937 resultados para STRUCTURE-BASED DRUG DESIGN
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En esta tesis se ha profundizado en el estudio y desarrollo de modelos de soporte para el aprendizaje colaborativo a distancia, que ha permitido proponer una arquitectura fundamentada en los principios del paradigma CSCL (Computer Supported Collaborative Learning). La arquitectura propuesta aborda un tipo de problema concreto que requiere el uso de técnicas derivadas del Trabajo Colaborativo, la Inteligencia Artificial, Interfaces de Usuario así como ideas tomadas de la Pedagogía y la Psicología. Se ha diseñado una solución completa, abierta y genérica. La arquitectura aprovecha las nuevas tecnologías para lograr un sistema efectivo de apoyo a la educación a distancia. Está organizada en cuatro niveles: el de Configuración, el de Experiencia, el de Organización y el de Análisis. A partir de ella se ha implementado un sistema llamado DEGREE. En DEGREE, cada uno de los niveles de la arquitectura da lugar a un subsistema independiente pero relacionado con los otros. La aplicación saca partido del uso de espacios de trabajo estructurados. El subsistema Configurador de Experiencias permite definir los elementos de un espacio de trabajo y una experiencia y adaptarlos a cada tipo de usuario. El subsistema Manejador de Experiencias recoge las contribuciones de los usuarios para construir una solución conjunta de un problema. Las intervenciones de los alumnos se estructuran basándose en un grafo conversacional genérico. Además, se registran todas las acciones de los usuarios para representar explícitamente el proceso completo que lleva a la solución. Estos datos también se almacenan en una memoria común que constituye el subsistema llamado Memoria Organizativa de Experiencias. El subsistema Analizador estudia las intervenciones de los usuarios. Este análisis permite inferir conclusiones sobre la forma en que trabajan los grupos y sus actitudes frente a la colaboración, teniendo en cuenta además el conocimiento subjetivo del observador. El proceso de desarrollo en paralelo de la arquitectura y el sistema ha seguido un ciclo de refinamiento en cinco fases con sucesivas etapas de prototipado y evaluación formativa. Cada fase de este proceso se ha realizado con usuarios reales y se han considerado las opiniones de los usuarios para mejorar las funcionalidades de la arquitectura así como la interfaz del sistema. Esta aproximación ha permitido, además, comprobar la utilidad práctica y la validez de las propuestas que sustentan este trabajo.---ABSTRACT---In this thesis, we have studied in depth the development of support models for distance collaborative learning and subsequently devised an architecture based on the Computer Supported Collaborative Learning paradigm principles. The proposed architecture addresses a specific problem: coordinating groups of students to perform collaborative distance learning activities. Our approach uses Cooperative Work, Artificial Intelligence and Human-Computer Interaction techniques as well as some ideas from the fields of Pedagogy and Psychology. We have designed a complete, open and generic solution. Our architecture exploits the new information technologies to achieve an effective system for education purposes. It is organised into four levels: Configuration, Experience, Organisation and Reflection. This model has been implemented into a system called DEGREE. In DEGREE, each level of the architecture gives rise to an independent subsystem related to the other ones. The application benefits from the use of shared structured workspaces. The configuration subsystem allows customising the elements that define an experience and a workspace. The experience subsystem gathers the users' contributions to build joint solutions to a given problem. The students' interventions build up a structure based on a generic conversation graph. Moreover, all user actions are registered in order to represent explicitly the complete process for reaching the group solution. Those data are also stored into a common memory, which constitutes the organisation subsystem. The user interventions are studied by the reflection subsystem. This analysis allows us inferring conclusions about the way in which the group works and its attitudes towards collaboration. The inference process takes into account the observer's subjective knowledge. The process of developing both the architecture and the system in parallel has run through a five-pass cycle involving successive stages of prototyping and formative evaluation. At each stage of that process, we have considered the users' feedback for improving the architecture's functionalities as well as the system interface. This approach has allowed us to prove the usability and validity of our proposal.
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RESUMEN Las empresas tienen programas que acceden a sus bases de datos, estos programas pueden quedarse obsoletos o dejar de serles útiles por alguna razón y deben ser actualizados o reemplazados. Sin embargo la base de datos se suele mantener, ya que la estructura de la información no cambia. Llegado el momento de actualizar o migrar ese software que accede a la base de datos, se puede recurrir a una estructura de clases, las cuales están basadas en la metainformación de la base de datos, y así facilitar el desarrollo del nuevo software. La herramienta desarrollada en este proyecto accede a la metainformación de la base de datos, obtiene la estructura de las tablas y a través de plantillas genera las clases necesarias para empezar el nuevo software. Al estar la herramienta basada en plantillas, adaptar éstas a un nuevo lenguaje es sencillo, haciendo la herramienta mucho más polivalente. En conclusión, una herramienta de este tipo puede facilitar el desarrollo de un nuevo software siempre que la estructura de la base de datos se mantenga intacta haciendo que el nuevo proyecto se desarrolle de forma más rápida. ABSTRACT Companies have software that access their databases, this software can become obsolete or fail to be useful for some reason and must be upgraded or replaced. However the database is usually maintained as the information does not change. It is for this reason that when you migrate the software that accesses the database can use a class structure based on information in the database to facilitate the development of new software. The tool developed in this project accesses the metadata of the database to obtain the structure of the tables and through templates generate the necessary classes to start the new software. Being template‐based tool, adapt these to a new language is simple, making a more versatile tool. In conclusion, a tool of this kind can facilitate the development of a new software provided that the structure of the database is intact making the new project develops more quickly.
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Structural genomics aims to solve a large number of protein structures that represent the protein space. Currently an exhaustive solution for all structures seems prohibitively expensive, so the challenge is to define a relatively small set of proteins with new, currently unknown folds. This paper presents a method that assigns each protein with a probability of having an unsolved fold. The method makes extensive use of protomap, a sequence-based classification, and scop, a structure-based classification. According to protomap, the protein space encodes the relationship among proteins as a graph whose vertices correspond to 13,354 clusters of proteins. A representative fold for a cluster with at least one solved protein is determined after superposition of all scop (release 1.37) folds onto protomap clusters. Distances within the protomap graph are computed from each representative fold to the neighboring folds. The distribution of these distances is used to create a statistical model for distances among those folds that are already known and those that have yet to be discovered. The distribution of distances for solved/unsolved proteins is significantly different. This difference makes it possible to use Bayes' rule to derive a statistical estimate that any protein has a yet undetermined fold. Proteins that score the highest probability to represent a new fold constitute the target list for structural determination. Our predicted probabilities for unsolved proteins correlate very well with the proportion of new folds among recently solved structures (new scop 1.39 records) that are disjoint from our original training set.
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PALI (release 1.2) contains three-dimensional (3-D) structure-dependent sequence alignments as well as structure-based phylogenetic trees of homologous protein domains in various families. The data set of homologous protein structures has been derived by consulting the SCOP database (release 1.50) and the data set comprises 604 families of homologous proteins involving 2739 protein domain structures with each family made up of at least two members. Each member in a family has been structurally aligned with every other member in the same family (pairwise alignment) and all the members in the family are also aligned using simultaneous superposition (multiple alignment). The structural alignments are performed largely automatically, with manual interventions especially in the cases of distantly related proteins, using the program STAMP (version 4.2). Every family is also associated with two dendrograms, calculated using PHYLIP (version 3.5), one based on a structural dissimilarity metric defined for every pairwise alignment and the other based on similarity of topologically equivalent residues. These dendrograms enable easy comparison of sequence and structure-based relationships among the members in a family. Structure-based alignments with the details of structural and sequence similarities, superposed coordinate sets and dendrograms can be accessed conveniently using a web interface. The database can be queried for protein pairs with sequence or structural similarities falling within a specified range. Thus PALI forms a useful resource to help in analysing the relationship between sequence and structure variation at a given level of sequence similarity. PALI also contains over 653 ‘orphans’ (single member families). Using the web interface involving PSI_BLAST and PHYLIP it is possible to associate the sequence of a new protein with one of the families in PALI and generate a phylogenetic tree combining the query sequence and proteins of known 3-D structure. The database with the web interfaced search and dendrogram generation tools can be accessed at http://pa uling.mbu.iisc.ernet.in/~pali.
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ACTIVITY is a database on DNA/RNA site sequences with known activity magnitudes, measurement systems, sequence-activity relationships under fixed experimental conditions and procedures to adapt these relationships from one measurement system to another. This database deposits information on DNA/RNA affinities to proteins and cell nuclear extracts, cutting efficiencies, gene transcription activity, mRNA translation efficiencies, mutability and other biological activities of natural sites occurring within promoters, mRNA leaders, and other regulatory regions in pro- and eukaryotic genomes, their mutant forms and synthetic analogues. Since activity magnitudes are heavily system-dependent, the current version of ACTIVITY is supplemented by three novel sub-databases: (i) SYSTEM, measurement systems; (ii) KNOWLEDGE, sequence-activity relationships under fixed experimental conditions; and (iii) CROSS_TEST, procedures adapting a relationship from one measurement system to another. These databases are useful in molecular biology, pharmacogenetics, metabolic engineering, drug design and biotechnology. The databases can be queried using SRS and are available through the Web, http://wwwmgs.bionet.nsc.ru/systems/Activity/.
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Cell-cell adhesion in zonula adherens and desmosomal junctions is mediated by cadherins, and recent crystal structures of the first domain from murine N-cadherin provide a plausible molecular basis for this adhesive action. A structure-based sequence analysis of this adhesive domain indicates that its fold is common to all extracellular cadherin domains. The cadherin folding topology is also shown to be similar to immunoglobulin-like domains and to other Greek-key beta-sandwich structures, as diverse as domains from plant cytochromes, bacterial cellulases, and eukaryotic transcription factors. Sequence similarities between cadherins and these other molecules are very low, however, and intron patterns are also different. On balance, independent origins for a favorable folding topology seem more likely than evolutionary divergence from an ancestor common to cadherins and immunoglobulins.
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Polímeros de coordenação têm atraído a atenção de pesquisadores na última década por conta de sua incrível versatilidade e virtualmente infinito número de possibilidades de combinação de ligantes orgânicos e centros metálicos. Estes compostos normalmente herdam as características magnéticas, eletrônicas e espectroscópicas de seus componentes base. Entretanto, apesar do crescente número de trabalhos na área, ainda são raros os polímeros de coordenação que apresentem condutividade elétrica. Para este fim, utilizou-se a N,N\'-bis(4-piridil)-1,4,5,8-naftaleno diimida, ou NDI-py, que pertence a uma classe de compostos rígidos, planares, quimicamente e termicamente estáveis e que já foram extensamente estudados por suas propriedades fotoeletroquímicas e semicondução do tipo n. O primeiro polímero de coordenação sintetizado, MOF-CoNDI-py-1, indicou ser um polímero linear, de estrutura 1D. O segundo, MOF-CoNDI-py-2, que conta com ácido tereftálico como ligante suporte, é um sólido cristalino com cela unitária monoclínica pertencente ao grupo espacial C2/c, determinado por difração de raios-X de monocristal. A rede apresenta um arranjo trinuclear de íons Co(II) alto spin com coordenados em uma geometria de octaedro distorcido, enquanto os ligantes NDI-py se encontram em um arranjo paralelo na estrutura, em distâncias apropriadas para transferência eletrônica. Com o auxílio de cálculo teóricos a nível de DFT, foi realizado um estudo aprofundado dos espectros eletrônicos e vibracionais, com atribuição das transições observadas, tanto para o MOF-CoNDI-py-2 quanto para o ligante NDI-py livre. A rede de coordenação absorve em toda a região do espectro eletrônico analisada, de 200 nm a 2500 nm, além de apresentar luminescência com característica do ligante. Dispositivos eletrônicos fabricados com um cristal do MOF-CoNDI-py-2 revelaram condutividades da ordem de 7,9 10-3 S cm -1, a maior já observada para um MOF. Além de elevada, a condutividade elétrica dos cristais demonstrou-se altamente anisotrópica, sendo significativamente menos condutor em algumas direções. Os perfis de corrente versus voltagem foram analisados em termos de mecanismos de condutividade, sendo melhores descritos por um mecanismo limitado pelo eletrodo to tipo Space-Charge Limited Current, concordando com a proposta de condutividade através dos planos de NDI-py na rede. A condutividade dos cristais também é fortemente dependente de luz, apresentando fotocondução quando irradiado por um laser vermelho, de 632 nm, enquanto apresenta um comportamento fotorresistivo frente a uma fonte de luz branca. Estes resultados, combinados, trazem um MOF em uma estrutura incomum e com elevada condutividade elétrica, modulada por luz, em medidas diretas de corrente. Não existem exemplos conhecidos de MOFs na literatura com estas características.
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According to the last global burden of disease published by the World Health Organization, tumors were the third leading cause of death worldwide in 2004. Among the different types of tumors, colorectal cancer ranks as the fourth most lethal. To date, tumor diagnosis is based mainly on the identification of morphological changes in tissues. Considering that these changes appears after many biochemical reactions, the development of vibrational techniques may contribute to the early detection of tumors, since they are able to detect such reactions. The present study aimed to develop a methodology based on infrared microspectroscopy to characterize colon samples, providing complementary information to the pathologist and facilitating the early diagnosis of tumors. The study groups were composed by human colon samples obtained from paraffin-embedded biopsies. The groups are divided in normal (n=20), inflammation (n=17) and tumor (n=18). Two adjacent slices were acquired from each block. The first one was subjected to chemical dewaxing and H&E staining. The infrared imaging was performed on the second slice, which was not dewaxed or stained. A computational preprocessing methodology was employed to identify the paraffin in the images and to perform spectral baseline correction. Such methodology was adapted to include two types of spectral quality control. Afterwards the preprocessing step, spectra belonging to the same image were analyzed and grouped according to their biochemical similarities. One pathologist associated each obtained group with some histological structure based on the H&E stained slice. Such analysis highlighted the biochemical differences between the three studied groups. Results showed that severe inflammation presents biochemical features similar to the tumors ones, indicating that tumors can develop from inflammatory process. A spectral database was constructed containing the biochemical information identified in the previous step. Spectra obtained from new samples were confronted with the database information, leading to their classification into one of the three groups: normal, inflammation or tumor. Internal and external validation were performed based on the classification sensitivity, specificity and accuracy. Comparison between the classification results and H&E stained sections revealed some discrepancies. Some regions histologically normal were identified as inflammation by the classification algorithm. Similarly, some regions presenting inflammatory lesions in the stained section were classified into the tumor group. Such differences were considered as misclassification, but they may actually evidence that biochemical changes are in course in the analyzed sample. In the latter case, the method developed throughout this thesis would have proved able to identify early stages of inflammatory and tumor lesions. It is necessary to perform additional experiments to elucidate this discrepancy between the classification results and the morphological features. One solution would be the use of immunohistochemistry techniques with specific markers for tumor and inflammation. Another option includes the recovering of the medical records of patients who participated in this study in order to check, in later times to the biopsy collection, whether they actually developed the lesions supposedly detected in this research.
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This paper shows an empirical study about the anaphoric accessibility space in Spanish dialogues. According to this study, antecedents of pronominal and adjectival anaphors can almost always (95.9%) be found in the noun phrases set taken from spaces defined using a structure based on adjacency pairs. Furthermore, a proposal of a reliable annotation scheme for Spanish dialogues is presented in order to define this anaphoric accessibility space. Using this annotation scheme, anaphora resolution algorithms can locate the adequate set of anaphor antecedent candidates.
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Small molecules designed to mimic specific structural components of a protein (peptide strands, sheets, turns, helices, or amino acids) can be expected to display agonist or antagonist biological responses by virtue of interacting with the same receptors that recognize the protein. Here we describe some minimalist approaches to structural mimetics of amino acids and of strand, turn, or helix segments of proteins. The designed molecules show potent and selective inhibition of protease, transferase, and phospholipase enzymes, or antagonism of G-protein coupled or transcriptional receptors, and have potent anti-tumour, anti-inflammatory, or antiviral activity.
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Background: The multitude of motif detection algorithms developed to date have largely focused on the detection of patterns in primary sequence. Since sequence-dependent DNA structure and flexibility may also play a role in protein-DNA interactions, the simultaneous exploration of sequence-and structure-based hypotheses about the composition of binding sites and the ordering of features in a regulatory region should be considered as well. The consideration of structural features requires the development of new detection tools that can deal with data types other than primary sequence. Results: GANN ( available at http://bioinformatics.org.au/gann) is a machine learning tool for the detection of conserved features in DNA. The software suite contains programs to extract different regions of genomic DNA from flat files and convert these sequences to indices that reflect sequence and structural composition or the presence of specific protein binding sites. The machine learning component allows the classification of different types of sequences based on subsamples of these indices, and can identify the best combinations of indices and machine learning architecture for sequence discrimination. Another key feature of GANN is the replicated splitting of data into training and test sets, and the implementation of negative controls. In validation experiments, GANN successfully merged important sequence and structural features to yield good predictive models for synthetic and real regulatory regions. Conclusion: GANN is a flexible tool that can search through large sets of sequence and structural feature combinations to identify those that best characterize a set of sequences.
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The schema of an information system can significantly impact the ability of end users to efficiently and effectively retrieve the information they need. Obtaining quickly the appropriate data increases the likelihood that an organization will make good decisions and respond adeptly to challenges. This research presents and validates a methodology for evaluating, ex ante, the relative desirability of alternative instantiations of a model of data. In contrast to prior research, each instantiation is based on a different formal theory. This research theorizes that the instantiation that yields the lowest weighted average query complexity for a representative sample of information requests is the most desirable instantiation for end-user queries. The theory was validated by an experiment that compared end-user performance using an instantiation of a data structure based on the relational model of data with performance using the corresponding instantiation of the data structure based on the object-relational model of data. Complexity was measured using three different Halstead metrics: program length, difficulty, and effort. For a representative sample of queries, the average complexity using each instantiation was calculated. As theorized, end users querying the instantiation with the lower average complexity made fewer semantic errors, i.e., were more effective at composing queries. (c) 2005 Elsevier B.V. All rights reserved.
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Cyclotides are peptides from plants of the Rubiaceae and Violaceae families that have the unusual characteristic of a macrocylic backbone. They are further characterized by their incorporation of a cystine knot in which two disulfides, along with the intervening backbone residues, form a ring through which a third disulfide is threaded. The cyclotides have been found in every Violaceae species screened to date but are apparently present in only a few Rubiaceae species. The selective distribution reported so far raises questions about the evolution of the cyclotides within the plant kingdom. In this study, we use a combined bioinformatics and expression analysis approach to elucidate the evolution and distribution of the cyclotides in the plant kingdom and report the discovery of related sequences widespread in the Poaceae family, including crop plants such as rice ( Oryza sativa), maize ( Zea mays), and wheat ( Triticum aestivum), which carry considerable economic and social importance. The presence of cyclotide-like sequences within these plants suggests that the cyclotides may be derived from an ancestral gene of great antiquity. Quantitative RT-PCR was used to show that two of the discovered cyclotide-like genes from rice and barley ( Hordeum vulgare) have tissue-specific expression patterns.
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Motivation: While processing of MHC class II antigens for presentation to helper T-cells is essential for normal immune response, it is also implicated in the pathogenesis of autoimmune disorders and hypersensitivity reactions. Sequence-based computational techniques for predicting HLA-DQ binding peptides have encountered limited success, with few prediction techniques developed using three-dimensional models. Methods: We describe a structure-based prediction model for modeling peptide-DQ3.2 beta complexes. We have developed a rapid and accurate protocol for docking candidate peptides into the DQ3.2 beta receptor and a scoring function to discriminate binders from the background. The scoring function was rigorously trained, tested and validated using experimentally verified DQ3.2 beta binding and non-binding peptides obtained from biochemical and functional studies. Results: Our model predicts DQ3.2 beta binding peptides with high accuracy [area under the receiver operating characteristic (ROC) curve A(ROC) > 0.90], compared with experimental data. We investigated the binding patterns of DQ3.2 beta peptides and illustrate that several registers exist within a candidate binding peptide. Further analysis reveals that peptides with multiple registers occur predominantly for high-affinity binders.
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The medically significant genus Chlamydia is a class of obligate intracellular bacterial pathogens that replicate within vacuoles in host eukaryotic cells termed inclusions. Chlamydia's developmental cycle involves two forms; an infectious extracellular form, known as an elementary body (EB), and a non-infectious form, known as the reticulate body (RB), that replicates inside the vacuoles of the host cells. The RB surface is covered in projections that are in intimate contact with the inclusion membrane. Late in the developmental cycle, these reticulate bodies differentiate into the elementary body form. In this paper, we present a hypothesis for the modulation of these developmental events involving the contact-dependent type III secretion (TTS) system. TTS surface projections mediate intimate contact between the RB and the inclusion membrane. Below a certain number of projections, detachment of the RB provides a signal for late differentiation of RB into EB. We use data and develop a mathematical model investigating this hypothesis. If the hypothesis proves to be accurate, then we have shown that increasing the number of inclusions per host cell will increase the number of infectious progeny EB until some optimal number of inclusions. For more inclusions than this optimum, the infectious yield is reduced because of spatial restrictions. We also predict that a reduction in the number of projections on the surface of the RB (and as early as possible during development) will significantly reduce the burst size of infectious EB particles. Many of the results predicted by the model can be tested experimentally and may lead to the identification of potential targets for drug design. © Society for Mathematical Biology 2006.