Complex flexibility of the transforming growth factor beta superfamily.

The transforming growth factors beta (TGF-beta s) are important modulators of growth and differentiation. They are intermolecular disulfide-bonded homodimeric molecules. The monomer fold has a conserved cystine knot and lacks a hydrophobic core. The biological specificity of a given member of the family is believed to be determined by the conformational flexibility of the variable loop regions of the monomer. The monomer subunit assembly in the dimer is stabilized mainly by hydrophobic contacts and a few hydrogen bonds. Since these interactions are nondirectional, we examined subunit assemblies of TGF-beta by using conformational analysis. The different subunit assemblies in TGF-beta 2 dimer were characterized in terms of the intersubunit disulfide torsion. Our analyses show that the subunit assemblies fall into two states: the crystallographically observed gauche+conformation and the previously not reported gauche--conformation, both having almost identical interaction energies. Furthermore, there is significant flexibility in the subunit assembly within the gauche+ and the gauche- states of the disulfide bond. The monomer subunit assembly is independent of the variations about the loop regions. The variations in the loop regions, coupled with flexibility in the monomer assembly, lead to a complex flexibility in the dimer of the TGF-beta superfamily. For the TGF-beta superfamily, the cystine knot acts as a scaffold and complex flexibility provides for biological selectivity. Complex flexibility might provide an explanation for the diverse range of biological activities that these important molecules display.

Avaliação de boas práticas em saúde mental na atenção psicossocial

A partir do redirecionamento do modelo assistencial no Brasil emerge a necessidade de discussão da reinvenção de práticas alinhadas com o cenário de transformações. As práticas agora devem se desenvolver no sentido de superar o isolamento das grades, dos muros e das chaves, do apagamento do sujeito, da supressão de sintomas e das personalidades dos sujeitos em sofrimento psíquico. Diante disso, é que este estudo tem como objetivos avaliar boas práticas em saúde mental na atenção psicossocial no contexto de um município da região Sul do Brasil. Para tanto, organizou-se como uma pesquisa avaliativa construtivista, com enfoque responsivo, a medida que desenvolve um consenso critico entre os grupos de interesse. Está baseada na Avaliação de Quarta Geração, proposta por Guba e Lincoln (2011), que emerge como opção metodológica e se articula com o referencial teórico das \"Boas Práticas em Saúde Mental Comunitária\", proposto por Thornicroft e Tansella (2010). Este é apresentado de modo a identificar boas práticas na saúde mental, com base na articulação de 3 eixos indispensáveis e indissociáveis: a ética, como princípio fundamental que deverá orientar o planejamento, a assistência e a avaliação dos serviços. A evidência deve embasar as intervenções e serviços. E a experiência como uma evidência do que vem sendo produzido nas experiências locais e regionais de organização da rede de serviços. Como resultado do processo as práticas de Acolhimento, Projeto Terapêutico Singular e Transferência de Cuidados emergiram para discussão. O Acolhimento torna-se concreto nas ações da Porta Aberta, e significa escuta qualificada no momento em que a necessidade emerge, além de representar a oferta de atenção de qualidade baseada no processo relacional que fortalece o estabelecimento de vínculos e a construção de projetos de vida. O Projeto Terapêutico Singular apresenta-se como uma boa prática, a medida que é capaz de dar resposta singularizada e individualizada às necessidades do sujeito, de modo a oportunizar como resultado uma pessoa capaz de andar na vida. É definido de forma compartilhada entre equipe, usuário e família, segundo os objetivos terapêuticos para cada sujeito, e utiliza o técnico de referência, as mini equipes, as oficinas terapêuticas, os grupos terapêuticos, as assembleias, enfim, ofertas e propostas que permitem ao sujeito retomar o envolvimento com os espaços da cidade, no caminho da produção de vida. Com relação à Transferência de Cuidados, esta possibilita ao sujeito que vive o processo não só circular em uma rede de serviços, mas, acima de tudo, buscar, com suporte dela, sua emancipação. Para tanto, investe em práticas que estimulem a autonomia dos sujeitos, por meio de instrumentos como o Acompanhamento Terapêutico, Grupo de Apoio à Alta, espaços de decisões e discussões, estímulo à busca e resolução de problemas, atividades de reconhecimento dos espaços da cidade, transporte, cultura e lazer. Além disso, investe nas ações com a Atenção Básica, a partir do Apoio Matricial com processos de formação continuada com as equipes, e mapeamento da situação da saúde mental nos territórios. Ao final deste estudo, é possível concluir que o modelo de atenção psicossocial demonstrou potencialidade de produzir boas práticas na atenção à saúde mental, e que estas tem transformado a vida dos sujeitos em sofrimento psíquico, bem como tem auxiliado no processo de reconquista de espaços sociais

Desenvolvimento de um elemento combustível instrumentado para o reator de pesquisa IEA-R1

Após o aumento de potência do reator IEA-R1 de 2 MW para 5 MW observou-se um aumento da taxa de corrosão nas placas laterais de alguns elementos combustíveis e algumas dúvidas surgiram com relação ao valor de vazão utilizada nas análises termo-hidráulicas. A fim de esclarecer e medir a distribuição de vazão real pelos elementos combustíveis que compõe o núcleo do reator IEA-R1, um elemento combustível protótipo, sem material nuclear, chamado DMPV-01 (Dispositivo para Medida de Pressão e Vazão), em escala real, foi projetado e construído em alumínio. A vazão no canal entre dois elementos combustíveis é muito difícil de estimar ou ser medida. Esta vazão é muito importante no processo de resfriamento das placas laterais. Este trabalho apresenta a concepção e construção de um elemento combustível instrumentado para medir a temperatura real nestas placas laterais para melhor avaliar as condições de resfriamento do combustível. Quatorze termopares foram instalados neste elemento combustível instrumentado. Quatro termopares em cada canal lateral e quatro no canal central, além de um termopar no bocal de entrada e outro no bocal de saída do elemento. Existem três termopares para medida de temperatura do revestimento e um para a temperatura do fluido em cada canal. Três séries de experimentos, para três configurações distintas, foram realizadas com o elemento combustível instrumentado. Em dois experimentos uma caixa de alumínio foi instalada ao redor do núcleo para reduzir o escoamento transverso entre os elementos combustíveis e medir o impacto na temperatura das placas externas. Dada a tamanha quantidade de informações obtidas e sua utilidade no projeto, melhoria e capacitação na construção, montagem e fabricação de elementos combustíveis instrumentados, este projeto constitui um importante marco no estudo de núcleos de reatores de pesquisa. As soluções propostas podem ser amplamente utilizadas para outros reatores de pesquisa.

The ubiquitin-proteasome system in retinal health and disease

The ubiquitin–proteasome system (UPS) is the main intracellular pathway for modulated protein turnover, playing an important role in the maintenance of cellular homeostasis. It also exerts a protein quality control through degradation of oxidized, mutant, denatured, or misfolded proteins and is involved in many biological processes where protein level regulation is necessary. This system allows the cell to modulate its protein expression pattern in response to changing physiological conditions and provides a critical protective role in health and disease. Impairments of UPS function in the central nervous system (CNS) underlie an increasing number of genetic and idiopathic diseases, many of which affect the retina. Current knowledge on the UPS composition and function in this tissue, however, is scarce and dispersed. This review focuses on UPS elements reported in the retina, including ubiquitinating and deubiquitinating enzymes (DUBs), and alternative proteasome assemblies. Known and inferred roles of protein ubiquitination, and of the related, SUMO conjugation (SUMOylation) process, in normal retinal development and adult homeostasis are addressed, including modulation of the visual cycle and response to retinal stress and injury. Additionally, the relationship between UPS dysfunction and human neurodegenerative disorders affecting the retina, including Alzheimer's, Parkinson's, and Huntington's diseases, are dealt with, together with numerous instances of retina-specific illnesses with UPS involvement, such as retinitis pigmentosa, macular degenerations, glaucoma, diabetic retinopathy (DR), and aging-related impairments. This information, though still basic and limited, constitutes a suitable framework to be expanded in incoming years and should prove orientative toward future therapy design targeting sight-affecting diseases with a UPS underlying basis.

Laws made and past by William Penn: Absolute Proprietary and Governour in Chief of the province of Pennsylvania and territories thereunto belonging, with the advice and consent of the freemen thereof in genrall assembly met at Newcastle...1700....and [as amended] at Philadelphia...1701

Contains one of the few original copies of Penn's laws as first passed and as revised and extended in the following year. During the interval between the two Assemblies, while Penn was absent in England, the first series of laws were found to be impracticable, and new amendments were made for which Penn had no choice but to agree to.

THE DESIGN AND SYNTHESIS OF SILOXANE PRECURSORS FOR CHIRAL PERIODIC MESOPOROUS ORGANOSILICA MATERIALS

The development of cost-effective and reliable methods for the synthesis and separation of asymmetric compounds is paramount in helping to meet society’s ever-growing demand for chiral small molecules. Of these methods, chiral heterogeneous supports are particularly appealing as they allow for the reuse of the chiral source. One such support, based on the synergy between chiral organic units and structurally stable inorganic silicon scaffolds are periodic mesoporous organosilicas (PMOs). In the work described herein, I examine some of the factors governing the transmission of chirality between chiral dopants and prochiral bulk phases in chiral PMO materials. In particular, the exploration of 1,1’-binaphthalene-bridged chiral dopants with a focus on the point of attachment into the materials. Moreover, the effects of ordering in the materials are examined and reveal that chirality transfer is more facile in materials with molecular-scale order then those containing amorphous walls. Secondly, the issues surrounding the synthesis and purification of aryl-triethoxysilanes as siloxane precursors are addressed. Both the introduction of a two-carbon linker and the direct attachment of allyl and mixed allyldiethoxysilane species are explored. This work demonstrates that allyldiethoxysilanes are ideal, in that they are stable enough to permit facile synthesis, while still being able to hydrolyze completely to produce well-ordered materials. Lastly, the production of new bulk phases for chiral PMO materials is examined by introducing new prochiral nitrogen-containing siloxane precursors. Biphenyldiamine and bipyridine-bridged siloxane precursors are readily synthesized on reasonable scales. Their use as the bulk siloxane precursor in the production of PMO materials however, is precluded by insufficient gelation and additional siloxane precursors are necessary for the production of ordered materials. In addition to the research detailed above that forms the body of this thesis, two short works are appended. The first details the production of polythiophene assemblies mediated through coordination nanospaces, while the second explores the production of N-heterocyclic carbene functionalized gold nanoparticles through ligand exchange.

Legitimising EU Policymaking: What Role for National Parliaments? EPC Discussion Paper, 28 January 2014

The ‘euro crisis’ has sparked a renewed interest in how national parliaments can help to improve the democratic nature of European decision making. According to various treaties, assemblies in the Member States are now guaranteed a full spectrum of rights including access to information, participation and the ability to object to EU legislation. The authors of this Discussion Paper argue that there is still room to refine and promote a more responsible use of existing instruments. Moreover, the possibility of adding new mechanisms to the available toolkit is part of the discussion on the topic but the authors warn that any proposals must be carefully considered on a case-by-case basis, especially in the context of the European economic governance reform process. Ultimately, according to the authors, the most straightforward and effective way for national parliaments to strengthen their direct involvement in EU policy formulation is to focus on building capacity to perform their two key domestic responsibilities: to hold their own governments to account, also on EU affairs, and to maintain the link with voters, including by communicating and debating ‘Europe’ at ‘home’.

Insight into the evolution of the Solanaceae from the parental genomes of Petunia hybrida

Petunia hybrida is a popular bedding plant that has a long history as a genetic model system. We report the whole-genome sequencing and assembly of inbred derivatives of its two wild parents, P. axillaris N and P. inflata S6. The assemblies include 91.3% and 90.2% coverage of their diploid genomes (1.4 Gb; 2n = 14) containing 32,928 and 36,697 protein-coding genes, respectively. The genomes reveal that the Petunia lineage has experienced at least two rounds of hexaploidization: the older gamma event, which is shared with most Eudicots, and a more recent Solanaceae event that is shared with tomato and other solanaceous species. Transcription factors involved in the shift from bee to moth pollination reside in particularly dynamic regions of the genome, which may have been key to the remarkable diversity of floral colour patterns and pollination systems. The high-quality genome sequences will enhance the value of Petunia as a model system for research on unique biological phenomena such as small RNAs, symbiosis, self-incompatibility and circadian rhythms.

Conservation of the oligomeric state of native VDAC1 in detergent micelles.

The voltage-dependent anion-selective channel (VDAC) is an intrinsic β-barrel membrane protein located within the mitochondrial outer membrane where it serves as a pore, connecting the mitochondria to the cytosol. The high-resolution structures of both the human and murine VDACs have been resolved by X-ray diffraction and nuclear magnetic resonance spectroscopy (NMR) in 2008. However, the structural data are not completely in line with the findings that were obtained after decades of research on biochemical and functional analysis of VDAC. This discrepancy may be related to the fact that structural biology studies of membrane proteins reveal specific static conformations that may not necessarily represent the physiological state. For example, overexpression of membrane proteins in bacterial inclusion bodies or simply the extraction from the native lipid environment using harsh purification methods (i.e. chaotropic agents) can disturb the physiological conformations and the supramolecular assemblies. To address these potential issues, we have developed a method, allowing rapid one step purification of endogenous VDAC expressed in the native mitochondrial membrane without overexpression of recombinant protein or usage of harsh chaotropic extraction procedures. Using the Saccharomyces cerevisiae isoform 1 of VDAC as a model, this method yields efficient purification, preserving VDAC in a more physiological, native state following extraction from mitochondria. Single particle analysis using transmission electron microscopy (TEM) demonstrated conservation of oligomeric assembly after purification. Maintenance of the native state was evaluated using functional assessment that involves an ATP-binding assay by micro-scale thermophoresis (MST). Using this approach, we were able to determine for the first time the apparent KD for ATP of 1.2 mM.

Laws of the State of Indiana, passed and published, at the ... session of the General Assembly.

Description based on: 2nd session (1817).

The booke of the Universall kirk of Scotland: wherein the headis and conclusionis devysit be the ministers and commissionaris of the particular kirks thereof, are especially expressed and contained;

Different edition published under title: Acts and proceedings of the General assemblies of the Kirk of Scotland, from the year M.D. LX.

Laws of the state of Indiana, passed at the ... session of the General Assembly.

The 44th regular session of the General Assembly was designated as the 45th regular session. The error in numbering has been continued by all the following assemblies.

Records of the ... Assembly.

Indexes to the Records cover both the Plenary meetings and Meetings of the committees ...

Records of the ... Assembly.

At head of title: League of Nations.

Direct and general support maintenance manual for transmission assembly, automatic, model TX 200-2A, Allison Division, GM, 2520-860-7342, transmission assembly, automatic, model TX 200-2B, Allison Division, GM, 2520-964-9207, transmission assembly, automatic, model TX 200-6, Allison Division, GM, 2520-045-3108.

Includes index.