La fibrose kystique (FK), causée par des mutations dans le gène codant pour le canal chlorure CFTR, est caractérisée par des infections bactériennes chroniques des voies aériennes (VA), impliquant en particulier Pseudomonas aeruginosa (PA) et Staphylococcus aureus (SA). Les facteurs de virulence (VirF) sécrétés par celles-ci sont responsables de la destruction progressive des VA et altèrent la capacité de réparation du tissu épithélial. Il existe cependant des molécules spécifiques permettant de corriger le défaut de CFTR et de moduler l’activité de canaux potassiques, deux actions qui pourraient favoriser la réparation épithéliale de par leur action. Leur efficacité pourrait toutefois être altérée par les VirF de P. aeruginosa ou S. aureus. Mon objectif a été d’identifier le potentiel de réparation épithélial du Trikafta et du ML277, modulateurs respectivement spécifiques des canaux CFTR et KvLQT1 (canal potassique sensible au voltage, du syndrome du QT long), impliqués dans les processus de réparation. Des cultures primaires de cellules bronchiques des VA de patients FK ont été traitées avec la triple combinaison de modulateurs de CFTR Trikafta, l’activateur de KvLQT1 ML277, et la combinaison de ces deux derniers, en plus d’être exposées aux VirF de cultures de P. aeruginosa ou S. aureus. L’efficacité de ces traitements sur les processus de réparation fut évaluée, suite à des lésions, selon la vitesse de réparation des plaies, la prolifération cellulaire et les dynamiques de migration guidée cellulaire. Les VirF de P. aeruginosa et S. aureus altèrent la vitesse de fermeture lésionnelle, la prolifération cellulaire et les dynamiques de migration cellulaire. Les traitements Trikafta et ML277 permettent cependant d’améliorer ces processus de la réparation épithéliale, et ce, en absence comme en présence des VirF bactériens nocifs à la réparation. La combinaison du Trikafta et du ML277 n’amène cependant pas l’effet additif espéré sur la réparation épithéliale. Ces résultats témoignent finalement de l’effet bénéfique du Trikafta et du ML277 sur la réparation épithéliale malgré la condition infectieuse, favorisant l’intégrité fonctionnelle de l’épithélium des VA FK. / Cystic fibrosis (CF), caused by mutations in the gene coding for the chloride channel CFTR, is characterized by chronic bacterial infections in the airways, particularly by Pseudomonas aeruginosa (PA) and Staphylococcus aureus (SA). The virulence factors (VirF) secreted by these bacteria are responsible for the progressive destruction of the airways and impair the repair process of the epithelia. Nevertheless, there are specific molecules that correct the CFTR defect and modulate potassium channel activity, both of which could be beneficial at promoting epithelial repair. However, their efficacy could be altered by P. aeruginosa or S. aureus VirF. My objective was to identify the repair potential of Trikafta and ML277, respectively specific modulators of CFTR and KvLQT1 channels, involved in repair processes. Primary cultures of airways epithelial cells from CF patients were treated with the triple combination of CFTR modulators Trikafta, the KvLQT1 activator ML277, and the combination of the latter two, in addition to being exposed to VirF from P. aeruginosa or S. aureus cultures. The efficacy of these treatments on repair processes was evaluated, following wound injury, by the rate of wound repair, cell proliferation and guided cell migration dynamics. P. aeruginosa and S. aureus VirF alter wound repair rates, cell proliferation and cell migration dynamics. Nevertheless, Trikafta and ML277 treatments improve these epithelial repair processes, both in the absence and presence of repair-damaging P. aeruginosa or S. aureus VirF. However, the combination of Trikafta and ML277 did not have the hoped-for additive effect on epithelial repair. Overall, these results show the beneficial effect of Trikafta and ML277 epithelial repair despite the infectious condition, promoting the functional integrity of the CF airways epithelia.

O trabalho apresenta de início uma investigação da evolução histórica do sistema viário de São Paulo como subsídio à compreensão da transformação que a cidade teve ao longo das décadas em sua configuração urbana e na forma pela qual as pessoas e veículos se deslocaram através da rede física de circulação. Foram analisados os aspectos viários dos planos urbanos, em muitos casos entendidos como planos viários, e da legislação urbanística de parcelamento do solo no período de 1895 a 2004. A partir dos resultados da investigação realizada, bem como da análise crítica das normas e manuais em vigor na cidade de São Paulo, em especial aqueles que tratam do estabelecimento da seção transversal típica das vias, o presente trabalho tem como objetivo propor uma contribuição à revisão da classificação viária da cidade de São Paulo. A revisão proposta recomenda que, na definição das funções que as vias possam ter dentro da rede viária urbana usualmente caracterizada pela relação entre os níveis de mobilidade e acessibilidade proporcionados ao tráfego veicular - sejam consideradas, de forma mais abrangente, as necessidades dos usuários não motorizados (pedestres e ciclistas) no que diz respeito às características geométricas da seção transversal. / The paper presents, at first, a research about the historic evolution of the roadway system in São Paulo as an aid to understand the changes the city went through, for decades, in its urban configuration and in the way people and vehicles moved through the circulation physical network. The paper analyzed the road aspects of urban plans which, many times were understood as roadway plans, and of the urban laws of land division during the period of 1895 to 2004. Based on the findings of the research, as well as the critical analysis of rules and manuals in effect in the City São Paulo, mainly those that address the establishment of a roadway-typical cross section, the present paper aims at suggesting a contribution to the roadway classification review of the City of São Paulo. The proposed review recommends, according to the definition of the roles that the roadways may play within the urban roadway network usually characterized by the relation between the mobility and accessibility levels provided to vehicle traffic to take into consideration, in a more comprehensive manner, the needs of those non-motorized users, (pedestrians and cyclists) in regard to the cross-section geometrical characteristics.

No estudo da história da urbanização de São Paulo foram constatadas grandes transformações nos lotes urbanos. Tomando como referência as plantas da cidade, a iconografia paulistana, além das legislações urbanas recuos, altura, Taxa de Ocupação e Coeficiente de Aproveitamento do lote foi feita uma organização cronológica. Observou-se a paisagem urbana, a volumetria e a implantação dos edifícios no lote, para finalmente fazer a biografia do fragmento analisado: a rua São Bento. / When studying the history of the urbanization of São Paulo great transformations in the urban lots had been evidenced. Taking as reference the urban plants of the city, paulistana iconography, beyond urban laws recoils, height, Tax of Occupation and Coefficient of Exploitation of the lot has been chronological organized. It has been observed the urban landscape, the volumetria and the implantation of the buildings in the lot, finally to produce the biography of a fragment analyzed: the street of São Bento.

<p>This study is a response to the dilemma of poor service delivery or the lack thereof. In this regard, this study posits the professionalisation of local government as part of the solution. The focus is on the administrative arm of local government, which is the major conduit for service delivery. Professionalisation of local government is a broader theme. For the present purposes, focus will be devoted to the competency component which entails attracting qualified personnel competent to discharge local government responsibilities. However, it is not limited to attracting already competent and professional staff. It also entails developing the skills of existing staff. This definition, in essence, relates to qualification through training, learning and specialisation.11 In essence, professionalisation of local government ensures that all employees act and behave in a professional way. In this regard, this study seeks to identify the competency standards set by the legislative framework and then explore the legal avenues for enforcing compliance, by the municipal administration, with such standards. This requires one to look at and answer the following questions: What constitutes municipal staff? / What is the content of the competency framework in question? / What are the enforcement mechanisms currently in place? / Whose role is it to enforce compliance with the competency framework? / Broadly speaking, enforcement can take two forms: hard enforcement and soft enforcement. The hard form of enforcement relates to giving incentives for compliance with the competency framework and dismissal for non-compliance. Softer enforcement, in turn, relates to correction and monitoring.</p>

<p>This study is a response to the dilemma of poor service delivery or the lack thereof. In this regard, this study posits the professionalisation of local government as part of the solution. The focus is on the administrative arm of local government, which is the major conduit for service delivery. Professionalisation of local government is a broader theme. For the present purposes, focus will be devoted to the competency component which entails attracting qualified personnel competent to discharge local government responsibilities. However, it is not limited to attracting already competent and professional staff. It also entails developing the skills of existing staff. This definition, in essence, relates to qualification through training, learning and specialisation.11 In essence, professionalisation of local government ensures that all employees act and behave in a professional way. In this regard, this study seeks to identify the competency standards set by the legislative framework and then explore the legal avenues for enforcing compliance, by the municipal administration, with such standards. This requires one to look at and answer the following questions: What constitutes municipal staff? / What is the content of the competency framework in question? / What are the enforcement mechanisms currently in place? / Whose role is it to enforce compliance with the competency framework? / Broadly speaking, enforcement can take two forms: hard enforcement and soft enforcement. The hard form of enforcement relates to giving incentives for compliance with the competency framework and dismissal for non-compliance. Softer enforcement, in turn, relates to correction and monitoring.</p>

O trabalho apresenta de início uma investigação da evolução histórica do sistema viário de São Paulo como subsídio à compreensão da transformação que a cidade teve ao longo das décadas em sua configuração urbana e na forma pela qual as pessoas e veículos se deslocaram através da rede física de circulação. Foram analisados os aspectos viários dos planos urbanos, em muitos casos entendidos como planos viários, e da legislação urbanística de parcelamento do solo no período de 1895 a 2004. A partir dos resultados da investigação realizada, bem como da análise crítica das normas e manuais em vigor na cidade de São Paulo, em especial aqueles que tratam do estabelecimento da seção transversal típica das vias, o presente trabalho tem como objetivo propor uma contribuição à revisão da classificação viária da cidade de São Paulo. A revisão proposta recomenda que, na definição das funções que as vias possam ter dentro da rede viária urbana usualmente caracterizada pela relação entre os níveis de mobilidade e acessibilidade proporcionados ao tráfego veicular - sejam consideradas, de forma mais abrangente, as necessidades dos usuários não motorizados (pedestres e ciclistas) no que diz respeito às características geométricas da seção transversal. / The paper presents, at first, a research about the historic evolution of the roadway system in São Paulo as an aid to understand the changes the city went through, for decades, in its urban configuration and in the way people and vehicles moved through the circulation physical network. The paper analyzed the road aspects of urban plans which, many times were understood as roadway plans, and of the urban laws of land division during the period of 1895 to 2004. Based on the findings of the research, as well as the critical analysis of rules and manuals in effect in the City São Paulo, mainly those that address the establishment of a roadway-typical cross section, the present paper aims at suggesting a contribution to the roadway classification review of the City of São Paulo. The proposed review recommends, according to the definition of the roles that the roadways may play within the urban roadway network usually characterized by the relation between the mobility and accessibility levels provided to vehicle traffic to take into consideration, in a more comprehensive manner, the needs of those non-motorized users, (pedestrians and cyclists) in regard to the cross-section geometrical characteristics.

Magister Legum - LLM / This study is a response to the dilemma of poor service delivery or the lack thereof. In this regard, this study posits the professionalisation of local government as part of the solution. The focus is on the administrative arm of local government, which is the major conduit for service delivery. Professionalisation of local government is a broader theme. For the present purposes, focus will be devoted to the competency component which entails attracting qualified personnel competent to discharge local government responsibilities. However, it is not limited to attracting already competent and professional staff. It also entails developing the skills of existing staff. This definition, in essence, relates to qualification through training, learning and specialisation.11 In essence, professionalisation of local government ensures that all employees act and behave in a professional way. In this regard, this study seeks to identify the competency standards set by the legislative framework and then explore the legal avenues for enforcing compliance, by the municipal administration, with such standards. This requires one to look at and answer the following questions: What constitutes municipal staff? ; What is the content of the competency framework in question? ; What are the enforcement mechanisms currently in place? ; Whose role is it to enforce compliance with the competency framework?; Broadly speaking, enforcement can take two forms: hard enforcement and soft enforcement. The hard form of enforcement relates to giving incentives for compliance with the competency framework and dismissal for non-compliance. Softer enforcement, in turn, relates to correction and monitoring. / South Africa

No estudo da história da urbanização de São Paulo foram constatadas grandes transformações nos lotes urbanos. Tomando como referência as plantas da cidade, a iconografia paulistana, além das legislações urbanas recuos, altura, Taxa de Ocupação e Coeficiente de Aproveitamento do lote foi feita uma organização cronológica. Observou-se a paisagem urbana, a volumetria e a implantação dos edifícios no lote, para finalmente fazer a biografia do fragmento analisado: a rua São Bento. / When studying the history of the urbanization of São Paulo great transformations in the urban lots had been evidenced. Taking as reference the urban plants of the city, paulistana iconography, beyond urban laws recoils, height, Tax of Occupation and Coefficient of Exploitation of the lot has been chronological organized. It has been observed the urban landscape, the volumetria and the implantation of the buildings in the lot, finally to produce the biography of a fragment analyzed: the street of São Bento.

El objetivo general es analizar la propuesta de reforzamiento con encamisado en estribos de puentes sometidos a socavación por la acción del agua durante la ocurrencia de las máximas avenidas. Para ello, se estudió al puente Morón ubicado sobre el río Rímac para asegurar su estabilidad. Se identificó que la principal causa de falla de los puentes es hidráulica y está asociada a la socavación producida por las máximas avenidas que se presentan en el periodo de diciembre-abril y se intensifican notablemente con la ocurrencia del Fenómeno El Niño. Para ello, se propuso realizar un encamisado de los estribos, propuesta que se comparó con otras alternativas utilizando metodologías sugeridas por expertos, la evaluación de las condiciones existentes en el terreno para validar la investigación. El nivel de investigación realizado es descriptivo, debido a que se caracterizará las obras de protección contra la socavación de estribos, comparando diversas alternativas con la propuesta de encamisado. Además, exploratorio, documental y se complementó con datos obtenidos de campo. Para luego calcular la socavación empleando la metodología propuesta por el HEC-18 con datos hidráulicos obtenidos en el modelamiento del tramo estudiado con el HEC-RAS. Los resultados indicaron que el puente Morón presenta falla hidráulica a causa de la socavación en estribos. Además, se determinó que es necesario proteger el talud del río con revestimiento de enrocado 476 m aguas arriba y 574 m aguas abajo del puente, por ubicarse en una curva, concluyendo que por razones técnico-económicas el encamisado es la mejor alternativa de protección. / The main objective is to analyze the proposal of jacketed reinforcement in bridge abutments subjected to scour by flowing water during major flood stage. For that purpose, the Morón Bridge located over the Rímac River was studied to ensure its stability. It was identified that the main reason of bridge failure is hydraulic and this is associated to the scour caused by the major flood stage in the December–April period, and it is significantly intensified by the El Niño Phenomenon. To that end, we proposed to carry out an abutment jacketing, this proposal was compared to other alternatives applying methodologies suggested by experts and the evaluation of existing conditions in the land in order to validate this research. The level of research is descriptive because it will characterize the protection works against undermining of bridge abutments, comparing various alternatives with the cladding proposal. In addition, exploratory, documentary and was supplemented with data obtained from the field. To then calculate the scour using the methodology suggested on HEC-18 with hydraulic data obtained in the modeling in the section studied in HEC-RAS. The results indicated that the Morón bridge presents failure is hydraulic to the scour in abutments. In addition, it was determined that it is necessary to protect the river slope with a riprap of 476 meters upstream and 574 meters downstream from the bridge for this being located in a curve, concluding the proposal of jacketed reinforcement of reinforced concrete is the best option for technical-economic and environmental reasons. / Tesis

O objeto de estudo deste trabalho são as avenidas perimetrais da Área Central da cidade de São Paulo descritas a partir do seu desempenho atual. A descrição das avenidas as aborda a partir do entendimento de como sistemas de mobilidade podem ser avaliados e descritos do ponto de vista urbanístico. A partir desta afirmação discuto alguns aspectos para sua caracterização, levando em conta a importância do transporte coletivo para os espaços da Área Central. Neste sentido, discuto a articulação entre perimetrais e radias, elementos que as vinculam ao sistema de transporte metropolitano; a existência de uma rede de espaços públicos na Área Central conflitantes com sua utilização como suporte das redes de transporte que atingem a Área Central; e, finalmente, a ideia de que as vias perimetrais não são um conjunto coerente de vias. Em outro eixo de análise, estudo o histórico de formação da área, visando o entendimento das condicionantes de projeto que foram responsáveis pela construção dos trechos que a compõem. Este histórico é pautado pela ideia de que é possível entender a formação da área através não só da construção de seus espaços mas também de como estes espaços foram utilizados como suporte das redes de transporte metropolitano. Finalmente, apresento alguns estudos de caso sobre a relação entre mobilidade e projeto urbano, agrupando projetos em duas linhas de discussão: a primeira, sobre projetos que tiveram o automóvel e sua relação com a cidade como referência; e a segunda sobre transporte coletivo sobre pneus e oportunidades urbanísticas advindas da reestruturação viária. A partir das análises sobre o desempenho atual e o histórico de formação das perimetrais faço considerações para o estabelecimento de parâmetros urbanísticos para intervenção na área. / The subject of this study are the perimetral routes of São Paulo\'s Central Area, which are described based on their current performance. The subject is addressed from the understanding that mobility systems can be described and evaluated from an urbanistic point of view. From this statement on, some aspects for it\'s characterization are discussed taking in consideration the importance of public transport to the Central Area. In that sense, the articulation between perimetral and radial routes is discussed, as well as the elements that bind them to the metropolitan transportation system; the existence of a network of public spaces in the Central Area that conflicts with it\'s use as a support to transportation networks; and finally, the idea that the perimetrical routes are not a coherent system of routes. Another analytical axis is the historical development of the area toward an understanding of the project\'s determining factors responsible for the construction of the sections that comprises it. This background is guided by the idea that it is possible to understand the formation of the Central Area, not only through the point of view of it\'s spatial construction but also trough the analysis of how these space were used as support to the metropolitan transport network. Finally some case studies are presented pertaining the relationship between mobility and urban projects, gathering projects in two lines of thoughts: the first being projects that had the relation between automobiles and the city as reference; the second about public transportation and urbanistic opportunities arousing from busways. Based on the analysis of the current performance and historical consolidation of the perimetral routes, considerations are made for the establishment of urbanistic parameters of intervention in the Central Area.