A tellurium-based cathepsin B inhibitor: Molecular structure, modelling, molecular docking and biological evaluation

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

A tellurium-based cathepsin B inhibitor: Molecular structure, modelling, molecular docking and biological evaluation

The crystallographically determined structure of biologically active 4,4-dichloro-1,3-diphenyl-4-telluraoct-2-en-1-one, 3, shows the coordination geometry for Te to be distorted psi-pentagonal bipyramidal based on a C2OCl3(lone pair) donor set. Notable is the presence of an intramolecular axial Te center dot center dot center dot O (carbonyl) interaction, a design element included to reduce hydrolysis. Raman and molecular modelling studies indicate the persistence of the Te center dot center dot center dot O(carbonyl) interaction in the solution (CHCl3) and gasphases, respectively. Docking studies of 3' (i.e. original 3 less one chloride) with Cathepsin B reveals a change in the configuration about the vinyl C = C bond. i.e. to E from Z (crystal structure). This isomerism allows the optimisation of interactions in the complex which features a covalent Te-SGCys29 bond. Crucially, the E configuration observed for 3' allows for the formation of a hypervalent Te center dot center dot center dot O interaction as well as an O center dot center dot center dot H-O hydrogen bond with the Gly27 and Glu122 residues, respectively. Additional stabilisation is afforded by a combination of interactions spanning the S1, S2, S1' and S2' sub-sites of Cathepsin B. The greater experimental inhibitory activity of 3 compared with analogues is rationalised by the additional interactions formed between 3' and the His110 and His111 residues in the occluding loop, which serve to hinder the entrance to the active site. (C) 2012 Elsevier B.V. All rights reserved.

A generalised dynamic model for char particle gasification with structure evolution and peripheral fragmentation

A generalised model for the prediction of single char particle gasification dynamics, accounting for multi-component mass transfer with chemical reaction, heat transfer, as well as structure evolution and peripheral fragmentation is developed in this paper. Maxwell-Stefan analysis is uniquely applied to both micro and macropores within the framework of the dusty-gas model to account for the bidisperse nature of the char, which differs significantly from the conventional models that are based on a single pore type. The peripheral fragmentation and random-pore correlation incorporated into the model enable prediction of structure/reactivity relationships. The occurrence of chemical reaction within the boundary layer reported by Biggs and Agarwal (Chem. Eng. Sci. 52 (1997) 941) has been confirmed through an analysis of CO/CO2 product ratio obtained from model simulations. However, it is also quantitatively observed that the significance of boundary layer reaction reduces notably with the reduction of oxygen concentration in the flue gas, operational pressure and film thickness. Computations have also shown that in the presence of diffusional gradients peripheral fragmentation occurs in the early stages on the surface, after which conversion quickens significantly due to small particle size. Results of the early commencement of peripheral fragmentation at relatively low overall conversion obtained from a large number of simulations agree well with experimental observations reported by Feng and Bhatia (Energy & Fuels 14 (2000) 297). Comprehensive analysis of simulation results is carried out based on well accepted physical principles to rationalise model prediction. (C) 2001 Elsevier Science Ltd. AH rights reserved.

Projeto de fundações e estrutura de ampliação de escola no Açores utilizando os eurocódigos estruturais

Trabalho de Projeto para obtenção do grau de Mestre em Engenharia Civil na Área de Especialização de Estruturas

Projeto de fundações e estrutura de ampliação de escola utilizando os eurocódigos estruturais

Trabalho Final de Mestrado para obtenção do grau de Mestre em Engenharia Civil na Área de Especialização estruturas

Influence diagnostics in Gaussian spatial linear models

Spatial linear models have been applied in numerous fields such as agriculture, geoscience and environmental sciences, among many others. Spatial dependence structure modelling, using a geostatistical approach, is an indispensable tool to estimate the parameters that define this structure. However, this estimation may be greatly affected by the presence of atypical observations in the sampled data. The purpose of this paper is to use diagnostic techniques to assess the sensitivity of the maximum-likelihood estimators, covariance functions and linear predictor to small perturbations in the data and/or the spatial linear model assumptions. The methodology is illustrated with two real data sets. The results allowed us to conclude that the presence of atypical values in the sample data have a strong influence on thematic maps, changing the spatial dependence structure.

NMR, Metabonomics and Molecular Profiles: Applications to the Quality Assessment of Foodstuffs

Nuclear Magnetic Resonance (NMR) is a branch of spectroscopy that is based on the fact that many atomic nuclei may be oriented by a strong magnetic field and will absorb radiofrequency radiation at characteristic frequencies. The parameters that can be measured on the resulting spectral lines (line positions, intensities, line widths, multiplicities and transients in time-dependent experi-ments) can be interpreted in terms of molecular structure, conformation, molecular motion and other rate processes. In this way, high resolution (HR) NMR allows performing qualitative and quantitative analysis of samples in solution, in order to determine the structure of molecules in solution and not only. In the past, high-field NMR spectroscopy has mainly concerned with the elucidation of chemical structure in solution, but today is emerging as a powerful exploratory tool for probing biochemical and physical processes. It represents a versatile tool for the analysis of foods. In literature many NMR studies have been reported on different type of food such as wine, olive oil, coffee, fruit juices, milk, meat, egg, starch granules, flour, etc using different NMR techniques. Traditionally, univariate analytical methods have been used to ex-plore spectroscopic data. This method is useful to measure or to se-lect a single descriptive variable from the whole spectrum and , at the end, only this variable is analyzed. This univariate methods ap-proach, applied to HR-NMR data, lead to different problems due especially to the complexity of an NMR spectrum. In fact, the lat-ter is composed of different signals belonging to different mole-cules, but it is also true that the same molecules can be represented by different signals, generally strongly correlated. The univariate methods, in this case, takes in account only one or a few variables, causing a loss of information. Thus, when dealing with complex samples like foodstuff, univariate analysis of spectra data results not enough powerful. Spectra need to be considered in their wholeness and, for analysing them, it must be taken in consideration the whole data matrix: chemometric methods are designed to treat such multivariate data. Multivariate data analysis is used for a number of distinct, differ-ent purposes and the aims can be divided into three main groups: • data description (explorative data structure modelling of any ge-neric n-dimensional data matrix, PCA for example); • regression and prediction (PLS); • classification and prediction of class belongings for new samples (LDA and PLS-DA and ECVA). The aim of this PhD thesis was to verify the possibility of identify-ing and classifying plants or foodstuffs, in different classes, based on the concerted variation in metabolite levels, detected by NMR spectra and using the multivariate data analysis as a tool to inter-pret NMR information. It is important to underline that the results obtained are useful to point out the metabolic consequences of a specific modification on foodstuffs, avoiding the use of a targeted analysis for the different metabolites. The data analysis is performed by applying chemomet-ric multivariate techniques to the NMR dataset of spectra acquired. The research work presented in this thesis is the result of a three years PhD study. This thesis reports the main results obtained from these two main activities: A1) Evaluation of a data pre-processing system in order to mini-mize unwanted sources of variations, due to different instrumental set up, manual spectra processing and to sample preparations arte-facts; A2) Application of multivariate chemiometric models in data analy-sis.

Interpreting Judgements using Knowledge Representation Methods and Computational Models of Argument

The goal of the present research is to define a Semantic Web framework for precedent modelling, by using knowledge extracted from text, metadata, and rules, while maintaining a strong text-to-knowledge morphism between legal text and legal concepts, in order to fill the gap between legal document and its semantics. The framework is composed of four different models that make use of standard languages from the Semantic Web stack of technologies: a document metadata structure, modelling the main parts of a judgement, and creating a bridge between a text and its semantic annotations of legal concepts; a legal core ontology, modelling abstract legal concepts and institutions contained in a rule of law; a legal domain ontology, modelling the main legal concepts in a specific domain concerned by case-law; an argumentation system, modelling the structure of argumentation. The input to the framework includes metadata associated with judicial concepts, and an ontology library representing the structure of case-law. The research relies on the previous efforts of the community in the field of legal knowledge representation and rule interchange for applications in the legal domain, in order to apply the theory to a set of real legal documents, stressing the OWL axioms definitions as much as possible in order to enable them to provide a semantically powerful representation of the legal document and a solid ground for an argumentation system using a defeasible subset of predicate logics. It appears that some new features of OWL2 unlock useful reasoning features for legal knowledge, especially if combined with defeasible rules and argumentation schemes. The main task is thus to formalize legal concepts and argumentation patterns contained in a judgement, with the following requirement: to check, validate and reuse the discourse of a judge - and the argumentation he produces - as expressed by the judicial text.

Análisis del comportamiento de uniones metálicas viga-soporte mediante modelo de elementos finitos y comparación de resultados con el modelo de nudos y barras

Para el proyecto y cálculo de estructuras metálicas, fundamentalmente pórticos y celosías de cubierta, la herramienta más comúnmente utilizada son los programas informáticos de nudos y barras. En estos programas se define la geometría y sección de las barras, cuyas características mecánicas son perfectamente conocidas, y sobre las cuales obtenemos unos resultados de cálculo concretos en cuanto a estados tensionales y de deformación. Sin embargo el otro componente del modelo, los nudos, presenta mucha mayor complejidad a la hora de establecer sus propiedades mecánicas, fundamentalmente su rigidez al giro, así como de obtener unos resultados de estados tensionales y de deformación en los mismos. Esta “ignorancia” sobre el comportamiento real de los nudos, se salva generalmente asimilando a los nudos del modelo la condición de rígidos o articulados. Si bien los programas de cálculo ofrecen la posibilidad de introducir nudos con una rigidez intermedia (nudos semirrígidos), la rigidez de cada nudo dependerá de la geometría real de la unión, lo cual, dada la gran variedad de geometrías de uniones que en cualquier proyecto se nos presentan, hace prácticamente inviable introducir los coeficientes correspondientes a cada nudo en los modelos de nudos y barras. Tanto el Eurocódigo como el CTE, establecen que cada unión tendrá asociada una curva momento-rotación característica, que deberá ser determinada por los proyectistas mediante herramientas de cálculo o procedimientos experimentales. No obstante, este es un planteamiento difícil de llevar a cabo para cada proyecto. La consecuencia de esto es, que en la práctica, se realizan extensas comprobaciones y justificaciones de cálculo para las barras de las estructuras, dejando en manos de la práctica común la solución y puesta en obra de las uniones, quedando sin justificar ni comprobar la seguridad y el comportamiento real de estas. Otro aspecto que conlleva la falta de caracterización de las uniones, es que desconocemos como afecta el comportamiento real de éstas en los estados tensionales y de deformación de las barras que acometen a ellas, dudas que con frecuencia nos asaltan, no sólo en la fase de proyecto, sino también a la hora de resolver los problemas de ejecución que inevitablemente se nos presentan en el desarrollo de las obras. El cálculo mediante el método de los elementos finitos, es una herramienta que nos permite introducir la geometría real de perfiles y uniones, y nos permite por tanto abordar el comportamiento real de las uniones, y que está condicionado por su geometría. Por ejemplo, un caso típico es el de la unión de una viga a una placa o a un soporte soldando sólo el alma. Es habitual asimilar esta unión a una articulación. Sin embargo, el modelo por elementos finitos nos ofrece su comportamiento real, que es intermedio entre articulado y empotrado, ya que se transmite un momento y el giro es menor que el del apoyo simple. No obstante, la aplicación del modelo de elementos finitos, introduciendo la geometría de todos los elementos estructurales de un entramado metálico, tampoco resulta en general viable desde un punto de vista práctico, dado que requiere invertir mucho tiempo en comparación con el aumento de precisión que obtenemos respecto a los programas de nudos y barras, mucho más rápidos en la fase de modelización de la estructura. En esta tesis se ha abordado, mediante la modelización por elementos finitos, la resolución de una serie de casos tipo representativos de las uniones más comúnmente ejecutadas en obras de edificación, como son las uniones viga-pilar, estableciendo el comportamiento de estas uniones en función de las variables que comúnmente se presentan, y que son: •Ejecución de uniones viga-pilar soldando solo por el alma (unión por el alma), o bien soldando la viga al pilar por todo su perímetro (unión total). •Disposición o no de rigidizadores en los pilares •Uso de pilares de sección 2UPN en cajón o de tipo HEB, que son los tipos de soporte utilizados en casi el 100% de los casos en edificación. Para establecer la influencia de estas variables en el comportamiento de las uniones, y su repercusión en las vigas, se ha realizado un análisis comparativo entre las variables de resultado de los casos estudiados:•Estados tensionales en vigas y uniones. •Momentos en extremo de vigas •Giros totales y relativos en nudos. •Flechas. Otro de los aspectos que nos permite analizar la casuística planteada, es la valoración, desde un punto de vista de costos de ejecución, de la realización de uniones por todo el perímetro frente a las uniones por el alma, o de la disposición o no de rigidizadores en las uniones por todo el perímetro. Los resultados a este respecto, son estrictamente desde un punto de vista económico, sin perjuicio de que la seguridad o las preferencias de los proyectistas aconsejen una solución determinada. Finalmente, un tercer aspecto que nos ha permitido abordar el estudio planteado, es la comparación de resultados que se obtienen por el método de los elementos finitos, más próximos a la realidad, ya que se tiene en cuenta los giros relativos en las uniones, frente a los resultados obtenidos con programas de nudos y barras. De esta forma, podemos seguir usando el modelo de nudos y barras, más versátil y rápido, pero conociendo cuáles son sus limitaciones, y en qué aspectos y en qué medida, debemos ponderar sus resultados. En el último apartado de la tesis se apuntan una serie de temas sobre los que sería interesante profundizar en posteriores estudios, mediante modelos de elementos finitos, con el objeto de conocer mejor el comportamiento de las uniones estructurales metálicas, en aspectos que no se pueden abordar con los programas de nudos y barras. For the project and calculation of steel structures, mainly building frames and cover lattices, the tool more commonly used are the node and bars model computer programs. In these programs we define the geometry and section of the bars, whose mechanical characteristics are perfectly known, and from which we obtain the all calculation results of stresses and displacements. Nevertheless, the other component of the model, the nodes, are much more difficulty for establishing their mechanical properties, mainly the rotation fixity coefficients, as well as the stresses and displacements. This "ignorance" about the real performance of the nodes, is commonly saved by assimilating to them the condition of fixed or articulated. Though the calculation programs offer the possibility to introducing nodes with an intermediate fixity (half-fixed nodes), the fixity of every node will depend on the real connection’s geometry, which, given the great variety of connections geometries that in a project exist, makes practically unviable to introduce the coefficients corresponding to every node in the models of nodes and bars. Both Eurocode and the CTE, establish that every connection will have a typical moment-rotation associated curve, which will have to be determined for the designers by calculation tools or experimental procedures. Nevertheless, this one is an exposition difficult to carry out for each project. The consequence of this, is that in the practice, in projects are extensive checking and calculation reports about the bars of the structures, trusting in hands of the common practice the solution and execution of the connections, resulting without justification and verification their safety and their real behaviour. Another aspect that carries the lack of the connections characterization, is that we don´t know how affects the connections real behaviour in the stresses and displacements of the bars that attack them, doubts that often assault us, not only in the project phase, but also at the moment of solving the execution problems that inevitably happen in the development of the construction works. The calculation by finite element model is a tool that allows us to introduce the real profiles and connections geometry, and allows us to know about the real behaviour of the connections, which is determined by their geometry. Typical example is a beam-plate or beam-support connection welding only by the web. It is usual to assimilate this connection to an articulation or simple support. Nevertheless, the finite element model determines its real performance, which is between articulated and fixed, since a moment is transmitted and the relative rotation is less than the articulation’s rotation. Nevertheless, the application of the finite element model, introducing the geometry of all the structural elements of a metallic structure, does not also turn out to be viable from a practical point of view, provided that it needs to invest a lot of time in comparison with the precision increase that we obtain opposite the node and bars programs, which are much more faster in the structure modelling phase. In this thesis it has been approached, by finite element modelling, the resolution of a representative type cases of the connections commonly used in works of building, since are the beam-support connections, establishing the performance of these connections depending on the variables that commonly are present, which are: •Execution of beam-support connections welding only the web, or welding the beam to the support for the whole perimeter. •Disposition of stiffeners in the supports •Use 2UPN in box section or HEB section, which are the support types used in almost 100% building cases. To establish the influence of these variables in the connections performance, and the repercussion in the beams, a comparative analyse has been made with the resulting variables of the studied cases: •Stresses states in beams and connections. •Bending moments in beam ends. •Total and relative rotations in nodes. •Deflections in beams. Another aspect that the study allows us to analyze, is the valuation, from a costs point of view, of the execution of connections for the whole perimeter opposite to the web connections, or the execution of stiffeners. The results of this analyse, are strictly from an economic point of view, without prejudice that the safety or the preferences of the designers advise a certain solution. Finally, the third aspect that the study has allowed us to approach, is the comparison of the results that are obtained by the finite element model, nearer to the real behaviour, since the relative rotations in the connections are known, opposite to the results obtained with nodes and bars programs. So that, we can use the nodes and bars models, more versatile and quick, but knowing which are its limitations, and in which aspects and measures, we must weight the results. In the last part of the tesis, are relationated some of the topics on which it would be interesting to approach in later studies, with finite elements models, in order to know better the behaviour of the structural steel connections, in aspects that cannot be approached by the nodes and bars programs.

Modelling a cable structure for a new wind energy production device

Dissertação apresentada na Faculdade de Ciências e Tecnologia da Universidade Nova de Lisboa para obtenção do grau de Mestre em Engenharia Mecânica Especialização em Concepção e Produção

Modelling the distribution of bats in relation to landscape structure in a temperate mountain environment

1. Landscape modification is often considered the principal cause of population decline in many bat species. Thus, schemes for bat conservation rely heavily on knowledge about species-landscape relationships. So far, however, few studies have quantified the possible influence of landscape structure on large-scale spatial patterns in bat communities. 2. This study presents quantitative models that use landscape structure to predict (i) spatial patterns in overall community composition and (ii) individual species' distributions through canonical correspondence analysis and generalized linear models, respectively. A geographical information system (GIS) was then used to draw up maps of (i) overall community patterns and (ii) distribution of potential species' habitats. These models relied on field data from the Swiss Jura mountains. 3. Fight descriptors of landscape structure accounted for 30% of the variation in bat community composition. For some species, more than 60% of the variance in distribution could be explained by landscape structure. Elevation, forest or woodland cover, lakes and suburbs, were the most frequent predictors. 4. This study shows that community composition in bats is related to landscape structure through species-specific relationships to resources. Due to their nocturnal activities and the difficulties of remote identification, a comprehensive bat census is rarely possible, and we suggest that predictive modelling of the type described here provides an indispensable conservation tool.

A theoretical model of the tridimensional structure of Bacillus thuringiensis subsp. medellin Cry 11Bb toxin deduced by homology modelling

Cry11Bb is an insecticidal crystal protein produced by Bacillus thuringiensis subsp. medellin during its stationary phase; this ¶-endotoxin is active against dipteran insects and has great potential for mosquito borne disease control. Here, we report the first theoretical model of the tridimensional structure of a Cry11 toxin. The tridimensional structure of the Cry11Bb toxin was obtained by homology modelling on the structures of the Cry1Aa and Cry3Aa toxins. In this work we give a brief description of our model and hypothesize the residues of the Cry11Bb toxin that could be important in receptor recognition and pore formation. This model will serve as a starting point for the design of mutagenesis experiments aimed to the improvement of toxicity, and to provide a new tool for the elucidation of the mechanism of action of these mosquitocidal proteins.

Gravity Modelling of the Crustal Structure Below Bavali Shear Zone And Adjacent Major Plutons Of Northern Kerala

The primary aim of the present study is to acquire a large amount of gravity data, to prepare gravity maps and interpret the data in terms of crustal structure below the Bavali shear zone and adjacent regions of northern Kerala. The gravity modeling is basically a tool to obtain knowledge of the subsurface extension of the exposed geological units and their structural relationship with the surroundings. The study is expected to throw light on the nature of the shear zone, crustal configuration below the high-grade granulite terrain and the tectonics operating during geological times in the region. The Bavali shear is manifested in the gravity profiles by a steep gravity gradient. The gravity models indicate that the Bavali shear coincides with steep plane that separates two contrasting crustal densities extending beyond a depth of 30 km possibly down to Moho, justifying it to be a Mantle fault. It is difficult to construct a generalized model of crustal evolution in terms of its varied manifestations using only the gravity data. However, the data constrains several aspects of crustal evolution and provides insights into some of the major events.