A Soluble Form of B Cell Maturation Antigen, a Receptor for the Tumor Necrosis Factor Family Member April, Inhibits Tumor Cell Growth

A proliferation-inducing ligand (APRIL) is a ligand of the tumor necrosis factor (TNF) family that stimulates tumor cell growth in vitro and in vivo. Expression of APRIL is highly upregulated in many tumors including colon and prostate carcinomas. Here we identify B cell maturation antigen (BCMA) and transmembrane activator and calcium modulator and cyclophilin ligand (CAML) interactor (TACI), two predicted members of the TNF receptor family, as receptors for APRIL. APRIL binds BCMA with higher affinity than TACI. A soluble form of BCMA, which inhibits the proliferative activity of APRIL in vitro, decreases tumor cell proliferation in nude mice. Growth of HT29 colon carcinoma cells is blocked when mice are treated once per week with the soluble receptor. These results suggest an important role for APRIL in tumorigenesis and point towards a novel anticancer strategy

A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape

Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways

A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape

Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways.Peer reviewe

Therapeutic efficacy of sonic hedgehog protein in experimental diabetic neuropathy

Orientadora : Drª Lucélia DonattiTese (doutorado) - Universidade Federal do Paraná, Setor de Ciências Biológicas, Programa de Pós-Graduação em Biologia Celular e Molecular. Defesa: Curitiba, 31/07/2014Inclui referências : f. 71-83Resumo: Os peixes que habitam o Oceano Antártico são extremamente adaptados ao frio, sendo seu metabolismo, bioquímico e fisiológico, eficiente em baixas temperaturas. Oscilações sazonais de luminosidade e do suprimento alimentar são também apontados como fatores determinantes da biodiversidade e limitantes da biomassa e da produtividade primária do Oceano Antártico. A tolerância a temperaturas mais altas dos organismos marinhos antárticos tem sido estudada devido à preocupação dos pesquisadores frente ao aquecimento global e da Península Antártica. Os poucos resultados existentes têm demonstrado que esses organismos são extremamente estenotérmicos e que alterações de temperatura podem ser letais. O sistema antioxidante representa um importante marcador de resposta dos organismos submetidos a situações de estresse e alterações de temperatura podem promover a geração de espécies reativas de oxigênio ocasionando danos celulares. Atualmente, a extrema estenotermia dos organismos marinhos antárticos também tem sido estudada através da expressão das proteínas do choque térmico (HSPs). Dentre a família das HSPs, a HSP70 apresenta síntese rápida e significativa diante de diferentes estressores, por isso é uma ferramenta útil para quantificar e prever níveis de estresse em organismos. As coletas e os bioensaios deste trabalho, foram realizados na Baía do Almirantado, Ilha Rei George, no Arquipélago das Shetlands do Sul, Península Antártica, onde se localiza a Estação Antártica Comandante Ferraz (EACF). O presente trabalho tem como objetivo investigar variações nos níveis de HSP70, nos níveis de atividade de várias enzimas antioxidantes (SOD, CAT, GPx, GR e GST) e nos níveis dos marcadores não enzimáticos (GSH, PC e LPO) do estresse oxidativo nos peixes antárticos, Notothenia rossii e Nottohenia coriiceps em condições naturais e de estresse térmico. Para tanto, três capítulos compõem este trabalho, onde o primeiro analisa o efeito da temperatura no metabolismo oxidativo de N. rossii e N. coriiceps; o segundo avalia os níveis de expressão de HSP70 no fígado de N. rossii e N. coriiceps submetidos a estresse térmico e o terceiro analisa ao longo do ano os níveis de atividades dos marcadores de estresse oxidativo em diferentes órgãos de N. rossii e N. coriiceps da Baia do Almirantado, Ilha Rei George, Península Antártica. Palavras-chaves: temperatura, sazonalidade, estresse oxidativo, peixes antárticos, proteína do choque térmico.Abstract: The fish that inhabit the Southern Ocean are highly adapted to the cold, and its metabolism, biochemical and physiological, efficient at low temperatures. Seasonal fluctuations of light and food supply are determinants of biodiversity and limiting biomass and primary productivity of the Southern Ocean. The tolerance to higher temperatures of Antarctic marine organisms have studied due to the concern of researchers against global warming and the Antarctic Peninsula. The few results have demonstrated that these organisms are extremely stenothermal and rapid temperature change can be lethal. The antioxidant system is an important response marker of organisms subjected to stress and temperature changes situations can promote the generation of reactive oxygen species causing cell damage. Currently, the extreme stenothermal of Antarctic marine organisms has studied through the expression of heat shock proteins (HSPs). Among the family of HSPs, the HSP70 has significant and rapid synthesis on different stressors, so it is a useful tool to quantify and predict stress levels in organisms. The experiments of were performed in Admiralty Bay, King George Island, in the Archipelago of the South Shetlands, Antarctic Peninsula, where is the Comandante Ferraz Antarctic Station (EACF). This study aims to investigate variations in the levels of HSP70 in the activity levels of several antioxidant enzymes (SOD, CAT, GPx, GR and GST) and the levels of non-enzymatic markers (GSH, PC and LPO) oxidative stress in Antarctic fish, Notothenia rossii and Nottohenia coriiceps in natural and heat stress conditions. Therefore, three chapters make this work, where the first examines the effect of temperature on the oxidative metabolism of N. rossii and N. coriiceps; the second evaluates the HSP70 expression levels in liver N. rossii and N. coriiceps submited to thermal stress and the third analyzes throughout the year, the activity levels of oxidative stress markers in different tissues of N. rossii and N. coriiceps of Admiralty Bay, King George Island, Antarctic Peninsula. Keywords: temperature, seasonality, oxidative stress, Antarctic fish, heat shock proteins