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The isolation and characterisation of sequences from the X and Y chromosomes will give some insight into the evolutionary relationship between these chromosomes, and may be of use in the study of X-linked disorders. The availability of cDNA and genomic sequences for the human STS locus (associated with the disorder, X-linked ichthyosis) has allowed a preliminary investigation of this locus in man and other species. The localisation of these sequences to Xp22.3, provides confirmation of the sub-regional assignment of the structural gene for STS. STS homologous sequences have been identified on the long arm of the Y chromosome. These sequences also appear present on the X and Y chromosomes of the chimpanzee. In other higher primates, they appear to be X-, but not Y-, linked, suggesting that the situation in man and chimpanzee is the result of a rearrangement between the X and Y chromosomes during the past 15 million years. Another region of X Y homology has been analysed. The locus DXYS27 maps to Yp and Xq21. Restriction enzyme analysis and direct sequence comparison has shown the two loci to be «99% homologous. Phylogenetic studies suggest that the locus is X-, but not Y-, linked in the chimpanzee, suggesting an evolutionarily recent transposition of material from the X to the Y chromosome. The mutations resulting in the X-Y differences appear to have occurred on both the X and Y chromosomes. It has been possible to demonstrate that the Y-specific locus is transferred to the X chromosome in many, but not all, aberrant X-Y interchanges resulting in XX maleness. A sequence has been isolated that detects a hypervariable locus at Xp11.3→Xcen (DXS255) . The hypervariability appears to be due to the presence of a tandemly repeated sequence of variable length. Attempts to clone this repeat have been unsuccessful, as it appears to be unstable in the vector/host systems employed. This sequence will be of value in linkage studies of disease loci known to be present in this region. Hypervariability at this locus has not been identified in other species, suggesting that the repeat sequence is an evolutionarily recent acquisition by the X chromosome. Taken together, the results obtained suggest that the simple model predicting an ancient origin for the bulk of the Y chromosome will have to be reassessed.

Le cytosquelette est un assemblage de protéines intracellulaires qui assure le maintien de la forme des cellules et la production de force. Ce cytosquelette est formé de trois types de polymères, dont les filaments d'actine qui sont impliqués dans des fonctions essentielles telles que la motilité cellulaire, la division cellulaire ou encore la morphogénèse. Les filaments d'actine s'agencent en structures organisées dont la dynamique est assurée par la polymérisation et le désassemblage des filaments, contrôlés spatio-temporellement. La plupart des structures d'actine sont dans un état stationnaire dynamique où l'assemblage est compensé par le désassemblage, ce qui permet de maintenir une concentration de monomères intracellulaire élevée. En effet, le réservoir d'actine in vivo est limité et la formation de nouvelles structures de filaments d'actine est dépendante d'un désassemblage efficace des structures les plus âgées. Le but de ma thèse a été d'étudier comment l'organisation architecturale des structures d'actine influence le désassemblage par la machinerie protéique composée de l'ADF/cofiline et d'un de ses cofacteurs Aip1.J'ai d'abord pu montrer que l'efficacité du désassemblage dépendait de l'agencement des filaments d'actine. Quand les réseaux branchés ne requièrent que l'action de l'ADF/cofiline pour être désassemblés efficacement, les faisceaux de filaments d'actine ont besoin de la présence simultanée de l'ADF/cofiline et de l'Aip1. Une étude à l'échelle moléculaire a ensuite été menée pour comprendre le mécanisme du désassemblage des filaments d'actine par ces deux protéines au niveau du filament individuel.Dans un second temps, j'ai développé un système expérimental composé de micropuits de taille comparable à la cellule. Cette technologie nous a permis de réaliser des expériences en milieu confiné, dans lequel le réservoir d'actine était limité de la même manière que le réservoir d'actine cellulaire. J'ai mis ce système a profit pour reconstituer le turnover d'une comète d'actine, un réseau branché formé à la surface d'une bille recouverte de nucléateurs de l'actine.Ce travail de thèse a permis d’établir des lois fondamentales contrôlant la dynamique de l’actine et plus particulièrement comment l’architecture de l’actine et l’environnement peuvent influencer le désassemblage de structures complexes. / The actin cytoskeleton is a major component of the internal architecture of eukaryotic cells. Actin filaments are organized into different structures, the dynamics of which is spatially and temporally controlled by the polymerization and disassembly of filaments. Most actin structures are in a dynamic steady state regime where the assembly is balanced by the disassembly, which maintains a high concentration of intracellular actin monomers. In vivo the pool of actin monomers is limited and the formation of new actin filament structures is dependent on an effective disassembly of the older structures. The goal of my thesis was to study the influence of different architectures of actin by the disassembly machinery made of ADF/cofilin and its cofactor Aip1.Firstly, I showed that the efficiency of the disassembly was dependent on the architecture of actin filaments organizations. Although the branched networks need only ADF/cofilin to be efficiently disassembled, the actin cables require the simultaneous action of ADF/cofilin and Aip1. Further investigations at the molecular scale indicate that the cooperation between ADF/cofilin and Aip1 is optimal above a certain threshold of molecules of ADF/cofilin bound to actin filaments. During my PhD I demonstrated that although ADF/cofilin is able to dismantle selectively branched networks through severing and debranching, the stochastic disassembly of actin filaments by ADF/cofilin and Aip1 represents an efficient alternative pathway for the full disassembly of all actin networks. We propose a model in which the binding of ADF/cofilin is required to trigger a structural change of the actin filaments, as a prerequisite for their disassembly by Aip1.Secondly, I developed an experimental system made of cell-sized microwells. This technology allowed us to develop experiments in a closed environment in which the actin pool is limited in the same way as the cellular environment. I used this experimental system to study how a limited pool of components limits both the assembly and the disassembly of a branched network.This thesis highlights the importance of developing new tools to obtain more “physiological” reconstituted systems in vitro to establish some of the general principles governing actin dynamics.

Submitted by Mario BC (mario@bc.ufrpe.br) on 2016-08-26T12:17:11Z No. of bitstreams: 1 Cleane de Souza Silva.pdf: 519250 bytes, checksum: 9a29ec3f85ee741e509613add0beead5 (MD5) / Made available in DSpace on 2016-08-26T12:17:12Z (GMT). No. of bitstreams: 1 Cleane de Souza Silva.pdf: 519250 bytes, checksum: 9a29ec3f85ee741e509613add0beead5 (MD5) Previous issue date: 2016-02-15 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / Among the insects described in the Curculionidae family, ten species are classified as belonging to the genus Rhynchophorus, among which seven are considered pests of coconut palm (Cocos nucifera) and other Aarecáceas. Among these, it stands out the severity of damage, the drill-the-eye-of-coconut tree, Rhynchophorus Palmarum (Linnaeus). This insect has American origin, and occurs throughout Brazil, infesting at least 12 plant families. Despite the recognition that species like the plague, few molecular studies have been documented about him, and all the information of these species and their populations fully based on morphological characteristics. Genetic studies see allowing investigate the genetic diversity between populations and between species and their evolutionary destiny over time. In this context, this study aimed to carry out a molecular study by molecular marker COX I seven people, distributed in four states in northeastern Brazil and identified primarily as R. Palmarum and analyze the genetic divergence between populations. Through the reconstruction of phylogeny it was detected the presence of two clearly distinct clades. Through the network haplotypes it was possible to detect the presence of only 12 haplotypes where the haplotype H1 is the most common because of its presence in 117 subjects divided in six of the seven populations studied. It was also observed that the FST index showed a high value, indicating genetic divergence estimated from FST parameter (0,00- 0.848) when compared to the population of Fortaleza (CE) with the other. / Entre os insetos descritos na família Curculionidae, dez espécies são classificadas como pertencentes ao gênero Rhynchophorus, dentre as quais, sete são consideradas pragas do coqueiro (Cocos nucifera) e demais Aarecáceas. Entre estas, destaca-se, pela severidade de danos, a broca-do-olho-do-coqueiro, Rhynchophorus palmarum (Linnaeus). Este inseto tem origem americana, e ocorre em todo território brasileiro, infestando pelo menos 12 famílias botânicas. Apesar do reconhecimento dessa espécie como praga, poucos estudos moleculares têm sido documentados a seu respeito, sendo toda a informação destas espécies e de suas populações totalmente baseados em características morfológicas. Estudos genéticos veem possibilitando investigar a diversidade genética entre populações e entre espécies, assim como seu destino evolutivo ao longo do tempo. Neste contexto, o presente trabalho teve como objetivo realizar um estudo molecular através do marcador molecular COX I de sete populações, distribuídas em quatro estados do nordeste do Brasil e identificadas, primariamente, como R. palmarum e analisar a divergência genética existente entre estas populações. Através da reconstrução da filogenia foi detectada a presença de dois clados claramente distintos. Através da rede de haplótipos foi possível detectar a presença de apenas 12 haplótipos onde o haplótipo H1 foi o mais frequente devido a sua presença em 117 indivíduos distribuídos entre seis das sete populações investigadas. Foi possível observar também que o índice de FST apresentou um alto valor, indicando divergência genética, estimado a partir do parâmetro FST (0,00- 0,848) quando comparado a população de Fortaleza (CE) com as demais.

Avec environ 49 000 nouvelles femmes touchées chaque année, le cancer du sein est le plus répandu des cancers féminins. Le dépistage du cancer du sein, ainsi que l'amélioration des traitements ont fait diminuer la mortalité mais il reste encore le plus meurtrier des cancers féminins en France. Le cancer du sein étant une maladie hétérogène, individualiser les traitements des patientes est désormais l'un des objectifs premiers des praticiens. C'est autour de cet objectif commun que se sont articulés les 2 projets de ce travail de thèse. D'une part, pour l'étude clinique, j'ai établi une base de données sur la stratégie néoadjuvante des cancers du sein opérables, regroupant 318 patientes traitées à l'institut Jean Godinot. Cette base nous permet de comparer nos résultats à ceux de la littérature, de mettre en avant l'intérêt de la chimiothérapie néoadjuvante pour déterminer de nouveaux facteurs pronostics, et de valider l'évaluation des résidus tumoraux dans le sein et les ganglions par l'index RDBN. D'autre part, l'étude expérimentale nous a permis d'améliorer nos connaissances sur les mécanismes moléculaires d'échappement tumoral. Nous avons ainsi démontré le rôle pro-tumoral de l'IL-17A mais aussi de l'IL-17E, ces deux cytokines pouvant être présentes dans le microenvironnement tumoral, et mis en évidence leur implication dans la dérégulation du cycle cellulaire à travers la génération des LMW-E et l'acquisition d'un mécanisme de chimiorésistance. / With around 49 000 new affected women each year, breast cancer is the most common of feminine cancers. Breast cancer screening, and treatments improvements make mortality decreased but it stays the most murderous of feminine cancers in France.Breast cancer being a heterogeneous disease, individualizing patients' treatments is now one of first goals of practitioner. It is around of this common aim that my 2 thesis projects are turned on.On the one side, for clinical study, I designed a database on the neoadjuvant strategy of operable breast cancers, assembling 318 patients treated at Jean Godinot institute. This database allow us to compare our results with literature ones, to highlight the interest of neoadjuvant chemotherapy to determine new prognostic factors, and to validate evaluation of residual disease in breast and nodes by RDBN index.On the other side experimental study allowed us to improve our knowledge on molecular mechanisms of tumor escape. We demonstrated pro-tumoral role of IL-17A but also of IL-17E, these two cytokines can be presents in tumoral microenvironment, and evidenced their implication in cell cycle dysregulation through generation of LMW-E and acquisition of chemoristance mechanisms.