Structural basis for selective inhibition of purine nucleoside phosphorylase from Schistosoma mansoni: Kinetic and structural studies

Selectivity plays a crucial role in the design of enzyme inhibitors as novel antiparasitic agents, particularly in cases where the target enzyme is also present in the human host. Purine nucleoside phosphorylase from Schistosoma mansoni (SmPNP) is an attractive target for the discovery of potential antischistosomal agents. In the present work, kinetic studies were carried out in order to determine the inhibitory potency, mode of action and enzyme selectivity of a series of inhibitors of SmPNP. In addition, crystallographic studies provided important structural insights for rational inhibitor design, revealing consistent structural differences in the binding mode of the inhibitors in the active sites of the SmPNP and human PNP (HsPNP) structures. The molecular information gathered in this work should be useful for future medicinal chemistry efforts in the design of new inhibitors of SmPNP having increased affinity and selectivity. (C) 2010 Elsevier Ltd. All rights reserved.

Molecular Basis of the Thermostability and Thermophilicity of Laminarinases: X-ray Structure of the Hyperthermostable Laminarinase from Rhodothermus marinus and Molecular Dynamics Simulations

Glycosyl hydrolases are enzymes capable of breaking the glycosidic linkage of polysaccharides and have considerable industrial and biotechnological applications. Driven by the later applications, it is frequently desirable that glycosyl hydrolases display stability and activity under extreme environment conditions, such as high temperatures and extreme pHs. Here, we present X-ray structure of the hyperthermophilic laminarinase from Rhodothermus marinus (RmLamR) determined at 1.95 angstrom resolution and molecular dynamics simulation studies aimed to comprehend the molecular basis, for the thermal stability of this class of enzymes. As most thermostable proteins, RmLamR contains a relatively large number of salt bridges, which are not randomly distributed on the structure. On the contrary, they form clusters interconnecting beta-sheets of the catalytic domain. Not all salt bridges, however, are beneficial for the protein thermostability: the existence of charge-charge interactions permeating the hydrophobic core of the enzymes actually contributes to destabilize the structure by facilitating water penetration into hydrophobic cavities, as can be seen in the case of mesophilic enzymes. Furthermore, we demonstrate that the mobility of the side-chains is perturbed differently in each class of enzymes. The side-chains of loop residues surrounding the catalytic cleft in the mesophilic laminarinase gain mobility and obstruct the active site at high temperature. By contrast, thermophilic laminarinases preserve their active site flexibility, and the active-site cleft remains accessible for recognition of polysaccharide substrates even at high temperatures. The present results provide structural insights into the role played by salt-bridges and active site flexibility on protein thermal stability and may be relevant for other classes of proteins, particularly glycosyl hydrolases.

An application of lattice basis reduction to polynomial identities for algebraic structures

The authors` recent classification of trilinear operations includes, among other cases, a fourth family of operations with parameter q epsilon Q boolean OR {infinity}, and weakly commutative and weakly anticommutative operations. These operations satisfy polynomial identities in degree 3 and further identities in degree 5. For each operation, using the row canonical form of the expansion matrix E to find the identities in degree 5 gives extremely complicated results. We use lattice basis reduction to simplify these identities: we compute the Hermite normal form H of E(t), obtain a basis of the nullspace lattice from the last rows of a matrix U for which UE(t) = H, and then use the LLL algorithm to reduce the basis. (C) 2008 Elsevier Inc. All rights reserved.

A fast and robust statistical test based on likelihood ratio with Bartlett correction to identify Granger causality between gene sets

We propose a likelihood ratio test ( LRT) with Bartlett correction in order to identify Granger causality between sets of time series gene expression data. The performance of the proposed test is compared to a previously published bootstrapbased approach. LRT is shown to be significantly faster and statistically powerful even within non- Normal distributions. An R package named gGranger containing an implementation for both Granger causality identification tests is also provided.

Methylmercury localization in Danio rerio retina after trophic and subchronic exposure: A basis for neurotoxicology

Methylmercury is a known neurotoxic organometal which affects visual functions and few studies concerns to wild fish are available. The autometallography mercury distribution in the retina of Danio rerio was mapped using light and electron microscopy. Abundant mercury deposits were found in the photoreceptor layer (outer and inner segments of the photoreceptors) and in the inner and outer nuclear layers. Occasionally, the presence of mercury deposits in plexiform layers was observed and very rarely in the ganglion cell layer. Also the occurrence of mercury deposits in cells from the disc region was observed, but not in the nerve fiber layer. An interesting difference was found between mercury accumulation in the central and peripheral regions of the retina. These results demonstrate that mercury after trophic exposure to Danio rerio is able to cross the blood-retina barrier and accumulate in the cells of the retina even under subchronic exposure. (C) 2010 Elsevier Inc. All rights reserved.

What is important for you? A qualitative interview study of living with diabetes and experiences of diabetes care to establish a basis for a tailored Patient-Reported Outcome Measure for the Swedish National Diabetes Register

OBJECTIVES: There is a growing emphasis on the perspective of individuals living with diabetes and the need for a more person-centred diabetes care. At present, the Swedish National Diabetes Register (NDR) lacks patient-reported outcome measures (PROMs) based on the perspective of the patient. As a basis for a new PROM, the aim of this study was to describe important aspects in life for adult individuals with diabetes. DESIGN: Semistructured qualitative interviews analysed using content analysis. SETTING: Hospital-based outpatient clinics and primary healthcare clinics in Sweden. PARTICIPANTS: 29 adults with type 1 diabetes mellitus (DM) (n=15) and type 2 DM (n=14). INCLUSION CRITERIA: Swedish adults (≥18 years) living with type 1 DM or type 2 DM (duration ≥5 years) able to describe their situation in Swedish. Purposive sampling generated heterogeneous characteristics. RESULTS: To live a good life with diabetes is demanding for the individual, but experienced barriers can be eased by support from others in the personal sphere, and by professional support from diabetes care. Diabetes care was a crucial resource to nurture the individual's ability and knowledge to manage diabetes, and to facilitate life with diabetes by supplying support, guidance, medical treatment and technical devices tailored to individual needs. The analysis resulted in the overarching theme 'To live a good life with diabetes' constituting the two main categories 'How I feel and how things are going with my diabetes' and 'Support from diabetes care in managing diabetes' including five different categories. CONCLUSIONS: Common aspects were identified including the experience of living with diabetes and support from diabetes care. These will be used to establish a basis for a tailored PROM for the NDR.

Smart visible sets para ambientes de rede

A visualização em tempo real de cenas complexas através de ambientes de rede é um dos desafios na computação gráfica. O uso da visibilidade pré-computada associada a regiões do espaço, tal como a abordagem dos Potentially Visible Sets (PVS), pode reduzir a quantidade de dados enviados através da rede. Entretanto, o PVS para algumas regiões pode ainda ser bastante complexo, e portanto uma estratégia diferente para diminuir a quantidade de informações é necessária. Neste trabalho é introduzido o conceito de Smart Visible Set (SVS), que corresponde a uma partição das informações contidas no PVS segundo o ângulo de visão do observador e as distâncias entre as regiões. Dessa forma, o conceito de “visível” ou de “não-visível” encontrado nos PVS é estendido. A informação referente ao conjunto “visível” é ampliada para “dentro do campo de visão” ou “fora do campo de visão” e “longe” ou “perto”. Desta forma a informação referente ao conjunto “visível” é subdividida, permitindo um maior controle sobre cortes ou ajustes nos dados que devem ser feitos para adequar a quantidade de dados a ser transmitida aos limites impostos pela rede. O armazenamento dos SVS como matrizes de bits permite ainda uma interação entre diferentes SVS. Outros SVS podem ser adicionados ou subtraídos entre si com um custo computacional muito pequeno permitindo uma rápida alteração no resultado final. Transmitir apenas a informação dentro de campo de visão do usuário ou não transmitir a informação muito distante são exemplos dos tipos de ajustes que podem ser realizados para se diminuir a quantidade de informações enviadas. Como o cálculo do SVS depende da existência de informação de visibilidade entre regiões foi implementado o algoritmo conhecido como “Dual Ray Space”, que por sua vez depende do particionamento da cena em regiões. Para o particionamento da cena em uma BSP-Tree, foi modificada a aplicação QBSP3. Depois de calculada, a visibilidade é particionada em diferentes conjuntos através da aplicação SVS. Finalmente, diferentes tipos de SVS puderam ser testados em uma aplicação de navegação por um cenário 3D chamada BSPViewer. Essa aplicação também permite comparações entre diferentes tipos de SVS e PVS. Os resultados obtidos apontam o SVS como uma forma de redução da quantidade de polígonos que devem ser renderizados em uma cena, diminuindo a quantidade de informação que deve ser enviada aos usuários. O SVS particionado pela distância entre as regiões permite um corte rápido na informação muito distante do usuário. Outra vantagem do uso dos SVS é que pode ser realizado um ordenamento das informações segundo sua importância para o usuário, desde que uma métrica de importância visual tenha sido definida previamente.

Estilos, comportamentos e práticas de influência dos negociadores do Rio de Janeiro

The purpose of this study is to research the negotiators characteristics living at Rio de Janeiro Metropolitan Region, as well as to analyze the perception they have about the importance of the some factors in the negotiation process namely: influence styles, behavior and practices. Another objective is to identify the negotiator¿s characteristics related to regional culture. In order to achieve those objectives, data were collected, through exploratory and descriptive research, in the Metropolitan Region. The studies identifies the specific characteristics of Rio de Janeito negotiators and includes a critical analysis of their influence styles, behavior and practices. A Questionary was applied on the basis of repeated feedback from respondents and factor analyses of various sets of behaviorally based statements. A sample for the version of the Self-Questionary consists of 100 individuals involved in negotiations. For the Other-Questionary, there are 193 groups of respondents. The results indicated that the Questionary is quite consistent with the a priory influence styles, behavior and practices model. The results also indicated that the Rio de Janeiro negotiators use more frequentely pull styles, than push or avoiding styles.

World Cup sets US live streaming record

The world cup has become the most streamed live sporting event in the US, as Americans tune in to this year´s tournament on their smartphones, tablets and computers in record numbers.

The analysis of foreign market entry strategies on the basis of different cultural backgrounds and environments: a qualitative study characterising the differences and similarities of Brazilian and European firms

Moving into a new and foreign market can be challenging, especially when such market has a different culture and working environment in comparison to the home market. Thus, it is of utter importance to adjust a company’s strategy to the new market conditions. Currently, there are no concrete guidelines of what aspects are most important when moving from a developing market such as Brazil into a more sophisticated market like Europe, or vice versa. The present study will examine two companies from the same industry, but with different cultural backgrounds and its strategic similarities and differences for operating in multiple international markets. The data was collected via semi-structured interviews with the Chief Executive Officers (CEOs’) from both companies, using an interview guideline that is based on three different theoretical frameworks. The aim is to give recommendations to these two industries of how to efficiently use existing theoretical frameworks and which aspects are most significant when moving into a new market while keeping in mind a company’s size and background.

Sheaves, local homeomorphisms and local sets as Hilbert locale modules

We give a thorough account of the various equivalent notions for \sheaf" on a locale, namely the separated and complete presheaves, the local home- omorphisms, and the local sets, and to provide a new approach based on quantale modules whereby we see that sheaves can be identi¯ed with certain Hilbert modules in the sense of Paseka. This formulation provides us with an interesting category that has immediate meaningful relations to those of sheaves, local homeomorphisms and local sets. The concept of B-set (local set over the locale B) present in [3] is seen as a simetric idempotent matrix with entries on B, and a map of B-sets as de¯ned in [8] is shown to be also a matrix satisfying some conditions. This gives us useful tools that permit the algebraic manipulation of B-sets. The main result is to show that the existing notions of \sheaf" on a locale B are also equivalent to a new concept what we call a Hilbert module with an Hilbert base. These modules are the projective modules since they are the image of a free module by a idempotent automorphism On the ¯rst chapter, we recall some well known results about partially ordered sets and lattices. On chapter two we introduce the category of Sup-lattices, and the cate- gory of locales, Loc. We describe the adjunction between this category and the category Top of topological spaces whose restriction to spacial locales give us a duality between this category and the category of sober spaces. We ¯nish this chapter with the de¯nitions of module over a quantale and Hilbert Module. Chapter three concerns with various equivalent notions namely: sheaves of sets, local homeomorphisms and local sets (projection matrices with entries on a locale). We ¯nish giving a direct algebraic proof that each local set is isomorphic to a complete local set, whose rows correspond to the singletons. On chapter four we de¯ne B-locale, study open maps and local homeo- morphims. The main new result is on the ¯fth chapter where we de¯ne the Hilbert modules and Hilbert modules with an Hilbert and show this latter concept is equivalent to the previous notions of sheaf over a locale.