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Esse estudo tem como objetivo caracterizar a presença de células globosas alveolares ou pneumócitos tipo II e o início da produção de lipoproteína surfactante, em bovinos, correlacionado com a idade gestacional. Para tanto, foram utilizados 28 fetos em idades gestacionais compreendidas entre quatro e oito meses de gestação e dois animais recém - nascido. Após a coleta os fetos foram dissecados, pesados e medidos, utilizando-se o método de Crow - Rump (CR). Para a descrição morfológica, foram coletados fragmentos pulmonares com cerca de 2 cm² cada e, em seguida, foram fixados em Liquido de Bouin e formalina a 10% para microscopia de luz e em glutaraldeído 2,5% para microscopia eletrônica de transmissão. Para o estudo bioquímico, foram feitas incisões na região da traquéia e introdução de cateter e, através deste, solução fisiológica 0,9% e assim obter o lavado pulmonar. O pulmão de fetos com idade gestacional de 4 meses encontravam-se em fase canalicular do desenvolvimento, sem presença de células globosas e nem aparecimento de bandas eletroforéticas compatíveis com presença de proteínas surfactantes. Nos fetos com 5 meses de idade gestacional, foi observado que o pulmão encontra-se em fase de saco terminal, com aparecimento de alvéolo primitivo formado por epitélio cúbico, com áreas formada por células pavimentosas e células globosas . Nas análises de eletroforese não foram identificadas proteínas surfactantes. No pulmão de fetos com 6 meses de idade gestacional, foram observados desenvolvimento na fase de saco terminal com a presença de pneumócitos tipo I e pneumócito tipo II, nesta fase foi possível observar, na análise eletroforética, o aparecimento de bandas em torno de 28 kDa, demonstrando a presença de SP - A, que é a proteína surfactante encontrada em maior quantidade. A partir dos 7 meses de idade gestacional a fase de saco terminal desenvolve-se ainda mais no pulmão fetal com o surgimento de uma vascularização mais intensa, os pneumócitos tipo I estão com aspecto mais pavimentoso e os pneumócitos tipo II, mais globosos. Na análise eletroforética do lavado brônquio - alveolar foram observadas bandas de proteínas surfactantes, com perfil eletroforético semelhante ao animal recém - nascido. No recém - nascido observou-se o pulmão na fase alveolar, com os pneumócitos tipo I e tipo II bem definidos. O perfil eletroforético do lavado brônquio - alveolar desse animal foi igual ao perfil do lavado de um animal adulto, apresentando as mesmas bandas no triplet. / The objective of this study is to characterize the presence of alveolar type II and the beginning of the surfactant lipoprotein production, in bovines, correlated with the gestacional age. For that to happen, 28 embryos in gestacional age, between four and eight months, and two newborn animals had been used. After the collection, the embryos were dismembered, weighed and measured, using the method of Crow - Rump (CR). For the morphologic description, pulmonary fragments of about 2cm2 each were collected. After that, they had been set in Bouin Liquid for light microscopy and in glutaraldeyde 2.5% for electronic microscopy transmission. For the biochemist study , incisions and the introduction of catheter were made in trachea area and, through this, physiological solution 0.9% were introduced, in order to obtain a pulmonary wash. The lung of embryos with gestacional age of 4 months, were found in the canalicular development phase, without presence of globule cells, nor appearance of compatible eletroforetic bands compatible with the presence of surfactant protein. In the 5 months gestacional age embryos, were observed that the lung was in theterminal sac fase, with the presence of primitive alveolus formed by cubical epithelium, with areas formed by pavimented cells and globule cells. In the analyses of eletroforese surfactants, proteins had not been identified. In the lung of embryos at 6 months of gestacional age, was observed development in the phase of terminal sac, with the presence of type I and alveolar type II. In this phase, was possible to observe, in the SDS -PAGE analysis, the appearance of bands around 28 kDa, demonstrating the SP-A presence -, which is the surfactant protein found in greater amount. From 7 months of gestacional age and up, the phase of terminal sac developed even more in the fetal lung, with the sprouting of a more intense vascularization. The alveolar type I had a more pavimented aspect and the alveolar type II, were globules. In the SDS-PAGE analysis of the bronchial - alveolar wash, surfactant protein bands had been observed, with similar profile from the newborn.In the newborn animal, lung in the alveolar phase was observed, with the alveolar type I and II well defined.The profile of the bronchial-alveolar wash of this animal was the same as the profile of the washed one of an adult animal, presenting the same bands in the triplet.

Submitted by Pedro Barros (pedro.silvabarros@ufpe.br) on 2018-06-29T19:10:32Z No. of bitstreams: 2 license_rdf: 811 bytes, checksum: e39d27027a6cc9cb039ad269a5db8e34 (MD5) DISSERTAÇÃO Thaís Lima Corrêa.pdf: 1826347 bytes, checksum: 3e2a4eaa7d0d1c4c2e98d8d8e9bec071 (MD5) / Made available in DSpace on 2018-06-29T19:10:32Z (GMT). No. of bitstreams: 2 license_rdf: 811 bytes, checksum: e39d27027a6cc9cb039ad269a5db8e34 (MD5) DISSERTAÇÃO Thaís Lima Corrêa.pdf: 1826347 bytes, checksum: 3e2a4eaa7d0d1c4c2e98d8d8e9bec071 (MD5) Previous issue date: 2017-02-21 / CAPES / Generalized Renewal Process (GRP) is a probabilistic model for repairable systems that can represent any of the five possible post-repair states of an equipment: as new condition, as old condition, as an intermediate state between new and old conditions, a better condition and a worse condition. GRP is often coupled with the Weibull distribution to model the equipment failure process and the Weibull-based GRP is able to accommodate three types of hazard rate functions: monotonically increasing, monotonically decreasing and constant. This work proposes a novel approach of GRP based on the q-Weibull distribution, which has the Weibull model as a particular case. The q-Weibull distribution has the capability of modeling two additional hazard rate behaviors, namely bathtub-shaped and unimodal curves. Such flexibility is related to a pair of parameters that govern the shape of the distribution, instead of a single parameter as in the Weibull model. In this way, the developed q-Weibull-based GRP is a more general framework that can model a variety of practical situations in the context of reliability and maintenance. The maximum likelihood problems associated with the qWeibull-based GRP using Kijima’s virtual age type I and II for the failure and time terminated cases are developed. The probabilistic and derivative-free heuristic Particle Swarm Optimization (PSO) is used to obtain the q-Weibull-based GRP paramaters’ estimates. The proposed methodology is applied to examples involving equipment failure data from literature and the obtained results indicate that the q-Weibull-based GRP may be a promising tool to model repairable systems. / O Processo de Renovação Generalizado (PRG) pode ser definido como um modelo probabilístico de sistemas reparáveis capaz de representar os cinco possíveis estados do sistema após o reparo: condição de um equipamento novo, condição de um equipamento antigo, um estado intermediário entre novo e antigo, melhor do que novo e pior do que antigo. O PRG costuma ser comumente empregado junto com a distribuição Weibull para a modelagem do processo de falhas dos equipamentos, no entanto, o modelo de GRP baseado na distribuição Weibull é capaz de considerar três comportamentos de taxa de falha: monotonicamente crescente, monotonicamente decrescente e constante. Este trabalho propõe uma nova abordagem para o PRG baseado na distribuição q-Weibull, que apresenta como um de seus casos particulares a distribuição Weibull. A distribuição q-Weibull apresenta a capacidade de modelar dois comportamentos de falha adicionais, denominadas curva da banheira e curva unimodal. Esta flexibilidade está relacionada a dois parâmetros que definem o formato da distribuição, ao invés de um único parâmetro como no caso da Weibull. Dessa forma, o modelo de PRG baseado na q-Weibull pode ser considerado uma estrutura mais geral de modelagem de uma variedade de situações práticas no contexto da confiabilidade e manutenção. São desenvolvidos estimadores de máxima verossimilhança para os casos de PRG baseada na distribuição q-Weibull sendo utilizadas as idades virtuais Kijima tipo I e II para os casos de dados censurados e não censurados. A heurística probabilística e livre de derivadas denominada Otimização via Nuvem de Partículas (Particle Swarm Optimization - PSO) é utilizada para obter os estimadores de máxima verossimilhança do modelo. O modelo proposto é aplicado a exemplos envolvendo falhas de equipamentos retirados da literatura e os resultados obtidos indicam que o PRG baseado na q-Weibull é uma ferramenta promissora na modelagem de sistemas reparáveis.

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L’amélioration de la surveillance de la sécurité des médicaments grâce à l’utilisation des bases de données médico-administratives est source de nombreuses promesses. L’objectif de cette thèse était de développer un système automatisé de détection et de priorisation des signaux de sécurité adapté aux bases de données médico-administratives, pour la surveillance de la sécurité des médicaments des maladies chroniques. Les antidiabétiques non insuliniques (ANI) ont été sélectionnés comme cas d’étude pour le développement et l’évaluation de ce système. Nous avons d’abord étudié le profil d’utilisation des ANI en France, et avons retrouvé un fort mésusage des inhibiteurs de la dipeptidylpeptidase-4 (DPP-4) ainsi qu’un risque accru de non observance avec ces derniers. Nous avons ensuite réalisé deux revues de la littérature qui nous ont permis de sélectionner, pour la détection, la méthode sequence symmetry analysis, et de construire, pour la priorisation, notre algorithme que nous avons structuré autour de la force, la nouveauté, l’impact du signal de sécurité, et les modalités d’utilisation du médicament. Nous avons enfin évalué, d’une part, les performances du système développé, dans une étude pilote sur les ANI qui a montré des résultats satisfaisants et permis d’identifier un nouveau signal de sécurité entre les inhibiteurs de la DPP-4 et les événements thromboemboliques veineux, et d’autre part, son acceptabilité auprès des décideurs de santé qui l’ont jugé positivement. Ces résultats nous invitent à poursuivre nos recherches sur l’amélioration et la validation du système développé. / The improvement of the surveillance of the drug safety by using healthcare databases is waited with hope for a decade. The objective of this thesis was to develop an automated system combining detection and prioritization of safety signals from healthcare databases, for the surveillance of drugs used in chronic diseases. Noninsulin glucose-lowering drugs (NIGLDs) were selected as a case study for the development and the assessment of the system. Firstly, we studied the patterns of use of the NIGLDs in France, and we found a large misuse with the dipeptidylpeptidase-4 (DPP-4) inhibitors and a higher risk of non-observance with their use. Secondly, we conducted two literature review, which allows us to select the sequence symmetry analysis for the detection and to develop our algorithm for the prioritization that we based on strength, novelty, impact of the safety signal, and patterns of drug use. Thirdly, we assessed the performance of the system, in a pilot study on NIGLDs that showed satisfying results and identified a new safety signal with the use of DPP-4 inhibitors and venous thromboembolic events, as well as its acceptability among stakeholders that judged it positively. These results invite us to pursue our researches to improve and to validate the developed system.

Grâce à leurs propriétés antioxydantes, les phénols de l’huile d’olive sont reconnus comme les acteurs principaux de la réduction de la mortalité cardiovasculaire et du diabète de type 2 associée au régime méditerranéen. Cependant, la forte métabolisation de l’hydroxytyrosol, principal composé phénolique de l’huile d’olive, en glucuronides, remet en question son activité biologique.Un premier objectif de ce travail de thèse a été de mettre en évidence l’importance des glucuronides dans l’amélioration de la fonction vasculaire grâce à un effet antioxydant. Néanmoins et contrairement à l’hydroxytyrosol, qui peut être transporté directement par la bilitranslocase, les glucuronides doivent, dans un premier temps, être déconjugués par la β-glucuronidase afin d’exercer leur activité biologique.Un deuxième objectif de ce travail de thèse a été de mettre en évidence leurs effets chez des rats atteints de syndrome métabolique. Nous avons pu constater que ni l’hydroxytyrosol, ni ses glucuronoconjugués ne modulaient la fonction vasculaire.Enfin, un troisième objectif a été de regarder la répercussion d’une supplémentation en hydroxytyrosol, sur les facteurs de risque cardiovasculaire dans un modèle de souris atteintes de diabète de type 2. La supplémentation en hydroxytyrosol a réduit la prise de poids, les masses adipeuses et a eu des effets hypotenseurs. Ces effets hypotenseurs semblent être dus à une de la fonction des cellules musculaires lisses puisque nos travaux montrent une relaxation endothélium-indépendante améliorée. Nos travaux donnent un nouvel éclairage sur les effets de l’hydroxytyrosol et ses métabolites, tous deux contribuant, potentiellement, à la réduction de l’incidence des maladies cardiovasculaires et du diabète de type 2. / Olive oil polyphenols are well-known to lower cardiovascular mortality and type 2 diabetes incidence associated to the Mediterranean diet. However, the high metabolization rate of hydroxytyrosol, the main phenolic compound of olive oil, into glucuronides, questions its real biological effect. The first objective of this thesis was to evidence the importance of glucuronides of Hydroxytyrosol in the enhancement of vascular function through antioxidative properties. It was found that, unlike to hydroxytyrosol that can be directly transported with bilitranslocase glucuronides have to be deconjugated by β-glucuronidase to exert their biological activity. A second objective was to evidence the effects of Hydroxytyrosol and glucuronides on vascular function in diet-induced metabolic syndrome rats. Neither hydroxytyrosol nor glucuronides modulated vascular function in this pathological context. A third objective was to show the effect of a chronic Hydroxytyrosol supplementation in refined olive oil on cardiovascular risk factors in a mice model of Metabolic Syndrome. Hydroxytyrosol supplementation was able to reduce weight gain, white adipose tissues mass and to lower blood pressure. These hypotensive effects seem to be due in smooth muscle cells function. In conclusion, our works highlight the importance of Hydroxytyrosol and its glucuronoconjugated metabolites, both contributing to the reduction of the incidence of cardiovascular risk factors associated to type 2 diabetes and Metabolic syndrome.

Une simple classification morphologique des galaxies de l'Univers local montre deux grandes familles: (1) les galaxies disques, avec des bras spiraux et dans deux-tiers des cas une barre stellaire; et (2) les galaxies elliptiques et lenticulaires, dites galaxies de type précoce ou early-type galaxies (ETGs), qui sont dominées par une composante stellaire sphéroidale. Les galaxies les plus massives de l'Univers local sont les ETGs. Ces galaxies présentent aussi une large variété de dynamique stellaire: elles peuvent avoir un champ de vitesse régulier et aligné avec la photométrie ou perpendiculaire à la photométrie; ne présenter aucune rotation globale; ou alors être composées de deux disques en contre-rotation l'un par rapport à l'autre (Kinematically Distinct Core ou KDC). Ces signatures dans la dynamique stellaire des ETGs et leur importante masse sont des signes d'interactions passées, en particulier des signes de fusions de galaxies. Le but principal de ma thèse est d'analyser un large échantillon de simulations numériques à haute résolution de fusions binaires de galaxies. Ces fusions sont dites "idéalisées" car elles ne prennent pas en compte le contexte cosmologique de formation des galaxies : deux galaxies en isolation sont lancées sur une orbite permettant la fusion de ces galaxies, le résultat final attendu de la fusion étant une ETG. L'analyse statistique de ce large échantillon de simulations nous permet de relier les conditions initiales de la fusion à la galaxie finale. J'ai démontré que le rapport de masse entre les spirales initiales et que l'orientation de leurs moments angulaires sont des points essentiels à la formation des ETGs avec peu ou beaucoup de rotation et des KDCs. La morphologie de la spirale (rapport Bulbe/Disque) est aussi un point important pour la formation des KDC mais son impact n'est pas clair et de nouvelles simulations sont nécessaires pour conclure. Durant ma thèse, j'ai aussi étudié l'importance de la résolution dans les simulations numériques de fusion de galaxies. J'ai montré que le nombre de particules et la taille des cellules utilisées ont une importance prépondérante dans les résultats finaux. Une trop faible résolution (i.e. peu de particules et une grille grossière) ne permet pas de suivre l'évolution rapide du potentiel gravitationnel lors de la fusion. Dans ce cas, certaines particules n'évacuent pas leur moment angulaire vers l'extérieur de la galaxie: la galaxie résultante de la fusion garde ainsi une plus forte rotation. A haute résolution, la dispersion de ces orbites est résolue, la galaxie résultante possède donc une faible rotation et peut former, sous certaines conditions initiales, un KDC. / A simple morphological classification of the galaxies in the local Universe shows two main families: (1) the disc galaxies, with spiral arms and in two-thirds of these galaxies a stellar bar; and (2) the elliptical and lenticular galaxies, labelled early-type galaxies (ETGs), which are dominated by a spheroidal stellar component. ETGs are among the most massive galaxies of the local Universe and present a red color, meaning that their stars are old. These galaxies also present a large diversity of stellar dynamics: they may have a regular rotation pattern aligned with the photometry or perpendicular to it; they can present no global rotation at all; or may hold a central stellar component with a rotation axis distinct from the outer stellar body called a Kinematically Distinct Core (KDC). These features observed in the dynamics of the ETGs and their large mass are clearly signs of past interactions, especially signs of galaxy mergers. The main goal of my thesis is to analyse a large sample of high-resolution numerical simulations of binary galaxy mergers. These binary mergers are called "idealized" because they do not take into account the full cosmological context of galaxy formation: two isolated spiral galaxies are launched in an orbit resulting in a merger of the galaxies, the final remnant is an ETG. The statistical analysis of this large sample of simulations enables us to link the initial conditions of the merger to the final merger remnant. I demonstrated that the mass ratio between the spiral progenitors and the orientation of their spins of angular momentum are the main drivers for the formation of fast and slow rotating ETGs and the KDCs. The morphology of the initial spiral (Bulge/Disc ratio) seems also to play a major role for the formation of the different types of ETGs but its impact is not completelly clear, and other simulations are planned to clarify this problem. During my thesis, I also studied the importance of the resolution in the numerical simulations of galaxy mergers. I showed that the number of particles and the size of the computational grid have a predominant role in the final product of the merger. A too low resolution (i.e. too few particles and a coarse grid) can not follow the rapid evolution of the gravitational potential during the merger. In this case, the angular momentum is not as efficiently transfered to the outer parts of the galaxy: the merger remnant keeps thus a strong and regular rotation. At higher resolution, the scattering of the orbit is resolved and the merger remnant may end-up with, under some special initial conditions, a slow rotation and may form a KDC.

Les études d'association pangénomiques (GWAS) ont permis l'identification de plusieurs dizaines de gènes et de polymorphismes nucléotidiques (SNPs) contribuant au risque de diabète de type 2.Plus généralement, les GWAS ont permis d'identifier des milliers de SNPs contribuant à des maladies complexes chez l'Homme.Cependant, la caractérisation fonctionnelle et les mécanismes biologiques impliquant ces SNPs et ces gènes restent en grande partie à explorer.En effet, les conséquences de ces polymorphismes sont complexes et peu connues. Une conséquence directe est l'altération de la protéine codée par un gène, voire une extinction complète de la transcription du gène (p.ex. via l’introduction d’un codon stop dans la séquence).Par ailleurs, ces polymorphismes peuvent avoir un rôle de régulation dans l'expression des gènes, par exemple, en perturbant la liaison de facteurs de transcription et d'enzymes impliqués dans la méthylation de l'ADN.Malgré des associations fortes des SNPS identifiés, ils ne peuvent expliquer la totalité de l'héritabilité du diabète de type 2, suggérant par le fait même des mécanismes d'interactions entre les différentes couches que représentent la génomique, la transcriptomique et l'épigénomique.Le changement de paradigme en statistique génétique et la disponibilité de données transcriptomiques et épigénomiques sont responsables de l'évolution du domaine, passant des analyses d'associations à des analyses transversales de type multi-omique, et permettant de fournir des éléments de réponse sur l’aspect fonctionnel des SNPs ou des gènes impliqués, et dans certains cas, permettant d'évaluer le lien causal de ces variants sur la pathologie.Les développements et applications méthodologiques proposés dans cette thèse sont variés, allant d’une approche similaire aux GWAS, mettant à profit les données longitudinales disponibles dans certaines cohortes (p.ex. D.E.S.I.R.), au moyen d'un modèle joint; de la caractérisation fonctionnelle de gènes candidats, identifiés par GWAS, dans la sécrétion d'insuline par une étude transcriptomique multi tissu et dans un modèle cellulaire; de l'identification d'un nouveau gène candidat (PDGFA) impliqué dans la dérégulation de la voie de l'insuline dans le diabète de type 2 via des mécanismes épigénétiques et transcriptomiques; et enfin de la caractérisation de l'effet sur le transcriptome de deux substituts du bisphénol A dans un modèle d’adipocyte primaire.L'augmentation des connaissances des processus biologiques dans lesquels sont impliqués les SNPs et gènes identifiés par GWAS pourrait permettre l'élaboration de stratégies diagnostiques plus efficaces, ainsi que l'identification de cibles thérapeutiques pour le traitement du diabète de type 2 et des complications associées (p.ex. insulinorésistance, NAFLD, cancer, etc.). Plus généralement, ces études multi-omiques ouvrent la voie à l'approche émergente que représente la médecine de précision, permettant le traitement et la prévention des pathologies tout en prenant en compte ce qui fait la spécificité d'un individu, à savoir son génome et son environnement, tous deux interagissant sur son transcriptome et son épigénome. / Genome-wide association studies (GWAS) have resulted in the identification of several dozen of genes and single nucleotide polymorphisms (SNPs) contributing to type 2 diabetes.More generally, GWAS have identified thousands of SNPs contributing to complex diseases in humans.However, the functional characterization and biological mechanisms involving these SNPs and genes remain largely to be explored. Indeed, the consequences of these polymorphisms are complex and little known.One direct consequence of the SNPs is the alteration of the protein encoded by a gene, or even a complete transcriptional gene silencing (e.g. codon stop in the sequence). Furthermore, these polymorphisms may have a regulatory role in gene expression, for example, by interfering with the binding of transcription factors and enzymes involved in DNA methylation.Despite the strong associations of identified SNPs, they cannot explain the full heritability of type 2 diabetes, suggesting interactions mechanisms between the different layers of -omics, such as genomics, transcriptomics and Epigenomics.The shift of paradigm in statistical genetics and the availability of transcriptomic and epigenomic data are responsible for the evolution of the discipline, moving from association studies to multi-omics, and providing insights on the functional aspect of the SNPs or genes involved, and in some cases allowing to evaluate the causal link of these variants on the pathology.The methodological developments and their applications proposed in this thesis are various, ranging from a similar approach to GWAS, leveraging the longitudinal data available in some cohorts (e.g. D.E.S.I.R.), using an joint model approach; the functional characterisation of candidate genes in insulin secretion by a multi tissue transcriptomic study and transcriptomic study in a cell model; the identification of a new candidate gene (PDGFA) involved in the deregulation of the insulin\\\'s pathway in type 2 diabetes through epigenetic and transcriptomic mechanisms; and finally, the characterisation of the effect on the transcriptome of two substitutes of bisphenol A in a primary adipocyte model.The increase of knowledge in biological processes involving SNPs and genes identified by GWAS could enable the development of more effective diagnostic strategies, and the identification of therapeutic targets for the treatment of type 2 diabetes and associated complications (e.g., insulin resistance, NAFLD, cancer, etc.).More generally, these multi-omics studies pave the way for the emerging approach of precision medicine, allowing the treatment and prevention of pathologies while taking into account what makes the specificity of an individual, namely his genome and his environment, both interacting on his transcriptome and his epigenome.