Sex-stratified genome-wide association studies including 270,000 individuals show sexual dimorphism in genetic loci for anthropometric traits.

Given the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals) and took forward 348 SNPs into follow-up (additional 137,052 individuals) in a total of 94 studies. Seven loci displayed significant sex-difference (FDR<5%), including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were genome-wide significant in women (P<5×10(-8)), but not in men. Sex-differences were apparent only for waist phenotypes, not for height, weight, BMI, or hip circumference. Moreover, we found no evidence for genetic effects with opposite directions in men versus women. The PPARG locus is of specific interest due to its role in diabetes genetics and therapy. Our results demonstrate the value of sex-specific GWAS to unravel the sexually dimorphic genetic underpinning of complex traits.

Bioinformatics-driven identification and examination of candidate genes for non-alcoholic fatty liver disease.

ObjectiveCandidate genes for non-alcoholic fatty liver disease (NAFLD) identified by a bioinformatics approach were examined for variant associations to quantitative traits of NAFLD-related phenotypes.Research Design and MethodsBy integrating public database text mining, trans-organism protein-protein interaction transferal, and information on liver protein expression a protein-protein interaction network was constructed and from this a smaller isolated interactome was identified. Five genes from this interactome were selected for genetic analysis. Twenty-one tag single-nucleotide polymorphisms (SNPs) which captured all common variation in these genes were genotyped in 10,196 Danes, and analyzed for association with NAFLD-related quantitative traits, type 2 diabetes (T2D), central obesity, and WHO-defined metabolic syndrome (MetS).Results273 genes were included in the protein-protein interaction analysis and EHHADH, ECHS1, HADHA, HADHB, and ACADL were selected for further examination. A total of 10 nominal statistical significant associations (P<0.05) to quantitative metabolic traits were identified. Also, the case-control study showed associations between variation in the five genes and T2D, central obesity, and MetS, respectively. Bonferroni adjustments for multiple testing negated all associations.ConclusionsUsing a bioinformatics approach we identified five candidate genes for NAFLD. However, we failed to provide evidence of associations with major effects between SNPs in these five genes and NAFLD-related quantitative traits, T2D, central obesity, and MetS.

Biological, clinical and population relevance of 95 loci for blood lipids.

Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P < 5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.

Reduced choroidal neovascularization by AAV-anti-VEGF shRNA delivery

VEGF plays an essential role in ocular angiogenic diseases including the late-stage form of AMD, the primary cause of vision loss in the western world. Over-expression of VEGF leads to development of vasculature emanating from the choroid, invading the subretinal space through breaks in Bruch's membrane. Strategies leading to long-term suppression of inappropriate ocular angiogenesis are required. A panel of 10 shRNAs targeting the coding region of human VEGF165 was tested in HEK293 cells and in the human retinal pigment epithelial cell line, ARPE-19. VEGF knock-down up to 92% was achieved by co-transfecting shRNAexpressing constructs with plasmid encoding the Renilla luciferase gene fused to the VEGF165 sequence. For in vivo delivery of the most potent shRNA cassette, both single-stranded and self-complementary rAAV vectors were packaged in serotype 8 capsids. Intramuscular administration in mice led to localized expression and 96% knock-down of endogenous VEGF. Using eGFP as a marker, efficient gene transfer of retinal pigment epithelial cells, the cells thought to be responsible for the abnormal VEGF production, was obtained by subretinal delivery of rAAV2.8 vectors. The capacity of rAAV-encoded shRNAs to silence endogenous VEGF gene expression was evaluated in the laser-induced murine model of choroidal neovascularization (CNV). In this mouse model of AMD, sizes of the CNV were found to be significantly reduced following rAAV-shRNA subretinal delivery. Thus, our results indicate that gene transfer combining AAV-mediated delivery with triggering of the endogenous RNAi pathway can be used for anti-VEGF therapy and holds great promise for the treatment of AMD.

Revisão analítica da biblioteca do futuro

Originalmente na forma de citações de consagrados autores norte-americanos, pontuando os mais significativos temas sobre a biblioteca do futuro, em um período de dez anos (1983-1994), este riquíssimo estado-da-arte é agora traduzido e condensado em língua portuguesa e devidamente autorizado pelo Council on Library Resources (CLR), de Washington, D.C., USA. Para maior alcance desta matéria emergente, adotou-se uma fala pessoal, didática e interpretativa, obedecendo, porém, à orgânica do original, na ordem a saber: introdução, visão do futuro, definições de bibliotecas digitais; publicação impressa versus digital, aplicações e instrumentos de acesso à informação tecnológica; editoração, papéis e motivação dos atores e projetos no sistema digital; projetos e bibliotecas do futuro, incluindo o perfil do bibliotecário de referência e o papel das escolas de biblioteconomia; para onde vão as bibliotecas na virada do século e um senso de urgência. Finda-se com uma bibliografia e um índice conjugado de autores e assuntos.

Informação digital no ensino presencial e no ensino a distância

Neste artigo, discutem-se o papel da informação digital e sua importância tanto para as universidades tradicionais quanto para as que adotam o paradigma de ensino a distância. Além disso, descreve-se a infra-estrutura básica necessária para a produção e disponibilização de acervo digital, destacando-se a criação de um Núcleo de Construção e Manutenção de Acervo Digital e de um Núcleo de Criação de Material Didático. Analisam-se também as diferenças relacionadas à disponibilização e pagamento de direitos autorais de documentos digitais disponibilizados em ambientes públicos ou restritos. Finalmente, apresentam-se as experiências dos autores no gerenciamento da informação digital disponibilizada aos alunos do ensino presencial.

Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways.

Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have increased the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q < 0.05). Loci influencing fasting insulin concentration showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional analysis of these newly discovered loci will further improve our understanding of glycemic control.

Un modelo de producción en gruta: el Alfar de Cabrera D'Anoia, Barcelona

La utilización de grutas y cuevas para llevar a cabo actividades productivas fue un hecho habitual en época medieval. Este trabajo pretende analizar un modelo de producción cerámica que se adapta a un espacio físico considerablemente limitado por las características geológicas del entorno. El alfar de Cabrera d¿Anoia constituye un ejemplo paradigmático de dicho modelo e ilustra un proceso de evolución cronológica y de transformación del entorno para satisfacer las necesidades de la producción cerámica.

La pileta del despoblado medieval de Revenga (Burgos): a propósito del lavado ritual de los difuntos y sus evidencias arqueológicas

Las excavaciones en el yacimiento de Revenga dieron a conocer los testimonios arqueológicos correspondientes a la iglesia de este despoblado, así como su extensa área funeraria. Aquellos trabajos localizaron en el interior del espacio litúrgico una enigmática pileta rupestre a la que se atribuyó inicialmente una función de carácter bautismal. Sin embargo, la revisión de los testimonios arqueológicos, así como el avance de las investigaciones, sugieren que dicha cavidad rupestre se debería relacionar, de forma más plausible, con el lavado de los difuntos, una costumbre funeraria muy arraigada en época medieval que estuvo integrada de forma ordinaria entre los ritos que rodeaban las exequias cristianas.

El despoblado altomedieval de Cuyacabras (Burgos): Realidad, principios y argumentos

The archaeological site of Cuyacabras (Quintanar de la Sierra, Burgos) is one of main early medieval reference settlements in Upper Arlanza basin lands and it attracts a great amount of visitors. The monumental featured half-caved church and the necropolis consisting of several burials dug into the rock present around the whole area are material evidences of an ancient hill town which has remained uninhabited from middle XIIIth century. New fieldworks on this whole site, excavated during the sixties, have been focused on improving the scientific impact of the site and setting up to date the records and information entries for the necropolis. All obtained data emphasize the weakness of several principles used to put in value the settlement, and they also suggest a revision of several-year-old discussions on one hand, and on the other one, they encourage scholars to propound new up to date theories which will fi t better with our knowledge"s current context.

Necropolis rupestres y el poblamiento altomedieval en el Alto Arlanza (Burgos)

El estudio del poblamiento altomedieval en el Alto Arlanza sigue vinculado, casi en exclusiva, al análisis que deriva de una visión difusa de sus necrópolis rupestres. Los problemas de visibilidad que plantean los testimonios materiales de estos asentamientos han provocado, como ha ocurrido en otros territorios, que el análisis arqueológico tradicional se haya focalizado en el estudio exclusivo de los elementos funerarios, por lo que disponemos en realidad de un registro parcial y claramente deficitario de las evidencias aldeanas. Poner de relieve la notable indefinición de estos testimonios y señalar las dificultades cronológicas que afecta a estas evidencias constituye dos elementos de reflexión necesarios para redefinir las nuevas estrategias en la construcción de un registro de calidad que permita adentrarnos con seguridad en la génesis del paisaje medieval y, en particular, en la formación de la red aldeana.

Impact of etanercept-methotrexate therapy on patient-reported outcomes in rheumatoid arthritis patients with up to 12 months of symptoms.

Background/Purpose: Patient-reported outcomes (PROs) in patients with rheumatoid arthritis (RA) are critical in evaluating RA treatment effects on function and health-related quality of life (HR-QoL). Significant improvement in PROs has been reported in RA studies of biologic agents, including etanercept (ETN), but most studies have been conducted in patients with established disease. In addition to assessing treatment effects in early RA, there is interest in therapeutic strategies that allow dose reduction or withdrawal of biologic therapy (biologic-free) after induction of response. The PRIZE trial is an ongoing, 3-period study to evaluate the efficacy of combined ETN and methotrexate (MTX) therapy in patients with early, moderate-to-severe RA and to assess whether efficacy (remission) can be maintained with ETN dose reduction or biologic-free (Period 2) or drug-free (Period 3). Herein we report PROs associated with ETN 50 mg QW plus MTX (ETN50/MTX) therapy administered for 52 wks in Period 1 (induction) of the PRIZE trial. Methods: In Period 1, MTX- and biologic-naı‥ve patients with early, active RA (symptom onset 12 mo from enrollment; DAS28 _3.2) received open-label ETN50/MTX for 52 wks. The starting dose of MTX was 10 mg QW; at the discretion of the investigator, titration was permitted up to a maximum of 25 mg QW to achieve remission. Corticosteroid boosts were administered to patients not achieving low disease state at wks 13 and 26, unless contraindicated or not tolerated. PROs were assessed using the Health Assessment Questionnaire (HAQ) total score; Patient Acceptable Symptom State (PASS); EuroQol-5 Dimensions (EQ-5D) total index; Short Form Health Survey (SF-36); Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue; Work Instability Scale for Rheumatoid Arthritis (RAWIS); and Work Productivity and Activity Impairment Questionnaire: Rheumatoid Arthritis (WPAI:RA). Results: A total of 306 patients received treatment in Period 1 (mITT population); 222 (73%) patients completed the period. The majority of patients were female (70%), with a mean age of 50 y, mean DAS28 of 6.0 (median, 6.0), and duration of disease symptoms from onset of 6.5 months (median, 6.3 mo). Significant and clinically meaningful improvements in PROs, including in HAQ, EQ-5D, SF-36, and FACIT-Fatigue, were demonstrated with ETN50/MTX therapy from baseline to the final on therapy visit (Table; P_0.0001). Similar improvements were observed in all dimensions of RA-WIS and WPAI:RA (Table; P_0.0001). Conclusion: Combination therapy with ETN50/MTX for 52 wks in patients with _12 mo of symptomatic, active RA resulted in significant, clinically important improvements in measures of physical function, including normal HAQ (66.6% of patients), HR-QoL, fatigue, and work productivity. These outcomes are consistent with those reported in prior studies in patients with more established disease.