Site-specific N-Linked Glycosylation of Receptor Guanylyl Cyclase C Regulates Ligand Binding, Ligand-mediated Activation and Interaction with Vesicular Integral Membrane Protein 36, VIP36

Guanylyl cyclase C (GC-C) is a multidomain, membrane-associated receptor guanylyl cyclase. GC-C is primarily expressed in the gastrointestinal tract, where it mediates fluid-ion homeostasis, intestinal inflammation, and cell proliferation in a cGMP-dependent manner, following activation by its ligands guanylin, uroguanylin, or the heat-stable enterotoxin peptide (ST). GC-C is also expressed in neurons, where it plays a role in satiation and attention deficiency/hyperactive behavior. GC-C is glycosylated in the extracellular domain, and differentially glycosylated forms that are resident in the endoplasmic reticulum (130 kDa) and the plasma membrane (145 kDa) bind the ST peptide with equal affinity. When glycosylation of human GC-C was prevented, either by pharmacological intervention or by mutation of all of the 10 predicted glycosylation sites, ST binding and surface localization was abolished. Systematic mutagenesis of each of the 10 sites of glycosylation in GC-C, either singly or in combination, identified two sites that were critical for ligand binding and two that regulated ST-mediated activation. We also show that GC-C is the first identified receptor client of the lectin chaperone vesicular integral membrane protein, VIP36. Interaction with VIP36 is dependent on glycosylation at the same sites that allow GC-C to fold and bind ligand. Because glycosylation of proteins is altered in many diseases and in a tissue-dependent manner, the activity and/or glycan-mediated interactions of GC-C may have a crucial role to play in its functions in different cell types.

Markov chain splitting methods in structural reliability integral estimation

Monte Carlo simulation methods involving splitting of Markov chains have been used in evaluation of multi-fold integrals in different application areas. We examine in this paper the performance of these methods in the context of evaluation of reliability integrals from the point of view of characterizing the sampling fluctuations. The methods discussed include the Au-Beck subset simulation, Holmes-Diaconis-Ross method, and generalized splitting algorithm. A few improvisations based on first order reliability method are suggested to select algorithmic parameters of the latter two methods. The bias and sampling variance of the alternative estimators are discussed. Also, an approximation to the sampling distribution of some of these estimators is obtained. Illustrative examples involving component and series system reliability analyses are presented with a view to bring out the relative merits of alternative methods. (C) 2015 Elsevier Ltd. All rights reserved.

First-principles study of the influence of different interfaces and core types on the properties of CdSe/CdS core-shell nanocrystals

With the expanding field of nanoengineering and the production of nanocrystals (NCs) with higher quality and tunable size, having reliable theoretical calculations to complement the experimental results is very important. Here we present such a study of CdSe/CdS core-shell NCs using density functional theory, where we focus on dependence of the properties of these NCs on core types and interfaces between the core and the shell, as well as on the core/shell ratio. We show that the density of states and the absorption indices depend rather weakly on the type of interface and core type. We demonstrate that the HOMO wavefunction is mainly localised in the core of the nanocrystal, depending primarily on the core/shell ratio. On the other hand the LUMO wavefunction spreads more into the shell of the nanocrystal, where its confinement in the core is almost the same in each of the studied structural models. Furthermore, we show that the radiative lifetimes decrease with increasing core sizes due to changes in the dipolar overlap integral of the HOMO and LUMO wavefunctions. In addition, the electron-hole Coulomb interaction energies follow a similar pattern as the localisation of the wavefunctions, with the smaller NCs having higher Coulomb interaction energies.

First Structural View of a Peptide Interacting with the Nucleotide Binding Domain of Heat Shock Protein 90

The involvement of Hsp90 in progression of diseases like cancer, neurological disorders and several pathogen related conditions is well established. Hsp90, therefore, has emerged as an attractive drug target for many of these diseases. Several small molecule inhibitors of Hsp90, such as geldanamycin derivatives, that display antitumor activity, have been developed and are under clinical trials. However, none of these tested inhibitors or drugs are peptide-based compounds. Here we report the first crystal structure of a peptide bound at the ATP binding site of the N-terminal domain of Hsp90. The peptide makes several specific interactions with the binding site residues, which are comparable to those made by the nucleotide and geldanamycin. A modified peptide was designed based on these interactions. Inhibition of ATPase activity of Hsp90 was observed in the presence of the modified peptide. This study provides an alternative approach and a lead peptide molecule for the rational design of effective inhibitors of Hsp90 function.

Stress intensity factors calculation in anti-plane fracture problem by orthogonal integral extraction method based on femol

For an anti-plane problem, the differential operator is self-adjoint and the corresponding eigenfunctions belong to the Hilbert space. The orthogonal property between eigenfunctions (or between the derivatives of eigenfunctions) of anti-plane problem is exploited. We developed for the first time two sets of radius-independent orthogonal integrals for extraction of stress intensity factors (SIFs), so any order SIF can be extracted based on a certain known solution of displacement (an analytic result or a numerical result). Many numerical examples based on the finite element method of lines (FEMOL) show that the present method is very powerful and efficient.

The mixed-type integral equations for transient elastodynamic plane crack problems

In the present paper, by use of the boundary integral equation method and the techniques of Green fundamental solution and singularity analysis, the dynamic infinite plane crack problem is investigated. For the first time, the problem is reduced to solving a system of mixed-typed integral equations in Laplace transform domain. The equations consist of ordinary boundary integral equations along the outer boundary and Cauchy singular integral equations along the crack line. The equations obtained are strictly proved to be equivalent with the dual integral equations obtained by Sih in the special case of dynamic Griffith crack problem. The mixed-type integral equations can be solved by combining the numerical method of singular integral equation with the ordinary boundary element method. Further use the numerical method for Laplace transform, several typical examples are calculated and their dynamic stress intensity factors are obtained. The results show that the method proposed is successful and can be used to solve more complicated problems.

Numerical-Value Perturbation Method with Application of Solving Convective-Diffusion Integral Equation

The convective--diffusion equation is of primary importance in such fields as fluid dynamics and heat transfer hi the numerical methods solving the convective-diffusion equation, the finite volume method can use conveniently diversified grids (structured and unstructured grids) and is suitable for very complex geometry The disadvantage of FV methods compared to the finite difference method is that FV-methods of order higher than second are more difficult to develop in three-dimensional cases. The second-order central scheme (2cs) offers a good compromise among accuracy, simplicity and efficiency, however, it will produce oscillatory solutions when the grid Reynolds numbers are large and then very fine grids are required to obtain accurate solution. The simplest first-order upwind (IUW) scheme satisfies the convective boundedness criteria, however. Its numerical diffusion is large. The power-law scheme, QMCK and second-order upwind (2UW) schemes are also often used in some commercial codes. Their numerical accurate are roughly consistent with that of ZCS. Therefore, it is meaningful to offer higher-accurate three point FV scheme. In this paper, the numerical-value perturbational method suggested by Zhi Gao is used to develop an upwind and mixed FV scheme using any higher-order interpolation and second-order integration approximations, which is called perturbational finite volume (PFV) scheme. The PFV scheme uses the least nodes similar to the standard three-point schemes, namely, the number of the nodes needed equals to unity plus the face-number of the control volume. For instanc6, in the two-dimensional (2-D) case, only four nodes for the triangle grids and five nodes for the Cartesian grids are utilized, respectively. The PFV scheme is applied on a number of 1-D problems, 2~Dand 3-D flow model equations. Comparing with other standard three-point schemes, The PFV scheme has much smaller numerical diffusion than the first-order upwind (IUW) scheme, its numerical accuracy are also higher than the second-order central scheme (2CS), the power-law scheme (PLS), the QUICK scheme and the second-order upwind(ZUW) scheme.

The strategic behavior of rational novices

There is a growing amount of experimental evidence that suggests people often deviate from the predictions of game theory. Some scholars attempt to explain the observations by introducing errors into behavioral models. However, most of these modifications are situation dependent and do not generalize. A new theory, called the rational novice model, is introduced as an attempt to provide a general theory that takes account of erroneous behavior. The rational novice model is based on two central principals. The first is that people systematically make inaccurate guesses when they are evaluating their options in a game-like situation. The second is that people treat their decisions similar to a portfolio problem. As a result, non optimal actions in a game theoretic sense may be included in the rational novice strategy profile with positive weights.

The rational novice model can be divided into two parts: the behavioral model and the equilibrium concept. In a theoretical chapter, the mathematics of the behavioral model and the equilibrium concept are introduced. The existence of the equilibrium is established. In addition, the Nash equilibrium is shown to be a special case of the rational novice equilibrium. In another chapter, the rational novice model is applied to a voluntary contribution game. Numerical methods were used to obtain the solution. The model is estimated with data obtained from the Palfrey and Prisbrey experimental study of the voluntary contribution game. It is found that the rational novice model explains the data better than the Nash model. Although a formal statistical test was not used, pseudo R^2 analysis indicates that the rational novice model is better than a Probit model similar to the one used in the Palfrey and Prisbrey study.

The rational novice model is also applied to a first price sealed bid auction. Again, computing techniques were used to obtain a numerical solution. The data obtained from the Chen and Plott study were used to estimate the model. The rational novice model outperforms the CRRAM, the primary Nash model studied in the Chen and Plott study. However, the rational novice model is not the best amongst all models. A sophisticated rule-of-thumb, called the SOPAM, offers the best explanation of the data.

Ortho-positronium annihilation: steps toward computing the first order radiative corrections

The 0.2% experimental accuracy of the 1968 Beers and Hughes measurement of the annihilation lifetime of ortho-positronium motivates the attempt to compute the first order quantum electrodynamic corrections to this lifetime. The theoretical problems arising in this computation are here studied in detail up to the point of preparing the necessary computer programs and using them to carry out some of the less demanding steps -- but the computation has not yet been completed. Analytic evaluation of the contributing Feynman diagrams is superior to numerical evaluation, and for this process can be carried out with the aid of the Reduce algebra manipulation computer program.

The relation of the positronium decay rate to the electronpositron annihilation-in-flight amplitude is derived in detail, and it is shown that at threshold annihilation-in-flight, Coulomb divergences appear while infrared divergences vanish. The threshold Coulomb divergences in the amplitude cancel against like divergences in the modulating continuum wave function.

Using the lowest order diagrams of electron-positron annihilation into three photons as a test case, various pitfalls of computer algebraic manipulation are discussed along with ways of avoiding them. The computer manipulation of artificial polynomial expressions is preferable to the direct treatment of rational expressions, even though redundant variables may have to be introduced.

Special properties of the contributing Feynman diagrams are discussed, including the need to restore gauge invariance to the sum of the virtual photon-photon scattering box diagrams by means of a finite subtraction.

A systematic approach to the Feynman-Brown method of Decomposition of single loop diagram integrals with spin-related tensor numerators is developed in detail. This approach allows the Feynman-Brown method to be straightforwardly programmed in the Reduce algebra manipulation language.

The fundamental integrals needed in the wake of the application of the Feynman-Brown decomposition are exhibited and the methods which were used to evaluate them -- primarily dis persion techniques are briefly discussed.

Finally, it is pointed out that while the techniques discussed have permitted the computation of a fair number of the simpler integrals and diagrams contributing to the first order correction of the ortho-positronium annihilation rate, further progress with the more complicated diagrams and with the evaluation of traces is heavily contingent on obtaining access to adequate computer time and core capacity.

Rational design of zinc phosphide heterojunction photovoltaics

The prospect of terawatt-scale electricity generation using a photovoltaic (PV) device places strict requirements on the active semiconductor optoelectronic properties and elemental abundance. After reviewing the constraints placed on an "earth-abundant" solar absorber, we find zinc phosphide (α-Zn₃P₂) to be an ideal candidate. In addition to its near-optimal direct band gap of 1.5 eV, high visible-light absorption coefficient (>10⁴ cm^-1), and long minority-carrier diffusion length (>5 μm), Zn₃P₂ is composed of abundant Zn and P elements and has excellent physical properties for scalable thin-film deposition. However, to date, a Zn₃P₂ device of sufficient efficiency for commercial applications has not been demonstrated. Record efficiencies of 6.0% for multicrystalline and 4.3% for thin-film cells have been reported, respectively. Performance has been limited by the intrinsic p-type conductivity of Zn₃P₂ which restricts us to Schottky and heterojunction device designs. Due to our poor understanding of Zn₃P₂ interfaces, an ideal heterojunction partner has not yet been found.

The goal of this thesis is to explore the upper limit of solar conversion efficiency achievable with a Zn₃P₂ absorber through the design of an optimal heterojunction PV device. To do so, we investigate three key aspects of material growth, interface energetics, and device design. First, the growth of Zn₃P₂ on GaAs(001) is studied using compound-source molecular-beam epitaxy (MBE). We successfully demonstrate the pseudomorphic growth of Zn₃P₂ epilayers of controlled orientation and optoelectronic properties. Next, the energy-band alignments of epitaxial Zn₃P₂ and II-VI and III-V semiconductor interfaces are measured via high-resolution x-ray photoelectron spectroscopy in order to determine the most appropriate heterojunction partner. From this work, we identify ZnSe as a nearly ideal n-type emitter for a Zn₃P₂ PV device. Finally, various II-VI/Zn₃P₂ heterojunction solar cells designs are fabricated, including substrate and superstrate architectures, and evaluated based on their solar conversion efficiency.

Symmetric representation of an integral domain over a subdomain

Let F(θ) be a separable extension of degree n of a field F. Let Δ and D be integral domains with quotient fields F(θ) and F respectively. Assume that Δ ᴝ D. A mapping φ of Δ into the n x n D matrices is called a Δ/D rep if (i) it is a ring isomorphism and (ii) it maps d onto dI_n whenever d ϵ D. If the matrices are also symmetric, φ is a Δ/D symrep.

Every Δ/D rep can be extended uniquely to an F(θ)/F rep. This extension is completely determined by the image of θ. Two Δ/D reps are called equivalent if the images of θ differ by a D unimodular similarity. There is a one-to-one correspondence between classes of Δ/D reps and classes of Δ ideals having an n element basis over D.

The condition that a given Δ/D rep class contain a Δ/D symrep can be phrased in various ways. Using these formulations it is possible to (i) bound the number of symreps in a given class, (ii) count the number of symreps if F is finite, (iii) establish the existence of an F(θ)/F symrep when n is odd, F is an algebraic number field, and F(θ) is totally real if F is formally real (for n = 3 see Sapiro, “Characteristic polynomials of symmetric matrices” Sibirsk. Mat. Ž. 3 (1962) pp. 280-291), and (iv) study the case D = Z, the integers (see Taussky, “On matrix classes corresponding to an ideal and its inverse” Illinois J. Math. 1 (1957) pp. 108-113 and Faddeev, “On the characteristic equations of rational symmetric matrices” Dokl. Akad. Nauk SSSR 58 (1947) pp. 753-754).

The case D = Z and n = 2 is studied in detail. Let Δ’ be an integral domain also having quotient field F(θ) and such that Δ’ ᴝ Δ. Let φ be a Δ/Z symrep. A method is given for finding a Δ’/Z symrep ʘ such that the Δ’ ideal class corresponding to the class of ʘ is an extension to Δ’ of the Δ ideal class corresponding to the class of φ. The problem of finding all Δ/Z symreps equivalent to a given one is studied.

Propagation properties of off-axis Hermite-cosh-Gaussian beam combinations through a first-order optical system

Based on the Collins integral formula, the analytic expressions of propagation of the coherent and the incoherent off-axis Hermite-cosh-Gaussian (HChG) beam combinations with rectangular symmetry passing through a paraxial first-order optical system are derived, and corresponding numerical examples are given and analysed. The resulting beam quality is discussed in terms of power in the bucket (PIB). The study suggests that the resulting beam cannot keep the initial intensity shape during the propagation and the beam quality for coherent mode is not always better than that for incoherent mode. Reviewing the numerical simulations of Gaussian, Hermite-Gaussian (HG) and cosh Gaussian (ChG) beam combinations indicates that the Hermite polynomial exerts a chief influence on the irradiance profile of composite beam and far field power concentration.

Criação e trajetória de uma Agência no âmbito do Estado integral : o caso do SEBRAE

Este trabalho procura investigar o processo que deu origem ao Serviço Brasileiro de Apoio às Micro e Pequenas Empresas (SEBRAE), assim como a sua trajetória desde a criação até os dias atuais. O SEBRAE foi constituído, em 1972, no âmbito do Ministério de Planejamento e Coordenação Geral (MPCG) do governo Garrastazu Médici (1969-1974). A partir do fim dos anos 70, quando a crise do capital começou a produzir efeitos no país, a agência iniciou um processo paulatino de transformação, culminando na sua privatização, ocorrida no primeiro ano do governo Collor de Mello (1990-1992). Este processo consolidou a sua passagem definitiva da sociedade política para a sociedade civil e alterou, em grande medida, a função da agência junto ao bloco no poder. Ainda que algumas operações não tenham sofrido mudanças significativas, os seus agentes incorporaram definitivamente o papel de formuladores e de disseminadores de ideologia em apoio à consolidação de uma nova fase do capital. Neste sentido, o SEBRAE cumpre, nos dias atuais, o papel de produzir consenso na sociedade em torno da importância econômica e social das micro e pequenas empresas, auxilia a formulação de políticas públicas e leis voltadas para esta questão e, por fim, assume a função ética do Estado, através da qual realiza a tarefa educativa dos indivíduos visando ao "universal". A história da agência é analisada à luz das reflexões de Gramsci sobre hegemonia e Estado integral, capazes de, entre outros aspectos, auxiliar a compreensão das relações mediatas estabelecidas entre agências da sociedade civil e o bloco no poder

Uma experiência de formação de professores em serviço: curso de atualização de professores de escolas de horário integral

Esta investigação tem como tema a proposta de formação de professores em serviço do Curso de Atualização de Professores de Escola de Horário Integral, realizado no segundo governo de Leonel Brizola, no Estado do Rio de Janeiro (1991 1994), durante o Segundo Programa Especial de Educação (II PEE). Este estudo objetivou analisar a proposta de formação de professores em serviço, focalizando este Curso como uma das iniciativas desta formação e, partindo dela identificar contribuições significativas, produzidas naquele tempo e espaço específico, que possam enriquecer e suscitar questões para os debates atuais sobre a formação continuada de professores. Ao empreender esta tarefa se julgou necessário delinear a trajetória do I E II PEE para melhor compreensão da evolução deste plano e de sua proposta de formação de professores, até a elaboração do Curso. Após a retomada do II PEE, frente à necessidade de reestruturação pedagógica dos Centros Integrados de Educação Pública (CIEPs) foi criado o Curso, em convênio com a UERJ. O ponto mais importante identificado nesta proposta de formação foi considerar a escola como lócus de formação continuada tendo como base o saber do professor neste processo. Aspecto como se pode constatar, de grande relevância atualmente nas discussões sobre a temática, mas que naquele momento foi uma inovação. Supõe-se que os resultados deste trabalho poderão contribuir para ampliar os debates em torno das questões voltadas para a formação continuada de professores, e ainda, ampliar os debates, bem oportunos, sobre criação de diferentes alternativas de escolas públicas de horário integral, com suas proposta de formação para atender a uma necessidade da sociedade contemporânea e fundamentar ações de gestores das políticas públicas de Educação.

Atenção integral ao idoso no contexto da estratégia da saúde da família: um olhar sobre a formação e práticas médicas

A Estratégia de Saúde da Família (ESF) foi criada como a principal iniciativa de reorientação do modelo assistencial no SUS, ao mesmo tempo em que a população brasileira envelhecia. As equipes da SF estão lidando com a atenção à saúde deste contingente populacional sob a influência de aspectos técnicos, institucionais e culturais adversos como a sua frágil capacitação, a não interligação da rede, e o escasso valor social dado ao velho na sociedade. Este estudo foca a atenção ao idoso, no contexto da implementação da Estratégia e Saúde da Família (ESF), no Estado do Rio de Janeiro, utilizando metodologia qualitativa. Seu objetivo geral é conhecer a atenção ao idoso no contexto de trabalho da Estratégia de Saúde da Família no Estado do Rio de Janeiro. Especificamente pretendeu-se conhecer a percepção dos profissionais de saúde acerca do envelhecimento e suas consequências sobre a atenção ao idoso na ESF; discutir o papel da ESF numa rede de atenção ao idoso, analisando a organização da rede e analisar o processo de trabalho na atenção ao idoso. Utilizando métodos descritivos e analíticos, três conjuntos de dados foram articulados: dados sobre o contexto do Programa de Saúde da Família em cada município, dados relativos aos conhecimentos técnicos das equipes sobre atenção ao idoso e dados relativos à percepção dos profissionais sobre a atenção ao idoso na ESF. Como técnicas de coleta de dados foram utilizadas a entrevista individual, o grupo focal e a análise documental os dados. Foram realizados 54 entrevistas individuais e 6 grupos focais para a criação de Fluxogramas Descritores e Discussões de Casos. Participaram 6 equipes de 3 municípios do Estado do Rio de Janeiro. Da análise dos dados emergiu o papel de ESF na rede de atenção ao idoso, o que permite a determinação de conteúdos, habilidades e atitudes que precisam ser desenvolvidos como um todo nos profissionais, e nos médicos em particular. Também está clara a necessidade de articulação de uma rede de atenção ao idoso, integrada, composta por serviços e níveis de atenção diferentes e intersetorial, que permita uma prática de cuidado e a promoção de um envelhecimento saudável. Chegamos a conclusão que a formação e as práticas destes profissionais, em particular do médico, precisam ser entendidas de um modo integrado e inseridas na graduação e pós-graduação. O treinamento das equipes, já instaladas, deveria ser trabalhado dentro das premissas da educação permanente e acompanhado de um trabalho de articulação de uma rede de atenção para o idoso, de forma a permitir seu resolutividade. Desenvolver as competências para os profissionais de saúde da ESF, sem desenvolver a competência do sistema de saúde não terá efeito significativo na qualidade da atenção prestada.