Resumo: O trator agrícola é uma das principais fontes de energia e de trabalho no meio rural. A utilização correta de pneus, tanto em relação ao seu tipo quanto a calibração de sua pressão interna, são fatores que influem significativamente no seu desempenho. Outros fatores de regulagem do trator; tais como, a lastragem e a velocidade de deslocamento ideal para cada condição de superfície de solo, são fatores que modificam sua eficiência trativa. Esse trabalho foi realizado com o objetivo de comparar o desempenho operacional e energético de um trator equipado com pneus radiais e com pneus diagonais, em três condições de lastragem líquida (0%, 37,5% e 75% de água), três condições superficiais de um Nitossolo Vermelho Distrófico (superfície firme, superfície mobilizada e superfície firme com cobertura de restos da cultura do milho) e três condições de deslocamento, distinguidas pela mudança de marchas do trator que correspondem as seguintes velocidades teóricas: 4 km.h-1, 5km.h-1 e 7 km.h-1, informadas no painel do trator. Foi utilizado o delineamento experimental simples em faixas, correspondendo às condições superficiais do solo e um arranjo fatorial de 2x3x3 (pneus, lastros, e velocidades) em cada faixa, distribuídos em blocos ao acaso, com três repetições, totalizando 162 unidades experimentais. Esses fatores foram arranjados para permitir a avaliação dos efeitos das variáveis individualmente ou em grupos, sendo todos os dados submetidos à análise de variância, aplicando o teste de Tukey a 5% de probabilidade, para a comparação das médias...(Resumo completo, clicar acesso eletrônico abaixo) / Abstract: The agricultural tractor is one of principal source of energy and power in rural land. The correct utilization of tires, related to the construction type and internal inflation pressure, both are factors that interfere significantly on its performance. Other factors of tractor adjustment, such as ballasting and ideal forward speed for each condition of soil surface are factors that modify its tractive efficiency. This research was carried out with the aim to compare the operational and energetic performance of a tractor equipped with radial tires and with bias ply tires, in three conditions of liquid ballast (0%, 37,5% and 75% of water), three conditions of surface in a Nitossolo Vermelho Distrófico (rigid surface, mobilized surface and rigid surface covered with remaining leaves of corn after its harvest) and three distinct conditions of forward speed, performed by changing the tractor gears (B1, B2 and C1), that are correlated to the following theoretical forward speed: 4 km.h-1, 5km.h-1 and 7 km.h-1, informed on tractor panel. The experiment design was in simple strips related to soil surface conditions and a factorial settlement 2x3x3 (tires, ballasts, surfaces, and forward speeds) in each strip, divided in random blocks replicated three times, totalizing 162 experimental units. These factors were arranged in order to permit an evaluation of the effects of variables individually or in groups. All data were analyzed statistically using Tukey test at 5% of probability to compare the means. To realize...(Complete abstract, click electronic access below) / Orientador: Kléber Pereira Lanças / Coorientador: Antonio Gabriel Filho / Banca: Saulo Philipe Sebastião Guerra / Banca: Paulo Roberto Arbex Silva / Mestre

Made available in DSpace on 2014-06-11T19:24:40Z (GMT). No. of bitstreams: 0 Previous issue date: 2008-02-15Bitstream added on 2014-06-13T19:31:27Z : No. of bitstreams: 1 monteiro_la_me_botfca.pdf: 514192 bytes, checksum: 1bee58c13636c9333836a8b89b794984 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / O trator agrícola é uma das principais fontes de energia e de trabalho no meio rural. A utilização correta de pneus, tanto em relação ao seu tipo quanto a calibração de sua pressão interna, são fatores que influem significativamente no seu desempenho. Outros fatores de regulagem do trator; tais como, a lastragem e a velocidade de deslocamento ideal para cada condição de superfície de solo, são fatores que modificam sua eficiência trativa. Esse trabalho foi realizado com o objetivo de comparar o desempenho operacional e energético de um trator equipado com pneus radiais e com pneus diagonais, em três condições de lastragem líquida (0%, 37,5% e 75% de água), três condições superficiais de um Nitossolo Vermelho Distrófico (superfície firme, superfície mobilizada e superfície firme com cobertura de restos da cultura do milho) e três condições de deslocamento, distinguidas pela mudança de marchas do trator que correspondem as seguintes velocidades teóricas: 4 km.h-1, 5km.h-1 e 7 km.h-1, informadas no painel do trator. Foi utilizado o delineamento experimental simples em faixas, correspondendo às condições superficiais do solo e um arranjo fatorial de 2x3x3 (pneus, lastros, e velocidades) em cada faixa, distribuídos em blocos ao acaso, com três repetições, totalizando 162 unidades experimentais. Esses fatores foram arranjados para permitir a avaliação dos efeitos das variáveis individualmente ou em grupos, sendo todos os dados submetidos à análise de variância, aplicando o teste de Tukey a 5% de probabilidade, para a comparação das médias... / The agricultural tractor is one of principal source of energy and power in rural land. The correct utilization of tires, related to the construction type and internal inflation pressure, both are factors that interfere significantly on its performance. Other factors of tractor adjustment, such as ballasting and ideal forward speed for each condition of soil surface are factors that modify its tractive efficiency. This research was carried out with the aim to compare the operational and energetic performance of a tractor equipped with radial tires and with bias ply tires, in three conditions of liquid ballast (0%, 37,5% and 75% of water), three conditions of surface in a Nitossolo Vermelho Distrófico (rigid surface, mobilized surface and rigid surface covered with remaining leaves of corn after its harvest) and three distinct conditions of forward speed, performed by changing the tractor gears (B1, B2 and C1), that are correlated to the following theoretical forward speed: 4 km.h-1, 5km.h-1 and 7 km.h-1, informed on tractor panel. The experiment design was in simple strips related to soil surface conditions and a factorial settlement 2x3x3 (tires, ballasts, surfaces, and forward speeds) in each strip, divided in random blocks replicated three times, totalizing 162 experimental units. These factors were arranged in order to permit an evaluation of the effects of variables individually or in groups. All data were analyzed statistically using Tukey test at 5% of probability to compare the means. To realize...(Complete abstract, click electronic access below)

Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico / O microtrator à ideal para atividades desenvolvidas em pequenas Ãreas por otimizar o trabalho. O experimento foi desenvolvido na Universidade Federal do Cearà com o objetivo de avaliar a eficiÃncia energÃtica e operacional de um conjunto mecanizado microtrator-rotoencanteirador em trÃs marchas, pressÃo de inflaÃÃo e lastragem dos pneus, com e sem lastro. Para obtenÃÃo dos dados de eficiÃncia energÃtica utilizou-se um microtrator, instrumentado com sensores indutivos nas rodas para medir a patinagem, provetas para medida do consumo de combustÃvel e cÃlula de carga para obter a forÃa de trabalho na barra de traÃÃo. As variÃveis estudadas foram velocidade de trabalho, patinagem dos rodados, consumo horÃrio de combustÃvel, consumo especÃfico de combustÃvel, forÃa de traÃÃo na barra e potÃncia disponÃvel. Realizou-se dois experimentos fatoriais para cada variÃvel avaliada, o primeiro com o microtrator sem lastro e outro com o uso de lastros, cada experimento era composto de dois fatores: marchas (1Â, 2 e 3Â) e pressÃo de inflaÃÃo dos pneus (82,74; 96,53 e 110,32 kPa). Os dados foram submetidos a anÃlise de variÃncia, foi realizado o teste de comparaÃÃo de mÃdias de Tukey ao nÃvel de 5% de significÃncia utilizando o Software Assistat 7.6. Os maiores valores de velocidades foram encontrados com o microtrator trabalhando sem lastro na terceira marcha. A maior patinagem foi encontrada na terceira marcha com o microtrator sem lastro e para as diferentes pressÃes foi sem lastro na pressÃo de 82,74kPa. O maior consumo horÃrio foi registrado na terceira marcha sem lastro, para as pressÃes foi de 96,53 kPa sem lastro. Para o consumo especÃfico o maior valor encontrado foi de 3483,04 g.kW-1.h-1, com o microtrator com lastro e 3267,48 g.kW-1.h-1 na pressÃo de 82,74 kPa. A forÃa de traÃÃo na primeira marcha foi de 6,02 kN, na segunda 4,81 kN e na terceira de 3,2 kN, todas nÃo variaram com a mudanÃa de pressÃo, trabalhando sem lastro. Com lastro a forÃa foi de 4,81kN, 3,2 kN e 2,00 kN na primeira, segunda e terceira marcha respectivamente. A maior potencia encontrada foi na segunda marcha sem lastro. Entre as pressÃes a maior foi de 0,48 kW na pressÃo de 82,74 kW. A maior Ãrea de solo mobilizada foi de 0,082 m2 na primeira marcha com 96,53 kPa quando se trabalhou sem lastro. Com o lastro a maior Ãrea foi de 0,82 m2 na primeira marcha com 82,74 kPa. A melhor eficiÃncia do sistema foi na primeira marcha a 82,74 kPa com lastro, 74,56%. / The microtractor is ideal for activities in small areas by optimizing the work. The experiment was conducted at the Federal University of Cearà in order to evaluate the energy efficiency and operating a mechanized set microtractor rotoencanteirador-in three-speed, inflation pressure and tire ballast, with and without ballast. To obtain data for energy efficiency used a microtractor, instrumented with inductive sensors to measure wheel slippage, beakers to measure the fuel consumption and load cell for the workforce in the drawbar. The variables studied were working speed skating rotated, hourly fuel consumption, specific fuel consumption, power drawbar pull and power available. We conducted two factorial experiments for each variable evaluated, the first with microtractor without ballast and another with the use of weights, each experiment consisted of two factors: gears (1st, 2nd and 3rd) and inflation pressure of tires (82,74; 96,53 and 110,32 kPa). Data were subjected to analysis of variance test was used for comparison Tukey test at 5% significance level using the Software Assistat 7.6. The highest values were found with speeds microtractor working without ballast in third gear. The largest slip was found in third gear with microtractor without ballast and for different pressures was unbacked pressure of 82,74 kPa. The highest hourly consumption was recorded in third gear without ballast to the pressures of 96,53 kPa was without ballast. For the specific consumption the highest value was 3483.04 g.kW-1.h-1, with microtractor backed and 3267,48 g.kW-1.h-1 at a pressure of 82,74 kPa. The tensile strength in first gear was 6,02 kN, 4,81 kN in the second and third of 3,2 kN, all did not change with the change of pressure, working without ballast. Backed force was 4,81 kN, 3,2 kN and 2,00 kN in the first, second and third gear respectively. The greatest power was found in second gear without ballast. Among the most pressure was 0,48 kW at a pressure of 82,74 kW. The largest land area of 0,082 m2 was mobilized in first gear with 96,53 kPa when working without ballast. With the ballast was the largest area of 0,82 m2 in first gear with 82,74 kPa. The best efficiency of the system was in first gear to 82,74 kPa backed, 74.56%.

CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / Na agricultura familiar a utilizaÃÃo de microtratores como fonte de potÃncia à uma forma para otimizar o trabalho no campo. Objetivou-se com este trabalho avaliar a eficiÃncia energÃtica de um microtrator de duas rodas submetido Ãs marchas (1Â, 2 e 3Â) com variaÃÃo de cargas (0, 200 e 400 kg) para trÃs superfÃcies do solo (pista de asfalto, solo firme e mobilizado) e avaliar o nÃvel de ruÃdo emitido pelo microtrator parado e em movimento a diferentes posiÃÃes e raios de afastamentos. Na avaliaÃÃo da eficiÃncia energÃtica utilizou-se um microtrator marca Yanmar instrumentado com sensores indutivos, fluxÃmetros e cÃlula de carga. A estabilidade e as cargas impostas ao microtrator ensaiado foram feitas atravÃs de um comboio de um pulverizador de barra acoplado ao microtrator. Para a mediÃÃo do nÃvel de ruÃdo foi utilizado um dosÃmetro pessoal de ruÃdo e um decibelÃmetro. As variÃveis analisadas foram: patinagem dos rodados, consumo horÃrio e especÃfico de combustÃvel, forÃa de traÃÃo, potÃncia na barra, velocidade de deslocamento e nÃvel de ruÃdo. A anÃlise dos dados foi realizada atravÃs da estatÃstica descritiva utilizando o programa computacional Excel. Os resultados mostraram que na pista de asfalto os valores mÃdios de patinagem foram de 2,4 a 4,9%, 1,9 a 3,9% e de 1,5 a 3,0%, respectivamente, na 1Â, 2 e 3 marcha, os valores mÃdios de consumo horÃrio de combustÃvel foram de 2,6 L.h-1 (1 marcha), 2,8 L.h-1 (2 marcha) e de 3,1 L.h-1 (3 marcha), o consumo especÃfico de combustÃvel foi de 1150,4 a 1374,0 g.kW-1.h-1 (1 marcha), 1057,7 a 1261,7 g.kW-1.h-1 (2 marcha) e de 948,2 a 1108,3 g.kW-1.h-1 (3 marcha), a potÃncia foi de 0,9 a 1,1 kW, 1,1 a 1,3 kW e de 1,3 a 1,5 kW, respectivamente, na 1Â, 2 e 3 marcha e a velocidade de deslocamento foi de 1,3 a 1,2 km.h-1 (1 marcha), 1,5 a 1,3 km.h-1 (2 marcha) e de 1,7 a 1,6 km.h-1 (3 marcha). O solo firme apresentou Ãndices de patinagem de 5,9 a 9,9%, 5,0 a 8,6% e de 4,3 a 7,9%, respectivamente, na 1Â, 2 e 3 marcha, os valores mÃdios de consumo horÃrio de combustÃvel foram de 3,3 L.h-1 (1 marcha), 3,4 L.h-1 (2 marcha) e de 3,5 L.h-1 (3 marcha), o consumo especÃfico de combustÃvel foi de 1092,3 a 1130,8 g.kW-1.h-1 (1 marcha), 1012,4 a 1025,4 g.kW-1.h-1 (2 marcha) e de 948,7 a 948,2 g.kW-1.h-1 (3 marcha), a potÃncia foi de 1,3 a 1,5 kW, 1,5 a 1,7 kW e de 1,7 a 1,9 kW, respectivamente, na 1Â, 2 e 3 marcha e a velocidade de deslocamento foi de 1,2 a 1,1 km.h-1 (1 marcha), 1,3 a 1,3 km.h-1 (2 marcha) e de 1,5 a 1,4 km.h-1 (3 marcha). No solo mobilizado os valores mÃdios de patinagem foram de 11,9 a 16,9%, 11,2 a 15,5% e de 16,6 a 14,0%, respectivamente, na 1Â, 2 e 3 marcha, os valores mÃdios de consumo horÃrio de combustÃvel foram de 4,3 L.h-1 (1 marcha), 4,9 L.h-1 (2 marcha) e de 5,4 L.h-1 (3 marcha), o consumo especÃfico de combustÃvel foi de 1055 a 1198,8 g.kW-1.h-1 (1 marcha), 1020,1 a 1161,3 g.kW-1.h-1 (2 marcha) e de 993,8 a 1125,3 g.kW-1.h-1 (3 marcha), a potÃncia foi de 1,6 a 2,0 kW, 2,2 a 2,3 kW e de 2,3 a 2,6 kW respectivamente, na 1Â, 2 e 3 marcha e a velocidade de deslocamento foi de 1,2 a 1,0 km.h-1 (1 marcha), 1,3 a 1,1 km.h-1 (2 marcha) e de 1,4 a 1,1 km.h-1 (3 marcha). O solo mobilizado apresentou os maiores valores para a patinagem, consumo horÃrio de combustÃvel, forÃa de traÃÃo e potÃncia disponÃvel na barra quando comparado com o solo firme e a pista de asfalto. O nÃvel de ruÃdo medido com o microtrator parado prÃximo ao ouvido do operador foi elevado quando se utiliza rotaÃÃes maiores, diminuindo com o aumento do raio de afastamento.

This thesis addresses a research study predicated on practice in order to explore aspects of participation in Performance Art. The study makes a contribution to knowledge in participative performance practice and the positive deployment of using interruptive processes; this is in order to provoke participation within the context of Performance Art as well as gain a better understanding of the operations of power relations at play. Within the discourse of impoliteness study (Bousfield, 2008; Culpeper, 2011 et al.), there is a term that deserves much greater attention: interruption . Examining interruption and exploiting its virtues using practice brings out some productive insights that go beyond abstract theorisation. Working in response to Nicolas Bourriaud s conception (1998) of participation in Relational Aesthetics as a means of attacking power relations, I use my practice as an artist/performance provocateur and amplify consideration of my previous usage of interruption in order to provoke participation and then interrogation of power relations. Slapstick and heckling as extreme versions of interruptive processes that are physical in nature are put forward as tactics of interruption that extend comedy tactics within my practice. Circumventing commentary of interruption that often posits the term and its affiliation with impoliteness and capacity to be disruptive as negative (Bilmes, 1997), interruption is used for the purposes of my study as the key strategy that underpins the performance Lost for Words (2011) and the collaborative project Contract with a Heckler (2013), and are presented as prime examples of the operations of interruption in practice. Lost for Words supports the difficulties of participation when interruptive processes connected to physical and bodily slapstick are structurally engineered into a live performance and Contract with a Heckler supports power relations when live performance is predicated upon physical and linguistic interruptive processes relating to heckling. Both Lost for Words and Contract with a Heckler demonstrate a complex knitting of theory and practice whereby argument is supported by the undertaking of action (by the necessity of experiencing interruption in practice). The written dimension of the thesis operates in conjunction with the accompanying photographs and video recordings included here as documentation serving to deconstruct the examples of practice presented. Writing adds detail in the form of critical analysis, reflective commentary and personal experience to the supplied documentation and is used as a tool to communicate that working with interruption on a theoretical, practical and emotional level can be exciting, provocative and dangerous.

Le but de ce travail de thèse est d'identifier les mécanismes moléculaires mis en jeu lors du frottement de polymères liquides sur une paroi solide.Dans une première partie, nous avons étudié l'influence de la température T sur le glissement de fondus. Grâce à la technique de vélocimétrie par photoblanchiment, nous avons mesuré la longueur de glissement de PDMS pour plusieurs températures et vérifié l'hypothèse de Navier, qui permet de définir le coefficient de frottement interfacial k comme le rapport entre la viscosité et la longueur de glissement. Loin de la température de transition vitreuse, k augmente exponentiellement avec 1/T, tendance que nous avons vérifiée par une mesure indépendante pour des lentilles de PDMS réticulé. Ainsi, le mécanisme de frottement d'un fondu de polymère est un processus thermiquement activé. La comparaison des énergies d'activation du frottement et de la viscosité prédit le sens de variation de la longueur de glissement avec la température.Le second volet de notre travail s'est focalisé sur l'identification des mécanismes moléculaires du frottement de solutions semi-diluées de polymère. Les expériences de glissement pour des solutions de PS dans le DEP nous ont permis de mettre en évidence un régime transitoire de glissement des solutions, correspondant à une mise en glissement du fluide. Nous avons proposé un modèle de glissement d'un fluide de Maxwell en accord quantitatif avec les expériences.Dans le régime de glissement stationnaire, nous avons étudié l'influence de la fraction volumique φ en polymère sur le frottement des solutions. En régime newtonien, la loi d'échelle mesurée pour k φ en fonction de la fraction volumique met en évidence la dépendance du coefficient de frottement interfacial avec l'écart à la température de transition vitreuse des solutions. Nous attribuons le frottement des solutions de PS dans le DEP au frottement des blobs sur la paroi et non à la formation d'une couche déplétée en polymère.Enfin des expériences de réflectivité de neutrons nous ont permis d'observer directement l'interface solide / solution de polymère. Nous avons mis en évidence l'existence d'une couche adsorbée en polymère. Nous avons mesuré son profil de concentration en fonction de la distance à la paroi. L'interdigitation des chaînes libres et de surface affecte le glissement des solutions. / The aim of this work is to identify the molecular mechanisms driving the friction of liquid polymers on a solid substrate.First, we studied the effect of the temperature T on the slippage properties of PDMS melts. Using a velocimetry technique based on photobleaching, we measured the temperature dependence of the slip length of PDMS and checked the validity of Navier’s hypothesis, which defines the friction coefficient k as the ratio between the bulk viscosity to the slip length. Far above the glass transition temperature, k(T) increases exponentially with 1/T, a result that we confirmed with an independent measurement of k for the friction of crosslinked PDMS lenses. The friction mechanism of melts is a thermally activated process. The comparison of the activation energies for the friction and for the viscosity allows one to predict if the slip length increases or deacreases with temperature.We then focused our work on the identification of the friction mechanisms of semi diluted polymer solutions. Based on slip experiments of PS in DEP solutions, we evidenced a transient onset of slippage regime. Considering the viscoelasticity of the fluid and its friction properties, we developed a mechanical model of friction of a Maxwell-like fluid that well describes our experimental data.In the stationary slippage regime, we studied the influence of the polymer volume fraction φ on the slippage of solutions of polymer. In the Newtonian regime, the measured scaling law for k φ as a function of the volume fraction highlights the dependence of the friction coefficient on the distance to the glass transition temperature of the solution. Thus, the friction of the PS in DEP solutions can be attributed to the friction of blobs on the surface, rather than to the existence of a depletion layer.We directly observed the solid / polymer solution interface thanks to neutron reflectivity: these experiments reveal the formation of an adsorbed polymer layer and we could measure its concentration profile close to the solid wall. The interdigitation between volume and surface polymer chains plays a key role in the slippage of the solutions.

Melanoma, a malignant neoplasm of melanocytes, is the most lethal form of skin cancer. A majority of melanomas are driven by activating mutations in the kinase BRAF, which drives cellular proliferation through constitutive stimulation of the mitogen-activated protein kinase (MAPK) signaling pathway. Intriguingly, expression of oncogenic BRAF alone in vivo is insufficient to promote melanoma; rather, its expression leads to the development of benign nevi (moles) comprised of growth-arrested melanocytes. The acquisition of additional genetic or epigenetic changes is therefore critical for melanocytes to evade arrest and drive melanomagenesis, however the identity of these changes remains incompletely understood. Here we demonstrate that expression of oncogenic BRAF leads to activation of the Hippo tumor suppressor pathway in vitro, which acts to limit melanocyte proliferation through the inhibition of the pro-growth transcriptional co-activators YAP and TAZ. Melanocyte-specific inactivation of Hippo signaling in vivo, via deletion of the Hippo kinases Lats1/2 alone, or in conjunction with oncogenic Braf expression, potently induces melanoma development in mice. Collectively, our data reveal that the Hippo tumor suppressor pathway represents an important barrier to melanoma development, and implicates YAP and TAZ as new therapeutic targets for the treatment of human melanoma.

Cellular senescence is a permanent cell cycle arrest that is induced as a response to cellular stress. Replicative senescence is a well-described mechanism that limits the replicative capacity of cells and must be overcome by cancer cells. Oncogene-induced senescence (OIS) is a form of premature senescence and a potent tumor suppressor mechanism. OIS is induced in normal cells as a result of deregulated oncogene or tumor suppressor gene expression. An exciting area of research is the identification of novel targets that induce senescence in cancer cells as a therapeutic approach. In this study, a novel mechanism is described where the inhibition of Hsp90 in small cell lung cancer (SCLC) cells induced premature senescence rather than cell death. The senescence induced following Hsp90 inhibition was p21-dependent and the loss of p21 allowed SCLC cells to bypass the induction of senescence. Additionally, we identified a novel mechanism where the depletion of PKCι induced senescence in glioblastoma multiforme (GBM) cells. PKCι depletion-induced senescence did not activate the DNA-damage response pathway and was p21-dependent. Further perturbations of mitosis, using an aurora kinase inhibitor, increased the number of senescent cells when combined with PKCι depletion. This suggests that PKCι depletion-induced senescence involves defects in mitotic progression. Senescent glioblastoma cells at a basal level of senescence in culture, induced by p21 overexpression, and induced after PKCι depletion had aberrant centrosomes. Mitotic slippage is an early exit from mitosis without cell division that occurs when the spindle assembly checkpoint (SAC) is not satisfied. Senescent glioblastoma cells had multiple markers of mitotic slippage. Therefore, PKCι depletion-induced senescence involves mitotic slippage and results in aberrant centrosomes. A U87MG cell line with a doxycycline-inducible shRNA targeting PKCι was developed to deplete PKCι in established xenografts. PKCι was depleted in established glioblastoma xenografts in mice and resulted in decreased cell proliferation, delayed tumor growth and improved survival. This study has demonstrated that both Hsp90 and PKCι are novel targets to induce senescence in cancer cells as a potential therapeutic approach.

Tandem amino acid repeats, also known as homopolimeric tract or homopeptides, are very common features of eukaryotic genomes and are present in nearly one-fifth of human encoded proteins. These structures have attracted much interest in the early 1990s when a number of neurological diseases associated with repeat expansion mutations were discovered in humans. Despite their abundance in coding proteins, little is known about their functional consequences. Two scenarios have been proposed. In one, tandem amino acid repeat is considered a neutral structure generated by slippage event and eventually tolerated in protein as long as it does not disrupt the protein function. However, an increasing number of studies proposed that tandem amino acid repeats may be involved in important functional or structural roles. For instance, tandem amino acid repeats had been found to be especially abundant in transcription factors and developmental proteins, where they can potentially modulate protein-protein interaction, exert an effect on gene transcriptional activity, or act as spacer between different protein domains. In addition, several studies have linked changes in repeat size to modification in developmental processes. Despite the advancement made in the last decade, little is known about the selective forces that shape their evolution. The aim of this thesis has been to gain further insight onto the evolutionary dynamics of tandem amino acid repeats by studying the different types of mutations that occur in the amino acid component of the human proteome, by studying the relationship between variability and abundance of amino acid tandem with the evolutionary constraints operating on the proteins, and by studying their conservation and distribution across various vertebrate genomes in both coding and non-coding sequences. The integration of these approaches enabled us to outline an evolutionary model of these structures.

Cellular senescence is a permanent cell cycle arrest that is induced as a response to cellular stress. Replicative senescence is a well-described mechanism that limits the replicative capacity of cells and must be overcome by cancer cells. Oncogene-induced senescence (OIS) is a form of premature senescence and a potent tumor suppressor mechanism. OIS is induced in normal cells as a result of deregulated oncogene or tumor suppressor gene expression. An exciting area of research is the identification of novel targets that induce senescence in cancer cells as a therapeutic approach. In this study, a novel mechanism is described where the inhibition of Hsp90 in small cell lung cancer (SCLC) cells induced premature senescence rather than cell death. The senescence induced following Hsp90 inhibition was p21-dependent and the loss of p21 allowed SCLC cells to bypass the induction of senescence. Additionally, we identified a novel mechanism where the depletion of PKCι induced senescence in glioblastoma multiforme (GBM) cells. PKCι depletion-induced senescence did not activate the DNA-damage response pathway and was p21-dependent. Further perturbations of mitosis, using an aurora kinase inhibitor, increased the number of senescent cells when combined with PKCι depletion. This suggests that PKCι depletion-induced senescence involves defects in mitotic progression. Senescent glioblastoma cells at a basal level of senescence in culture, induced by p21 overexpression, and induced after PKCι depletion had aberrant centrosomes. Mitotic slippage is an early exit from mitosis without cell division that occurs when the spindle assembly checkpoint (SAC) is not satisfied. Senescent glioblastoma cells had multiple markers of mitotic slippage. Therefore, PKCι depletion-induced senescence involves mitotic slippage and results in aberrant centrosomes. A U87MG cell line with a doxycycline-inducible shRNA targeting PKCι was developed to deplete PKCι in established xenografts. PKCι was depleted in established glioblastoma xenografts in mice and resulted in decreased cell proliferation, delayed tumor growth and improved survival. This study has demonstrated that both Hsp90 and PKCι are novel targets to induce senescence in cancer cells as a potential therapeutic approach.