A hipercolesterolemia familiar (HF) é uma doença autossômica dominante causada por mutações no gene do receptor de LDL (LDLR) (cromossomo 19p13.1 - p13.3), que alteram parcialmente ou totalmente a função do LDLR. A HF é também uma das doenças genéticas mais comuns com freqüências estimadas de heterozigotos e homozigotos de 1/500 e 1/1.000.000, respectivamente. Manifesta-se com altos níveis de LDL colesterol, arco corneal, xantomas tendíneos e sintomas prematuros de doença coronariana.. A grande heterogeneidade observada na manifestação clínica desta doença pode ser explicada, ao menos parcialmente, pelo amplo espectro de mutações no gene do LDLR. O presente estudo teve por objetivo a caracterização molecular do gene LDLR em pacientes com HF do Rio Grande do Sul (RS), Brasil. Para isso, foram obtidas amostras de DNA de 40 indivíduos provenientes de cinco macrorregiões do Estado, representando seis diferentes populações de ascendência européia, para a realização do seqüenciamento direto do gene do LDLR, com posterior análise por meio das ferramentas de bioinformática. Quinze mutações pontuais foram identificadas no gene do LDLR, a saber: c.408C>T (D115D), c.1616C>T (P518L), c.1773C>T (N570N) e c.2243A>G (D727G) na região codificadora, IVS6+36G>A, IVS6+171G>A, IVS11+56C>T, IVS11- 69G>T, IVS11-55A>C, IVS15-136A>G, IVS16+46C>T e IVS17-42A>G na região intrônica, e *52G>A, *105T>G e *141G>A na região 3\'-UTR. Destas, oito ainda não foram descritas na literatura (três situadas nos exons, quatro nos introns e uma na região 3\'-UTR). A mutação*52G>A foi previamente identificada em pacientes com HF da região Sudeste do Brasil, sugerindo que possa exercer um importante efeito na patogênese da HF em pacientes brasileiros. Em relação às macrorregiões do RS, os portugueses, italianos e espanhóis apresentaram o maior número de mutações dentre os grupos étnicos analisados. Assim, os resultados obtidos confirmam que existe um amplo de espectro de mutações no gene do LDLR. As mutações nas regiões intrônicas precisam ser investigadas sobre seu efeito potencial no desenvolvimento de HF. Considerando que este é o primeiro estudo que teve por objetivo a caracterização molecular de pacientes com HF no RS, novos estudos que visem a elucidação das bases moleculares da HF devem ser realizados, a fim de obter uma melhor caracterização genética desta doença no Brasil. / Familial hypercholesterolemia (FH) is an autosomal dominant disorder caused by mutations in the low-density lipoprotein receptor (LDLR) gene (chromosome 19p13.1 - p13.3), which alter partially or totally the LDLR function. FH is also one of the most common inherited disorders with frequencies of heterozygotes and homozygotes estimated to be 1/500 and 1/1.000.000, respectively. Affected individuals display high levels of LDL cholesterol, arcus corneae, tendon xanthomas and premature symptomatic coronary heart disease. The extensive heterogeneity observed in the clinical manifestation of this disorder may be explained, at least partially, by the broad spectrum of mutations identified in the LDLR gene. The present study had as the main goal the molecular characterization of the LDLR gene in patients with FH from Rio Grande do Sul (RS) State, Brazil. For this, DNA samples were obtained from 40 individuals living in five macroregions of RS, representing six different isolated populations of European ascendancy. The LDLR gene was subjected to the direct sequencing with further analysis through bioinformatics tools. Fifteen punctual mutations were identified in the LDLR gene, namely: c.408C>T (D115D), c.1616C>T (P518L), c.1773C>T (N570N) and c.2243A>G (D727G) in the coding region, IVS6+36G>A, IVS6+171G>A, IVS11+56C>T, IVS11-69G>T, IVS11-55A>C, IVS15-136A>G, IVS16+46C>T and IVS17-42A>G in the intronic region, and *52G>A, *105T>G and *141G>A in the 3\'-UTR region. Of these, eight were not yet described in the literature (three situated in exons, four in introns and one in 3\'- UTR region). The *52G>A mutation was previously identified in FH patients from Southeast Brazil, suggesting that it can exert an important effect in the pathogenesis of FH in Brazilian patients. In relation to the macroregions of Rio Grande do Sul, Portuguese, Italian and Spanish subjects carried the highest number of mutations among the ethnic groups analyzed. Thus, the results obtained confirm the existence of a broad spectrum of mutations in the LDLR gene. The mutations in intronic regions need to be investigated in relation to its potential effect in the development of FH. Taking into account that this is the first study that had as the goal the molecular characterization of FH patients in RS, further studies aimed at elucidating the molecular bases of FH should be performed, in order to obtain the better characterization of this disease in Brazil.

Orientadores: Gisele Busichia Baioco, Regina Lúcia de Oliveira Moraes / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Tecnologia / Made available in DSpace on 2018-08-24T15:26:05Z (GMT). No. of bitstreams: 1 Guedes_GustavoBartz_M.pdf: 5989312 bytes, checksum: 0e3053f8f1adcbcf13039b8caeb8a87e (MD5) Previous issue date: 2014 / Resumo: Sistemas de software evoluem ao longo do tempo devido a novos requisitos ou a alterações nos já existentes. As mudanças são ainda mais presentes nos métodos de desenvolvimento de software iterativos e incrementais, como os métodos ágeis, que pressupõem a entrega contínua de módulos operacionais de software. Os métodos ágeis, como o Scrum e a Programação Extrema, são baseados em aspectos gerenciais do projeto e em técnicas de codificação do sistema. Entretanto, mudanças nos requisitos provavelmente terão reflexo no esquema da base de dados, que deverá ser alterado para suportá-los. Quando o sistema se encontra em produção, alterações no esquema da base de dados são onerosas, pois é necessário manter a semântica dos dados em relação à aplicação. Portanto, este trabalho de mestrado apresenta o processo evolutivo de modularização de bases de dados, uma abordagem para projetar a base de dados de modo iterativo e incremental. A modularização é executada no projeto conceitual e amplia a capacidade de abstração do esquema de dados gerado facilitando as evoluções futuras. Por fim, foi desenvolvida uma ferramenta que automatiza o processo evolutivo de modularização de bases de dados, chamada de Evolutio DB Designer. Essa ferramenta permite modularizar o esquema da base de dados e gerar automaticamente o esquema relacional a partir dos módulos de bases de dados / Abstract: Software systems evolve through time due to new requirements or changing in the existing ones. The need for constant changes is even more present on the iterative and incremental software development methods, such as those based on the agile methodology, that demand continuous delivery of operational software modules. The agile development methods, like Scrum and Extreme Programming, are based on management aspects of the project and techniques for software coding. However, changes in the requirements will probably affect the database schema, which will have to be modified to accommodate them. In a production system, changes to the database schema are costly, because from the application¿s perspective the data semantics needs to be maintained. Therefore, the present work presents the evolutionary database modularization design process, an approach for the iterative and incremental design of the database. The modularization process is executed during the conceptual design improving the abstraction capacity of the generated data schema resulting in a graceful schema evolution. In addition, a tool that automates the evolutionary database modularization design process was developed, called Evolutio DB Designer. It allows the modular design of the database schema and automatically generates the relational data schema based on the database modules / Mestrado / Tecnologia e Inovação / Mestre em Tecnologia

Orientador: : Carlos Roque Duarte Correia / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Química / Made available in DSpace on 2018-08-24T05:38:03Z (GMT). No. of bitstreams: 1 Martinez_PabloDavidGrigol_D.pdf: 10635816 bytes, checksum: b6d50b746463694bb1ef50352d36d1e3 (MD5) Previous issue date: 2013 / Resumo: O emprego de enecarbamatos endocíclicos como substratos na organocatálise foi avaliado na primeira parte deste trabalho. Explorou-se a ação catalítica de ácidos fosfóricos na reação de Friedel-Crafts envolvendo enecarbamatos di e trissubstiuídos como eletrófilos. Foram empregados indóis, furanos, naftol e sesamol como nucleófílos neste tipo de reação. Foi possível desenvolver um protocolo operacional simples e em condições brandas capaz de fornecer bons rendimentos. A diastereosseletividade observada com enecarbamatos trissubstituídos favoreceu o produto trans numa faixa de 2,7:1 até 95:5. Usando ácidos fosfóricos quirais, a enantiosseletividade também foi verificada, atingindo-se excesso enantiomérico de 20% até o momento, fato que demonstra a potencialidade da metodologia. Posteriormente, realizou-se um estudo sobre a preparação de aminoálcoois a pela hidrogenólise de 2-aril-3-epoxipirrolidinas. Esses substratos foram obtidos pela arilação de Heck-Matsuda em enecarbamatos derivados do ácido L-piroglutâmico como etapa chave. Observou-se que a estereoquímica dos substituintes da pirrolidina apresentou decisiva influência para as condições reacionais e rendimento da hidrogenólise, permitindo em alguns casos a clivagem de até duas ligações numa única reação. Os aminoálcoois obtidos a partir desta metodologia foram utilizados na síntese concisa da 2-epi-bulgecinina bem como de bases esfingóides exemplificada na síntese de análogo da esfingosina / Abstract: In the first part of this work, the use of endocyclic enecarbamates as substrates in organocatalysis was evaluated. The effect of phosphoric acids as catalysts in promoting Friedel-Crafts reactions involving di and trisubstituted enecarbamates as electrophiles was explored. Different arenes were employed as nucleophiles like indols, furans, naftol and sesamol. It was possible to develop a simple protocol with mild conditions and good yields. The diastereoselectivity observed with trisubstituted enecarbamates favored the trans product in a range of 2.7:1 to 95:5. By using chiral phosphoric acids, the enantioselectivity achieved, so far, was 20% ee, evidencing the potentiality of this methodology. Later, hydrogenolysis reactions over 2-aryl-3-epoxypyrrolidines were performed to prepare aminoalcohols. The key step to synthesize the former pyrrolidines was the Heck-Matsuda reaction of enecarbamates obtained from L-pyroglutamic acid. The stereochemistry of the substituents in the hydrogenolytic step did influence the experimental conditions and yields, allowing in some cases two bonds cleavage in one pot. The aminoalcohols prepared in this methodology were used in a short synthesis of 2-epibulgecinine and in preparation of sphingoid bases exemplified in the synthesis of sphingosine analogue / Doutorado / Quimica Organica / Doutor em Ciências

Récemment, les ontologies ont été largement adoptées par différentes entreprises dans divers domaines. Elles sontdevenues des composantes centrales dans bon nombre d'applications. Ces modèles conceptualisent l'univers du discours auxmoyens de concepts primitifs et parfois redondants (calculés à partir de concepts primitifs). Au début, la relation entreontologies et base de données a été faiblement couplée. Avec l'explosion des données sémantiques, des solutions depersistance assurant une haute performance des applications ont été proposées. En conséquence, un nouveau type de base dedonnées, appelée base de données à base ontologique (BDBO) a vu le jour. Plusieurs types de BDBO ont été proposés, ilsutilisent différents SGBD. Chaque BDBO possède sa propre architecture et ses modèles de stockage dédiés à la persistancedes ontologies et de ses instances. A ce stade, la relation entre les bases de données et les ontologies devient fortementcouplée. En conséquence, plusieurs études de recherche ont été proposées sur la phase de conception physique des BDBO.Les phases conceptuelle et logique n'ont été que partiellement traitées. Afin de garantir un succès similaire au celui connupar les bases de données relationnelles, les BDBO doivent être accompagnées par des méthodologies de conception et desoutils traitant les différentes étapes du cycle de vie d'une base de données. Une telle méthodologie devrait identifier laredondance intégrée dans l'ontologie. Nos travaux proposent une méthodologie de conception dédiée aux bases de données àbase ontologique incluant les principales phases du cycle de vie du développement d'une base de données : conceptuel,logique, physique ainsi que la phase de déploiement. La phase de conception logique est réalisée grâce à l'incorporation desdépendances entre les concepts ontologiques. Ces dépendances sont semblables au principe des dépendances fonctionnellesdéfinies pour les bases de données relationnelles. En raison de la diversité des architectures des BDBO et la variété desmodèles de stockage utilisés pour stocker et gérer les données ontologiques, nous proposons une approche de déploiement àla carte. Pour valider notre proposition, une implémentation de notre approche dans un environnement de BDBO sousOntoDB est proposée. Enfin, dans le but d'accompagner l'utilisateur pendant le processus de conception, un outil d'aide à laconception des bases de données à partir d'une ontologie conceptuelle est présenté / Recently, ontologies have been widely adopted by small, medium and large companies in various domains. Theyhave become central components in many applications. These models conceptualize the universe of discourse by means ofprimitive and sometimes redundant concepts (derived from primitive concepts). At first, the relationship between ontologiesand database was loosely coupled. With the explosion of semantic data, persistence solutions providing high performanceapplications have been proposed. As a consequence, a new type of database, called ontology-based database (OBDB) isborn. Several types of OBDB have been proposed including different architectures of the target DBMS and storage modelsfor ontologies and their instances. At this stage, the relationship between databases and ontologies becomes strongly coupled.As a result, several research studies have been proposed on the physical design phase of OBDB. Conceptual and logicalphases were only partially treated. To ensure similar success to that known by relational databases, OBDB must beaccompanied by design methodologies and tools dealing with the different stages of the life cycle of a database. Such amethodology should identify the redundancy built into the ontology. In our work, we propose a design methodologydedicated to ontology-based databases including the main phases of the lifecycle of the database development: conceptual,logical and physical as well as the deployment phase. The logical design phase is performed thanks to the incorporation ofdependencies between concepts and properties of the ontologies. These dependencies are quite similar to the functionaldependencies in traditional databases. Due to the diversity of the OBDB architectures and the variety of the used storagemodels (triplet, horizontal, etc.) to store and manage ontological data, we propose a deployment ‘à la carte. To validate ourproposal, an implementation of our approach in an OBDB environment on OntoDB is proposed. Finally, in order to supportthe user during the design process, a tool for designing databases from a conceptual ontology is presented.

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El alcance del presente proyecto de fin de carrera el análisis y diseño de los procesos que componen el conjunto de ITIL como son: La Gestión de Configuraciones y La Gestión de Cambios; elaborada para el área de TI de la empresa importadora y distribuidora de vidrios y aluminios. El presente proyecto tiene como finalidad establecer una guía de buenas prácticas en el área de TI, la cual pueda ser consultada al realizarse las tareas que involucran los procesos de gestión de configuraciones y gestión de cambios. La presente propuesta está dirigida a todas las organizaciones y/o empresas que manejen recursos de TI. Por lo tanto, las recomendaciones o buenas prácticas tratarán de ser las más genéricas posibles para poder apartase fácilmente a cualquier ambiente. Todos los requerimientos serán tomados de ITIL v3 ya que este constituye un marco de trabajo de las mejores prácticas destinadas a facilitar la entrega de servicios de tecnologías de la información (TI) de alta calidad. Cabe resaltar que no se realizará la implantación de un sistema propiamente dicho en el presente proyecto de fin de carrera dado el tiempo limitado que se tiene para realizar el proyecto y la resistencia al cambio de parte de la gerencia general de la empresa.

Divers types de pneus sont utilisés par les véhicules pendant la période hivernale, et le choix et l'usage de ceux-ci dépendent de plusieurs facteurs. Parmi ces variétés figurent les pneus à crampons (PAC), réputés pour leur capacité à améliorer l'adhérence, la qualité de conduite et à réduire la distance de freinage pendant l'hiver. Ces pneus ont gagné en popularité auprès de nombreux conducteurs. Cependant, l'utilisation de ces pneus présente des inconvénients majeurs comme la formation accélérée d'ornières d'usure sur les chaussées en enrobés, suscitant ainsi un débat sur la nécessité d'une réglementation plus stricte pour ce type de pneus et sur l'impact qu'ils ont sur les chaussées. La littérature met en lumière des avancées significatives dans la compréhension des mécanismes d'interaction entre l'enrobé et les PAC. Ces recherches ont permis d'identifier des paramètres clés influençant le phénomène d'usure, notamment la vitesse des véhicules, les conditions climatiques, le volume du trafic, la fréquence de passages des PAC, ainsi que les matériaux employés dans la conception et la construction des chaussées. De plus, les études examinent en détail les cadres normatifs internationaux de l'utilisation des PAC, les propriétés techniques des crampons et les performances mesurées dans des configurations variées d'enrobés, selon leurs formulations spécifiques et leurs caractéristiques mécaniques. Cette étude implique l'analyse des données du Ministère des Transports et de la Mobilité Durable du Québec (MTMD) sur une sélection (30) de tronçons d'autoroutes et de routes nationales en enrobés touchées par les ornières d'usure dans différentes régions du Québec. Six de ces tronçons ont été sélectionnés pour le prélèvement par carottage d'éprouvettes dans les ornières d'usure et entre celles- ci. Une procédure de caractérisation visuelle de ces carottes a d'abord été développée pour déterminer l'épaisseur de l'ornière d'usure affectant les tronçons étudiés, de même que la texture de surface du revêtement. Les carottes ont ensuite subi une batterie d'essais de laboratoire, incluant la détermination de la densité brute, maximale et du pourcentage de vides, ce dernier étant confirmé par tomodensitométrie. Une nouvelle base de données a été développée à partir des informations historiques accumulées par le MTMD entre 2000 et 2021 sur les 30 tronçons sélectionnés. Ces données ont permis d'identifier plusieurs paramètres tels que la localisation, le type d'enrobé, la profondeur des ornières, les réhabilitations effectuées, le débit de circulation, le pourcentage de véhicules équipés de PAC par région, la masse des véhicules moyenne régionale, ainsi que le taux annuel d'orniérage en fonction du nombre de passages de PAC. Cette base de données permettra de valider un modèle de prédiction de la durée de vie des chaussées flexibles face au phénomène d'orniérage causé par l'utilisation des PAC. / Various types of tires are used by vehicles during the winter season, and their choice and use depend on a number of parameters. Among these types are studded tires (ST), renowned for their ability to improve grip, ride quality and reduce braking distance during winter. These tires have gained in popularity with many drivers. However, the use of these tires has major drawbacks such as the accelerated formation of wear ruts on asphalt pavements, creating a debate on the need for stricter regulations for this type of tire and the impact they have on pavements. This study involves the analysis of data from the Ministère des Transports et de la Mobilité Durable du Québec (MTMD) on a selection (30) of sections of asphalt highways and national roads affected by wear ruts in different regions of Quebec. Six of these sections were selected for core sampling in and between wear ruts. A visual characterization procedure for these cores was first developed to determine the thickness of the wear rut affecting the sections studied, as well as the surface texture of the pavement. The cores were then subjected to a series of laboratory tests, including determination of bulk and maximum density, and percentage of voids, the latter confirmed by computed tomography. A new database has been developed based on historical information accumulated by MTMD between 2000 and 2021 on the 30 selected sections. This database has made it possible to identify a number of parameters, such as location, asphalt type, rut depth, rehabilitations carried out, traffic flow, percentage of ST- equipped vehicles per region, average regional vehicle mass, and annual rutting rate as a function of the number of ST passes. This database will be used to validate a model for predicting the service life of flexible pavements in the face of rutting caused by the use of ST.

Les unités linguistiques sous-lexicales (p.ex., la syllabe, le phonème ou le phone) jouent un rôle crucial dans le traitement langagier. En particulier, le traitement langagier est profondément influencé par la distribution de ces unités. Par exemple, les syllabes les plus fréquentes sont articulées plus rapidement. Il est donc important d’avoir accès à des outils permettant de créer du matériel expérimental ou clinique pour l’étude du langage normal ou pathologique qui soit représentatif de l’utilisation des syllabes et des phones dans la langue orale. L’accès à ce type d’outil permet également de comparer des stimuli langagiers en fonction de leurs statistiques distributionnelles, ou encore d’étudier l’impact de ces statistiques sur le traitement langagier dans différentes populations. Pourtant, jusqu’à ce jour, aucun outil n’était disponible sur l’utilisation des unités linguistiques sous-lexicales du français oral québécois. Afin de combler cette lacune, un vaste corpus du français québécois oral spontané a été élaboré à partir d’enregistrements de 184 locuteurs québécois. Une base de données de syllabes et une base de données de phones ont ensuite été construites à partir de ce corpus, offrant une foule d’informations sur la structure des unités et sur leurs statistiques distributionnelles. Le fruit de ce projet, intitulé SyllabO +, sera rendu disponible en ligne en accès libre via le site web http://speechneurolab.ca/fr/syllabo dès la publication de l’article le décrivant. Cet outil incomparable sera d’une grande utilité dans plusieurs domaines, tels que les neurosciences cognitives, la psycholinguistique, la psychologie expérimentale, la phonétique, la phonologie, l’orthophonie et l’étude de l’acquisition des langues. / Linguistic sublexical units (e.g., syllables, phonemes or phones) have a crucial role in language processing. More specifically, language processing is greatly influenced by the distribution of these units in a language. For example, frequent syllables are produced more rapidly. It is thus important to have access to tools enabling the creation of experimental or clinical material that is representative of syllable and phoneme/phone use in language. Access to such tools also allows the comparison of language stimuli according to their distributional statistics, as well as the study of the impact of these statistics on language processing in different populations. However, to this day, there was no tool available on syllable and phone use for Quebec oral French. To circumvent this problem, a vast corpus of oral spontaneous French was elaborated from the recordings of 184 Quebec speakers. A syllable database and a phone database were then built from this corpus, offering a wealth of information on the structure and distributional statistics of syllables and phones. The project, named SyllabO +, will be made available online (open-access), via this website: http://speechneurolab.ca/en/syllabo as soon as the article describing it is published. We believe SyllabO + will prove immensely useful in many fields, such as cognitive neurosciences, psycholinguistics, experimental psychology, phonetics, phonology, speech therapy and the study of language acquisition.