insulin resistance. We hypothesized that genes implicated in insulin resistance pathways might be uncovered by accounting for differences in body mass index (BMI) and potential interactions between BMI and genetic variants. We applied a joint meta-analysis approach to test associations with fasting insulin and glucose on a genome-wide scale. We present six previously unknown loci associated with fasting insulin at P < 5 × 10(-8) in combined discovery and follow-up analyses of 52 studies comprising up to 96,496 non-diabetic individuals. Risk variants were associated with higher triglyceride and lower high-density lipoprotein (HDL) cholesterol levels, suggesting a role for these loci in insulin resistance pathways. The discovery of these loci will aid further characterization of the role of insulin resistance in T2D pathophysiology.

Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function.

In conducting genome-wide association studies (GWAS), analytical approaches leveraging biological information may further understanding of the pathophysiology of clinical traits. To discover novel associations with estimated glomerular filtration rate (eGFR), a measure of kidney function, we developed a strategy for integrating prior biological knowledge into the existing GWAS data for eGFR from the CKDGen Consortium. Our strategy focuses on single nucleotide polymorphism (SNPs) in genes that are connected by functional evidence, determined by literature mining and gene ontology (GO) hierarchies, to genes near previously validated eGFR associations. It then requires association thresholds consistent with multiple testing, and finally evaluates novel candidates by independent replication. Among the samples of European ancestry, we identified a genome-wide significant SNP in FBXL20 (P = 5.6 × 10(-9)) in meta-analysis of all available data, and additional SNPs at the INHBC, LRP2, PLEKHA1, SLC3A2 and SLC7A6 genes meeting multiple-testing corrected significance for replication and overall P-values of 4.5 × 10(-4)-2.2 × 10(-7). Neither the novel PLEKHA1 nor FBXL20 associations, both further supported by association with eGFR among African Americans and with transcript abundance, would have been implicated by eGFR candidate gene approaches. LRP2, encoding the megalin receptor, was identified through connection with the previously known eGFR gene DAB2 and extends understanding of the megalin system in kidney function. These findings highlight integration of existing genome-wide association data with independent biological knowledge to uncover novel candidate eGFR associations, including candidates lacking known connections to kidney-specific pathways. The strategy may also be applicable to other clinical phenotypes, although more testing will be needed to assess its potential for discovery in general.

Pedotransfer functions related to spatial variability of water retention attributes for lowland soils

The estimation of non available soil variables through the knowledge of other related measured variables can be achieved through pedotransfer functions (PTF) mainly saving time and reducing cost. Great differences among soils, however, can yield non desirable results when applying this method. This study discusses the application of developed PTFs by several authors using a variety of soils of different characteristics, to evaluate soil water contents of two Brazilian lowland soils. Comparisons are made between PTF evaluated data and field measured data, using statistical and geostatistical tools, like mean error, root mean square error, semivariogram, cross-validation, and regression coefficient. The eight tested PTFs to evaluate gravimetric soil water contents (Ug) at the tensions of 33 kPa and 1,500 kPa presented a tendency to overestimate Ug 33 kPa and underestimate Ug1,500 kPa. The PTFs were ranked according to their performance and also with respect to their potential in describing the structure of the spatial variability of the set of measured values. Although none of the PTFs have changed the distribution pattern of the data, all resulted in mean and variance statistically different from those observed for all measured values. The PTFs that presented the best predictive values of Ug33 kPa and Ug1,500 kPa were not the same that had the best performance to reproduce the structure of spatial variability of these variables.

Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders.

Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate-increasing and heart rate-decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.

Pedotransfer functions to predict water retention for soils of the humid tropics: a review

Over the past three decades, pedotransfer functions (PTFs) have been widely used by soil scientists to estimate soils properties in temperate regions in response to the lack of soil data for these regions. Several authors indicated that little effort has been dedicated to the prediction of soil properties in the humid tropics, where the need for soil property information is of even greater priority. The aim of this paper is to provide an up-to-date repository of past and recently published articles as well as papers from proceedings of events dealing with water-retention PTFs for soils of the humid tropics. Of the 35 publications found in the literature on PTFs for prediction of water retention of soils of the humid tropics, 91 % of the PTFs are based on an empirical approach, and only 9 % are based on a semi-physical approach. Of the empirical PTFs, 97 % are continuous, and 3 % (one) is a class PTF; of the empirical PTFs, 97 % are based on multiple linear and polynomial regression of n th order techniques, and 3 % (one) is based on the k-Nearest Neighbor approach; 84 % of the continuous PTFs are point-based, and 16 % are parameter-based; 97 % of the continuous PTFs are equation-based PTFs, and 3 % (one) is based on pattern recognition. Additionally, it was found that 26 % of the tropical water-retention PTFs were developed for soils in Brazil, 26 % for soils in India, 11 % for soils in other countries in America, and 11 % for soils in other countries in Africa.

Common variants in mendelian kidney disease genes and their association with renal function.

Many common genetic variants identified by genome-wide association studies for complex traits map to genes previously linked to rare inherited Mendelian disorders. A systematic analysis of common single-nucleotide polymorphisms (SNPs) in genes responsible for Mendelian diseases with kidney phenotypes has not been performed. We thus developed a comprehensive database of genes for Mendelian kidney conditions and evaluated the association between common genetic variants within these genes and kidney function in the general population. Using the Online Mendelian Inheritance in Man database, we identified 731 unique disease entries related to specific renal search terms and confirmed a kidney phenotype in 218 of these entries, corresponding to mutations in 258 genes. We interrogated common SNPs (minor allele frequency >5%) within these genes for association with the estimated GFR in 74,354 European-ancestry participants from the CKDGen Consortium. However, the top four candidate SNPs (rs6433115 at LRP2, rs1050700 at TSC1, rs249942 at PALB2, and rs9827843 at ROBO2) did not achieve significance in a stage 2 meta-analysis performed in 56,246 additional independent individuals, indicating that these common SNPs are not associated with estimated GFR. The effect of less common or rare variants in these genes on kidney function in the general population and disease-specific cohorts requires further research.

Genome-wide association and functional follow-up reveals new loci for kidney function.

Chronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genome-wide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD.

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.