Formation of a Unique Cluster of G-Quadruplex Structures in the HIV-1 nef Coding Region: Implications for Antiviral Activity

G-quadruplexes are tetraplex structures of nucleic acids that can form in G-rich sequences. Their presence and functional role have been established in telomeres, oncogene promoters and coding regions of the human chromosome. In particular, they have been proposed to be directly involved in gene regulation at the level of transcription. Because the HIV-1 Nef protein is a fundamental factor for efficient viral replication, infectivity and pathogenesis in vitro and in vivo, we investigated G-quadruplex formation in the HIV-1 nef gene to assess the potential for viral inhibition through G-quadruplex stabilization. A comprehensive computational analysis of the nef coding region of available strains showed the presence of three conserved sequences that were uniquely clustered. Biophysical testing proved that G-quadruplex conformations were efficiently stabilized or induced by G-quadruplex ligands in all three sequences. Upon incubation with a G-quadruplex ligand, Nef expression was reduced in a reporter gene assay and Nef-dependent enhancement of HIV-1 infectivity was significantly repressed in an antiviral assay. These data constitute the first evidence of the possibility to regulate HIV-1 gene expression and infectivity through G-quadruplex targeting and therefore open a new avenue for viral treatment. © 2013 Perrone et al

HIV-1 Nucleocapsid Protein Unfolds Stable RNA G-Quadruplexes in the Viral Genome and Is Inhibited by G-Quadruplex Ligands

The G-quadruplexes that form in the HIV-1 RNA genome hinder progression of reverse transcriptase in vitro, but not in infected cells. We investigated the possibility that the HIV-1 nucleocapsid protein NCp7, which remains associated with the viral RNA during reverse transcription, modulated HIV-1 RNA G-quadruplex stability. By electrophoresis, circular dichroism, mass spectrometry, and reverse transcriptase stop assays, we demonstrated that NCp7 binds and unfolds the HIV-1 RNA G-quadruplexes and promotes DNA/RNA duplex formation, allowing reverse transcription to proceed. The G-quadruplex ligand BRACO-19 was able to partially counteract this effect. These results indicate NCp7 as the first known viral protein able to unfold RNA G-quadruplexes, and they explain how the extra-stable HIV-1 RNA G-quadruplexes are processed; they also point out that the reverse transcription process is hindered by G-quadruplex ligands at both reverse transcriptase and NCp7 level. This information can lead to the development of more effective anti-HIV-1 drugs with a new mechanism of action

Metodologia para padronizar informações climáticas dos cenários futuros no banco de dados geográfico do projeto CLIMAPEST.

Estudos sobre os impactos das mudanças climáticas globais são importantes para atenuar seus possíveis impactos negativos. O objetivo deste trabalho foi desenvolver metodologia para padronizar as informações fornecidas pelos modelos climáticos globais do Quarto Relatório do IPCC (Painel Intergovernamental sobre Mudanças Climáticas), utilizando métodos de interpolação de dados a fim de que os planos de informação no banco de dados do SIG possuam as mesmas características de resolução espacial e limites geográficos

Avaliação dos cenários futuros na região nordeste do Brasil utilizando modelos climáticos globais: tendências de temperatura.

O Nordeste é a região brasileira mais vulnerável ao aquecimento global. Os modelos climáticos globais são a melhor ferramenta para projetar cenários prováveis de alterações climáticas para o futuro, apesar da incerteza envolvida. O objetivo deste trabalho foi realizada uma avaliação da tendência da temperatura média nos cenários futuros previstos pelos modelos climáticos globais do IPCC para região Nordeste do Brasil. Foi realizada uma análise estatística básica dos dados de comparação entre os modelos. Foi possível agrupar os modelos em 5 grupos, desde modelos estimando temperaturas médias comparativamente inferiores em todos os meses a outros com valores superiores em todos os meses

Dyads of G-Quadruplex Ligands Triggering DNA Damage Response and Tumour Cell Growth Inhibition at Subnanomolar Concentration

Naphthalene diimide (NDI) dyads exhibiting a different substitution pattern and linker length have been synthesised and evaluated as G-quadruplex (G4) ligands, by investigating their cytotoxicity in selected cell lines. The dyads with the long C7 linker exhibit extremely low IC50 values, below 10\u2005nm, on different cancer cell lines. Contrary, the dyads with the shorter C4 linker were much less effective, with IC values increasing up to 1\u2005\u3bcm. Among the three dyads with the longest linker, small differences in the IC50 values emerge, suggesting that the linker length plays a more important role than the substitution pattern. We have further shown that the dyads are able to induce cellular DNA damage response, which is not limited to the telomeric regions and is likely the origin of their cytotoxicity. Both absorption titration and dynamic light scattering of the most cytotoxic dyads in the presence of hTel22 highlight their ability to induce effective G4 aggregation, acting as non-covalent cross-linking agents

Carcass and meat quality traits in lineages of Nellore breed

The aim of this study was to evaluate the differences between lineages of Nellore breed for carcass and meat quality traits. Thirteen lineages of Nellore breed were evaluated from data of carcass and meat quality of 516 animals for estimating the expected progeny difference for hot carcass weight, rib eye area, fat thickness, marbling and shear force values at 7, 14 and 21 days of ageing. The founder Golias reached the better values of expected progeny difference for hot carcass weight (+1.20kg), rib eye area (+0.88cm), marbling (+3.47un) and average shear force (-0,09kg), and Akasamu the better value for fat thickness (+0.05mm). The differences between lineages of Nellore breed found in this study couldbe used to select sires for genetic improvement of carcass and meat quality traits in Brazilian beef cattle herds.O objetivo deste estudo foi avaliar diferenças entre linhagens da raça Nelore para características de carcaça e qualidade de carne. Foram avaliadas treze linhagens da raça Nelore para as características de peso de carcaça quente, área de olho de lombo, espessura de gordura subcutânea, marmoreio e força de cisalhamento aos 7,14 e 21 dias de maturação. Para isso, foram utilizadas informações fenotípicas de 516 animais da raça Nelore e estimadas as diferenças esperadas na progênie para comparação entre as linhagens. Dentre os genearcas estudados, Golias obteve os melhores valores das diferenças esperadas na progênie para peso de carcaça quente (+1,20kg), área de olho de lombo (+0,88cm), marmoreio (+3,47un) e força de cisalhamento média (-0,09kg) e Akasamu para espessura de gordura subcutânea (+0,05mm). As diferenças entre linhagens da raça Nelore encontradas neste estudo podem ser utilizadas na escolha de touros para melhoria genética de características de carcaça e carne em rebanhos de gado de corte brasileiros.Universidade Federal de São Paulo (UNIFESP) Departamento de Medicina Veterinária Faculdade de Zootecnia e Engenharia de AlimentosDepartamento de ZootecniaUniversidade Federal de Uberlândia Instituto de Genética e BioquímicaUniversidade do Estado de Santa Catarina Departamento de ZootecniaUSP Departamento de ZootecniaUNIFESP, Depto. de Medicina Veterinária Faculdade de Zootecnia e Engenharia de AlimentosSciEL

An overview of the first 5 years of the ENIGMA obsessive–compulsive disorder working group: The power of worldwide collaboration

Abstract Neuroimaging has played an important part in advancing our understanding of the neurobiology of obsessive?compulsive disorder (OCD). At the same time, neuroimaging studies of OCD have had notable limitations, including reliance on relatively small samples. International collaborative efforts to increase statistical power by combining samples from across sites have been bolstered by the ENIGMA consortium; this provides specific technical expertise for conducting multi-site analyses, as well as access to a collaborative community of neuroimaging scientists. In this article, we outline the background to, development of, and initial findings from ENIGMA's OCD working group, which currently consists of 47 samples from 34 institutes in 15 countries on 5 continents, with a total sample of 2,323 OCD patients and 2,325 healthy controls. Initial work has focused on studies of cortical thickness and subcortical volumes, structural connectivity, and brain lateralization in children, adolescents and adults with OCD, also including the study on the commonalities and distinctions across different neurodevelopment disorders. Additional work is ongoing, employing machine learning techniques. Findings to date have contributed to the development of neurobiological models of OCD, have provided an important model of global scientific collaboration, and have had a number of clinical implications. Importantly, our work has shed new light on questions about whether structural and functional alterations found in OCD reflect neurodevelopmental changes, effects of the disease process, or medication impacts. We conclude with a summary of ongoing work by ENIGMA-OCD, and a consideration of future directions for neuroimaging research on OCD within and beyond ENIGMA