Prospective study of insulin-like growth factor-I, insulin-like growth factor-binding protein 3, genetic variants in the IGF1 and IGFBP3 genes and risk of coronary artery disease.

Although experimental studies have suggested that insulin-like growth factor I (IGF-I) and its binding protein IGFBP-3 might have a role in the aetiology of coronary artery disease (CAD), the relevance of circulating IGFs and their binding proteins in the development of CAD in human populations is unclear. We conducted a nested case-control study, with a mean follow-up of six years, within the EPIC-Norfolk cohort to assess the association between circulating levels of IGF-I and IGFBP-3 and risk of CAD in up to 1,013 cases and 2,055 controls matched for age, sex and study enrolment date. After adjustment for cardiovascular risk factors, we found no association between circulating levels of IGF-I or IGFBP-3 and risk of CAD (odds ratio: 0.98 (95% Cl 0.90-1.06) per 1 SD increase in circulating IGF-I; odds ratio: 1.02 (95% Cl 0.94-1.12) for IGFBP-3). We examined associations between tagging single nucleotide polymorphisms (tSNPs) at the IGF1 and IGFBP3 loci and circulating IGF-I and IGFBP-3 levels in up to 1,133 cases and 2,223 controls and identified three tSNPs (rs1520220, rs3730204, rs2132571) that showed independent association with either circulating IGF-I or IGFBP-3 levels. In an assessment of 31 SNPs spanning the IGF1 or IGFBP3 loci, none were associated with risk of CAD in a meta-analysis that included EPIC-Norfolk and eight additional studies comprising up to 9,319 cases and 19,964 controls. Our results indicate that IGF-I and IGFBP-3 are unlikely to be importantly involved in the aetiology of CAD in human populations.

Meta-analysis and imputation refines the association of 15q25 with smoking quantity.

Smoking is a leading global cause of disease and mortality. We established the Oxford-GlaxoSmithKline study (Ox-GSK) to perform a genome-wide meta-analysis of SNP association with smoking-related behavioral traits. Our final data set included 41,150 individuals drawn from 20 disease, population and control cohorts. Our analysis confirmed an effect on smoking quantity at a locus on 15q25 (P = 9.45 x 10(-19)) that includes CHRNA5, CHRNA3 and CHRNB4, three genes encoding neuronal nicotinic acetylcholine receptor subunits. We used data from the 1000 Genomes project to investigate the region using imputation, which allowed for analysis of virtually all common SNPs in the region and offered a fivefold increase in marker density over HapMap2 (ref. 2) as an imputation reference panel. Our fine-mapping approach identified a SNP showing the highest significance, rs55853698, located within the promoter region of CHRNA5. Conditional analysis also identified a secondary locus (rs6495308) in CHRNA3.

Comparative analysis of the transcriptome across distant species.

The transcriptome is the readout of the genome. Identifying common features in it across distant species can reveal fundamental principles. To this end, the ENCODE and modENCODE consortia have generated large amounts of matched RNA-sequencing data for human, worm and fly. Uniform processing and comprehensive annotation of these data allow comparison across metazoan phyla, extending beyond earlier within-phylum transcriptome comparisons and revealing ancient, conserved features. Specifically, we discover co-expression modules shared across animals, many of which are enriched in developmental genes. Moreover, we use expression patterns to align the stages in worm and fly development and find a novel pairing between worm embryo and fly pupae, in addition to the embryo-to-embryo and larvae-to-larvae pairings. Furthermore, we find that the extent of non-canonical, non-coding transcription is similar in each organism, per base pair. Finally, we find in all three organisms that the gene-expression levels, both coding and non-coding, can be quantitatively predicted from chromatin features at the promoter using a 'universal model' based on a single set of organism-independent parameters.

BAFF binds to the tumor necrosis factor receptor-like molecule B cell maturation antigen and is important for maintaining the peripheral B cell population.

The tumor necrosis factor (TNF) family member B cell activating factor (BAFF) binds B cells and enhances B cell receptor-triggered proliferation. We find that B cell maturation antigen (BCMA), a predicted member of the TNF receptor family expressed primarily in mature B cells, is a receptor for BAFF. Although BCMA was previously localized to the Golgi apparatus, BCMA was found to be expressed on the surface of transfected cells and tonsillar B cells. A soluble form of BCMA, which inhibited the binding of BAFF to a B cell line, induced a dramatic decrease in the number of peripheral B cells when administered in vivo. Moreover, culturing splenic cells in the presence of BAFF increased survival of a percentage of the B cells. These results are consistent with a role for BAFF in maintaining homeostasis of the B cell population.

Comportamento de cultivares de uva sem sementes no submédio São Francisco

Com o objetivo de introduzir, avaliar e selecionar variedades de uva sem sementes, adaptadas às condições tropicais semi-áridas e oferecer novas alternativas aos viticultores do Vale do São Francisco, implantou-se, em 1994, uma coleção com dezenove variedades de uvas sem sementes no Campo Experimental de Bebedouro, da Embrapa Semi-Árido, em Petrolina - PE. Foram avaliadas treze variedades ao longo dos anos de 1997 e 1998, correspondendo a cinco ciclos de produção. As variedades utilizadas foram Vênus, Arizul, Beauty Seedless, Thompson Seedless, Marroo Seedless, Canner, CG 39915, Pasiga, Saturn, Emperatriz, A1581, Paulistinha e Loose Perlette, enxertadas sobre o porta-enxerto IAC 572 ('Campinas'). Foram avaliados aspectos relacionados ao desenvolvimento vegetativo e produtivo das plantas e características e composição química dos frutos. Todas as variedades apresentaram cachos com tamanho pequeno. As variedades Vênus e Marroo Seedless destacaram-se em relação ao diâmetro de bagas, apresentando, respectivamente, 17,83 e 18,26 mm, sem a necessidade de aplicação de reguladores de crescimento. O teor de sólidos solúveis totais foi elevado na maioria das variedades, enquanto a acidez total titulável foi reduzida, resultando em relações SST/ATT satisfatórias. As variedades Vênus e Marroo Seedless foram as mais produtivas, com produtividades anuais de 24 t/ha e 20 t/ha, respectivamente.

Brotação e fertilidade de gemas em uvas sem sementes no Vale do São Francisco

Com o objetivo de avaliar a porcentagem de brotação e índice de fertilidade de gemas de cinco variedades de uvas sem sementes em cinco diferentes datas de poda, realizou-se um experimento no Campo Experimental de Bebedouro, da Embrapa Semi-Árido, em Petrolina-PE. O delineamento experimental foi em parcelas subdivididas, constituídas por cinco variedades de uvas sem sementes como tratamentos principais e cinco diferentes épocas de poda como tratamentos secundários, utilizando-se dez repetições constituídas por uma planta. As variedades utilizadas foram Perlette, Thompson Seedless, Marroo Seedless, Catalunha e Superior Seedless, e as épocas de poda foram: 18 e 19/12/2000; 18 a 21/06/2001; 23 a 29/10/2001; 29/01 a 05/02/2002 e 08 a 12/04/2002. As variáveis estudadas foram a porcentagem de brotação e o índice de fertilidade real das gemas determinado pela razão número de cachos por número de gemas. A fertilidade real de gemas foi analisada entre a 1ª e 10ª gema da vara. Os maiores valores médios para brotação e fertilidade foram observados nas variedades Marroo Seedless e Perlette, sendo que as podas realizadas nos meses de junho de 2001 e abril de 2002 favoreceram o aumento da brotação e da fertilidade das gemas na maioria das variedades.

Caracterização fenológica e requerimentos térmicos de variedades de uvas sem sementes no Vale do São Francisco

O comportamento fenológico e requerimentos térmicos de variedades de uvas sem sementes foram estudados nas condições do Vale do São Francisco durante os anos de 2001-2002, em seis diferentes datas de poda (12/2000, 04/2001, 06/2001, 10/2001, 01-02/2002 e 04/2002). O experimento foi realizado no Campo Experimental de Bebedouro, em Petrolina-PE. As variedades utilizadas foram Superior Seedless (Festival), Thompson Seedless, Catalunha, Perlette e Marroo Seedless, enxertadas sobre porta-enxerto IAC 572 ('Jales'). Avaliou-se a duração em dias dos estádios fenológicos, gemas dormentes (data de poda) a gemas inchadas (1), gemas inchadas a início de brotação (2), início de brotação a 5-6 folhas separadas (3), 5-6 folhas separadas a início de floração (4), início de floração à plena-floração (5), plena-floração a "chumbinho" (6), "chumbinho" à "ervilha" (7), "ervilha" a ½ baga (8), ½ baga a início de maturação (9) e início de maturação à maturação plena (10). Os requerimentos térmicos foram obtidos em termos de graus-dia (GD) necessários para atingir cada fase fenológica a partir da poda. O ciclo fenológico médio variou de 89 dias e 1.315 GD na variedade Superior Seedless a 105 dias e 1.514 GD na variedade Perlette, destacando-se as variedades Superior Seedless e Marroo Seedless como precoces e as demais com ciclo intermediário. Os períodos compreendidos entre o início e final da maturação, ½ baga a início de maturação e 5 a 6 folhas separadas a início de floração apresentaram a maior duração entre todos os subperíodos em todas as variedades.

Caracterización mecánica de rollizos de sabina (Juniperus thurifera L.) de Castilla y León. Prueba de clasificación visual y evaluación mediante resonancia

El present treball es centra en la fusta en roll per a ús estructural de savina turífera (Juniperus thurifera L.) de Castella i Lleó. En ell s'ha caracteritzat mecànicament aquest material, determinant la resistència a flexió, el mòdul d'elasticitat i la densitat. En funció d'aquests tres paràmetres s'ha assignat una classe resistent al material. S'han avaluat diferents classificacions visuals per agrupar la població en subgrups en funció de les seves singularitats visuals, caracteritzant mecànicament cada un d'aquests subgrups. Així mateix s'ha avaluat el mètode de freqüència de ressonància com a estimador dels paràmetres mecànics. Aquesta metodologia està basada en la lectura de la freqüència sonora del material, a partir d'aquesta freqüència s'han proposat models per a estimar el mòdul d'elasticitat i la resistència a flexió del roll de savina.

Expresiones para la determinación del factor de fricción en ríos de fuerte pendiente

Con base en una selección de 145 datos pertenecientes a ríos de montaña de fuerte pendiente (³ 1%) se han desarrollado cinco expresiones para determinar el factor de fricción de Darcy-Weisbach. La primera expresión se fundamenta en la aplicación para flujo turbulento rugoso en lámina libre de la ley semilogarítmica de Prandtl-Kárman, que es función de la sumersión relativa (relación entre el calado medio y la rugosidad equivalente). La segunda y tercera corresponden a correciones de la primera para flujo macrorrugoso, propuestas por Thompson y Campbell (1979) y Aguirre-Pe y Fuentes (1990) respectivamente. La cuarta ecuación consiste una en potencia de la sumersión relativa, mientras que la quinta corrige la fórmula anterior incorporando una potencia de la pendiente, tal y como propugnan Meunier (1989) y Rickenmann (1990). Las expresiones derivadas presentan un ajuste significativo, si se tienen en cuenta las limitaciones hidrométricas existentes en ríos de material grueso y fuerte pendiente. Destaca el mayor ajuste conseguido con las ecuaciones con las ecuaciones del tipo potencial frente a las del tipo semilogarítmico. Se ha encontrado, asimismo, una capacidad de predicción ligeramente superior en aquellas expresiones que incluyen modificaciones respecto a la ecuación original, ecuaciones del tipo segundo, tercero y quinto anteriormente indicado.

Identification of potential HIV restriction factors by combining evolutionary genomic signatures with functional analyses.

BACKGROUND: Known antiretroviral restriction factors are encoded by genes that are under positive selection pressure, induced during HIV-1 infection, up-regulated by interferons, and/or interact with viral proteins. To identify potential novel restriction factors, we performed genome-wide scans for human genes sharing molecular and evolutionary signatures of known restriction factors and tested the anti-HIV-1 activity of the most promising candidates. RESULTS: Our analyses identified 30 human genes that share characteristics of known restriction factors. Functional analyses of 27 of these candidates showed that over-expression of a strikingly high proportion of them significantly inhibited HIV-1 without causing cytotoxic effects. Five factors (APOL1, APOL6, CD164, TNFRSF10A, TNFRSF10D) suppressed infectious HIV-1 production in transfected 293T cells by >90% and six additional candidates (FCGR3A, CD3E, OAS1, GBP5, SPN, IFI16) achieved this when the virus was lacking intact accessory vpr, vpu and nef genes. Unexpectedly, over-expression of two factors (IL1A, SP110) significantly increased infectious HIV-1 production. Mechanistic studies suggest that the newly identified potential restriction factors act at different steps of the viral replication cycle, including proviral transcription and production of viral proteins. Finally, we confirmed that mRNA expression of most of these candidate restriction factors in primary CD4+ T cells is significantly increased by type I interferons. CONCLUSIONS: A limited number of human genes share multiple characteristics of genes encoding for known restriction factors. Most of them display anti-retroviral activity in transient transfection assays and are expressed in primary CD4+ T cells.

Movilidad intergeneracional y emparejamiento selectivo en España

This paper examines the role of assortative mating in the intergenerational economic mobility in Spain. Sons and daughters usually marry individuals with similar characteristics, which may lower mobility. Our empirical strategy employs the Two-sample two-stage least squares estimator to estimate the intergenerational income elasticity in absence of data for two generations not residing in the same household. Our findings suggest that assortative mating plays an important role in the intergenerational transmission process. On average about 50 per 100 of the covariance between parents’ income and child family’s incomecan be accounted for by the person the child is married to

Redox Signaling by the RNA Polymerase III TFIIB-Related Factor Brf2.

TFIIB-related factor 2 (Brf2) is a member of the family of TFIIB-like core transcription factors. Brf2 recruits RNA polymerase (Pol) III to type III gene-external promoters, including the U6 spliceosomal RNA and selenocysteine tRNA genes. Found only in vertebrates, Brf2 has been linked to tumorigenesis but the underlying mechanisms remain elusive. We have solved crystal structures of a human Brf2-TBP complex bound to natural promoters, obtaining a detailed view of the molecular interactions occurring at Brf2-dependent Pol III promoters and highlighting the general structural and functional conservation of human Pol II and Pol III pre-initiation complexes. Surprisingly, our structural and functional studies unravel a Brf2 redox-sensing module capable of specifically regulating Pol III transcriptional output in living cells. Furthermore, we establish Brf2 as a central redox-sensing transcription factor involved in the oxidative stress pathway and provide a mechanistic model for Brf2 genetic activation in lung and breast cancer.

Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair.

Menopause timing has a substantial impact on infertility and risk of disease, including breast cancer, but the underlying mechanisms are poorly understood. We report a dual strategy in ∼70,000 women to identify common and low-frequency protein-coding variation associated with age at natural menopause (ANM). We identified 44 regions with common variants, including two regions harboring additional rare missense alleles of large effect. We found enrichment of signals in or near genes involved in delayed puberty, highlighting the first molecular links between the onset and end of reproductive lifespan. Pathway analyses identified major association with DNA damage response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomization analyses supported a causal effect of later ANM on breast cancer risk (∼6% increase in risk per year; P = 3 × 10(-14)), likely mediated by prolonged sex hormone exposure rather than DDR mechanisms.

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In the past 2 decades, there has been an increase in both basic science research detailing the anatomy and biomechanics of the native posterior cruciate ligament (PCL) and outcome studies evaluating manage- ment of the ruptured PCL. While the methodology of the latter continues to improve, results based on the current level of evidence must be interpreted cautiously (18). The focus of many recent studies has been double-bundle versus single-bundle reconstruction techniques. The theoretical advantage goes to double-bundle techniques, but a clinical difference in outcome has not been consistently demonstrated (8,17). Some biomechanical studies have reported improved control of posterior laxity with double-bundle reconstruc- tion; however, results appear to be more dependent on tunnel position and graft tensioning (13). In acute isolated symptomatic PCL injuries in which the posteromedial bundle and the meniscofemoral ligament remain intact, a single-bundle augmentation procedure may be the preferred surgical technique. In more complex PCL ruptures with associated injuries involving the posterolateral structures (PLS) or medial collateral ligament, more benefit may be derived from double-bundle reconstruction. Again, cadaveric testing of double-bundle PCL reconstruction has not consistently outperformed single-bundle techniques in combined PCL/PLS injury (3). Multi-ligamentous injuries are commonly associated with PCL rupture (15), and their management should be considered carefully in the decision to reconstruct one or both of the functionally dis- tinct PCL bundles. However, the technical complexity of double-bundle reconstruction, the longer surgical time required, as well as the inconclusive clinical outcome are all factors that must be weighed carefully.

Paranoia and post-traumatic stress disorder in the months after a physical assault: a longitudinal study examining shared and differential predictors.

Background: Being physically assaulted is known to increase the risk of the occurrence of post-traumatic stress disorder (PTSD) symptoms but it may also skew judgements about the intentions of other people. The objectives of the study were to assess paranoia and PTSD after an assault and to test whether theory-derived cognitive factors predicted the persistence of these problems. Method: At 4 weeks after hospital attendance due to an assault, 106 people were assessed on multiple symptom measures (including virtual reality) and cognitive factors from models of paranoia and PTSD. The symptom measures were repeated 3 and 6 months later. Results: Factor analysis indicated that paranoia and PTSD were distinct experiences, though positively correlated. At 4 weeks, 33% of participants met diagnostic criteria for PTSD, falling to 16% at follow-up. Of the group at the first assessment, 80% reported that since the assault they were excessively fearful of other people, which over time fell to 66%. Almost all the cognitive factors (including information-processing style during the trauma, mental defeat, qualities of unwanted memories, self-blame, negative thoughts about self, worry, safety behaviours, anomalous internal experiences and cognitive inflexibility) predicted later paranoia and PTSD, but there was little evidence of differential prediction. Conclusions: Paranoia after an assault may be common and distinguishable from PTSD but predicted by a strikingly similar range of factors.