Characterization of the retinoid orphan-related receptor-alpha coactivator binding interface: A structural basis for ligand-independent transcription

The retinoid orphan-related receptor-alpha (RORalpha) is a member of the ROR subfamily of orphan receptors and acts as a constitutive activator of transcription in the absence of exogenous ligands. To understand the basis of this activity, we constructed a homology model of Rill using the closely related TRbeta as a template. Molecular modeling suggested that bulky hydrophobic side chains occupy the RORa ligand cavity leaving a small but distinct cavity that may be involved in receptor stabilization. This model was subject to docking simulation with a receptor-interacting peptide from the steroid receptor coactivator, GR-interacting protein-1, which delineated a coactivator binding surface consisting of the signature motif spanning helices 3-5 and helix 12 [activation function 2 (AF2)]. Probing this surface with scanning alanine mutagenesis showed structural and functional equivalence between homologous residues of RORalpha and TRbeta. This was surprising (given that Rill is a ligand-independent activator, whereas TRbeta has an absolute requirement for ligand) and prompted us to use molecular modeling to identify differences between Rill and TRbeta in the way that the All helix interacts with the rest of the receptor. Modeling highlighted a nonconserved amino acid in helix 11 of RORa (Phe491) and a short-length of 3.10 helix at the N terminus of AF2 which we suggest i) ensures that AF2 is locked permanently in the holoconformation described for other liganded receptors and thus 2) enables ligand-independent recruitment of coactivators. Consistent with this, mutation of RORa Phe491 to either methionine or alanine (methionine is the homologous residue in TRbeta), reduced and ablated transcriptional activation and recruitment of coactivators, respectively. Furthermore, we were able to reconstitute transcriptional activity for both a deletion mutant of Ill lacking All and Phe491 Met, by overexpression of a GAL-AF2 fusion protein, demonstrating ligand-independent recruitment of AF2 and a role for Phe491 in recruiting AF2.

Hepatic xenobiotic metabolism of cylindrospermopsin in vivo in the mouse

Cylindrospermopsin (CYN) is a hepatotoxin isolated from the blue-green alga Cylindrospermopsis raciborskii. The role of both glutathione (GSH) and the cytochrome P450 enzyme system (P450) in the mechanism of toxicity of CYN has been previously investigated in in vitro systems. We have investigated the role of GSH and P450 in vivo in mice. Mice pre-treated with buthionine sulphoximine and diethyl maleate to deplete hepatic GSH prior to dosing with 0.2 mg/kg CYN showed a seven-day survival rate of 5/13 while the control group rate was 9/14. Dosing mice with 0.2 mg/kg CYN produced a small decrease in hepatic GSH with a characteristic rebound effect at 24 h, The magnitude of this effect is however small and combined with the non-significant difference in survival rates after GSH depletion suggest depletion of GSH by CYN could not be a primary mechanism for CYN toxicity, Conversely, pro-treatment with piperonyl butoxide, a P450 inhibitor, protected mice against CYN toxicity giving a survival rate of 10/10 compared with 4/10 in the control group (p < 0.05 Chi squared) and was protective at doses up to 0.8 mg/kg, suggesting activation of CYN by P450 is of primary importance in the mechanism of action. (C) 2002 Elsevier Science Ltd. All rights reserved.

Keratinocyte Growth factor (KGF) in hematology and oncology

Keratinocyte Growth factor (KGF) is an epithelial cell growth factor of the fibroblast growth factor family and is produced by fibroblasts and microvascular endothelium in response to proinflammatory cytokines and steroid hormones. KGF is a heparin binding growth factor that exerts effects on epithelial cells in a paracrine fashion through interaction with KGF receptors. Preclinical data has demonstrated that KGF can prevent lung and gastrointestinal toxicity following chemotherapy and radiation and preliminary clinical data in the later setting supports these findings. In the experimental allogeneic bone marrow transplant scenario KGF has shown significant ability to prevent graft-versus-host disease by maintaining gastrointestinal tract integrity and acting as a cytokine shield to prevent subsequent proinflammatory cytokine generation. Within this setting KGF has also shown an ability to prevent experimental idiopathic pneumonia syndrome by stimulating production of surfactant protein A, promoting alveolar epithelialization and attenuating immune-mediated injury. Perhaps most unexpectantly, KGF appears able to maintain thymic function during allogeneic stern cell transplantation and so promote T cell engraftment and reconstitution. These data suggest that KGF will find a therapeutic role in the prevention of epithelial toxicity following intensive chemotherapy and radiotherapy protocols and in allogeneic stem cell transplantation.

Long-range automaton models of earthquakes: Power-law accelerations, correlation evolution, and mode-switching

We introduce a conceptual model for the in-plane physics of an earthquake fault. The model employs cellular automaton techniques to simulate tectonic loading, earthquake rupture, and strain redistribution. The impact of a hypothetical crustal elastodynamic Green's function is approximated by a long-range strain redistribution law with a r(-p) dependance. We investigate the influence of the effective elastodynamic interaction range upon the dynamical behaviour of the model by conducting experiments with different values of the exponent (p). The results indicate that this model has two distinct, stable modes of behaviour. The first mode produces a characteristic earthquake distribution with moderate to large events preceeded by an interval of time in which the rate of energy release accelerates. A correlation function analysis reveals that accelerating sequences are associated with a systematic, global evolution of strain energy correlations within the system. The second stable mode produces Gutenberg-Richter statistics, with near-linear energy release and no significant global correlation evolution. A model with effectively short-range interactions preferentially displays Gutenberg-Richter behaviour. However, models with long-range interactions appear to switch between the characteristic and GR modes. As the range of elastodynamic interactions is increased, characteristic behaviour begins to dominate GR behaviour. These models demonstrate that evolution of strain energy correlations may occur within systems with a fixed elastodynamic interaction range. Supposing that similar mode-switching dynamical behaviour occurs within earthquake faults then intermediate-term forecasting of large earthquakes may be feasible for some earthquakes but not for others, in alignment with certain empirical seismological observations. Further numerical investigation of dynamical models of this type may lead to advances in earthquake forecasting research and theoretical seismology.

Relations between high and low power groups: The importance of legitimacy

Using a social identity perspective, two experiments examined the effects of power and the legitimacy of power differentials on intergroup bias. In Experiment 1, 125 math-science students were led to believe that they had high or low representation in a university decision-making body relative to social-science students and that this power position was either legitimate or illegitimate. Power did not have an independent effect on bias; rather, members of both high and low power groups showed more bias when the power hierarchy was illegitimate than when it was legitimate. This effect was replicated in Experiment 2 (N =105). In addition, Experiment 2 showed that groups located within an unfair power hierarchy expected the superordinate power body to be more discriminatory than did those who had legitimately high or low power. The results are discussed in terms of their implications for group relations.

Differences in lung function, growth parameters and frequency of hospital admissions between adolescents with cystic fibrosis-related diabetes and controls

As survival of patients with CF increases,glucose intolerance and cystic fibrosisrelated diabetes (CFRD),ar e increasingly recognised common complications. CFRD may be preceded by a pre-diabetic state. Using markers identified as being associated with CFRD may improve targeted screening. Aim: To identify features consistently predicting CFRD in paediatric patients. Patients diagnosed with CFRD between January 1997–January 2002 were compared with age and sex matched controls. Clinical,micr obiological, and hospitalisation data was collected at time of CFRD diagnosis,and at six monthly intervals for 3 yr prior to diagnosis. Eight patients with CFRD were identified,mean age 13.7 yr (S.D. 3.49) at time of diagnosis. Control patients underwent OGTT to ensure normal glucose tolerance. Patients with CFRD had a lower FEV1 up to 12 months prior to diagnosis however, this was only significant at diagnosis. There was no difference in weight and height z scores between the 2 groups; however,the decrease in weight and height z scores in the CFRD group over 3 yr prior to diagnosis was significant. Mean number of days in hospital and admissions per patient significantly increased in the CFRD group,6 months prior to diagnosis. No other significant differences were observed between the 2 groups. Conclusions: This study has shown a difference in lung function,gr owth parameters and frequency of hospital admissions between patients with CFRD and controls. These differences may be utilised as tools for targeted screening in the paediatricyadolescent population. Further larger scale studies are required to improve guidelines for targeted screening in this population.

Heat resistance of Bacillus spores when adhered to stainless steel and its relationship to spore hydrophobicity

Twenty-one strains of Bacillus (10 B. stearothermophilus, 3 B. cereus, and 8 B. licheniformis strains) were assayed for spore surface hydrophobicity on the basis of three measures: contact angle measurement (CAM), microbial adhesion to hydrocarbons (MATH), and hydrophobic interaction chromatography (HIC). On the basis of the spore surface characteristics obtained from these assays, along with data on the heat resistance of these spores in water, eight strains of Bacillus (three B. stearothermophilus, three B. cereus, and two B. licheniformis strains) either suspended in water or adhering to stainless steel were exposed to sublethal heat treatments at 90 to 110degreesC to determine heat resistance (D-value). Significant increases in heat resistance (ranging from 3 to 400%) were observed for the eight strains adhering to stainless steel. No significant correlation was found between these heat resistance increases and spore surface characteristics as determined by the three hydrophobicity assays. There was a significant positive correlation between the hydrophobicity data obtained by the MATH assay and those obtained by the HIC assay, but these data did not correlate with those obtained by the CAM assay.

Sistema de acompanhamento do estoque de benef??cios

Sistema de Acompanhamento do Estoque de Benef??cios disponibiliza semanalmente, atrav??s da intranet, em tabelas e gr??ficos, todas as informa????es relacionadas ?? evolu????o do estoque de benef??cios em cada ag??ncia da Previd??ncia Social. Elaborado para o acompanhamento do Plano de Desrepresamento da Diretoria de Benef??cios, ele ?? considerado uma inova????o no INSS por permitir uma consulta r??pida e a coleta de insumos (benef??cios represados, despachados, indeferidos, deferidos etc.) numa ??nica fonte. Com tais informa????es, ?? poss??vel ter um diagn??stico r??pido da situa????o real, em rela????o a estoque de benef??cios, de cada ag??ncia da Previd??ncia Social, das Ger??ncias-Executivas e de todo o Brasil, o que auxilia no processo de tomada de decis??o

Sistema integrado de passagens e di??rias: SIPAD

O Sistema Integrado de Passagens e Di??rias (SIPAD), foi concebido no conceito de integra????o de dados e utiliza uma base de dados ??nica que evita o retrabalho e a inconsist??ncia de informa????es. O sistema tem por objetivo tornar mais ??gil, transparente e desburocratizado o processo de solicita????o, gerenciamento e controle de passagens e di??rias no ??mbito do Minist??rio da Sa??de. O SIPAD permite, em tempo real, o atendimento dos pedidos de viagens mediante requisi????es eletr??nicas com alto grau de confiabilidade e seguran??a. O sistema permite ainda o controle f??sico e a gest??o financeira de todos os pedidos de viagem; o c??lculo autom??tico de valores de di??rias inclusive em moeda estrangeira; o acompanhamento de trechos de viagens e conex??es internacionais com indica????o dos aeroportos; o controle e presta????o de contas de viagens; o desconto autom??tico do valor do vale refei????o por UF. A seguran??a do SIPAD ?? garantida por sistema que permite acessos escalonados por n??veis de senha , a partir de perfis previamente definidos. No SIPAD pode-se realizar consultas on line e emiss??o automatizada de relat??rios operacionais e gerenciais com interface gr??fica. Os resultados ap??s a implanta????o , em 01/07/99, j?? causam impactos significativos. A economia estimada para o ano 2000, apenas em uma unidade gestora do Minist??rio, ?? de redu????o de 113.606 folhas de papel; elimina????o de 23.346 etiquetas; elimina????o de 40.468 assinaturas de gestores e ordenadores de despesa; elimina????o de 58.369 procedimentos de carimbo em pap??is; elimina????o de 11.673 registros de controle e 58.459 tramita????es de documentos

Normas de conduta para a vida p??blica

Texto conhecido como "Relat??rio Nolan", publicado originalmente na Gr??-Bretanha em 1995, aborda temas relativos aos padr??es de comportamento ??tico dos servidores p??blicos e dos pol??ticos, parlamentares e altos dirigentes de governo. O relat??rio est?? estruturado em quatro cap??tulos compreendendo: no primeiro, a introdu????o do tema; no segundo, quest??es sobre os parlamentares; no terceiro, quest??es sobre ministros e servidores; e no quarto, sobre os "quangos" (??rg??os p??blicos n??o-estatais).

Servidores p??blicos federais: perfil - 2013

Traz um panorama atual da for??a de trabalho na administra????o p??blica, al??m de sua evolu????o ao longo dos anos. Os dados apresentados t??m como fonte as edi????es n?? 81, de janeiro de 2003, e n?? 201, de janeiro de 2013, do Boletim Estat??stico de Pessoal editado pela Secretaria de Gest??o P??blica do Minist??rio do Planejamento (Segep/MP). Os n??meros s??o referentes aos meses de dezembro de 2002 e de 2012. Al??m disso, est??o inclusos apenas os servidores p??blicos federais cuja remunera????o prov??m do Tesouro Nacional e que possuem registro no Sistema Integrado de Administra????o de Recursos Humanos (Siape) do Governo Federal.

Servidores p??blicos federais: aposentadorias e pens??es - 2013

Traz estat??sticas sobre servidores p??blicos federais aposentados, militares reformados e instituidores de pens??o, ou seja, o servidor cujo falecimento gerou concess??o de pens??o a seus dependentes. Tendo em vista as reformas previdenci??rias ocorridas ao longo dos ??ltimos 15 anos, o estudo retrata a evolu????o e as mudan??as nos perfis das aposentadorias na administra????o p??blica federal.

Saberes em gest??o p??blica: um ambiente colaborativo de constru????o do conhecimento e de dissemina????o das inova????es em gest??o p??blica

Apresenta o SabeRES em Gest??o P??blica (www.saberes.seap.pr.gov.br), um reposit??rio institucional de acesso livre, aberto a todos os temas relativos ?? gest??o nas organiza????es p??blicas, com ampla tipologia multim??dia de documentos. Inserida no Movimento Mundial do Open Access, dos Recursos Educacionais Abertos e da Ecologia do Conhecimento (pol??tica de compartilhamento), a Escola de Governo do Paran?? desenvolveu, em 2008, um espa??o digital de armazenamento, preserva????o, divulga????o e acesso ?? produ????o do conhecimento em Gest??o P??blica. A metodologia constou de uma an??lise SWOT, seguida de planejamento gr??fico e estrutural, defini????o da arquitetura (conte??do e forma), constru????o da interface gr??fica com ferramenta XOOPS (software livre) e defini????o da ??rvore inicial de menus. Ap??s a constru????o da arquitetura da informa????o come??ou o treinamento da equipe para a gest??o e a manuten????o, a inser????o dos documentos (publica????es, artigos, v??deos, materiais de curso), a disponibiliza????o e a difus??o na Internet, a constitui????o de C??mara T??cnica para apreciar os documentos recebidos e a gest??o continuada do SabeRES. Definiu-se que no SabeRES em Gest??o P??blica ser??o inclu??das publica????es em gest??o p??blica de outros Estados, do Conselho Nacional de Secret??rios de Estado da Administra????o (CONSAD) e da Rede Nacional de Escolas de Governo. A tend??ncia ?? que num futuro pr??ximo seja poss??vel oportunizar o auto-arquivamento dos documentos, preenchendo os metadados relacionados ao seu tema. Al??m disso, espera-se que o sistema estabelecido pela Institui????o seja compat??vel e gere interoperabilidade com o portal de reposit??rios O??sis do Instituto Brasileiro de Informa????o em Ci??ncia e Tecnologia (IBICT) / Minist??rio da Ci??ncia e Tecnologia. Partindo do princ??pio que s?? se cria conhecimento novo a partir da informa????o que est?? acess??vel, com a cria????o do SabeRES em Gest??o P??blica amplia-se a visibilidade e a acessibilidade da produ????o do conhecimento, para que se produza cada vez mais e com mais qualidade

Desenvolvimento e implanta????o do sistema Sancad

Recentemente, a expans??o do n??mero de munic??pios conveniados com a FNS fez aumentar a demanda por novos projetos de melhoria dos sistemas de ??gua e esgotos. Ao mesmo tempo, a FNS enfrentava car??ncia de pessoal t??cnico especializado, dificuldades de admiss??o de novos profissionais e limita????o de recursos para a contrata????o de projetos atrav??s de empresas privadas, inviabilizando o atendimento das demandas pela forma tradicional. Diante disso, servidores da FNS desenvolveram um software para projetos de redes de esgotos sanit??rios, utilizando os recursos modernos da computa????o gr??fica (CAD ??? Computer Aided Design). Acoplado ao CAD, prop??s-se a cria????o de um m??dulo de dimensionamento, resultando numa ferramenta completa de elabora????o de projetos, em ambiente computacional Windows, contemplando as v??rias etapas t??picas de um trabalho na ??rea, desde a digitaliza????o do levantamento topogr??fico, lan??amento da rede, c??lculos, planilhas, desenho e montagem final das pranchas geradas. Este sistema foi denominado Sancad. A utiliza????o do Sancad permitiu uma redu????o m??dia de 60 a 70% no tempo de elabora????o de projetos, significando uma forma de atender a um n??mero maior de demandas e de suprir a car??ncia de profissionais na FNS. Al??m disso, a utiliza????o do Sancad tem mostrado ganhos em termos de qualidade, corre????o e confiabilidade do produto final obtido. As previs??es iniciais quanto ?? abrang??ncia de utiliza????o do Sancad foram amplamente superadas, tendo o mesmo se tornado um padr??o para a ??rea de projetos de saneamento da FNS, estando instalado em 12 unidades da Funda????o em todo o Brasil e em processo de instala????o em outras. O Sancad tornou-se objeto de interesse de t??cnicos de saneamento e de estudantes de engenharia e arquitetura de institui????es p??blicas e privadas, que receberam treinamento a fim de conhec??-lo e utiliz??-lo. Finalmente, o sucesso da experi??ncia tem contribu??do para a dissemina????o da cultura de computa????o gr??fica e a ades??o dos profissionais da FNS e das autarquias municipais conveniadas ?? nova tecnologia. Neste mesmo sentido, ressalta-se a utiliza????o de teodolitos eletr??nicos ??? conhecidos como Esta????o Total ??? para a gera????o de plantas topogr??ficas j?? em formato digital, para serem usadas pelo Sancad, com novos ganhos de qualidade e produtividade na elabora????o dos projetos de saneamento

Manual de identidade visual: Reposit??rio Institucional da Escola Nacional de Administra????o P??blica (Enap)

A identidade visual contida neste manual ?? o conjunto de informa????es gr?????cas que formalizam a personalidade visual do Reposit??rio institucional da Escola Nacional de Administra????o P??blica - ENAP. O projeto de identidade visual envolve a cria????o do logotipo e s??mbolo e tamb??m um conjunto de elementos institucionais e regras que regem a aplica????o da identidade em impressos administrativos, letreiros, ve??culos, uniformes, entre outros elementos, de acordo com a necessidade de cada institui????o. Neste manual est??o as informa????es que disciplinam o uso da marca Reposit??rio institucional da ENAP e seus elementos, garantindo a identidade visual junto ao p??blico alvo, institui????es e o mercado.