In this dissertation, the problem of planning the motion of m Unmanned Vehicles (UVs) (or simply vehicles) through n points in a plane is considered. A motion plan for a vehicle is given by the sequence of points and the corresponding angles at which each point must be visited by the vehicle. We require that each vehicle return to the same initial location(depot) at the same heading after visiting the points. The objective of the motion planning problem is to choose at most q(≤ m) UVs and find their motion plans so that all the points are visited and the total cost of the tours of the chosen vehicles is a minimum amongst all the possible choices of vehicles and their tours. This problem is a generalization of the wellknown Traveling Salesman Problem (TSP) in many ways: (1) each UV takes the role of salesman (2) motion constraints of the UVs play an important role in determining the cost of travel between any two locations; in fact, the cost of the travel between any two locations depends on direction of travel along with the heading at the origin and destination, and (3) there is an additional combinatorial complexity stemming from the need to partition the points to be visited by each UV and the set of UVs that must be employed by the mission. In this dissertation, a sub-optimal, two-step approach to motion planning is presented to solve this problem:(1) the combinatorial problem of choosing the vehicles and their associated tours is based on Euclidean distances between points and (2) once the sequence of points to be visited is specified, the heading at each point is determined based on a Dynamic Programming scheme. The solution to the first step is based on a generalization of Held-Karp’s method. We modify the Lagrangian heuristics for finding a close sub-optimal solution. In the later chapters of the dissertation, we relax the assumption that all vehicles are homogenous. The motivation of heterogenous variant of Multi-depot, Multiple Traveling Salesmen Problem (MDMTSP) derives form applications involving Unmanned Aerial Vehicles (UAVs) or ground robots requiring multiple vehicles with different capabilities to visit a set of locations.

This study focuses on two types of routing problems based on standard Traveling Salesman Problem, which are TSP with pickup and delivery (TSPPD) and TSP with backhauls (TSPB). In both of these problems, there are two types of customers, i.e. &ldquo / delivery customers&rdquo / demanding goods from depot and &ldquo / pickup customers&rdquo / sending goods to depot. The objective is to minimize the cost of the tour that visits every customer once without violating the side constraints. In TSPB, delivery customers should precede the pickup customers, whereas the vehicle capacity should not be exceeded in TSPPD. The aim of the study is to propose good Evolutionary Algorithms (EA) for these two problems and also analyze the adaptability of an EA, originally designed for the standard TSP, to the problems with side constraints. This effort includes commenting on the importance of feasibility of the solutions in the population with respect to these side constraints. Having this in mind, different EA strategies involving feasible or infeasible solutions are designed. These strategies are compared by quantitative experiments realized over a set of problem instances and the results are given.

Submitted by Ana Maria Fiscina Sampaio (fiscina@bahia.fiocruz.br) on 2014-05-22T14:08:18Z No. of bitstreams: 1 Raimundo Coutinho Junior. Perfil de ativação... 2014 .pdf: 1722380 bytes, checksum: 909bc68a97d8e0a06206d205cd3557f7 (MD5) / Made available in DSpace on 2014-05-22T14:08:18Z (GMT). No. of bitstreams: 1 Raimundo Coutinho Junior. Perfil de ativação... 2014 .pdf: 1722380 bytes, checksum: 909bc68a97d8e0a06206d205cd3557f7 (MD5) Previous issue date: 2013 / Fundação Oswaldo Cruz. Centro de Pesquisa Gonçalo Moniz. Salvador, BA, Brasil / O vírus linfotrópico das células T humanas do tipo 1 (HTLV-1) é o agente etiológico da mielopatia associada ao HTLV / paraparesia espástica tropical (HAM / TSP ), que ocorre em menos de 5 % dos indivíduos infectados. A resposta imune controla parcialmente a infecção, porém pode estar ligada a patogênese da doença. O objetivo deste estudo foi caracterizar fenotipicamente as subpopulações de linfócitos T, em pacientes assintomáticos e com diagnóstico de HAM/TSP. Foram avaliados 103 pacientes acompanhados no Centro de HTLV da Escola Bahiana de Medicina e Saúde Pública (EBMSP) e 19 controles não infectados. Os pacientes foram categorizados de acordo com o grau de certeza do diagnóstico de HAM/TSP: possível (Ps), provável (Pb) e definido (D), além de pacientes assintomáticos (ASS). O perfil fenotípico (CD25, CD45RA, CD45RO, HLA-DR, CD25, CCR-7, CD62L) das subpopulações de linfócitos T CD4+ e T CD8+ e a expressão da proteína Tax de FoxP3 na subpopulação T CD4+ foram avaliados por citometria de fluxo. A carga proviral do HTLV foi quantificada por reação em cadeia da polimerase (PCR) em tempo real. As proporções dos linfócitos TCD4+HLA-DR+ e TCD8+HLA-DR foram significativamente maiores nos pacientes com HAM/TSP Ps, Pb e D comparados aos controles não infectados (p=0,003). Comparando-se o grupo de infectados, as proporções de linfócitos TCD4+ e TCD8+ expressando HLA-DR foram significantemente maiores em pacientes com HAM/TSP-Ps e D comparados a pacientes assintomáticos (p<0,0001). Além disso, houve uma correlação positiva entre porcentagem de linfócitos T CD4+ HLA-DR+ e a carga proviral (r=0,5, p=0,0003). As proporções de linfócitos T CD4+CD25+ foram maiores nos pacientes com HAM/TSP D comparados aos controles não infectados. Observou-se um aumento na proporção de células reguladoras (T CD4+FOXP3+) nos indivíduos assintomáticos e nos pacientes com HAM/TSP-D comparados a indivíduos não infectados (p=0,04). A carga proviral HTLV-1 foi maior no grupo de pacientes HAM/TSP-D do que em pacientes assintomáticos (p=0,0001). Observa-se uma diferença estatística entre a proporção de células CD4+TAX+ dos indivíduos assintomáticos (0,26%) e os pacientes HAM/TSP-Ps (5,26%) (p=0,04). Em conclusão, os pacientes com HAM/TSP Ps, Pb e D apresentam um perfil fenotípico de ativação celular, comparados aos controles não infectados. Além disso, os pacientes com HAM/TSP Pb e D apresentam maior expressão de HLA-DR nas subpopulações de linfócitos T CD4+ e T CD8+, comparados aos assintomáticos, indicando um perfil imunológico semelhante nestes dois subgrupos de pacientes. / The human T-cell lymphotropic vírus type 1(HTLV-1) is the etiological agent of HTLV- associated myelopathy/ Tropical spastic paraparesis(HAM/TSP), wich occurs in less then 5% of the infected individuals. The immune response partially controls the infection, but may be linked to the pathogenesis of disease. The aim of this study was to characterize phenotipically T lymphocyte subpopulations in asymptomatic and in patients diagnosed with HAM/TSP. We evaluated 103 patients treated at the center for HTLV of Bahia School of Medicine and Public Health (EBMSP) and 19 uninfected controls. Patients were categorized as asymptomatic and according to the degree of certainty of the diagnosis of HAM/TSP: Possible(Ps), Probable(Pb) and Definite(D). The phenotypic profile (CD25, CD45RA, CD45RO, HLA-DR, CCR-7, CD62L) subpopulation of CD4+ and CD8+ T Cells and expression of the protein Tax and Foxp3 in the subpopulation CD4+ T cells were evaluated by flow cytometry. The HTLV proviral load was quantified by polymerase chain reaction (PCR) in real time. The proportions of CD4+ and CD8+ expressing HLA-DR+ were significantly higher in patients (p<0.0001). In addition there were a correlation between CD4+ HLA-DR+ or CD8+ HLA-DR+ and the proviral load(R=0,5;p<0,0001). The proportions of CD4+CD25+ were higher in patients with HAM/TSP D compared to infected controls. There was an increased proportion of regulatory cells (CD4+Foxp3+) of asymptomatic individuals and patients HAM/TSP D, compared to the uninfected individuals (p=0.04). . There is a statistical difference between the proportion of CD4+TAX+ asymptomatic individuals (0.26%) patients and HAM/TSP-Ps (5.26%) (p = 0.04 ) . In conclusion, patients with HAM/TSP Ps, Pb and D exhibit a phenotypic profile of cell activation, compared to uninfected controls. In addition, patients with HAM/TSP Pb and D show higher expression of HLA -DR in subpopulations of T lymphocytes CD4+ and CD8+ T cells, compared to asymptomatic, indicating an immunological profile similar in both groups of patients

La Bone Morphogenetic Protein-1 (BMP-1) est une métalloprotéase impliquée dans la maturation et l'activation de nombreuses molécules extracellulaires. Parmi celles-ci, on trouve notamment les collagènes fibrillaires, les protéines les plus abondante chez l'Homme, ainsi que les facteurs de croissance de la superfamille du TGF-ß, des protéines pléiotropes. Au travers de ses fonctions, BMP-1 joue un rôle crucial au cours du développement embryonnaire mais également durant les processus physiologiques et pathologiques de remodelage tissulaire (cicatrisation, fibroses, croissance osseuse, cancers...).Le projet présenté dans ce manuscrit a consisté à étudier plusieurs fonctions importantes de BMP-1 au niveau moléculaire et à caractériser les conséquences de ces activités au niveau de plusieurs types cellulaires.Dans un premier temps, un test quantitatif a été mis au point afin de pouvoir étudier en temps réel l'effet de BMP-1 sur les collagènes fibrillaires ainsi que les mécanismes de sa régulation. Par la suite, de nouveaux substrats de BMP-1 ont été mis en évidence, parmi lesquels des co-récepteurs du TGF-ß (Bétaglycan, CD109) ainsi qu'une protéine matricellulaire (TSP-1). L'étude de ces activités a permis de caractériser les multiples voies par lesquelles BMP-1 est capable de réguler l'activité du facteur de croissance TGF-ß.De plus, nous avons mis en évidence que le clivage de ces différents substrats entraine une modulation importante du phénotype de plusieurs lignées cellulaires (HT1080, HEK-293T) avec des effets au niveau de l'adhésion, la prolifération et la migration cellulaire. En conclusion, ce travail révèle que les activités de BMP-1 s'étendent bien au-delà de ce qui est actuellement décrit / Bone Morphogenetic Protein (BMP-1) is a metalloprotease known to be involved in the maturation and activation of several important extracellular proteins, including fibrillar collagens and growth factors of the TGF-beta superfamily. As a consequence, it is essential for embryonic development and tissue remodeling and has been clearly involved in lethal diseases such as fibrosis and cancer.This thesis project focused on the major molecular functions of BMP-1 and their implications for the phenotype of several cell types. First, a quantitative and real-time assay was developed to study the effect of BMP-1 and associated regulatory proteins on fibrillar collagens. Then, new BMP-1 substrates, such as TGF-ß co-receptors (Betaglycan and CD109) and matricellular proteins (TSP-1) were characterized in detail. Especially, we evidenced that these activities played a major role in the regulation of the TGF-ß pathway.Furthermore, we shown that these BMP-1 activities induce major phenotype changes (adhesion, proliferation, migration) in several cell lines including HT1080 and HEK-293T. Altogether, this work reveals that BMP-1 substrates extend far beyond what is presently described and open several perspectives for future studies

Les capillaires sanguins sont des éléments essentiels pour le maintien des fonctions du tissu adipeux comme du muscle squelettique. L’obésité induit une raréfaction capillaire intense dans ces tissus, altérant leur microenvironnement et aboutissant en définitif à des dysfonctions métaboliques systémiques. Malgré l’importance de la microcirculation adipeuse, les mécanismes moléculaires régulant la plasticité de ce réseau capillaire, processus appelé angio-adaptation, restent méconnus. L’activité physique exerce de multiples effets bénéfices chez l’obèse, stimulant notamment la croissance vasculaire dans le muscle squelettique. Dans ce tissu, la réponse angio-adaptative au cours de l’obésité et à l’exercice est sous le contrôle de l’axe Mdm2/FoxOs. Ces facteurs régulent la balance entre le signal pro-angiogénique du VEGF-A et anti-angiogénique de la TSP-1, équilibrant ainsi les processus de croissance et régression capillaire. Nous proposons l’existence d’un mécanisme de signalisation similaire, impliqué dans la régulation du processus angio-adaptatif des tissus adipeux et musculaires. Nous avons alors étudié les effets de 7 semaines d’exercice physique volontaire, chez des souris C57Bl/6 rendues obèses par un régime riche en graisses et en sucre, sur la microcirculation et le microenvironnement du tissu adipeux blanc viscéral et sous-cutané, ainsi que du brun interscapulaire. Il a été retrouvé chez les souris obèses un puissant frein angiostatique, exercé par FoxOs et conduisant à une raréfaction capillaire dans les tissus adipeux. Les 7 semaines d’exercice physique ont conduit à l’augmentation de Mdm2, la levée de ce frein et une croissance vasculaire au sein des différents tissus adipeux, associés à l’amélioration du microenvironnement adipocytaire, avec une baisse de l’hypoxie, de la fibrose et une redistribution des cellules inflammatoires. De plus, la stimulation de l’angiogenèse adipeuse chez l’obèse, via l’exercice et l’action pro-angiogénique de Mdm2, a permis d’améliorer l’insulino-sensibilité du tissu adipeux viscéral, d’activer le processus de browning au sein du tissu adipeux sous-cutané et de réduire le whitening du tissu adipeux brun. Il en résulte une amélioration de l’ensemble des paramètres cardiométaboliques systémiques. Ces données démontrent l’efficacité thérapeutique de l’exercice physique dans la lutte contre l’obésité et ses pathologies associées, mais offrent également de nouvelles perspectives de thérapies moléculaires ciblant l’angio-adaptation du tissu adipeux chez l’Homme obèse. / Blood capillaries are essential elements for maintaining adipose tissue and skeletal muscle functions. Obesity induces intense capillary rarefaction in these tissues, altering their microenvironment and ultimately resulting in systemic metabolic dysfunction. Despite the importance of adipose microcirculation, molecular mechanisms regulating adipose capillary network plasticity, a process called angio-adaptation, remains unknown. Physical exercise exerts multiple beneficial effects in obese patient, including skeletal muscle vascular growth stimulation. In this tissue, angio-adaptive response during obesity and exercise is under the control of the Mdm2/FoxOs axis. These factors regulate harmonization between VEGF-A pro-angiogenic signal and TSP-1 anti-angiogenic, thus balancing growth and capillary regression processes. We made the hypothesis of the existence of a similar signaling mechanism, involved in the angio-adaptive process regulation of adipose and muscular tissues. Therefore, we studied the effects of 7 weeks-voluntary physical exercise in C57Bl/6 obese mice induced by a diet rich in fats and sugar, on microcirculation and microenvironment of visceral and subcutaneous white adipose tissue, as well as interscapular brown adipose tissue. Obese mice presented a powerful angiostatic control in all adipose tissues, under FoxOs protein regulation, leading to capillary rarefaction. Physical exercise led to the increase of Mdm2 expression, repressing the angiostatic control in favor of adipose vascular regrowth. This phenomenon was also associated with adipocytes microenvironment improvement, a decrease in hypoxia, fibrosis and redistribution of inflammatory cells. In addition, adipose angiogenesis stimulation in obese mice, through exercise and the Mdm2 pro-angiogenic action, improved visceral adipose tissue insulin sensitivity, activated browning process within subcutaneous adipose tissue and reducing whitening of brown adipose tissue. The overall result is an improvement of all systemic cardiometabolic parameters. These data demonstrate the therapeutic efficacy of physical exercise against obesity and its associated pathologies, but also offer new prospects for molecular therapies targeting the adipose angio-adaptation in obese humans.

Malgré la multiplicité des études démontrant le comportement fascinant des animaux dans leur milieu naturel, quelques domaines de recherches demeurent difficiles à aborder. Ainsi, l’étude de certains aspects cognitifs nécessite un certain contrôle sur l’environnement afin de dissocier les influences écologiques et sociales de l’implication cognitive ; par exemple la cognition spatiale incluant la mémoire spatiale, les mécanismes d’orientation spatiale, ainsi que leur implication dans la navigation, tel que par la planification. L’étude de la cognition spatiale des chimpanzés sauvages s’est déroulée dans le Parc national de Taï, une forêt tropicale dense où les ressources potentielles sont abondantes et réparties sur un territoire de 25 km², avec une visibilité d’environ 30 mètres. De plus, les chimpanzés vivent dans une société du type fission-fusion, impliquant de multiples relations sociales. Toutefois, l’enregistrement précis de la position et des activités des chimpanzés, ainsi qu’une carte botanique précise, nous a permis de dissocier les effets écologiques, sociaux et cognitifs afin de mieux comprendre les relations entre ces différents facteurs. Par cette étude, nous montrons que les chimpanzés ont développé un mécanisme permettant une navigation précise grâce à une carte Euclidienne contenant des informations sur la direction et la distances vers des ressources connues. Ce mécanisme est extrêmement adapté et efficace par la connaissance précise de la localisation de milliers de ressources dans leur habitat. Ces capacités permettent d’augmenter leur efficacité en sélectionnant les ressources les plus productives, en les planifiant à l’avance et, de manière plus avancée, en planifiant le parcours le plus court à travers ces différentes ressources durant la journée lorsque la pression sociale requière une meilleure précision dans le choix des ressources. Ces découvertes illustrent d’abord les capacités extraordinaires des chimpanzés, et deuxièmement que les aspects cognitifs peuvent être expliqués dans le milieu naturel des animaux. / Whereas numerous studies demonstrated fascinating behaviour of animals in their natural habitat, some important areas of research were difficult to tackle in the field. This is the case of many studies on cognitive aspects that required controlled environment to dissociate ecological and social influence from cognition. One of these important areas of research is the spatial cognition including spatial memory, spatial orientation mechanisms and the practical use of these abilities to travel efficiently, such as planning skills. This study on spatial cognition in wild chimpanzees took place in Taï National Park, a tropical dense forest where potential food resources are highly abundant in their 25 km² territory, and the visibility is approximately 30 meters. Adding to this complexity, chimpanzees live in a fission-fusion society, maintaining relationships with each other. Nevertheless, with a precise recording of chimpanzee’s location and activities and a precise botanic map of the territory, we were able to dissociate the ecological, social and cognitive effects and understand some relationships between these factors. Here, we showed that wild chimpanzees developed a precise mechanism to navigate efficiently in their large area using a Euclidean map containing accurate information about direction and distance to the known resources. This mechanism is highly adapted and efficient as the chimpanzees have a precise knowledge of the resources location in their area, remembering the location of thousand trees location. These highly developed abilities allowed them to increase their efficiency by selecting the most productive resources, planning them in advanced and on a higher level to plan the shortest path through these major resources during the day when the social pressure induce a higher precision in resource selection. These findings highlight first the outstanding spatial abilities of wild chimpanzees and second that cognition can be better explained in animals’ natural complex environment. / Trotz zahlreicher Studien, die das faszinierende Verhalten von Wildtieren in ihrer natürlichen Umwelt dokumentieren, bleiben einige Studienfelder schwer erfassbar. So ist zum Beispiel bei der Erforschung von bestimmten kognitiven Aspekten die Rücksichtnahme auf den Umweltfaktor erforderlich, damit Umwelt- und Sozialeinfluss von den kognitiven Faktoren unterschieden werden können. Zu diesen Untersuchungsfeldern gehört die Raumkognition, welche das Raumgedächtnis, die Mechanismen der Raumorientierung sowie deren effizientes Nutzen durch die Schimpansen, z.B. durch ihre Fähigkeit zum Planen, einschließt. Die vorgestellte Studie über Raumkognition bei wild lebenden Schimpansen wurde im Nationalpark von Tai durchgeführt, das heißt, in einem dichten tropischen Wald, wo potentielle Ressourcen bei einer Sichtweite von ungefähr 30 Metern auf einem 25 qm großen Areal reichlich verteilt sind. Hinzu kommt, dass Schimpansen in einer Fission-Fusion Gesellschaftsstruktur leben, die vielfache soziale Beziehungen fördern. Jedoch, mit einer genauen Registrierung der räumlichen Lage und der Aktivitäten der Schimpansen und anhand einer präzisen botanischen Karte des Gebiets, konnten wir die Umwelt-, Sozial- und kognitiven Effekte gegeneinander abgrenzen und somit die zwischen diesen unterschiedlichen Faktoren bestehenden Beziehungen erfassen. In dieser Studie zeigen wir, dass Schimpansen einen besonderen Mechanismus zur Raumorientierung auf ihrem Gebiet entwickelt haben. Dabei verfügen sie über eine euklidische Mind-Karte mit präzisen Informationen über Richtungen und Entfernungen zu den bekannten Ressourcen. Durch ein genaues Wissen über die Verteilung der Nahrungsressourcen auf ihrem Gebiet ist dieser Mechanismus hoch effizient. Dank dieser Fähigkeiten werden Schimpansen immer effizienter, indem sie die ergiebigsten Ressourcen auswählen, dabei planende Fähigkeiten einsetzen und weiterhin indem sie an einem Tag die kürzeste Strecke zu den verschiedenen Ressourcen ausmachen, wenn der soziale Druck höchste Präzision in der Wahl der Nahrungsressourcen erfordert. Diese Erkenntnisse erhellen zuallererst die außergewöhnlichen Fähigkeiten der wild lebenden Schimpansen und beweisen, dass sich kognitive Mechanismen bei wild lebenden Tieren in ihrer natürlichen Umwelt besser erklären lassen.

Na cidade de São Paulo, cerca de 50 mil pessoas são portadoras do HTLV-1. O HTLV-1 é o agente causador da paraparesia espástica tropical/mielopatia associada com o HTLV-1 (TSP/HAM) e os mecanismos desta patogênese são obscuros. A TSP/HAM é considerada uma doença imuno-mediada e algumas citocinas, podem estar associadas, com a desmielinização da membrana de mielina da coluna espinhal, provavelmente, estimuladas pela presença de antígenos virais. A PCR em tempo real é uma técnica utilizada para a detecção de citocinas e apresenta maior sensibilidade na expressão de mRNA e carga proviral do HTLV-1. Objetivos: Detecção de citocinas pelas técnicas sorológicas e de biologia molecular (PCR em tempo real) que auxiliaram no aconselhamento e avaliação de pacientes infectados pelo HTLV-1, além de uma avaliação da carga proviral dos pacientes com infecção pelo HTLV-1. Casuística: Grupo I: indivíduos soronegativos para HCV, HIV-1 e HTLV-1 (Controle); Grupo II: pacientes HTLV-1 assintomáticos; Grupo III: pacientes com TSP/HAM. Observamos que o INF-<font face=\"symbol\">g apresenta-se alterado na infecção HTLV-1, sendo um dos fatores mais importantes da evolução para TSP/HAM, ambos os ensaios apresentaram o mesmo resultado. A carga proviral pode ser um marcador de progressão para a TSP/HAM. A interação complexa existente entre o HTLV-1 e as células responsáveis pela liberação de citocinas e <font face=\"symbol\">b-quimiocinas pró-inflamatórias, assim como elementos de ativação celular, resultam na ativação imunológica. Isto, lentamente, pode levar ao processo inflamatório crônico que atua diretamente no micro ambiente neuronal e/ou membrana de mielina da coluna espinhal, em alguns portadores de HTLV-1. Com a persistente ativação do sistema imunológico, este processo provocará destruição das células gliais e dos neurônios, dando início ao processo de desmielinização. / In São Paulo, about 50 thousand people are HTLV-1 carriers. HTLV-1 is the agent that causes tropical spastic paraparesis and HTLV-1 associated myelopathy (TSP/HAM) despite the mechanisms of this disease are still unclear. TSP/HAM is considered an immune mediated illness and some cytokines might be involved with axonal damage and demyelination, most pronounced in the midthoracic spinal cord, probably stimulated by the presence of viral antigens. Real Time PCR is a used technique to cytokine detection and shows higher sensitivity on mRNA expression and HTLV-1 proviral load. Objectives: cytokine detection through molecular biology (Real time PCR) and serologic techniques that helped on advising and assessment of HTLV-1 infected patients and also on their proviral load. Casuistic: Group I: seronegative individuals for HCV, HIV-1 and HTLV-1 (control); Group II: asymptomatic HTLV-1 infected patients; Group III: TSP/HAM patients. We\'ve been observed that <font face=\"symbol\">g-interferon presents changing on the HTLV-1 infection, being one of the most important factors to TSP/HAM progression, both essays showed the same results. The proviral load may be an important marker for TSP/HAM development.

Na cidade de São Paulo, cerca de 50 mil pessoas são portadoras do HTLV-1. O HTLV-1 é o agente causador da paraparesia espástica tropical/mielopatia associada com o HTLV-1 (TSP/HAM) e os mecanismos desta patogênese são obscuros. A TSP/HAM é considerada uma doença imuno-mediada e algumas citocinas, podem estar associadas, com a desmielinização da membrana de mielina da coluna espinhal, provavelmente, estimuladas pela presença de antígenos virais. A PCR em tempo real é uma técnica utilizada para a detecção de citocinas e apresenta maior sensibilidade na expressão de mRNA e carga proviral do HTLV-1. Objetivos: Detecção de citocinas pelas técnicas sorológicas e de biologia molecular (PCR em tempo real) que auxiliaram no aconselhamento e avaliação de pacientes infectados pelo HTLV-1, além de uma avaliação da carga proviral dos pacientes com infecção pelo HTLV-1. Casuística: Grupo I: indivíduos soronegativos para HCV, HIV-1 e HTLV-1 (Controle); Grupo II: pacientes HTLV-1 assintomáticos; Grupo III: pacientes com TSP/HAM. Observamos que o INF-<font face=\"symbol\">g apresenta-se alterado na infecção HTLV-1, sendo um dos fatores mais importantes da evolução para TSP/HAM, ambos os ensaios apresentaram o mesmo resultado. A carga proviral pode ser um marcador de progressão para a TSP/HAM. A interação complexa existente entre o HTLV-1 e as células responsáveis pela liberação de citocinas e <font face=\"symbol\">b-quimiocinas pró-inflamatórias, assim como elementos de ativação celular, resultam na ativação imunológica. Isto, lentamente, pode levar ao processo inflamatório crônico que atua diretamente no micro ambiente neuronal e/ou membrana de mielina da coluna espinhal, em alguns portadores de HTLV-1. Com a persistente ativação do sistema imunológico, este processo provocará destruição das células gliais e dos neurônios, dando início ao processo de desmielinização. / In São Paulo, about 50 thousand people are HTLV-1 carriers. HTLV-1 is the agent that causes tropical spastic paraparesis and HTLV-1 associated myelopathy (TSP/HAM) despite the mechanisms of this disease are still unclear. TSP/HAM is considered an immune mediated illness and some cytokines might be involved with axonal damage and demyelination, most pronounced in the midthoracic spinal cord, probably stimulated by the presence of viral antigens. Real Time PCR is a used technique to cytokine detection and shows higher sensitivity on mRNA expression and HTLV-1 proviral load. Objectives: cytokine detection through molecular biology (Real time PCR) and serologic techniques that helped on advising and assessment of HTLV-1 infected patients and also on their proviral load. Casuistic: Group I: seronegative individuals for HCV, HIV-1 and HTLV-1 (control); Group II: asymptomatic HTLV-1 infected patients; Group III: TSP/HAM patients. We\'ve been observed that <font face=\"symbol\">g-interferon presents changing on the HTLV-1 infection, being one of the most important factors to TSP/HAM progression, both essays showed the same results. The proviral load may be an important marker for TSP/HAM development.

Submitted by Renata Lopes (renatasil82@gmail.com) on 2017-04-25T14:57:44Z No. of bitstreams: 1 thainansantostheodoro.pdf: 6277443 bytes, checksum: 64fdae570574b42d13c86c42cedaca9e (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2017-04-25T15:29:25Z (GMT) No. of bitstreams: 1 thainansantostheodoro.pdf: 6277443 bytes, checksum: 64fdae570574b42d13c86c42cedaca9e (MD5) / Made available in DSpace on 2017-04-25T15:29:25Z (GMT). No. of bitstreams: 1 thainansantostheodoro.pdf: 6277443 bytes, checksum: 64fdae570574b42d13c86c42cedaca9e (MD5) Previous issue date: 2016-09-05 / Esta dissertação apresenta uma técnica de simulação híbrida no domínio do tempo de programas de transitórios eletromecânicos e eletromagnéticos usando o MatLab/ Simulink, a qual confere eficiência computacional e precisão, tanto na análise de sistemas de potência, quanto de controle, sobretudo em situações nas quais fenômenos eletromagnéticos e eletromecânicos se sobrepõe, como é o caso da integração de grandes parques eólicos. Para que ocorra a interação entre os dois programas é necessário a adequação das grandezas de fasores para formas de onda e vice versa, assim, é apresentada uma nova abordagem de extração de fasores instantâneos a partir do DSOGI com boa eficiência computacional com perda desprezível de informações. A comunicação regular entre os programas é feita através do protocolo de comunicação baseado na plataforma TCP/IP, que possibilita a representação de modelos distribuídos e a divisão do esforço computacional. São apresentados resultados de simulação para a integração de um parque eólico, representado por um aerogerador DFIG, à uma rede de 29 barras e 7 geradores. Todo o sistema foi representado em um programa de transitórios eletromagnéticos para comparação com os resultados do programa híbrido. Os resultados se mostraram encorajadores já que houve diminuição de quase 70% do tempo de processamento. / This dissertation presents a hybrid simulation technique in the time domain of electromechanical and electromagnetic transient programs using the MatLab/Simulink, which confers computational efficiency and precision, in both power system and control analysis, mainly in situations where electromagnetic and electromechanical phenomena overlap, such as the integration of large wind farms. In order to guarantee the interaction between the two programs it is necessary to adapt the phasor magnitudes to waveforms and vice versa, thus, a new approach is presented for the extraction of instantaneous phasors using the DSOGI approach, with good computational efficiency and negligible loss of information. The regular communication between the programs is done through the communication protocol based on the TCP/IP platform, which allows the representation of distributed models and enables the division of computational effortt between computers. Simulation results are presented for the integration of a wind farm, represented by a DFIG, to a network of 29 bars and 7 generators. The entire system was represented in an electromagnetic transient program for comparison with the results of the hybrid program. The results were encouraging since there was a decrease of almost 70 % of the processing time.

Abstract Ovarian cancer is the leading cause of death from gynaecological cancers in the Western world. Ovarian cancer comprises of tumours with distinct behaviour and individually different responses to chemotherapy, even within the same histology. Unfortunately, there are no molecular markers in clinical use to either distinguish between patients with better and worse prognosis or to predict individual chemosensitivity. The comprehension of the molecular effects of chemotherapeutic drugs is a prerequisite for finding predictive molecular factors for chemoresponse and prognosis. Some proteins in molecular pathways contributing to DNA damage response, angiogenesis and oxidative stress have been implicated in ovarian cancer prognosis. In this study, the responses in p53 pathway and among angiogenesis-related factors to chemotherapeutic drugs were analysed in ovarian cancer cell lines. In OVCAR-3 cells with mutated p53, cisplatin but not docetaxel induced p14ARF, an important regulator of p53, at mRNA and protein level. Cisplatin also significantly increased the mRNA expression of angiogenesis-related factors TSP-1, BMP-4, ET-1 and PlGF-2 while an equivalent dose of docetaxel had only minor effects. In clinical ovarian carcinomas, the expression of BMP-4, TSP-1 and CD105 as well as the marker of oxidative stress derived DNA damage, 8-OHdG, and peroxiredoxin antioxidants were analysed by immunohistochemistry. High expression of BMP-4 and cytoplasmic peroxiredoxin IV were associated with better prognosis, while high 8-OHdG expression associated with shorter survival. Explant cultures of fresh ovarian tumour tissue were used for the evaluation of individual responses of p53 and Hdm2 after in vitro treatments of the explant cultures by carboplatin or docetaxel. Major differences between the individual tumours were found, especially in the responses of p53 to carboplatin. The results of this study suggest, that BMP-4, 8-OHdG and peroxiredoxin IV may serve as prognostic markers in ovarian cancer. The differences shown in the molecular responses to platinum and taxane drugs may have value in tailoring individual chemotherapy. Also, fresh ovarian cancer tissue explant culture is worth further studies as a predictive method for analysing individual tumour responses for chemotherapeutic agents. / Tiivistelmä Munasarjasyöpä on suurinta kuolleisuutta aiheuttava gynekologinen syöpä läntisessä maailmassa. Munasarjakasvaimet eroavat toisistaan niin käyttäytymiseltään kuin yksilölliseltä sytostaattihoitovasteeltaan, jopa sama histologisen tyypin sisällä. Kliinisessä käytössä ei valitettavasti ole sellaisia molekulaarisia merkkiaineita, jotka erottaisivat toisistaan paremman ja huonomman ennusteen kasvaimet tai ennustaisivat yksilöllistä solunsalpaajaherkkyyttä. Hoitovastetta ja potilaan prognoosia ennustavien merkkiaineiden löytämisen edellytys on kemoterapian molekyylitason vaikutusten ymmärtäminen. DNA vaurion tunnistamiseen, angiogeneesiin ja oksidatiiviseen stressiin liittyvien vaikutusreittien joillakin proteiineilla on ehdotettu olevan ennusteellista merkitystä munasarjasyövässä. Tässä väitöskirjatyössä analysoitiin munasarjasyöpäsoluja käyttäen p53 vaikutusreitin ja eräiden angiogeneesiin liittyvien tekijöiden vasteita sytostaateille. Mutatoitunutta p53 proteiinia kantavissa OVCAR-3 soluissa sisplatiini, toisin kuin dosetakseli, indusoi p53 proteiinin tärkeää säätelijää, p14ARF:a sekä mRNA- että proteiinitasolla. Sisplatiini lisäsi merkittävästi myös usean angiogeneesiin liittyvän tekijän (TSP-1, BMP-4, ET-1 ja PlGF-2) mRNA:ta. Dosetakselin vaikutukset vastaavalla annoksella olivat vähäiset. Kliinisissä munasarjasyövissä BMP-4, TSP-1 ja CD105 sekä oksidatiivisen stressin aiheuttaman DNA-vaurion merkkiaineen, 8-OHdG:n sekä peroksiredoksiiniantioksidanttien ilmeneminen analysoitiin immunohistokemiallisesti. BMP-4:n ja sytoplasmisen peroksiredoksiini IV:n vahva ilmentyminen liittyivät parempaan ennusteeseen, kun taas 8-OHdG:n vahva ilmentyminen liittyi huonompaan elinajan ennusteeseen. Tuoreen munasarjasyöpäkudoksen eksplanttiviljelyn avulla selvitettiin p53 ja Hdm2 proteiinien vasteita syöpäkudoksen karboplatiini- tai dosetakseli-käsittelyille. Selkeitä yksilökohtaisia eroja havaittiin erityisesti karboplatiinin aiheuttamissa p53 vasteissa niin eri potilaiden kuin eri histologisten kasvaintyyppien välillä. Tämän väitöskirjatutkimuksen tulokset antavat viitteitä BMP-4:n, 8-OHdG:n ja peroksiredoksiinin mahdollisesta ennusteellisesta merkityksestä munasarjasyövässä. Erot platinayhdisteiden ja taksaanien välillä saattavat osoittautua merkittäviksi yksilöllisiä syövän hoitoja räätälöitäessä. Tuoreen munasarjasyöpäkudoksen eksplanttiviljelyn mahdollisuuksia yksilöllisten kasvainten hoitovasteiden ennustamisessa kannattaa selvittää jatkotutkimuksin.