Submitted by Ana Damasceno (ana.damasceno@unipampa.edu.br) on 2016-10-10T19:11:40Z No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) Padrões de distribuição e estrutura genética de schinus molle l. na região do pampa brasileiro.pdf: 1391928 bytes, checksum: 2218d5b0fe88623d4d79a44918949a55 (MD5) / Made available in DSpace on 2016-10-10T19:11:41Z (GMT). No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) Padrões de distribuição e estrutura genética de schinus molle l. na região do pampa brasileiro.pdf: 1391928 bytes, checksum: 2218d5b0fe88623d4d79a44918949a55 (MD5) Previous issue date: 2014-08-08 / Um dos principais aspectos para a ecologia de populações e evolução é o entendimento da conectividade entre os indivíduos e seus grupos. O bioma Pampa apresenta diversos componentes florísticos de grande importância ecológica, e sua estrutura de campo, estépico-savana, vem sendo fragmentada e impactada pelo sistema de produção e pela falta de manejo desse bioma naturalmente frágil. A partir da informação da diversidade genética de populações nativas é possível entender o atual estado de fragmentação ambiental, esclarecer se há fluxo-gênico entre populações, e sugerir formas de manejo que possam garantir a sobrevivência da biodiversidade local. Nesse estudo, Schinus molle L. (Anacardiaceae) foi empregada para avaliar a dinâmica ecológica, a diversidade e a estrutura genética em espécies arbóreas no bioma Pampa. A dinâmica de expansão prevista para a espécie foi determinada através de modelagem de nichos ecológicos e estrutura e diversidade genética foram avaliadas em nove populações amostradas dentro do bioma Pampa stricto sensu, utilizando marcadores microssatélite e AFLP. O mapa da modelagem de nichos ecológicos de S. molle sugere a expansão da espécie sobre o campo, como um fenômeno natural da dinâmica ecológica do bioma. A estrutura genética intra- e inter-populacional sugere limitações ao fluxo gênico e, a diversidade genética intra-populacional é baixa se comparada a espécies com as mesmas características biológicas. O isolamento entre populações e o pequeno tamanho destas parece ser o principal fator interferindo negativamente no ambiente. A manutenção de conexões entre as populações é a ação imediata sugerida para preservar a espécie e o bioma. / One of the main aspects for the population ecology and evolution is the understanding of the connectivity among individuals and their groups. The Pampa biome presents several floristic elements of high ecological importance and its grassy structure, steppic-savanna, has been fragmented and impacted by the production system and by the absence of management of this naturally fragile biome. From the information about genetic diversity of native populations, it is possible to understand the current status of the environment degradation, highlighting the presence of gene flow among populations and to suggest management strategies that could guarantee the survival of the local biodiversity. In this study, Schinus molle L. (Anacardiaceae) was employed to evaluate the ecological dynamic, the genetic diversity and structure in tree species of the Pampa biome. The expected expansion dynamic for this species was determined through ecological niche modeling and the genetic diversity and structure were evaluated in nine populations sampled within the Pampa stricto sensu, using microsatellite and AFLP markers. The ecological niche modeling map of S. molle suggests the species expansion over the grassland as a natural phenomenon of the biomes ecological dynamic. The intra- and inter-population genetic structure suggests limitations to the gene flow and the intra-population genetic structure is low in comparison to species with the same biological traits. The isolation among populations and their small size seems to be the main factor negatively interfering in the environment. The maintenance of connections among the populations is the immediate action suggested to safeguard the species and the biome.

Made available in DSpace on 2016-04-26T18:13:12Z (GMT). No. of bitstreams: 1 Norma Leonor Hall Freire.pdf: 6406046 bytes, checksum: cd28bded16f8ac7ebd6ee1cd95a0d3e9 (MD5) Previous issue date: 2013-06-24 / A text has the ability to preserve the memory of their prior contexts. Without this function there would be no Story. If a text remained in the observer's consciousness only as itself, the past would be as a mosaic of disconnected fragments. Did mine, in the approach of the Conto de Amaro, the words of Yury Lotman. The objective of the present research in relation to Conto de Amaro, a 15thcentury narrative produced in the monastery of Alcobaça in Portugal, regarded as an enigma in the context of medieval literature is, before unveiling the origins, give a voice to the narrative. For that other texts were needed. The internal element of the tale of Amaro that allows better visibility of similar situations is the distinct temporalities living in the same narrative space. The application of the comparative method to this larger constellation with the 14 texts of research support, produced an extensive network of meanings embedded in some way to the Conto de Amaro that you can call its own memory. The identification of these meanings in the communicative mediation of culture mapped by Jesús Martín-Barbero - socialibility, institutionality, technicality, and rituality- allowed an interpretation of the tale of Amaro on several levels that are its own by adding understanding the text. At the same time, generated the perception of two distinct logics operating inside and outside the text, which called for understanding. One of them, different from that which is characteristic of descriptive and explanatory thought that, somehow, can be called the language of names. The functioning of names is so different on the set of natural languages, they can be considered a separate language. Their presence, however, is sensitive in the substrate of the cultures and the heterogeneity of human consciousness. The space they inhabit is mosaicado, their temporality is distinct and their nature is symbols. In the research, I indicate its presence and made a few comments. Among the authors who helped immensely in understanding the goal I quote Jerusa Pires Ferreira, Aron Gurevitch, Claude Lévi-Strauss, Yuri Lotman, Roman Jakobson, Boris Uspenski, Vyacheslav Ivanov and Santo Amaro / Um texto tem a capacidade de preservar a memória de seus prévios contextos. Sem essa função não haveria História. Se um texto permanecesse na consciência do observador apenas como si mesmo, o passado se apresentaria a nós como um mosaico de fragmentos desconexos. Fiz minhas, na abordagem do Conto de Amaro, as palavras de Iuri Lotman. O objetivo da presente pesquisa em relação ao Conto de Amaro, uma narrativa do século XV produzida no mosteiro de Alcobaça em Portugal, considerada como um enigma no âmbito da literatura medieval é, antes que descortinar origens, dar uma voz à narrativa. Para isso outros textos foram necessários. O elemento interno do Conto de Amaro que permite melhor visibilidade de situações semelhantes é o de temporalidades distintas convivendo num mesmo espaço narrativo. A aplicação do método comparativo a essa constelação ampliada com a pesquisa de 14 textos de apoio, produziu uma ampla rede de significados incorporados de alguma forma ao Conto de Amaro e que podem ser chamados de sua memória. A identificação desses significados nas mediações comunicativas da cultura mapeadas por Jesús Martín-Barbero - socialidade, institucionalidade, tecnicidade, e ritualidade - permitiu uma interpretação do Conto de Amaro em vários níveis que lhe são próprios, acrescentando entendimento ao texto. Ao mesmo tempo, gerou a percepção de duas lógicas distintas em funcionamento dentro e fora no texto, que solicitavam compreensão. Uma delas, diferente da que é característica do pensamento descritivo e explicativo e que, de algum modo, pode ser chamada língua dos nomes próprios. O funcionamento dos nomes próprios é tão diferente no conjunto das línguas naturais, que eles podem ser considerados uma língua à parte. Sua presença, no entanto, é sensível no substrato das culturas e na heterogeneidade da consciência humana. O espaço que habitam é mosaicado, sua temporalidade é distinta e sua natureza é de símbolos. Na pesquisa que apresento, limitei-me a indicar sua presença e fiz alguns comentários. Entre os autores que auxiliaram imensamente na compreensão do objetivo cito Jerusa Pires Ferreira, Aron Gurevitch, Claude Lévi-Strauss, Iuri Lotman, Roman Jakobson, Boris Uspenski, Vyacheslav Ivanov e Santo Amaro

O estudo teve por objetivos caracterizar quantitativa e qualitativamente as principais classes taxonômicas da meso e macrofauna edáfica presentes em fragmentos de Floresta Estacional Semi Decidual (domínio de Mata Atlântica) e em diferentes modelos de reflorestamentos com espécies da Mata Atlântica. As áreas utilizadas pertencem à Faculdade de Ciências Agronômicas, UNESP, em Botucatu/SP. Os experimentos foram instalados em três solos usados intensivamente com exploração agrícola e pastagem: Nitossolo Vermelho (NV) textura argilosa, Argissolo Vermelho-Amarelo (PVA) Distrófico textura média e Latossolo Vermelho-Amarelo (LVA) Distrófico textura areia franca. O delineamento usado foi o de blocos casualizados, com três blocos e seis tratamentos. Um tratamento foi demarcado sobre floresta natural (Fragmento) e outros cinco tratamentos instalados sobre áreas revegetadas: testemunha, semeadura direta, sistema Taungya modificado, consorciação de espécies nativas de rápido crescimento com espécies comerciais para madeira e mistura de espécies nativas em modelos de plantio-restauração. As amostragens semestrais foram realizadas durante dois anos. A mesofauna foi extraída pelo método de Berleusse-Tüllgren modificado e a macrofauna pelo método dos monolitos. Os dados de densidade dos organismos foram analisados pelo teste de médias não-paramétrico de Friedman e pela análise multivariada de Agrupamento (Cluster Analysis). Nos tratamentos com cobertura vegetal mais densa e solo menos perturbado (Fragmento, Testemunha e Sem.Direta), foram verificadas as maiores densidades de organismos da meso e macrofauna edáfica. Houve uma relação direta entre a densidade de organismos e os atributos físicos e químicos dos solos; no solo mais úmido, de menor temperatura média, mais permeável, mais fértil e mais rico em matéria orgânica, NV, foram encontradas as maiores densidades de organismos da meso e macrofauna edáfica. Dentre as subordens de mesofauna, os oribatídeos foram encontrados com maior densidade em todos os solos e, os Astigmatas e Prostigmatas, em menores quantidades. Na macrofauna, o grupo das Oligochaetas foi o mais encontrado no NV, seguido do Formicidae; os grupos Isoptera, Coleoptera e Formicidae foram os mais encontrados no PVA e LVA. Independente do tipo de solo, a densidade de organismos da mesofauna edáfica foi maior no verão que no inverno. Para a macrofauna, as variações estacionais da densidade de organismos ocorreram somente no LVA, com 54% no verão, e foram influenciadas pelas condições físicas e químicas do solo. / The purposes of this study was to point out quantitaty and qualitivetely the main taxononomics classes of the meso and macrofauna soil, on fragments of Seasonal Semideciuos Tropical Forest (Atlantic Forest) and prototypes of Atlantic Fores reforestation programs, using native species. The reserched areas belong to Faculdade de Ciências Agronômicas, UNESP, located in Botucatu, SP, Brazil. The experiments took place in three different soil previously used heavily for agriculture and cattle: Alfisol clayey texture, Ultisol medium texture and Oxisol sandy texture. The experiment was marked by random blocks, with three replications and six treatments. One treatment was done over the natural forest followed by five other done over reforested lands: test, direct seeding, modified Taungya system, mix from native fast growing species with species used commercially and another mix from native species in restoration-planting model. The semestral samples were collectes for a period of two years. The Berleusse-Tüllgren modified method were used to extrat the mesofauna, and the Monolitos method to extract the macrofauna. The density data of the organisms were analyzed using the Friedman's non-parametric medias test as well as multivariate Cluster Analysis. On denser vegetation and less stressed soil (Fragment, Test and Direct Seeding), our treatment resulted on a higher density of organisms of meso and macrofauna. A relation between the density of organisms and the physical and quimical caracteristic of the soil was clearly defined: on a humid soil, low average temperature, permeable, higher degree of fertility and richer on organic matter, NV, it was detect the higher density of soil meso and macrofauna. Within the suborder of the mesofauna, the Oribatida could be found on higher density on all different types of soils and a smaller number in regards to the Astigmatas and Prostigmatas under the same circunstances. On the macrofauna, the Oligochaetas was found on higher density on the Alfisol, followed by Formicidae; the Isoptera, Coleoptera and Formicidae showes a bigger presence on the Ultisol and Oxisol. Independent of soil type, the density of soil mesofauna organisms was higher on the summer than the winter. For macrofauna, the density variation of organisms, based on the different climate seasons, ocurred only on the Oxisol, with a 54% in the summer, and had suffere the physical and quimical influence of the soil.

Esta tese propõe o desenvolvimento de SMAs centrados em organizações de forma disciplinada, mesmo nos casos em que os modelos organizacionais de agentes utilizados não estejam incorporados aos métodos oferecidos pela Engenharia de Software Orientada a Agentes (AOSE). A fim de atingir tal objetivo, esta tese adota os princípios da Engenharia de Método Situational e propõe o Ateliê Medee, que permite a composição de métodos situacionais para SMAs usando fragmentos de método adequados à situação de cada projeto. Este ateliê oferece um repositório de fragmentos de método que contempla distintas fases de desenvolvimento de um projeto, tais como elucidação de requisitos, análise, design, e implementação, envolvendo os principais componentes de um SMA, como agentes, ambientes, interações e organizações. Tal repositório contém fragmentos extraídos de diversas abordagens para o desenvolvimento de SMAs, entre elas os métodos Gaia, Tropos, Ingenias, PASSI, e os modelos organizacionais MOISE+ e OperA. Além disso, esta tese mostra como tais métodos situationais podem contribuir no estabelecimento de um ciclo de melhoria do método de desenvolvimento para SMAs. Este ciclo aplica os princípios da Engenharia de Software a fim de prover um procedimento empírico para a adaptação, avaliação e melhoria de métodos situacionais para o desenvolvimento de SMAs centrados em organizações. Dessa forma, este ciclo contribui para uma utilização mais ampla de aplicações orientadas a agentes pela indústria.de software. Finalmente, esta tese apresenta um estudo de caso conduzido para investigar o uso do Ateliê Medee na composição de métodos situacionais para SMAs. Este estudo de caso envolveu o desenvolvimento de SMAs centrados em organizações para resolver o problema proposto pelo Torneio de Programação Multiagentes usando dois métodos situacionais distintos, compostos a partir de fragmentos de método extraídos de Tropos, Gaia e MOISE+. / This thesis proposes the development of organization centered MAS in a disciplined way, even though some agent organizational models are not currently incorporated into AOSE methods. In order to do that, this thesis proposes the Medee Framework for composing MAS situational methods out of method fragments according to a given project situation, by applying the principles proposed by Situational Method Engineering. Thus, it offers a method fragment repository that covers different development phases, like requirements, analysis, design, implementation, as well as the main components of a MAS application, such as agents, environments, interactions, and organizations. Such a repository has been sourced from several MAS development approaches, as such Gaia, Tropos, Ingenias, PASSI, MOISE, and OperA. Furthermore, this doctoral dissertation shows how such MAS situational methods could contribute to establish a method improvement cycle. Such a cycle applies principles of the Software Engineering discipline to provide an empirical procedure for tailoring, evaluating, and enhancing MAS situational methods. In this way, this cycle allows the continuous improvement of the Medee Method Repository, towards a steady and well founded path for MAS method maturation and, consequently, for a broader utilization of agent-oriented software development in the software industry. Finally, this dissertation presents a case study conducted to investigate the use of the Medee Framework for composing MAS situational methods, sourced mainly from Tropos, Gaia, and MOISE+. Moreover, these situational methods were used within an improvement cycle for MAS development methods. This case study, called the USP Farmer project, involved the development of organization centered MAS to solve the problem proposed by the Multiagent Programming Contest.

<div>Computational Chemistry has proven to be an effective means of solving chemical problems. The two main tools of Computational Chemistry - quantum mechanics and molecular mechanics, have provided viable avenues to probe such chemical problems at an electronic or molecular level, with varying levels of accuracy and speed. In this work, attempts have been made to combine the speed of molecular mechanics and the accuracy of quantum mechanics to work across multiples scales of time and length, effectively resulting in simulations of large chemical systems without compromising the accuracy.</div><div><br></div><div>The primary tool utilized for methods development and application in this work is the Effective Fragment Potential (EFP) method. The EFP method is a computational technique for studying non-covalent interactions in complex systems. EFP is an accurate \textit{ab initio} force field, with accuracy comparable to many Density Functional Theory (DFT) methods, at significantly lower computational cost. EFP decomposes intermolecular interactions into contributions from four terms: electrostatics, polarization, exchange-repulsion and dispersion.</div><div><br></div><div>In the first chapter, the possibility of applying EFP method to study large radical-water clusters is probed. An approximate theoretical model in which the transition dipole moments of excitations are computed using the information from the ground state orbitals is implemented.</div><div><br></div><div>A major challenge to broaden the scope of EFP is to overcome its limitation in describing only small and rigid molecules such as water, acetone, etc. In the second chapter, the extension of EFP method to large covalently bound biomolecules and polymers such as proteins, lipids etc., is described. Using this new method, referred to as BioEFP/mEFP, it is shown that the effect of polarization is non-negligible and must be accounted for when modeling photochemical and electron-transfer processes in photoactive proteins.</div><div><br></div><div>Another area of interest is the development of novel drug-target binding models, in which a chemically active part of the ligand is modified via functional group modification, while the rest of the system remains intact. In the third chapter, the development and application of a drug-target binding model is explained.<br></div><div><br></div><div><div>Lastly, in the fourth and final chapter, we show the derivation for working equations corresponding to the coupling gradient term describing the dispersion interactions between quantum mechanical and effective fragment potential regions.</div><div><br></div><div>The primary focus of this work is to explore and expand the boundaries of multiscale QM/MM simulations applied to chemical and biomolecular systems. We believe that the work described here leads to exciting pathways in the future in terms of modeling novel systems and processes such as heterogeneous catalysis, QSAR, crystal structure prediction, etc.</div></div>

We examine how logical reasoning in the two-variable guarded fragment with counting quantifiers can be integrated with databases in the presence of certain integrity constraints, called path-functional dependencies. In more detail, we establish that the problems of satisfiability and finite satisfiability for the two-variable guarded fragment with counting quantifiers, a database, and binary path-functional dependencies are EXPTIME-complete; we also establish that the data complexity of these problems is NP-complete. We establish that query answering for the above fragment (with a database and binary path-functional dependencies) is 2-EXPTIME-complete with respect to arbitrary models, and provide a 2-EXPTIME upper bound for finite models. Finally, we establish that the data complexity of query answering is coNP-complete, both with respect to arbitrary and finite models.

Jusqu'à présent, les modifications de la réplication de l'ADN entre cellules normales et cancéreuses ont été peu étudiées. Dans ce travail, nous avons utilisé le séquençage des fragments d'Okazaki, une technique récemment développée au laboratoire, pour déterminer la directionalité des fourches de réplication dans plusieurs lymphomes de Burkitt (LB), qui surexpriment l'oncoprotéine Myc à la suite de translocations chromosomiques spécifiques, ainsi que dans des lignées lymphoblastoides contrôles (LLC) et dans des léiomyosarcomes (LMS). Les profils de directionalité des fourches de réplication permettent de déduire la localisation et l'efficacité des sites d'initiation et de terminaison de la réplication le long du génome. Nous avons observé de nombreuses (~2000) différences de zones d'initiation entre les lignées Raji (LB) et GM06990 (LLC) ainsi qu'entre les lignées BL 79 et IARC385, une paire LB/LLC provenant d'un même patient. Nous avons détecté un nombre comparable de différences en comparant deux à deux les lignées étudiées. Cependant, les profils de BL79 et de Raji (deux LB) sont un peu plus proches l'un de l'autre que de la lignée contrôle GM06990. Ceci suggère l'existence de changements de la réplication récurrents dans les lignées LB. L'importance des différences observées entre les lignées IARC385 et GM06990 indique de façon surprenante une grande variabilité entre les LLC normales, provenant de différents individus. De façon intéressante, de nombreuses différences observées entre les lignées LB et LLC sont associées à des changements de l'expression des gènes ou de la liaison de l'oncoprotéine Myc. La comparaison des profils des deux LMS avec tous les profils disponibles au laboratoire montre que c'est à celui de fibroblastes normaux (IMR90) qu'ils ressemblent le plus. Ceci suggère que les cellules de tumeurs musculaires lisses auraient subi une transformation fibroblastique au cours de la tumorigénèse. Des données récentes suggèrent que les champs magnétiques peuvent perturber certains processus cellulaires comme l'assemblage du cytosquelette. Nous avons utilisé le séquençage de fragment d'Okazaki pour rechercher d'éventuels effets d'un champ magnétique sur la réplication de l'ADN chez la levure. Aucun effet du champ magnétique sur la directionalité des fourches de réplication n'a été détecté. / Changes in DNA replication profiles between cancer and normal cells have been poorly explored. In this work, sequencing of Okazaki fragments, a novel methodology developed in the laboratory, was used to determine replication fork directionality (RFD) in several Burkitt's lymphomas (BL), which overexpress the Myc oncoprotein due to specific chromosomal translocations, and control normal lymphoblastoid cell lines (LCL), and in leiomyosarcomas (LMC). RFD profiles allow to infer the location and efficiency of replication initiation and termination sites genome-wide. A larger number (~2000) of differences in replication initiation zones were observed genome-wide between Raji (BL) and GM06990 (LCL), and between BL79 and IAR385, a BL / LCL pair of cell lines established from a single patient. Comparably large numbers of changes were slightly more similar to each other than to GM06990. This suggests the occurrence of some recurrent replication changes in BL cell lines. The large number of changes observed between IARC385 and GM06990 also indicates an unexpectedly large variation between normal LCLs of different individuals. Interestingly, many changes in RFD profiles between BLs and and LCLs are associated with cell-type specific gene expression and differential binding of the Myc oncoprotein. Comparison of the two LMS profiles with all RFD profiles available in the laboratory reveals that they most resemble normal fibroblasts (IMR90). This suggests that the smooth muscle cancer cells might have undergone a fibroblastic transformation during tumorigenesis. Magnetic fields have been reported to perturb cellular processes such as cytoskeleton assembly. Sequencing of Okazaki fragments was used in a preliminary investigation of the possible effects of magnetic fields on DNA replication in yeast cells. No effect of magnetic fields on replication fork directionality were observed.

En 1993, l’Organisation Mondiale de la Santé déclarait que la tuberculose était « une urgence de santé publique mondiale ». Plus de 20 ans après, cette maladie infectieuse causée par Mycobacterium tuberculosis, reste toujours un problème à l’échelle de la planète. Malgré des progrès très importants enregistrés dans la lutte contre la tuberculose dans le monde, l’OMS estime que 9 millions de personnes ont contracté cette maladie en 2013 et que 1,5 million sont morts durant cette même année. De plus, l'émergence de la tuberculose multirésistante nécessite le développement de nouveaux outils et de nouvelles stratégies thérapeutiques. Récemment, deux nouveaux composés, bedaquiline et delamanid ont reçu une autorisation temporaire d’utilisation dans le but de renforcer l’arsenal thérapeutique. Néanmoins, il existe toujours la possibilité que la bactérie puisse rapidement développer des résistances liées au mécanisme d’action de ces nouveaux médicaments. C’est pour toutes ces raisons que l’arsenal thérapeutique doit être renforcé. Ce travail de thèse repose sur la découverte et l'optimisation de nouveaux composés antituberculeux selon des approches dont le point de départ commun est le criblage de petites molécules appelées fragments.La première partie de ce manuscrit présente la continuité d’un travail démarré au cours de la thèse de Baptiste Villemagne et qui a pour but de potentialiser l’activité de l'éthionamide, un médicament antituberculeux utilisé pour le traitement de seconde intention. Le répresseur transcriptionnel EthR a été validé comme élément clé dans la bioactivation de l’éthionamide. Les inhibiteurs de cette cible, développés selon une approche par fragments ont permis de potentialiser l'activité de l'éthionamide in vitro. Cependant, la faible stabilité microsomale de ces composés a limité leur utilisation in vivo. L’étude de la métabolisation du composé tête de série et la modification structurale de ce dernier a permis le développement des nouveaux inhibiteurs d’EthR présentant des propriétés pharmacocinétiques et physico-chimiques désormais acceptables pour la réalisation de tests in vivo.La deuxième partie de cette thèse s’est concentrée sur la synthèse d’inhibiteurs de MabA, une &#946;-cétoacyl-ACP réductase mycobactérienne participant à la synthèse des acides gras à longue chaîne, précurseurs des acides mycoliques qui sont les constituants majeurs de la paroi mycobactérienne. Cette enzyme a été montrée comme étant indispensable à la survie de la bactérie mais aucun inhibiteur à ce jour n’a été identifié. Le criblage d’une chimiothèque de fragments sur MabA a été réalisé via deux tests différents (un test d’affinité pour la cible (TSA) et un test enzymatique). Les hits ainsi identifiés ont été resynthétisés et testés dans un test fonctionnel. Les étapes d’optimisation de l’activité des hits reconfirmés sont ainsi décrites. Ces résultats ont permis de développer des composés présentant des activités de l’ordre du micromolaire. Dans la troisième partie, un travail de conception et de synthèse de nouveaux fragments, visant à compléter la chimiothèque actuelle a été effectué. Les fragments originaux contenant un motif isoxazoline ont été synthétisés à partir d’alcènes et d’aldoximes utilisés en tant que synthons de départ, selon une réaction de cycloaddition 1,3-dipolaire. L’analyse conformationnelle de ces fragments a permis de montrer que ces structures venaient enrichir l’espace de la diversité, notamment par l’introduction d'un motif permettant le déploiement des substituants dans les trois dimensions de l’espace. La solubilité expérimentale de ces fragments a été également mesurée et nous avons pu montrer que ces molécules étaient adaptées au criblage. / In 1993, the World Health Organization (WHO) declared Tuberculosis (TB) as a global public health emergency. Over 20 years later, this infectious disease caused by Mycobacterium tuberculosis, remains a major public health problem. Despite the significant progress in the fight against TB worldwide, WHO estimates that 9 million people contracted the disease in 2013 and 1.5 million died in that year. In addition, the emergence of multidrug-resistant tuberculosis (MDR-TB) requires the development of new tools and new therapeutic strategies. Recently, two new compounds, bedaquiline and delamanid were approved in MDR-TB treatment in order to strengthen the actual MDR-TB chemotherapy. Nevertheless, there is always the possibility that the tubercle bacillus can quickly develop resistance related to the mechanism of action of these new drugs. Therefore, the actual therapeutic arsenal must be strengthened. This thesis is based on the discovery and optimization of new anti-TB compounds starting from the screening of small molecules called fragments.The first part of this thesis is the continuation of the research project which was started during the thesis of Baptiste Villemagne. This work aims to develop compounds that can boost the activity of ethionamide, a second-line drug used to treat MDR-TB. The transcriptional repressor EthR has been validated as a key element in the bioactivation of ethionamide. EthR inhibitors were identified using a fragment-based approach and were optimized to potentiate the activity of ethionamide in vitro. However, the low microsomal stability of the lead compound has limited its use in vivo. The metabolism study of the lead compound and key structural modifications allowed a development of new potent EthR inhibitors having acceptable pharmacokinetic and physico-chemical properties for in vivo testing.The second part of this thesis focused on the synthesis of MabA inhibitors. MabA is a mycobacterial &#946;-ketoacyl-ACP reductase involved in the synthesis of long-chain fatty acids, precursors of mycolic acids, which are major constituents of the mycobacterial cell wall. This enzyme has been shown to be essential for the survival of the bacteria but until now no inhibitor has been identified. Screening of a library of fragment molecules on MabA was performed via two different assays (affinity assay using TSA and an enzymatic assay). The identified hits were re-synthesized and tested in a functionnal assay. The optimization steps to improve the activity of the hits are also described. Compounds with activity in the micromolar range were discovered.In the third part, a design and synthesis of new fragments is described. The aim of this project is to build a collection of original fragments showing a 3D-structure scaffold amenable for rapid derivatization. The fragments that contain an original isoxazoline motif were synthesized from alkenes and aldoxime as starting building-blocks by using 1,3-dipolar cycloaddition. The conformational analysis of these structures has shown that they were, as expected, able to deploy substituents in the 3D space. The experimental solubility of these fragments was also measured and the results demonstrated that these molecules are suitable for the screening against new biological targets to help kick-start hit discovery program.

Submitted by Luciana Ferreira (lucgeral@gmail.com) on 2017-07-25T11:29:51Z No. of bitstreams: 2 Tese - Maria do Carmo Correa Lagos - 2017.pdf: 2467574 bytes, checksum: 6103756464e3e1a5794c7464d5406eac (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Approved for entry into archive by Luciana Ferreira (lucgeral@gmail.com) on 2017-07-25T11:30:31Z (GMT) No. of bitstreams: 2 Tese - Maria do Carmo Correa Lagos - 2017.pdf: 2467574 bytes, checksum: 6103756464e3e1a5794c7464d5406eac (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Made available in DSpace on 2017-07-25T11:30:31Z (GMT). No. of bitstreams: 2 Tese - Maria do Carmo Correa Lagos - 2017.pdf: 2467574 bytes, checksum: 6103756464e3e1a5794c7464d5406eac (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2017-06-30 / The central theme of this thesis is about the edge effect from the fragmentation of ecosystems and our central objective is to contribute to the knowledge about this effect in forest fragments in the Cerrado and Atlantic Forest biomes. In this sense, we propose here two different approaches for each of these biomes: In the Cerrado Biome the great "Knowledge Gap" on the production of Litter in fragments of this biome was emphasized and we propose possible measures to fill these gaps.In the Atlantic Forest an approach was taken on the edge effect in forest fragments, where we verified how this effect occurs from the edge to the center of the fragments using the NDVI vegetation Index. In addition, it was verified the most suitable model to analyze the dynamics of the edge effect. When evaluating the quality of the linear model and the nonlinear model we found that the nonlinear model was the most adequate for the description of the edge effect in the Atlantic Forest biome. Based on the study of all these aspects about the edge effect, we hope to subsidize works on fragmentation in these two Biomes and also contribute to the execution of projects that aim at the conservation of forest fragments in a wide scale / O tema central dessa tese é sobre o efeito de borda proveniente da fragmentação de ecossistemas e o nosso objetivo principal é o de contribuir para o conhecimento sobre esse efeito em formações savânicas e florestais nos biomas Cerrado e Mata Atlântica. Nesse sentido, propomos aqui duas abordagens diferentes para cada um desses biomas: No Bioma Cerrado foi enfatizado a grande “Lacuna de Conhecimento” sobre a produção de Serapilheira em fragmentos desse bioma e propomos possíveis medidas para o preenchimento dessas lacunas. Na Mata Atlântica foi realizada uma abordagem sobre o efeito de borda em fragmentos florestais, onde verificamos como esse efeito ocorre desde a borda ao centro dos fragmentos utilizando o Índice de vegetação NDVI. Além disso, foi verificado qual o modelo mais adequado para analisar a dinâmica do efeito de borda. Ao avaliar a qualidade do modelo-linear e o modelo não – linear constatamos que o modelo não-linear foi o mais adequado para a descrição do efeito de borda no bioma Mata Atlântica. Com base no estudo de todos esses aspectos relacionados ao efeito de borda, esperamos subsidiar trabalhos sobre fragmentação nesses dois Biomas e ainda contribuir para a execução de projetos que visam a conservação de fragmentos florestais em uma escala ampla.

Cette thèse porte sur l'élaboration d'un vecteur particulaire lipidique reconnaissant activement<br />les tissus cérébraux après son administration par voie intraveineuse. Ce système devrait favoriser l'accumulation au sein du cerveau, de molécules thérapeutiques dans le cadre du traitement des maladies cérébrales comme les gliomes malins. La première partie de notre travail consistait à greffer sur la surface de nanocapsules lipidiques (LNC) des anticorps<br />monoclonaux d'origine murine (OX26) ou des fragments Fab' dirigés contre le récepteur à la transferrine de rat, surexprimé sur l'endothélium cérébral. Des immunonanocapsules portant entre 16 et 183 anticorps entiers et entre 42 et 173 fragments Fab' ont été obtenues. Leur capacité à s'associer aux cellules endothéliales cérébrales de rat a ensuite été vérifiée. De<br />plus, 24 h après leur administration chez le rat, la concentration dans le cerveau des OX26-<br />immunonanocapsules et des Fab'-immunonanocapsules était respectivement 2 et 1,5 fois plus<br />élevée que celle des LNC dépourvues de ligands.