Time and dose-dependent effects of phenobarbital on the rat liver miRNAome.

In a previous study we had shown that treatment of male Fischer rats with exogenous chemicals for three months resulted in prominent, mode-of-action dependent effects on liver microRNA (miRNA) (Koufaris et al., 2012). Here we investigated how the effects of chemicals on liver miRNA in male Fischer rats relate to the length and dose of exposure to phenobarbital (PB), a drug with multiple established hepatic effects. Importantly, although acute PB treatment (1-7 days) had significant effects on liver mRNA and the expected effects on the liver phenotype (transient hyperplasia, hepatomegaly, cytochrome P450 induction), limited effects on liver miRNA were observed. However, at 14 days of PB treatment clear dose-dependent effects on miRNA were observed. The main effect of PB treatment from days 1 to 90 on liver miRNA was found to be the persistent, progressive, and highly correlated induction of the miR-200a/200b/429 and miR-96/182 clusters, occurring after the termination of the xenobiotic-induced transient hyperplasia. Moreover, in agreement with their reported functions in the literature we found associations between perturbations of miR-29b and miR-200a/200b by PB with global DNA methylation and zeb1/zeb2 proteins respectively. Our data suggest that miRNA are unlikely to play an important role in the acute responses of the adult rodent liver to PB treatment. However, the miRNA responses to longer PB exposures suggest a potential role for maintaining liver homeostasis in response to sub-chronic and chronic xenobiotic-induced perturbations. Similar studies for more chemicals are needed to clarify whether the temporal and dose pattern of miRNA-toxicant interaction identified here for PB are widely applicable to other xenobiotics. © 2013 Elsevier Ireland Ltd

Catalytic deficiency of O-GlcNAc transferase leads to X-linked intellectual disability

O-GlcNAc transferase (OGT) is an X-linked gene product that is essential for normal development of the vertebrate embryo. It catalyses the O-GlcNAc posttranslational modification of nucleocytoplasmic proteins and proteolytic maturation of the transcriptional coregulator Host cell factor 1 (HCF1). Recent studies have suggested that conservative missense mutations distal to the OGT catalytic domain lead to X-linked intellectual disability in boys, but it is not clear if this is through changes in the O-GlcNAc proteome, loss of protein–protein interactions, or misprocessing of HCF1. Here, we report an OGT catalytic domain missense mutation in monozygotic female twins (c. X:70779215 T &gt; A, p. N567K) with intellectual disability that allows dissection of these effects. The patients show limited IQ with developmental delay and skewed X-inactivation. Molecular analyses revealed decreased OGT stability and disruption of the substrate binding site, resulting in loss of catalytic activity. Editing this mutation into the Drosophila genome results in global changes in the O-GlcNAc proteome, while in mouse embryonic stem cells it leads to loss of O-GlcNAcase and delayed differentiation down the neuronal lineage. These data imply that catalytic deficiency of OGT could contribute to X-linked intellectual disability.</p

Uso Pessoal das Tecnologias no Trabalho: Motivadores e Efeitos à Distração Profissional

Apesar dos inúmeros benefícios que as Tecnologias de Informação (TI) – proporcionam a seus usuários, os efeitos adversos da utilização indiscriminada dos dispositivos tecnológicos pessoais no ambiente de trabalho é um tema pouco explorado. Este estudo analisa os aspectos individuais motivadores do uso particular de Tecnologias de Informação no trabalho e a relação da Distração Digital como um componente significativo sobre a perda de atenção dos profissionais durante a execução de suas atividades. A pesquisa evidencia que os aspectos ligados à dependência tecnológica são as principais causas do Uso Pessoal das Tecnologias no ambiente de trabalho. Entre esses motivadores, a perda do Controle do Impulso de uso da TI é o fator mais significativo ao Uso Pessoal das Tecnologias em ambientes profissionais, comparada a outros fatores analisados. A pesquisa também revela que a Distração Digital provoca significativa perda de concentração dos profissionais e que a Utilização Pessoal da TI no ambiente de trabalho é reflexo direto da redução do Engajamento do profissional no seu trabalho. Além disso, o estudo revela que o uso particular das aplicações que promovem interação social não é subterfúgio dos profissionais que manifestaram fraco Suporte Social dos seus pares no local de atuação profissional

A holistic framework of corporate website favourability

This paper extends the current knowledge of corporate website favourability (CWF) by developing a comprehensive conceptual model of its influence on corporate image, corporate reputation, loyalty and identification. The paper reviews previous studies on corporate websites from the perspectives of marketing, management, corporate identity and corporate visual identity in order to inform our understanding of the antecedents and consequences of CWF. The propositions and the conceptual framework present an approach by which a corporation can design and manage a favourable corporate website. A number of important contributions are offered: First, the paper adds to the understanding of CWF; second, it discusses the antecedents of CWF by drawing upon the existing literature; third, it is beneficial for practitioners in shaping CWF strategies, and fourth, it offers possible consequences of CWF and provides a framework for future testing