L’utilisation de thérapies ciblées afin d’augmenter la fenêtre thérapeutique des traitements, notamment en oncologie, se développe de plus en plus. Les immunoconjugués font partie de l’arsenal de ces thérapies ciblées. En effet, il s’agit de vectoriser, grâce à un anticorps ciblant un antigène surexprimé sur les cellules cancéreuses, une molécule hautement cytotoxique comme les dérivés d’auristatines. L’espèce résultant est appelée antibody-drug conjugate (ADC). Ce faisant, l’efficacité du composé est augmentée et les potentiels effets secondaires sont limités. Plusieurs technologies permettant l’accroche de l’agent cytotoxique à l’anticorps existent avec différents dégrés d’homogénéité du produit final et différents niveaux de difficultés de mise en œuvre. De nos jours, les avancées technologiques permettent de concevoir des immunoconjugués (ADCs) présentant un chargement en molécule cytotoxique (DAR, drug-to-antibody ratio) contrôlé du point de vue du nombre et de la position (régio-spécifique). / The use of targeted therapies in order to increase the therapeutic window of treatments, especially in oncology, is growing. Immunoconjugates are part of the arsenal of these targeted therapies. Indeed, they aim at delivering, thanks to an antibody directed against overexpressed cancer cell antigens, a highly cytotoxic molecule like auristatins derivatives. The resulting species is called an antibody-drug-conjugate (ADC). By doing so, efficacy of the compound is increased and potential side-effects are limited. Several technologies for grafting the cytotoxic agent to the antibody exist with different levels of homogeneity of the final compound and different levels of difficulty of implementation. Nowadays, technological breakthroughs permit the design of immunoconjugates (ADCs) displaying a controlled drug-to-antibody ratio (DAR) in terms of quantity and position (site-specific).

The use of serpentine boundary layer ingesting (BLI) diffusers offers a significant benefit to the performance of Blended Wing Body aircraft. However, the inherent diffuser geometry combined with a thick ingested boundary layer creates strong secondary flows that lead to severe flow distortion at the engine face, increasing the possibility of engine surge. This study investigated the use of enabling active flow control methods to reduce engine-face distortion. An ejector-pump based system of fluidic actuators was used to directly manage the diffuser secondary flows. This system was modeled computationally using a boundary condition jet modeling method, and tested in an ejector-driven wind tunnel facility. This facility is capable of simulating the high-altitude, high subsonic Mach number conditions representative of BWB cruise conditions, specifically a cruise Mach number of 0.85 at an altitude of 39,000 ft. The tunnel test section used for this experiment was designed, built, and tested as a validation tool for the computational methods. This process resulted in the creation of a system capable of efficiently investigating and testing the fundamental mechanisms of flow control in BLI serpentine diffusers at a minimum of time and expense. Results of the computational and wind tunnel analysis confirmed the large potential benefit of adopting fluidic actuators to control flow distortion in serpentine BLI inlets. Computational analysis showed a maximum 71% reduction in flow distortion at the engine face through the use of the Pyramid 1 ejector scheme, and a 68% reduction using the Circumferential ejector scheme. However, the flow control systems were also found to have a significant impact on flow swirl. The Pyramid 1 ejector scheme was found to increase AIP flow swirl by 64%, while the Circumferential ejector scheme reduced flow swirl by 30%. Computational analyses showed that this difference was the result of jet interaction. By keeping the jet flows separate and distinct, the diffuser secondary flows could be more efficiently managed. For this reason, the most practically effective flow control scheme was the Circumferential ejector scheme. Experimental results showed that the computational analysis slightly over-predicted flow distortion. However, the trends are accurately predicted despite slight variances in freestream Mach number between runs and a slightly lower tested altitude. / Master of Science

A Região Metropolitana de São Paulo (RMSP) sofre de sérios problemas de congestionamento, assim como muitas outras cidades de grande porte. Uma possível solução, proposta por pesquisadores de transportes, economia e ciências ambientais, é a implantação de um sistema de congestion charging, chamada no Brasil de pedágio urbano. Um dos objetivos do presente trabalho foi estabelecer os conceitos relacionados a este assunto e ilustrar as principais questões relacionadas à sua implantação. Espera-se que este trabalho possa auxiliar o desenvolvimento de estudos de avaliação da viabilidade e de impactos de sistemas propostos de congestion charging. Para atingir este objetivo, toca-se em diversos assuntos, como a definição de congestionamento e as formas de medi-lo, a base conceitual e teórica dos sistemas de congestion charging e seus diversos esquemas de diferenciação. São expostas também as medidas de mitigação de congestionamento que já foram implantadas na RMSP, quais foram os estudos já desenvolvidos considerando este tipo de política para a RMSP, e casos em que sistemas de congestion charging já foi implantado. Neste trabalho, desenvolveu-se também um modelo de escolha discreta a partir dos dados da Pesquisa Origem e Destino 2007 do METRÔ, onde pessoas deveriam escolher entre \"Transporte Coletivo\" e \"Transporte Público\". Este modelo foi utilizado para avaliar o potencial de impacto na divisão modal e de arrecadação de um congestion charge aplicado ao centro expandido de São Paulo. Adverte-se, porém, que os resultados obtidos são meramente ilustrativos. Mostra-se, também, que é possível avaliar a capacidade ociosa do sistema de transporte coletivo a partir dos dados disponíveis de bilhetagem e de GPS dos ônibus. Este processo é exemplificado através do cálculo de capacidade de uma única viagem de um único ônibus, dada a dificuldade de automatização deste processo para abranger toda a frota. / The São Paulo Metropolitan Region (SPMR) suffers from severe traffic congestion, as do many other large-scale urban areas around the world. A possible solution to this issue, which has been suggested by transportation, economics and environmental researchers, is the implementation of a congestion charging system. One of the objectives of this project is to establish clear concepts and shed light on the main issues regarding these systems by means of a comprehensive literary review. It is expected that this project may help the development of in-depth studies carried in order to evaluate the viability and impacts of congestion charging proposals. In order to achieve this goal, many subjects are addressed, such as the definition of congestion, how its measured, the theoretical backgrounds that support congestion charging schemes, their different degrees of differentiation, which policies were enacted in order to reduce traffic congestion in São Paulo, what considerations and studies have already been developed for Brazil and São Paulo regarding these systems and where have these systems been successfully installed. Later chapters deal with another goal of this project: estimating how a congestion charging system would affect SPMR. This was achieved through a multinomial logit model, where decision-makers choose between \"Public Transportation\" and \"Private Automobile\". The results presented at this phase are merely indicative of certain tendencies and should not be considered final. This project also attempts to show that given the available Automated Fare Collection (AFC) data and Automated Vehicle Location (AVL) data, it is possible to estimate the current public transportation system\'s unused capacity. The author shows this by calculating the capacity of one bus trip using these data, but also explains the difficulties of expanding this analysis to the whole of SPMR\'s public transportation system.

A Região Metropolitana de São Paulo (RMSP) sofre de sérios problemas de congestionamento, assim como muitas outras cidades de grande porte. Uma possível solução, proposta por pesquisadores de transportes, economia e ciências ambientais, é a implantação de um sistema de congestion charging, chamada no Brasil de pedágio urbano. Um dos objetivos do presente trabalho foi estabelecer os conceitos relacionados a este assunto e ilustrar as principais questões relacionadas à sua implantação. Espera-se que este trabalho possa auxiliar o desenvolvimento de estudos de avaliação da viabilidade e de impactos de sistemas propostos de congestion charging. Para atingir este objetivo, toca-se em diversos assuntos, como a definição de congestionamento e as formas de medi-lo, a base conceitual e teórica dos sistemas de congestion charging e seus diversos esquemas de diferenciação. São expostas também as medidas de mitigação de congestionamento que já foram implantadas na RMSP, quais foram os estudos já desenvolvidos considerando este tipo de política para a RMSP, e casos em que sistemas de congestion charging já foi implantado. Neste trabalho, desenvolveu-se também um modelo de escolha discreta a partir dos dados da Pesquisa Origem e Destino 2007 do METRÔ, onde pessoas deveriam escolher entre \"Transporte Coletivo\" e \"Transporte Público\". Este modelo foi utilizado para avaliar o potencial de impacto na divisão modal e de arrecadação de um congestion charge aplicado ao centro expandido de São Paulo. Adverte-se, porém, que os resultados obtidos são meramente ilustrativos. Mostra-se, também, que é possível avaliar a capacidade ociosa do sistema de transporte coletivo a partir dos dados disponíveis de bilhetagem e de GPS dos ônibus. Este processo é exemplificado através do cálculo de capacidade de uma única viagem de um único ônibus, dada a dificuldade de automatização deste processo para abranger toda a frota. / The São Paulo Metropolitan Region (SPMR) suffers from severe traffic congestion, as do many other large-scale urban areas around the world. A possible solution to this issue, which has been suggested by transportation, economics and environmental researchers, is the implementation of a congestion charging system. One of the objectives of this project is to establish clear concepts and shed light on the main issues regarding these systems by means of a comprehensive literary review. It is expected that this project may help the development of in-depth studies carried in order to evaluate the viability and impacts of congestion charging proposals. In order to achieve this goal, many subjects are addressed, such as the definition of congestion, how its measured, the theoretical backgrounds that support congestion charging schemes, their different degrees of differentiation, which policies were enacted in order to reduce traffic congestion in São Paulo, what considerations and studies have already been developed for Brazil and São Paulo regarding these systems and where have these systems been successfully installed. Later chapters deal with another goal of this project: estimating how a congestion charging system would affect SPMR. This was achieved through a multinomial logit model, where decision-makers choose between \"Public Transportation\" and \"Private Automobile\". The results presented at this phase are merely indicative of certain tendencies and should not be considered final. This project also attempts to show that given the available Automated Fare Collection (AFC) data and Automated Vehicle Location (AVL) data, it is possible to estimate the current public transportation system\'s unused capacity. The author shows this by calculating the capacity of one bus trip using these data, but also explains the difficulties of expanding this analysis to the whole of SPMR\'s public transportation system.

Ce travail est constitué de deux volets indépendants qui s'intéressent respectivement à la géochimie isotopique du lithium et à la variabilité géochimique des MORB du Pacifique sud. L'utilisation des isotopes du lithium en Sciences de la Terre est abordée dans un premier temps au travers de l'étude des laves de la Chaîne des Puys. Les échantillons de cette série volcanique intraplaque permettent d'apporter des contraintes sur les valeurs de la composition isotopique du Li dans la croûte continentale inférieure et dans le manteau d'affinité HIMU sous le Massif Central. La deuxième étude s'intéresse au comportement du Li lors du refroidissement d'une lave. Pour cela, des analyses in situ de la composition isotopique du Li ont été réalisé au travers de phénocristaux d'olivine d'un échantillon de picrite. Ces mesures ont permis de mettre en évidence un processus de fractionnement isotopique dû à la diffusion du Li dans les cristaux. Le deuxième volet de ce travail présente les résultats de la campagne océanographique PACANTARCTIC2. L'analyse des rapports d'éléments en traces et de la composition isotopique des isotopes radiogéniques (Sr, Nd, Pb et Hf) dans les basaltes collectés entre 53°S et 39°S le long de la dorsale Pacifique-Antarctique, permet d'étudier la variabilité des basaltes de dorsale loin de tout point-chaud. Cette étude mets en évidence différentes échelles d'hétérogénéités géochimiques dans la source de ces MORB. Ces variations le long de l'axe correspondent aux différents types de segmentation de la dorsale.

La réalisation d'une mémoire quantique pour la lumière met en jeu les aspects les plus fondamentaux de l'interaction matière-rayonnement. Pour capturer l'information quantique portée par la lumière, le matériau doit être capable de se maintenir dans un état de superposition quantique. Le temps de stockage est limité par la durée de vie de cet état, caractérisée par le temps de cohérence. Les premières expériences ont été réalisées dans des vapeurs atomiques froides, bien connues. Plus récemment, les ions de terres rares en matrice cristalline (REIC) ont attiré l'attention par leurs long temps de cohérence, associés à de larges bandes passantes d'interaction. Pour exploiter ces bonnes propriétés, des protocoles spécifiques ont été proposés. Nous nous sommes tournés vers un dérivé prometteur de l'écho de photon, le Peigne Atomique de Fréquences (AFC, proposé en 2008), fondé sur la transmission du champ incident à travers un profil d'absorption spectralement périodique. Les premiers chapitres de ce manuscrit présentent ce protocole et les travaux effectués durant cette thèse pour en améliorer l'efficacité (i.e. la probabilité de capter et de restituer l'information incidente), en augmenter la bande passante et la capacité de multiplexage et en mesurer le bruit. Les chapitres suivants présentent un nouveau protocole, proposé dans notre groupe durant cette thèse, et baptisé ROSE (Revival Of Silenced Echo). Ce protocole, très proche de l'écho de photon, a été démontré et caractérisé expérimentalement. Il semble très prometteur en termes d'efficacité, de bande passante et de bruit.

Delaying stall is always an attractive option in the aerospace industry. The major benefit of delaying stall is increased lift during takeoff and landings as well as during high angle of attack situations. Devices, such as fluidic oscillators, can be integrated into wing flaps to help delay the occurrence of stall by adding energized air to the airflow on the upper surface of the wing flap. The energized air from the oscillator allows the airflow to remain attached to the upper surface of the wing flap. The fluidic oscillator being integrated in this thesis is an active flow control device (AFC). One common method for integrating any device into a wing flap is to remove a section of the flap and mechanically secure the device. A current trend in the aerospace industry is the increased use of fiber-reinforced composites to replace traditional metal components on aircraft. The traditional methods of device integration cause additional complications when applied to composite components as compared to metal components. This thesis proposes an alternative method for integration of the AFC devices, which occurs before the fabrication of wing flaps is completed and they are attached to the aircraft wing. Seven design concepts are created to reduce the complications from using current methods of integration on composite wing flaps. The concepts are based on four design requirements: aerodynamics, manufacturing, maintenance, and structure. Four of the design concepts created are external designs, which place the AFC on the exterior surface of the wing flap in two types of grooved channels. The other three designs place the AFC inside the wing flap skin and are categorized as internal designs. In order for the air exiting the AFC to reach the upper surface of the wing flap, slots are created in the wing flap skin for the internal designs. Within each of the seven design concepts two design variants are created based on foam or ribbed core types. Prototypes were created for all of the external design AFC devices and the side inserted AFC and retaining pieces. Wing flap prototypes were created for the rounded groove straight AFC design, the semi-circular groove with straight AFC, and the side inserted AFC designs. The wing flaps were created using the VARTM process with a vertical layup for the external designs. The rounded groove and semi-circular groove prototypes each went through three generations of prototypes until an acceptable wing flap was created. The side inserted design utilized the lessons learned through each generation of the external design prototypes eliminating the need for multiple generations. The lessons learned through the prototyping process helped refine the designs and determine the ease of manufacturing to be used in the design evaluation. The evaluation of the designs is based on the four design requirements stated above. The assessment of the designs uses two levels of evaluation matrices to determine the most fitting design concept. As a result of the evaluation, all four of the external designs and one of the internal designs are eliminated. The two remaining internal designs' foam core and ribbed variants are compared to establish the final design selection. The vertically inserted AFC foam core design is the most fitting design concept for the integration of an AFC device into a composite wing flap.

The existence of polymer constituent in piezoelectric fiber composites (PFCs) could lead to significant viscoelastic behaviors, affecting overall performance of PFCs. High mechanical and electrical stimuli often generate significant amount of heat, increasing temperatures of the PFCs. At elevated temperatures, most materials, especially polymers show pronounced time-dependent behaviors. Predicting time-dependent responses of the PFCs becomes important to improve reliability in using PFCs. We study overall performance of PFCs having unidirectional piezoceramic fibers, such as PZT fibers, dispersed in viscoelastic polymer matrix. Two types of PFCs are studied, which are active fiber composites (AFCs) and macro fiber composites (MFCs). AFCs and MFCs consist of unidirectional PZT fibers dispersed in epoxy placed between two interdigitated electrode and kapton layers. The AFCs have a circular fiber cross-section while the MFCs have a square fiber cross-section. Finite element (FE) models of representative volume elements (RVEs) of active PFCs, having square and circular fiber cross-sections, are generated for composites with 20, 40, and 60 percent fiber contents. Two FE micromechanical models having one fiber embedded in epoxy matrix and five fibers placed in epoxy matrix are considered. A continuum 3D piezoelectric element in ABAQUS FE is used. A general time-integral function is applied for the mechanical, electrical, and piezoelectric properties in order to incorporate the time-dependent effect and histories of loadings. The effective properties of PZT-5A/epoxy and PZT-7A/LaRC-SI piezocomposites determined from the FE micromechanical models are compared to available experimental data and analytical solutions in the literature. Furthermore, the effect of viscoelastic behaviors of the LaRC-SI matrix at an elevated temperature on the overall electro-mechanical and piezoelectric constants are examined.

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Submitted by Filipe dos Santos (fsantos@pucsp.br) on 2018-12-11T11:55:29Z No. of bitstreams: 1 Fernanda Vieira Kotzias.pdf: 3471482 bytes, checksum: 67b61f757300f836852265e45b5ff0a5 (MD5) / Made available in DSpace on 2018-12-11T11:55:29Z (GMT). No. of bitstreams: 1 Fernanda Vieira Kotzias.pdf: 3471482 bytes, checksum: 67b61f757300f836852265e45b5ff0a5 (MD5) Previous issue date: 2018-11-05 / The Trade Facilitation Agreement (TFA) represents an important step for Members of the World Trade Organization (WTO) towards the reduction of bureaucracy and transactional costs, as well to the increase in the transparency of foreign trade operations, in particular where Customs are concerned. The inclusion of this topic in WTO negotiations’ agenda was due to the perception that, as trade has become more liberalized, a new international regulatory architecture emerged, shifting the focus of policymakers from tariff barriers to other impediments to the cross-border movement of goods, particularly to those of an administrative and logistical nature. After almost twenty years of negotiations on its structure and content, the TFA was signed in 2013 during the Bali Conference and became effective in February 2017. Even though Brazil has only ratified the agreement in 2018 by means of Decree n. 9.326/2018, the Brazilian Government submitted its notification to WTO in 2016 designating 95.8% of the TFA commitments to be implemented immediately. The remaining 4.2% were scheduled to be implemented until December 2019. This was a bold position and has generated great expectations for operators and other interested parties in international trade. Nevertheless, Brazil remains poorly evaluated by national and international indicators that measure transaction costs, as most of the measures under the TFA continue to be totally or partially disregarded in practice, which is a major complain from the Brazilian private sector. In this context, the research problem addressed in this thesis is to identify the bottlenecks to the greater efficiency of the management of foreign trade in Brazil and evaluate the necessity of political, institutional and normative reforms and adjustments in order to foster the effective implementation of WTO trade facilitation obligations and increase Brazil’s integration into international trade. The proposed analysis is based on extensive bibliographical and documentary research, exploring doctrinal sources, national jurisprudence and WTO precedents to discuss the implications of the commitments signed within the scope of the WTO in the Brazilian legal system. From this, an attempt was made to inductively analyze the barriers to trade facilitation and legal uncertainty faced by trade operators. Finally, the research problem is addressed based on the study of foreign models and recommendations of international organizations. This thesis was structured in four chapters, in order to first present important concepts and delimitations in terms of trade facilitation and the way in which international obligations are internalized into the national legal order and discuss the Brazilian political-institutional structure regarding the regulation of foreign trade matters. Finally, based on the understandings and clarifications presented, recommendations are proposed for the implementation of trade facilitation in Brazil. Additionally, possible actions and reforms are directed to each of the main powers and articulators of Brazilian foreign trade individually, which are the Legislative Branch, the Executive Branch, the Judiciary Branch and the private sector / O Acordo sobre a Facilitação do Comércio (AFC) representa um passo importante dos Membros da Organização Mundial do Comércio (OMC) quanto à desburocratização, redução dos custos de transação e aumento da transparência nas operações de comércio internacional, sobretudo na atuação das Aduanas. A inclusão do tema na pauta de negociações da OMC deve-se à percepção dos Estados de que, à medida que o comércio se tornou mais liberalizado, houve uma mudança na arquitetura regulatória internacional, que direcionou parte do foco de contenção e eliminação de barreiras tarifárias para outros impedimentos ao movimento transfronteiriço de mercadorias, particularmente àqueles de natureza administrativa e logística. Após quase vinte anos de negociações sobre a estrutura normativa e o conteúdo do acordo, o AFC foi assinado em 2013 durante a Conferência de Bali, entrando em vigor em fevereiro de 2017. O Brasil ratificou o AFC apenas em abril de 2018, por meio do Decreto 9.326/2018, ainda que o governo brasileiro tenha notificado formalmente a OMC em 2016 sobre o seu compromisso de implementar imediatamente 95,8% do conteúdo do acordo, deixando apenas os 4,2% das obrigações restantes para implementação posterior, marcada para ocorrer até dezembro de 2019. Trata-se de posição arrojada e que despertou grande expectativa dos operadores e demais interessados no comércio internacional. Ocorre que o Brasil continua mal avaliado pelos indicadores nacionais e internacionais que medem custos de transação e grande parte das medidas contidas no acordo seguem sendo descumpridas total ou parcialmente na prática, sendo este um grande ponto de descontentamento do setor privado brasileiro. Nesse contexto, o problema de pesquisa que se pretende endereçar na presente tese volta-se à identificação dos gargalos à maior eficiência da gestão do comércio exterior brasileiro e à avaliação de reformas e ajustes necessários, em termos políticos, institucionais e normativos, para que o Brasil efetivamente implemente suas obrigações relativas à facilitação no âmbito da OMC e aumente sua integração ao comércio internacional. A análise proposta foi realizada a partir de ampla pesquisa bibliográfica e documental, explorando fontes doutrinárias e precedentes jurisprudenciais da OMC para discussão das implicações dos compromissos firmados no âmbito da OMC no ordenamento jurídico brasileiro. A partir disso, buscou-se, de modo indutivo, analisar os entraves existentes à facilitação do comércio e a insegurança jurídica causada aos operadores. Por fim, buscou-se responder o problema de pesquisa com base no estudo de modelos estrangeiros e recomendações de organismos internacionais. O trabalho foi estruturado em quatro capítulos, de forma a, primeiramente, apresentar conceitos e delimitações importantes em termos de facilitação do comércio e da forma como as obrigações internacionais são internalizadas no ordenamento jurídico nacional para, a partir disso, discutir a estrutura político-institucional e normativa do Brasil em matéria de comércio exterior. Por fim, a partir dos entendimentos e esclarecimentos apresentados, propõem-se recomendações para a efetivação da facilitação do comércio no Brasil, apresentando, de forma específica, ações e reformas direcionadas a cada um dos principais poderes e articuladores do comércio exterior brasileiro: o Poder Legislativo, o Poder Executivo, o Poder Judiciário e o setor privado