The cyclotides: Novel macrocyclic peptides as scaffolds in drug design

Cyclotides are a novel class of circular, disulfide-rich peptides (similar to 30 amino acids) that display a broad range of bioactivities and have exceptionally high stability. Their physical properties, which include resistance to thermal and enzymatic degradation, can be attributed to their unique cyclic backbone and knotted arrangement of disulfide bonds. The applicability of linear peptides as drugs is potentially limited by their susceptibility to proteolytic cleavage and poor bioavailability. Such limitations may be overcome by using the cyclotide framework as a scaffold onto which new activities may be engineered. The potential use of cyclotides for drug design is evaluated here, with reference to rapidly increasing knowledge of natural cyclotides and the emergence of new techniques in peptide engineering.

Solution Structures of the cis- and trans-Pro30 Isomers of a Novel 38-Residue Toxin from the Venom of Hadronyche Infensa sp. that Contains a Cystine-Knot Motif within Its Four Disulfide Bonds

The primary sequence and three-dimensional structure of a novel peptide toxin isolated from the Australian funnel-web spider Hadronyche infensa sp. is reported. ACTX-HI:OB4219 contains 38 amino acids, including eight-cysteine residues that form four disulfide bonds. The connectivities of these disulfide bonds were previously unknown but have been unambiguously determined in this study. Three of these disulfide bonds are arranged in an inhibitor cystine-knot (ICK) motif, which is observed in a range of other disulfide-rich peptide toxins. The motif incorporates an embedded ring in the structure formed by two of the disulfides and their connecting backbone segments penetrated by a third disulfide bond. Using NMR spectroscopy, we determined that despite the isolation of a single native homologous product by RP-HPLC, ACTX-HI:OB4219 possesses two equally populated conformers in solution. These two conformers were determined to arise from cis/trans isomerization of the bond preceding Pro30. Full assignment of the NMR spectra for both conformers allowed for the calculation of their structures, revealing, the presence of a triple-stranded antiparallel sheet consistent with the inhibitor cystine-knot (ICK) motif.

Large amplitude vibration of thermo-electro-mechanically stressed FGM laminated plates

This paper presents a large amplitude vibration analysis of pre-stressed functionally graded material (FGM) laminated plates that are composed of a shear deformable functionally graded layer and two surface-mounted piezoelectric actuator layers. Nonlinear governing equations of motion are derived within the context of Reddy's higher-order shear deformation plate theory to account for transverse shear strain and rotary inertia. Due to the bending and stretching coupling effect, a nonlinear static problem is solved first to determine the initial stress state and pre-vibration deformations of the plate that is subjected to uniform temperature change, in-plane forces and applied actuator voltage. By adding an incremental dynamic state to the pre-vibration state, the differential equations that govern the nonlinear vibration behavior of pre-stressed FGM laminated plates are derived. A semi-analytical method that is based on one-dimensional differential quadrature and Galerkin technique is proposed to predict the large amplitude vibration behavior of the laminated rectangular plates with two opposite clamped edges. Linear vibration frequencies and nonlinear normalized frequencies are presented in both tabular and graphical forms, showing that the normalized frequency of the FGM laminated plate is very sensitive to vibration amplitude, out-of-plane boundary support, temperature change, in-plane compression and the side-to-thickness ratio. The CSCF and CFCF plates even change the inherent hard-spring characteristic to soft-spring behavior at large vibration amplitudes. (C) 2003 Elsevier B.V. All rights reserved.

Unsaturated diffusivity functions for concrete derived from NMR images

Deterioration of concrete or reinforcing steel through excessive contaminant concentration is often the result of repeated wetting and drying cycles. At each cycle, the absorption of water carries new contaminants into the unsaturated concrete. Nuclear Magnetic Resonance (NMR) is used with large concrete samples to observe the shape of the wetting profile during a simple one-dimensional wetting process. The absorption of water by dry concrete is modelled by a nonlinear diffusion equation with the unsaturated hydraulic diffusivity being a strongly nonlinear function of the moisture content. Exponential and power functions are used for the hydraulic diffusivity and corresponding solutions of the diffusion equation adequately predict the shape of the experimental wetting profile. The shape parameters, describing the wetting profile, vary little between different blends and are relatively insensitive to subsequent re-wetting experiments allowing universal parameters to be suggested for these concretes.

Gerenciamento proteano de carreira entre universitários

A partir da segunda metade do século XX, mudanças no modo de produção capitalista começaram a afetar a relação que as empresas estabeleciam com o trabalhador. Diante de um mercado imprevisível, a carreira tradicional, marcada, entre outros aspectos, por empregos duradouros e com possibilidade de ascensão na hierarquia da organização, tornou-se menos recorrente. Paralelamente, começaram a despontar novas concepções sobre carreira, tendo a maioria um enfoque individualista. Dentre as novas proposições, o presente estudo tomou como referência a concepção de carreira proteana. Esse modelo, de origem norte-americana, tem como ideia central a noção de uma carreira que é gerida pelo indivíduo, e tem como meta o alcance do sucesso psicológico. Desta forma, ancora-se em duas principais dimensões: autogerenciamento e direcionamento para valores. Considerando os diversos estudos que descrevem as dificuldades enfrentadas por estudantes na transição da universidade para o mercado de trabalho, esta pesquisa objetivou compreender aspectos do gerenciamento proteano de carreira entre universitários brasileiros que já tinham concluído, pelo menos, a primeira metade do curso de graduação. Para tanto, o estudo foi dividido em dois artigos. O primeiro foi destinado ao desenvolvimento e validação da Escala de Atitudes de Carreira Proteana para universitários, tendo sido realizado com uma amostra de 1016 estudantes de 37 cursos diferentes, com idade variando entre 18 e 65 anos, e média de 24,52 (DP = 6,69 anos). O instrumento, denominado neste estudo de Escala de Gerenciamento Proteano de Carreira para Universitários (EGPC-U) atestou a estrutura de duas dimensões, evidenciada também na versão original da medida. Os índices de confiabilidade foram satisfatórios e superiores a 12 0,61, tendo o instrumento a possibilidade de ser utilizado em serviços de orientação profissional ou de carreira. O segundo artigo objetivou compreender como as dimensões do modelo proteano se relacionam com variáveis sóciodemográficas e com construtos psicossociais: personalidade, lócus de controle, saúde e satisfação com a vida, e envolveu alunos de duas áreas de conhecimento: humanas e exatas. A amostra foi composta por 525 alunos, sendo 245 da área de humanas e 280 de exatas, sendo 52% do sexo masculino. A idade dos participantes variou entre 18 e 30 anos e média de 22,59 anos (DP = 2,66 anos). A partir dos resultados do estudo 2, constatou-se que alunos da área de humanas, quando comparados a estudantes de exatas, tendem a apresentar média superior na dimensão de direcionamento para valores. Verificou-se ainda que os aspectos de conscienciosidade e lócus de controle interno são preditores significativos do autogerenciamento tanto entre alunos de humanas como de exatas e que a adoção de atitudes proteanas tende a impactar positivamente aspectos da saúde e da satisfação com a vida do indivíduo. O estudo, de um modo geral, permitiu verificar a existência de características proteanas entre universitários, como também possibilitou conhecer variáveis relacionadas às atitudes de autogerenciamento e direcionamento para valores. Destaca-se, porém, a necessidade de pesquisas complementares com a exploração de outras variáveis psicossociais que possam estar relacionadas ao gerenciamento proteano entre graduandos.

Surgical correction of scoliosis: Numerical analysis and optimization of the procedure

A previously developed model is used to numerically simulate real clinical cases of the surgical correction of scoliosis. This model consists of one-dimensional finite elements with spatial deformation in which (i) the column is represented by its axis; (ii) the vertebrae are assumed to be rigid; and (iii) the deformability of the column is concentrated in springs that connect the successive rigid elements. The metallic rods used for the surgical correction are modeled by beam elements with linear elastic behavior. To obtain the forces at the connections between the metallic rods and the vertebrae geometrically, non-linear finite element analyses are performed. The tightening sequence determines the magnitude of the forces applied to the patient column, and it is desirable to keep those forces as small as possible. In this study, a Genetic Algorithm optimization is applied to this model in order to determine the sequence that minimizes the corrective forces applied during the surgery. This amounts to find the optimal permutation of integers 1, ... , n, n being the number of vertebrae involved. As such, we are faced with a combinatorial optimization problem isomorph to the Traveling Salesman Problem. The fitness evaluation requires one computing intensive Finite Element Analysis per candidate solution and, thus, a parallel implementation of the Genetic Algorithm is developed.

Environmental sustainability in superior education: case study of Lisbon College of Health Technology

Over the centuries there has been a growing trend of societies and it is possible to verify their economic growth. This growth has provided an increased pressure on natural resources, often over-reaching the boundaries of each country, which has called into question the level of environmental sustainability in different countries. Sustainability is understood as a complex concept involving ecological, social, economic dimensions and temporal urban processes. Therefore, Firmino (2009) suggests that the ecological footprint (EF) allows people to establish dependency relations between human activities and the natural resources required for such activities and for the absorption of waste generated. According to Bergh & Verbruggen (1999) the EF is an objective, impartial and one-dimensional indicator that enables people to assess the sustainability. The Superior Schools have a crucial role in building the vision of a sustainable future as a reality, because in transmitting values and environmental principles to his students, are providing that they, in exercising his professional activity, make decisions weighing the environmental values. This ensures improved quality of life. The present study aims to determine the level of environmental sustainability of the Academic Community of Lisbon College of Health Technology (ESTeSL), by calculating the EF, and describe whether a relation between Footprint and various socio-demographic characteristics of the subjects.

Dispositional optimism is unidimensional or bidimensional? The Portuguese Revised Life Orientation Test

The aim of the study is to adapt and then discuss the appropriateness of the Life Orientation Test as a one or two dimension scale. The research includes two studies; one is composed of a sequential sample of 280 people with multiple sclerosis, 71% female, and another includes a convenience sample of 615 individuals from the community, 51.1% female. Because the construct is built upon a theoretical assumption that has one dimension, we examine the hypothesis of one or two factor solutions through confirmatory factor analysis, and the two-dimension solution premise demonstrates better adjustment for both samples. The other psychometric properties explored show appropriate results for the Portuguese sample, and similar to the original ones; the Test therefore seems appropriate for use in cross cultural studies. Based on our results, we discuss whether the questionnaire is a one or two dimension instrument, concluding that it appears appropriate to accept the recommendations of the original authors to use it as a one-dimensional tool and, when necessary, to use both dimensions. - RESUMO: El objetivo del estudio es adaptar y discutir la adecuación de la prueba de Orientación de la Vida en una o dos escalas de dimensión. La investigación engloba dos estudios, uno constituido por una muestra secuencial de 280 personas con esclerosis múltiple, 71% mujeres y otro con una muestra de conveniencia de la comunidad de 615 individuos, 51,1% del sexo femenino. Como el constructo se asienta sobre la presunción teórica de que tiene una dimensión, inspeccionamos la hipótesis de una o dos soluciones de factor a través del análisis factorial confirmatorio y la hipótesis de dos dimensiones manifiesta un mejor ajuste para ambas muestras. Las otras propiedades psicométricas exploradas muestran los resultados apropiados para la muestra portuguesa, y semejantes a los originales. Parece apropiado para los estudios culturales transversales. Basándonos en nuestros resultados, discutimos si el cuestionario es un instrumento de una o dos dimensiones, concluyéndose que parece conveniente seguir las recomendaciones de los autores originales, para utilizarlo como un instrumento unidimensional y, si fuera necesario necesario, utilizar cada una de las dimensiones.

Notas sobre o mundo social do livro: a construção do editor e da edição

Personagem-filtro, intérprete, mas também interventor, prescrevendo, legitimando e ordenando o universo tipográfico, o editor surge como figura múltipla e socialmente investida de atributos e práticas mediadoras na sua relação com o dado textual. Produtor de valor e materialidade, o editor inscreve o projecto do livro num espaço social colaborativo de trabalho, o campo da edição. Este artigo procura sistematizar teoricamente alguns tópicos relativos à articulação do editor com a construção social do campo editorial e a edificação da cultura impressa. Empreender semelhante exploração é abdicar forçosamente de uma visão linear, unidimensional e historicamente asséptica do mundo social e cultural do livro, cuja morfologia e suportes conhecem crescentemente os desafios da desmaterialização.

Pluralidade, mudança e produção de valor na edição de livros: notas sobre a edificação social da cultura impressa

Habitando um campo de intermediação, filtragem e interpretação, o editor assume um papel de legitimação, ordenação e prescrição do mundo pela via tipográfica. O esforço de realização de um livro não se restringe à génese autoral do texto. O livro resulta de um trabalho que implica acrescento simbólico e viabilidade de circulação, sem os quais o objecto se perde enquanto objecto de desejo, factor de aval de conteúdos ou elemento de alarde identitário. A existência de um livro corresponde em grande parte à acção editorial de o instituir socialmente como obra conhecida e reconhecida pelos seus receptores finais. Produtor de valor e materialidade, o editor inscreve o projecto do livro num espaço social colaborativo de trabalho, o campo da edição. Esta apresentação procura sistematizar teoricamente alguns tópicos relativos à articulação do editor com a construção social do campo editorial e a edificação da cultura impressa. Empreender semelhante exploração é abdicar forçosamente de uma visão linear, unidimensional e a-histórica do mundo social e cultural do livro, cuja morfologia e suportes conhecem crescentemente os desafios da desmaterialização.

Topological Complexity and Predictability in the Dynamics of a Tumor Growth Model with Shilnikov's Chaos

Dynamical systems modeling tumor growth have been investigated to determine the dynamics between tumor and healthy cells. Recent theoretical investigations indicate that these interactions may lead to different dynamical outcomes, in particular to homoclinic chaos. In the present study, we analyze both topological and dynamical properties of a recently characterized chaotic attractor governing the dynamics of tumor cells interacting with healthy tissue cells and effector cells of the immune system. By using the theory of symbolic dynamics, we first characterize the topological entropy and the parameter space ordering of kneading sequences from one-dimensional iterated maps identified in the dynamics, focusing on the effects of inactivation interactions between both effector and tumor cells. The previous analyses are complemented with the computation of the spectrum of Lyapunov exponents, the fractal dimension and the predictability of the chaotic attractors. Our results show that the inactivation rate of effector cells by the tumor cells has an important effect on the dynamics of the system. The increase of effector cells inactivation involves an inverse Feigenbaum (i.e. period-halving bifurcation) scenario, which results in the stabilization of the dynamics and in an increase of dynamics predictability. Our analyses also reveal that, at low inactivation rates of effector cells, tumor cells undergo strong, chaotic fluctuations, with the dynamics being highly unpredictable. Our findings are discussed in the context of tumor cells potential viability.

Besnoitia besnoiti protein disulfide isomerase (BbPDI): molecular characterization, expression and in silico modelling

Besnoitia besnoiti is an apicomplexan parasite responsible for bovine besnoitiosis, a disease with a high prevalence in tropical and subtropical regions and re-emerging in Europe. Despite the great economical losses associated with besnoitiosis, this disease has been underestimated and poorly studied, and neither an effective therapy nor an efficacious vaccine is available. Protein disulfide isomerase (PDI) is an essential enzyme for the acquisition of the correct three-dimensional structure of proteins. Current evidence suggests that in Neosporacaninum and Toxoplasmagondii, which are closely related to B. besnoiti, PDI play an important role in host cell invasion, is a relevant target for the host immune response, and represents a promising drug target and/or vaccine candidate. In this work, we present the nucleotide sequence of the B. besnoiti PDI gene. BbPDI belongs to the thioredoxin-like superfamily (cluster 00388) and is included in the PDI_a family (cluster defined cd02961) and the PDI_a_PDI_a'_c subfamily (cd02995). A 3D theoretical model was built by comparative homology using Swiss-Model server, using as a template the crystallographic deduced model of Tapasin-ERp57 (PDB code 3F8U chain C). Analysis of the phylogenetic tree for PDI within the phylum apicomplexa reinforces the close relationship among B. besnoiti, N. caninum and T. gondii. When subjected to a PDI-assay based on the polymerisation of reduced insulin, recombinant BbPDI expressed in E. coli exhibited enzymatic activity, which was inhibited by bacitracin. Antiserum directed against recombinant BbPDI reacted with PDI in Western blots and by immunofluorescence with B. besnoiti tachyzoites and bradyzoites.

Paranoia in the General Population : a revised version of the General Paranoia Scale for Adults

Background: Paranoid ideation has been regarded as a cognitive and a social process used as a defence against perceived threats. According to this perspective, paranoid ideation can be understood as a process extending across the normal-pathological continuum. Methods: In order to refine the construct of paranoid ideation and to validate a measure of paranoia, 906 Portuguese participants from the general population and 91 patients were administered the General Paranoia Scale (GPS), and two conceptual models (one - and tridimensional) were compared through confirmatory factor analysis (CFA). Results: Results from the CFA of the GPS confirmed a different model than the one-dimensional model proposed by Fenigstein and Vanable, which com-prised three dimensions (mistrust thoughts, persecutory ideas, and self-deprecation). This alternative model presented a better fit and increased sensitivity when compared with the one-dimensional model. Further data analysis of the scale revealed that the GPS is an adequate assessment tool for adults, with good psychometric characteristics and high internal consistency. Conclusion: The model proposed in the current work leads to further refinements and enrichment of the construct of paranoia in different populations, allowing the assessment of three dimensions of paranoia and the risk of clinical paranoia in a single measure for the general population.

Paranoia in the General Population : a revised version of the General Paranoia Scale for adolescents

The aim of the current study was to validate the General Paranoia Scale for Portuguese Adolescents population (GPS-A). This scale assesses the paranoid ideation in non-clinical population. Results from a confirmatory factor analysis of the scale on 1218 youths confirmed an alternative model to the one-dimensional model proposed by Fenigstein and Vanable (1992) comprising three different dimensions (Mistrust thoughts, persecutory ideas and depreciation). This alternative model presented a good fit: χ2 (162)= 727.200, p = .000; CFI = .925; RMSEA = .054, P(rmsea ≤0.05) = .000; PCFI = .788; AIC = 863.200. All items presented adequate factor loadings (λij ≥0.5) and individual reliability ((λij)2 ≥0.25). Further data analysis on the scale revealed that the GPS-A is an adequate assessment tool for adolescents, with good psychometric characteristics and high internal consistency.

Chemical reaction network of flavylium ions in heterogeneous media

Dissertação apresentada para a obtenção do Grau de Doutor em Química, especialidade em Química-Física, pela Universidade Nova de Lisboa, Faculdade de Ciências e Tecnologia