Made available in DSpace on 2016-04-26T18:15:25Z (GMT). No. of bitstreams: 1 Nadia Maria Lebedev Martinez Moreira.pdf: 4678006 bytes, checksum: 73d01e7fc9a37307118ccc3bbf867acb (MD5) Previous issue date: 2015-12-11 / Conselho Nacional de Desenvolvimento Científico e Tecnológico / The research aim to establish a direct relationship between its subjects, the Oracle and the Media. The main hypothesis is that the media has an oracular character. This reflection seems to be new within the Media Theory studies, and speculates that the future has a present event status. The oracles, or oracular character figures, when performing their predictions, design the future in the present, building scenarios that guide both the individual in his private life, as the society as a whole. The adopted methodological strategy sought to develop an archeology of the oracles in the West - especially the Oracle of Delphi, given its importance to the emergence of Western civilization and its institutions, including the media itself understanding them as backers of information, also a defining characteristic of the media. Researches concepts proposed by the Theory of Media in the reflections of Norval Baitello, Harry Pross and Flusser. Anxiety about the future is read from Soren Kierkegaard and Carl Gustav Jung. Within the concept of cultural anxiety Rafael Lopez-Pedraza, thinks the relationship of individuals and society in the future, this relationship also studied by Julian Jaynes in his deconstruction of the bicameral mind. Also Norbert Elias, who investigates what he calls a society of individuals. The hypothesis is tested trough media examples that analyze topics such as the economic crisis brought by the US housing bubble; Brazilian water crisis in 2015; and predictions about games results in sporting championships / A pesquisa procurou estabelecer uma relação direta entre seus objetos de estudo, o Oráculo e a Mídia. A hipótese principal é que a mídia possui um caráter oracular. Essa reflexão parece ser nova dentro dos estudos da Teoria da Mídia, e especula sobre o futuro como um estado de acontecimento presente. São os oráculos, ou de figuras de caráter oracular, que ao realizarem suas previsões, projetam o futuro no presente, construindo cenários que orientam tanto o indivíduo em sua vida particular, quanto à sociedade como um todo. A estratégia metodológica adotada buscou elaborar uma arqueologia dos oráculos no Ocidente principalmente do Oráculo de Delfos, dada sua importância fundante para o surgimento da civilização Ocidental e de suas instituições, entre elas, a própria mídia , entendendo-os como veiculadores de informações, característica também definidora do midiático. A pesquisa estuda conceitos propostos pela Teoria da Mídia nas reflexões de Norval Baitello, Harry Pross e Vilém Flusser. A angústia com relação ao futuro é lida a partir de Soren Kierkegaard e Carl Gustav Jung. Com o conceito ansiedade cultural de Rafael Lopez-Pedraza, pensa-se a relação dos indivíduos e da sociedade com o futuro, relação essa estudada também em Julian Jaynes com sua desconstrução da mente bicameral. Além de Norbert Elias, que investiga o que ele mesmo denomina de sociedade dos indivíduos. A hipótese é testada a partir de exemplos midiáticos que analisam temas como a crise econômica instaurada pela bolha imobiliária americana; a crise hídrica brasileira em 2015; e previsões feitas sobre resultados de jogos em campeonatos esportivos

Técnicas de visualização de informação, tais como as que utilizam posicionamento de pontos baseado na similaridade do conteúdo, são utilizadas para criar representações visuais de dados que evidenciem certos padrões. Essas técnicas são sensíveis à qualidade dos dados, a qual, por sua vez, depende de uma etapa de pré-processamento muito influente. Esta etapa envolve a limpeza do texto e, em alguns casos, a detecção de termos e seus pesos, bem como a definição de uma função de (dis)similaridade. Poucos são os estudos realizados sobre como esses cálculos de (dis)similaridade afetam a qualidade das representações visuais geradas para dados textuais. Este trabalho apresenta um estudo sobre o papel das diferentes medidas de (dis)similaridade entre pares de textos na geração de mapas visuais. Nos concentramos principalmente em dois tipos de funções de distância, aquelas computadas a partir da representação vetorial do texto (Vector Space Model (VSM)) e em medidas de comparação direta de strings textuais. Comparamos o efeito na geração de mapas visuais com técnicas de posicionamento de pontos, utilizando as duas abordagens. Para isso, foram utilizadas medidas objetivas para comparar a qualidade visual dos mapas, tais como Neighborhood Hit (NH) e Coeficiente de Silhueta (CS). Descobrimos que ambas as abordagens têm pontos a favor, mas de forma geral, o VSM apresentou melhores resultados quanto à discriminação de classes. Porém, a VSM convencional não é incremental, ou seja, novas adições à coleção forçam o recálculo do espaço de dados e das dissimilaridades anteriormente computadas. Nesse sentido, um novo modelo incremental baseado no VSM (Incremental Vector Space Model (iVSM)) foi considerado em nossos estudos comparativos. O iVSM apresentou os melhores resultados quantitativos e qualitativos em diversas configurações testadas. Os resultados da avaliação são apresentados e recomendações sobre a aplicação de diferentes medidas de similaridade de texto em tarefas de análise visual, são oferecidas / Information visualization techniques, such as similarity based point placement, are used for generating of visual data representation that evidence some patterns. These techniques are sensitive to data quality, which depends of a very influential preprocessing step. This step involves cleaning the text and in some cases, detecting terms and their weights, as well as definiting a (dis)similarity function. There are few studies on how these (dis)similarity calculations aect the quality of visual representations for textual data. This work presents a study on the role of the various (dis)similarity measures in generating visual maps. We focus primarily on two types of distance functions, those based on vector representations of the text (Vector Space Model (VSM)) and measures obtained from direct comparison of text strings, comparing the effect on the visual maps obtained with point placement techniques with the two approaches. For this, objective measures were employed to compare the visual quality of the generated maps, such as the Neighborhood Hit and Silhouette Coefficient. We found that both approaches have strengths, but in general, the VSM showed better results as far as class discrimination is concerned. However, the conventional VSM is not incremental, i.e., new additions to the collection force the recalculation of the data space and dissimilarities previously computed. Thus, a new model based on incremental VSM (Incremental Vector Space Model (iVSM)) has been also considered in our comparative studies. iVSM showed the best quantitative and qualitative results in several of the configurations considered. The evaluation results are presented and recommendations on the application of different similarity measures for text analysis tasks visually are provided

Ein wichtiges Gebiet der Finanzmathematik ist die Bestimmung von Auszahlungsprofilen, die den erwarteten Nutzen eines Agenten unter einer Budgetrestriktion maximieren. Wir charakterisieren optimale Auszahlungsprofile für einen Agenten, der unsicher ist in Bezug auf das genaue Marktmodell. Der hier benutzte Dualitätsansatz führt zu einem Minimierungsproblem für bestimmte konvexe Funktionale über zwei Mengen von Wahrscheinlichkeitsmaßen, das wir zunächst lösen müssen. Schließlich führen wir noch eine zweite Restriktion ein, die das Risiko beschränkt, das der Agent eingehen darf. Wir gehen dabei wie folgt vor: Kapitel 1. Wir betrachten das Problem, die f-Divergenz f(P|Q) über zwei Mengen von Wahrscheinlichkeitsmaßen zu minimieren, wobei f eine konvexe Funktion ist. Wir zeigen, dass unter der Bedingung "f( undendlich ) / undendlich = undendlich" Minimierer existieren, falls die erste Menge abgeschlossen und die zweite schwach kompakt ist. Außerdem zeigen wir, dass unter der Bedingung "f( undendlich ) / undendlich = 0" ein Minimierer in einer erweiterten Klasse von Martingalmaßen existiert, falls die zweite Menge schwach kompakt ist. Kapitel 2. Die Existenzresultate aus dem ersten Kapitel implizieren die Existenz eines Auszahlungsprofils, das das robuste Nutzenfunktional inf E_Q[u(X)] über eine Menge von finanzierbaren Auszahlungen maximiert, wobei das Infimum über eine Menge von Modellmaßen betrachtet wird. Die entscheidende Idee besteht darin, die minimierenden Maße aus dem ersten Kapitel als gewisse "worst-case"-Maße zu identifizieren. Kapitel 3. Schließlich fordern wir, dass das Risiko der Auszahlungsprofile beschränkt ist. Wir lösen das robuste Problem in einem unvollständigen Marktmodell für Nutzenfunktionen, die nur auf der positiven Halbachse definiert sind. In einem Beispiel vergleichen wir das optimale Auszahlungsprofil unter der Risikorestriktion mit den optimalen Auszahlungen ohne eine solche Restriktion und unter einer Value-at-Risk-Nebenbedingung. / Finding payoff profiles that maximize the expected utility of an agent under some budget constraint is a key issue in financial mathematics. We characterize optimal contingent claims for an agent who is uncertain about the market model. The dual approach that we use leads to a minimization problem for a certain convex functional over two sets of measures, which we first have to solve. Finally, we incorporate a second constraint that limits the risk that the agent is allowed to take. We proceed as follows: Chapter 1. Given a convex function f, we consider the problem of minimizing the f-divergence f(P|Q) over these two sets of measures. We show that, if the first set is closed and the second set is weakly compact, a minimizer exists if f( infinity ) / infinity = infinity. Furthermore, we show that if the second set of measures is weakly compact and f( infinifty ) / infinity = 0, then there is a minimizer in a class of extended martingale measures. Chapter 2. The existence results in Chapter 1 lead to the existence of a contingent claim which maximizes the robust utility functional inf E_Q[u(X)] over some set of affordable contingent claims, where the infimum is taken over a set of subjective or modell measures. The key idea is to identify the minimizing measures from the first chapter as certain worst case measures. Chapter 3. Finally, we require the risk of the contingent claims to be bounded. We solve the robust problem in an incomplete market for a utility function that is only defined on the positive halfline. In an example we compare the optimal claim under this risk constraint with the optimal claims without a risk constraint and under a value-at-risk constraint.

La Tesis Doctoral está dedicada al estudio de ciertas propiedades de los radios sucesivos de los cuerpos convexos (funcionales definidos a partir de circunradios e inradios de proyecciones o secciones del cuerpo). Comenzamos estableciendo las nociones básicas necesarias para el desarrollo de los contenidos. A continuación calculamos los radios sucesivos de familias particulares de conjuntos (p-bolas, anchura constante, cuerpos tangenciales), y estudiamos la conexión existente entre estos funcionales y los números de Gelfand y Kolmogorov. En el tercer capítulo consideramos el problema de Pukhov-Perel'man sobre la mejor cota superior para un cierto cociente de radios, determinando desigualdades para problemas de este tipo que van a permitir mejorar los resultados existentes en ciertos casos. Finalmente, estudiamos cómo se relacionan los radios sucesivos de la suma de Minkowski (Firey) de dos cuerpos convexos con los correspondientes funcionales de los conjuntos, obteniendo los resultados óptimos en todos los casos. / The Doctoral Thesis is focused in the study of some properties of the successive radii of convex bodies (functionals defined by means of circumradii and inradii of projections or sections of the set). We start establishing the basic notions that will be needed further on. Next, we compute the successive radii of particular families of sets (p-balls, constant width sets and tangential bodies), and study the connection between these functionals and the Gelfand and Kolmogorov numbers. In the third chapter we consider the Pukhov-Perel'man problem on the best upper bound for a particular ratio of radii, determining inequalities for some problems of this type which will allow to improve the known results in particular cases. Finally we study how the successive radii of the (Firey)-Minkowski addition of two convex bodies are related with the corresponding functionals of the sets, obtaining the optimal results in all cases.

No description available.

Facing the urgency of taking actions to guarantee the water supply to Brazil's Capital, the project called IWAS/ÁguaDF aims to provide scientific knowledge for the development of an Integrated Water Resources Management (IWRM) concept. The project is organized in multiple working groups wherein climate is considered as one of the main drivers. The water supply system of Distrito Federal (DF) is mainly dependent on three major complexes: river basins, waste water and drinking water. Anthropogenic climate change has the potential to affect these water complexes in a number of ways such as by losing storage capacity due to erosion and sedimentation, through altered persistency of dry events and due to increasing water demand. As a contribution to the IWAS/ÁguaDF project, this study focuses on the development of climate change projections for hydrological impact assessments at local/regional scale. The development of proper climate information is a challenging task. The level of complexity corresponds directly to the issues that concern impact modellers as well as technical aspects such as available observational data, human and computational resources. The identification of the needs for water-related issues gives the foundation for deriving proper climate projections. Before making projections, it is necessary to assess the current climate conditions, or baseline climate. Despite a better understanding of the regional aspects of the climate and the ongoing changes, the baseline climate provides the foundation for calibrating and validating climate models and downscaling methods. The General Circulation Models (GCMs) are the most preferred tools in simulating the response of the climate system to anthropogenic activities, like increasing greenhouse gases and aerosol emissions. However, the climate information required for regional impact studies, such as water resources management in DF, is of a spatial scale much finer than that provided by GCMs and therefore often demands a downscaling procedure. Hydrological models are usually sensitive to the temporal variability of precipitation at scales that are not well represented by GCMs. Statistical downscaling methods have the potential to bridge the mismatch between GCMs and impact models by adding local variability that is consistent with both the large-scale signal and local observations. The tool used (i.e., Statistical DownScaling Model - SDSM) is described as a hybrid of regression-based and stochastic weather generator. The systematic calibration adopted provides the appropriated predictors and model parameterization. The validation procedure takes into account the metrics relevant to the requirements of hydrological studies. Moreover, the downscaling approach considers several climate models (i.e., 18 GCMs) and emission scenarios (i.e., SRES A1B, A2, B1) in order to sample the widest sources of uncertainties available. In spite of the elevated level of uncertainties in the magnitude of change, most of the downscaled projections agree with positive changes in temperature and precipitation for the period of 2046-2065 when compared to the reference period (i.e., 1980-1999). Large ensembles are preferable but are often associated with massive amount of data which have limited application in hydrological impact studies. An alternative is to identify subsets of projections that are most likely and projections that have lower likelihood but higher impact. A set of representative climate projections is suggested for hydrological impact assessments. Although high resolution information is preferable, it relies on limited assumptions inherent to observations and coarse-resolution projections and, therefore, its use alone is not recommended. The combination of the baseline climate with large- and local-scale projections achieved in this study provides a wide envelope of climate information for assessing the sensitivity of hydrological systems in DF. A better understanding of the vulnerability of hydrological systems through the application of multiple sources of climate information and appropriate sampling of known uncertainties is perhaps the best way to contribute to the development of robust adaptation strategies. / Starkes Bevölkerungswachstum sowie Landnutzungs- und Klimawandel gefährden die Wasserversorgung der Metropolregion Brasília. Vor diesem Hintergrund soll das Projekt IWAS/ÁguaDF die wissenschaftlichen Grundlagen für ein Integriertes Wasserressourcen-Management (IWRM) im Distrito Federal (DF) erarbeiten. Das Projekt gliedert sich in drei klimasensitive Bereiche: Einzugsgebietsmanagement, Abwasseraufbereitung und Trinkwasserversorgung. Klimaänderungen können die Wasserversorgung im DF vielfältig beeinflussen, durch Veränderung der speicherbaren Wassermenge (Wasserdargebot, Speicherkapazität von Talsperren durch Sedimentation), der Dauer von Dürreperioden und des Wasserbedarfs (z.B. für Bewässerung). Klimaprojektionen für regionale hydrologische Impaktstudien stellen jedoch eine große Heraus-forderung dar. Ihre Komplexität richtet sich nach dem Bedarf des Impaktmodellierers und hängt zudem von technischen Voraussetzungen ab, wie der Verfügbarkeit von Beobachtungsdaten sowie von Personal- und Rechenressourcen. Die Ableitung geeigneter Maßnahmen für ein nachhaltiges Wasserressourcenmanagement im DF stellt hohe Ansprüche an die Qualität der zu entwickelnden Klimaprojektionen. Noch vor der Projektion müssen die gegenwärtigen klimatischen Bedingungen (Referenzklima) analysiert und bewertet werden. Die Analyse des Referenzklimas ermöglicht ein besseres Verständnis regionaler Unterschiede und aktueller Tendenzen und bildet die Grundlage für die Kalibrierung und Validierung von Klimamodellen und Downscaling-Methoden. Globale Klimamodelle (GCM) simulieren die Reaktion des Klimasystems auf anthropogene Treibhausgas- und Aerosolemissionen. Ihre räumliche Auflösung ist jedoch meist zu grob für regionale Klimaimpaktstudien. Zudem reagieren hydrologische Modelle meist sehr sensitiv auf zeitlich variable Niederschläge, welche in hoher zeitlicher Auflösung (Tagesschritte) ebenfalls nur unzureichend in GCM abgebildet werden. Statistische Downscaling-Verfahren können diese Inkohärenz zwischen GCM und Impaktmodellen reduzieren, indem sie das projizierte Klimasignal um lokale Variabilität (konsistent gegenüber den Beobachtungen) erweitern. Das in der vorliegenden Arbeit verwendete Tool, Statistical DownScaling Model - SDSM, vereint regressionsbasierte und stochastische Methoden der Wettergenerierung. Geeignete Prädiktoren und Modelparameter wurden durch systematische Kalibrierung bestimmt und anschließend validiert, wobei unter anderem auch hydrologisch relevante Gütekriterien verwendet wurden. Der gewählte Downscaling-Ansatz berücksichtigt zudem eine Vielzahl verschiedener Globalmodelle (18 GCM) und Emissionsszenarien (SRES A1B, A2 und B1) um die mit Klimaprojektionen verbundene hohe Unsicherheit möglichst breit abzudecken. Die Mehrheit der regionalen Projektionen weist auf eine Zunahme von Temperatur und Niederschlag hin (Zeitraum 2046 bis 2065 gegenüber Referenz-zeitraum, 1980 bis 1999), wenngleich die Stärke des Änderungssignals stark über das Ensemble variiert. Große Modellensemble sind zwar von Vorteil, sie sind jedoch auch mit einer erheblichen Datenmenge verbunden, welche für hydrologische Impaktstudien nur begrenzt nutzbar ist. Alternativ können einzelne „wahrscheinliche“ Projektionen verwendet werden sowie Projektionen, die weniger wahrscheinlich, aber mit einem starken Impakt verbunden sind. Ein solcher Satz repräsentativer Klimaprojektionen wurde für weitergehende Impaktstudien ausgewählt. Auch wenn in der Regel hochaufgelöste Klimaprojektionen angestrebt werden, ihr alleiniger Einsatz in Impaktstudien ist nicht zu empfehlen, aufgrund der vereinfachten Annahmen über die statistische Beziehung zwischen Beobachtungsdaten und den Modellergebnissen grob aufgelöster Globalmodelle. Der Vergleich des Referenzklimas mit großräumigen und lokalen Projektionen, wie er in dieser Arbeit durchgeführt wurde, liefert ein breites Spektrum an Klimainformationen zur Bewertung der Vulnerabilität hydrologischer Systeme im DF. Die Einbeziehung einer Vielzahl vorhandener Klimamodelle und die gezielte, den ermittelten Unsicherheitsbereich vollständig abdeckende Auswahl an Projektionen sollte die Entwicklung robuster Anpassungsstrategien bestmöglich unterstützen. / Diante do desafio de garantir o abastecimento de água potável da capital federal do Brasil, o projeto denominado IWAS/ÁguaDF tem como objetivo prover conhecimento científico para o desenvolvimento de um conceito de Gestão Integrada dos Recursos Hídricos (PGIRH). Afim de atingir esta proposta, o projeto é organizado em multiplos grupos de trabalho entre os quais o clima é considerado um dos principais fatores de influência. O sistema de abastecimento de água do Distrito Federal (DF) depende praticamente de três complexos: bacias hidrográficas, águas residuais e água potável. Mudanças climáticas causadas por ações antropogênicas apresentam um enorme potencial de impacto a estes complexos, por exemplo através de alterações no regime de chuvas, perda de volume dos reservatórios por assoriamento e aumento na demanda de água. Como contribuição ao projeto IWAS/ÁguaDF, este estudo tem como foco o desenvolvimento de projeções de mudanças climáticas para estudo de impacto nos recursos hídricos na escala local/regional. O nível de complexidade corresponde diretamente às questões levantadas pelos modeladores de impacto, bem como aspecto técnicos como a disponibilidade de dados observados e recursos humanos e computacionais. A identificação das necessidades de questões relacionadas à água no DF dão a base para derivar projeções climáticas adequadas. Antes de qualquer projeção futura, é indispensável avaliar as condições atuais do clima, também chamado de linha de base do clima. Além de fornecer a compreenção dos aspectos regionais do clima e mudaças em curso, a linha de base provê dados para a calibração e validação de modelos globais de clima e técnicas de regionalização (downscaling). Os Modelos de Circulação Geral (GCM) são as ferramentas mais adotadas na simulação da resposta do sistema climático às atividades antropogênicas, tais como aumento de emissões de gases do efeito estufa e aerosóis. No entanto, a informação necessária para estudos regionais de impacto, tais como gestão de recursos hídricos, é de escala espacial mais refinada do que a resolução espacial fornecida pelos GCMs e, dessa forma, técnicas de regionalização são frequentemente demandadas. Modelos hidrológicos são geralmente sensitivos à variabilidade temporal de precipitação em escalas não representadas pelos modelos globais. Métodos estatísticos de ‘downscaling’ apresentam um potencial para auxiliar no descompasso entre GCMs e modelos de impacto através da adição de variabilidade local consistente com o sinal de larga escala e as observações locais. A ferramenta utilizada (Statistical DownScaling Model - SDSM) é descrita como um híbrido entre regressão linear e gerador de tempo estocástico. A calibração sistemática adotada fornece apropriados preditores e uma parameterização consistente. O procedimento de validação do modelo leva em conta as métricas relevantes aos requerimentos dos estudos hidrológicos. Ainda, a abordagem aqui utilizada considera diversos modelos globais (isto é, 18 GCMs) e cenários de emissões (isto é, SRES A1B, A2 e B1) afim de contemplar as mais abrangentes fontes de incertezas disponíveis. Embora o elevado nível de incertezas na magnitude das mudançãs de clima, a grande maioria das projeções regionalizadas concordam com o aumento de temperatura e precipiatação para o período de 2046-2065 quando comparado com o período de referência (isto é, 1980-1999). Grandes conjuntos de projeções são preferíveis, mas são frequentement associados com uma quantidade exorbitante de dados os quais são de aplicação limiatada nos estudos de impacto. Uma alternativa é identificar sub-conjuntos de projeções que são as mais prováveis e projeções que são menos prováveis, porém apresentam maior impacto. Embora altas resoluções são preferíveis, estas baseiam-se em hipóteses inerentes às observações e projeções de larga escala e, dessa forma, não é recomendável o seu uso sozinho. A combinação do clima de base com projeções de resoluções baixas e altas fornece um amplo envelope de imformações climáticas para avaliar a sensitividade dos sistemas hidrológicos no DF. Um compreendimento mais apurado da vunerabilidade dos sistemas hidrológicos através da aplicação de multiplas fontes de informação e apropriada abordagem das incertezas conhecidas é talvez a melhor maneira para contribuir para o desenvolvimento de estratégias robustas de adaptação.

The development of new therapeutical approaches, devised to foster the regeneration of neuronal circuits after injury and/or in neurodegenerative diseases, is of great importance. The impairment of dopaminergic projections is especially severe, because these projections are involved in crucial brain functions such as motor control, reward and cognition. In the work presented here, organotypic brain slice co-cultures of (a) the mesostriatal and (b) the mesocortical dopaminergic projection systems consisting of tissue sections of the ventral tegmental area/substantia nigra (VTA/SN), in combination with the target regions of (a) the striatum (STR) or (b) the prefrontal cortex (PFC), respectively, were used to evaluate different approaches to stimulate neurite outgrowth: (i) inhibition of cAMP/cGMP turnover with 3’,5’ cyclic nucleotide phosphodiesterase inhibitors (PDE-Is), (ii) blockade of calcium currents with nimodipine, and (iii) the co-cultivation with bone marrow-derived mesenchymal stromal/stem cells (BM-MSCs). The neurite growth-promoting properties of the tested substances and cell populations were analyzed by neurite density quantification in the border region between the two brain slices, using biocytin tracing or tyrosine hydroxylase labeling and automated image processing procedures. In addition, toxicological tests and gene expression analyses were conducted. (i) PDE-Is were applied to VTA/SN+STR rat co-cultures. The quantification of neurite density after both biocytin tracing and tyrosine hydroxylase labeling revealed a growth promoting effect of the PDE2A-Is BAY60-7550 and ND7001. The application of the PDE10-I MP-10 did not alter neurite density in comparison to the vehicle control. (ii) The effects of nimodipine were evaluated in VTA/SN+PFC rat co-cultures. A neurite growth-promoting effect of 0.1 µM and 1 µM nimodipine was demonstrated in a projection system of the CNS. In contrast, the application of 10 µM nimodipine did not alter neurite density, compared to the vehicle control, but induced the activation of the apoptosis marker caspase 3. The expression levels of the investigated genes, including Ca2+ binding proteins (Pvalb, S100b), immediate early genes (Arc, Egr1, Egr2, Egr4, Fos and JunB), glial fibrillary acidic protein, and myelin components (Mal, Mog, Plp1) were not significantly changed (with the exception of Egr4) by the treatment with 0.1 µM and 1 µM nimodipine. (iii) Bulk BM-MSCs that were classically isolated by plastic adhesion were compared to the subpopulation Sca-1+Lin-CD45--derived MSCs (SL45-MSCs). The neurite growth-promoting properties of both MSC populations were quantified in VTA/SN+PFC mouse co-cultures. For this purpose, the MSCs were seeded on glass slides that were placed underneath the co-cultures. A significantly enhanced neurite density within the co-cultures was induced by both bulk BM-MSCs and SL45-MSCs. SL45-MSCs increased neurite density to a higher degree. The characterization of both MSC populations revealed that the frequency of fibroblast colony forming units (CFU-f ) is 105-fold higher in SL45-MSCs. SL45-MSCs were morphologically more homogeneous and expressed higher levels of nestin, BDNF and FGF2 compared to bulk BM-MSCs. Thus, this work emphasizes the vast potential for molecular targeting with respect to the development of therapeutic strategies in the enhancement of neurite regrowth.

To be able to make informed descicions regarding the research of new drug molecules (ligands), it is crucial to have access to information regarding the chemical interaction between the drug and its biological target (protein). Computer-based methods have a given role in drug research today and, by using methods such as molecular docking, it is possible to investigate the way in which ligands and proteins interact. Despite the acceleration in computer power experienced in the last decades many problems persist in modelling these complicated interactions. The main objective of this thesis was to investigate and improve molecular modelling methods aimed to estimate protein-ligand binding. In order to do so, we have utilised chemometric tools, e.g. design of experiments (DoE) and principal component analysis (PCA), in the field of molecular modelling. More specifically, molecular docking was investigated as a tool for reproduction of ligand poses in protein 3D structures and for virtual screening. Adjustable parameters in two docking software were varied using DoE and parameter settings were identified which lead to improved results. In an additional study, we explored the nature of ligand-binding cavities in proteins since they are important factors in protein-ligand interactions, especially in the prediction of the function of newly found proteins. We developed a strategy, comprising a new set of descriptors and PCA, to map proteins based on their cavity physicochemical properties. Finally, we applied our developed strategies to design a set of glycopeptides which were used to study autoimmune arthritis. A combination of docking and statistical molecular design, synthesis and biological evaluation led to new binders for two different class II MHC proteins and recognition by a panel of T-cell hybridomas. New and interesting SAR conclusions could be drawn and the results will serve as a basis for selection of peptides to include in in vivo studies.

Le Québec, comme la plupart des sociétés occidentales, fait face à un vieillissement de sa population, engendrant de nombreuses conséquences économiques, politiques et sociales. Une solution souvent envisagée est de compter sur l’immigration pour amoindrir, repousser ou même contrer certaines conséquences. C’est à cet effet que la migration de remplacement apporte sa contribution : elle a pour but de connaître le nombre d’immigrants nécessaire pour atteindre des objectifs démographiques précis, soit, dans le cadre de cette étude, éviter le déclin de la population totale, éviter le déclin de la population en âge de travailler et éviter que la part des 65 ans et plus dans la population totale dépasse 25%. Les résultats démontrent qu’il serait possible pour le Québec d’éviter le déclin de sa population si la fécondité ne diminue pas et si une bonne gestion de l’immigration est appliquée : la migration de remplacement n’est pas excessivement élevée. Cependant, accueillir trop d’immigrants avant que cela ne soit essentiel nuirait à l’atteinte de cet objectif. Le déclin de la population âgée entre 20 et 64 ans est quant à lui inévitable : peu importe le niveau de fécondité, la migration de remplacement est beaucoup plus élevée pour les deux prochaines décennies que tout ce qui a pu être envisagé pour le Québec. Finalement, l’immigration n’a pas d’impact significatif sur la structure par âge d’une population : il est donc tout à fait irréaliste de vouloir compter sur cette composante pour éviter que la part des 65 ans et plus dans la population totale ne dépasse 25%. La seule façon pour que cet objectif soit possible serait une augmentation rapide de la fécondité au seuil de renouvellement de la population. Cela signifie que l’immigration ne peut en aucun cas empêcher le vieillissement de la population ou avoir un impact significatif sur le processus. / Quebec, as most Western societies, is facing the ageing of its population, producing many economic, political and social impacts. One solution often considered is to rely on immigration to reduce, delay or even counter certain consequences. For this purpose, replacement migration is sometimes seen as a solution : it aims to establish the number of immigrants needed to reach specific demographic targets, which are, in this study, to prevent total population decline, to prevent working-age population decline and to prevent that the percentage of those 65 years and over exceeds 25% of the total population. The results show that it could be possible for Quebec to prevent the decline of its population if fertility is not decreasing and if immigration is well managed : replacement migration is not excessively high. However, raising the immigration level too quickly could impede to reach this objective. The decline of the population aged between 20 and 64 years is inevitable : no matter the level of fertility, replacement migration is much higher for the next two decades that what has been planned for Quebec. Finally, immigration has no significant impact on the age structure of a population: it is quite unrealistic to expect this component to prevent that the percentage of those 65 years and over in the total population exceeds 25%. The only way to reach this objective is a rapid increase of fertility at the replacement level. This means that immigration can in no way prevent the ageing of the population or have a significant impact on the process. / Récipiendaire du prix Jacques-Henripin décerné au meilleur mémoire de l'année 2008 en démographie canadienne.

Roll compaction is a continuous process commonly used in the pharmaceutical industry for dry granulation of moisture and heat sensitive powder blends. It is intended to increase bulk density and improve flowability. Roll compaction is a complex process that depends on many factors, such as feed powder properties, processing conditions and system layout. Some of the variability in the process remains unexplained. Accordingly, modeling tools are needed to understand the properties and the interrelations between raw materials, process parameters and the quality of the product. It is important to look at the whole manufacturing chain from raw materials to tablet properties. The main objective of this thesis was to investigate the impact of raw materials, process parameters and system design variations on the quality of intermediate and final roll compaction products, as well as their interrelations. In order to do so, we have conducted a series of systematic experimental studies and utilized chemometric tools, such as design of experiments, latent variable models (i.e. PCA, OPLS and O2PLS) as well as mechanistic models based on the rolling theory of granular solids developed by Johanson (1965). More specifically, we have developed a modeling approach to elucidate the influence of different brittle filler qualities of mannitol and dicalcium phosphate and their physical properties (i.e. flowability, particle size and compactability) on intermediate and final product quality. This approach allows the possibility of introducing new fillers without additional experiments, provided that they are within the previously mapped design space. Additionally, this approach is generic and could be extended beyond fillers. Furthermore, in contrast to many other materials, the results revealed that some qualities of the investigated fillers demonstrated improved compactability following roll compaction. In one study, we identified the design space for a roll compaction process using a risk-based approach. The influence of process parameters (i.e. roll force, roll speed, roll gap and milling screen size) on different ribbon, granule and tablet properties was evaluated. In another study, we demonstrated the significant added value of the combination of near-infrared chemical imaging, texture analysis and multivariate methods in the quality assessment of the intermediate and final roll compaction products. Finally, we have also studied the roll compaction of an intermediate drug load formulation at different scales and using roll compactors with different feed screw mechanisms (i.e. horizontal and vertical). The horizontal feed screw roll compactor was also equipped with an instrumented roll technology allowing the measurement of normal stress on ribbon. Ribbon porosity was primarily found to be a function of normal stress, exhibiting a quadratic relationship. A similar quadratic relationship was also observed between roll force and ribbon porosity of the vertically fed roll compactor. A combination of design of experiments, latent variable and mechanistic models led to a better understanding of the critical process parameters and showed that scale up/transfer between equipment is feasible.