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Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Parkinson’s Disease (PD) is the second most common neurodegenerative disease (NDD) affecting approximately 1 - 2% of the population older than 65 and it is characterized by both motor and non-motor symptoms such as rest tremors, stooping posture, and rigidity. The neuromolecular basis of PD is quite complex and that is why there is a need for in vitro systems that can be utilized for studies of PD and NDDs in general. Human-derived cell lines are a good candidate for in vitro systems since they are easy to manipulate and are a less costly alternative to post-mortem human tissue sections or animal models. In this study, I optimize the Lund human mesencephalic (LUHMES) cell line differentiation protocol by determining that the optimal seeding density of cells is 37 500 cells/ml and that the differentiation media can contain quadruple the recommended concentration of tetracycline hydrochloride. Additionally, I use the differentiated LUHMES cells to conduct an exploratory study by treating the cells with cerebrospinal fluid (CSF) from PD patients and CSF from healthy individuals to investigate the neuromodulatory effects of the CSF on the neuronal cell culture. Cell viability assay showed neurotoxicity 24 hours post-treatment for the control CSF and 48 hours post-treatment for both control and PD CSF. Immunohistochemistry showed differential expression of proteins of interest that reflect hallmarks of neurodegenerative diseases. Further studies are needed to reach conclusive results.

The rapid advances in technology and increase of tech investments across all the industries have promoted the emergence of several startups. Unfortunately, not all startups succeed despite of having good initial ideas. One reason to the poor business performance could be a lack of managerial control. Researchers and industry experts believe that performance management could support tech entrepreneurs to monitor and control the drivers that promote growth and their success. However, there is a lack of studies that could support these thoughts about its suitability for tech startups. Therefore, this study gathers empirical findings from Swedish tech startups as well as industry experts to discuss this issue. The findings show that a performance measurement system such as the Balanced Scorecard is a suitable practice for tech entrepreneurs. It also brings some insights about how the performance measurements evolve as the firms mature.

Le traitement du cancer à l’aide d’une exposition aux radiations ionisantes peut mener au développement de plusieurs effets secondaires importants, dont un retard de réparation et de régénération du tissu hématopoïétique. Les mécanismes responsables de ces effets demeurent encore inconnus, ce qui limite le développement de nouvelles approches thérapeutiques. À l’aide d’un modèle murin de prise de greffe, nos résultats démontrent que l’endommagement du microenvironnement par l’irradiation a un impact limitant sur le nichage hématopoïétique. Parce que le microenvironnement est composé principalement de cellules dérivées des cellules souches mésenchymateuses (CSM), nous avons évalué le potentiel des CSM à régénérer le tissu hématopoïétique par la reconstitution de la niche osseuse. Cette thérapie a mené à une augmentation remarquable du nichage hématopoïétique chez les souris irradiées. Les causes moléculaires impliquées dans le nichage hématopoïétiques sont encore inconnues, mais nous avons remarqué l’augmentation de la sécrétion de la cytokine « granulocyte-colony stimulating factor » (G-CSF) dans l’espace médullaire suite à l’irradiation. Le G-CSF est impliqué dans la mobilisation cellulaire et est fort possiblement nuisible à une prise de greffe. Nous avons évalué le potentiel d’une thérapie à base de CSM sécrétant le récepteur soluble du G-CSF afin de séquestrer le G-CSF transitoirement et les résultats obtenus démontrent que le blocage du G-CSF favorise le nichage hématopoïétique. Globalement, les données présentées dans ce mémoire démontrent que le microenvironnement osseux et le niveau de G-CSF dans la moelle sont importants dans le processus de nichage hématopoïétique et que la baisse du potentiel de régénération du tissu hématopoïétique suite à l’irradiation peut être renversée à l’aide d’une thérapie cellulaire de CSM génétiquement modifiées ou non. / Cancer treatment using ionizing radiation may lead to significant side effects, including delayed hematopoietic tissue repair and regeneration. The mechanisms mediating these defects remain unknown, thus limiting the development of new therapeutic approaches. Using a mouse engraftment model, our results show that microenvironment damage by irradiation limits hematopoietic homing. Since the microenvironment is mainly composed of mesenchymal stem cells (MSCs)-derived cells, we evaluated the potential of MSCs to improve hematopoietic tissue regeneration by bone marrow niche reconstitution. This therapy led to remarkable enhancement of hematopoietic homing in irradiated mice. The molecular causes involved in hematopoietic homing remain unknown, but we noticed an increased in “granulocyte-colony stimulating factor” (G-CSF) secretion within the medullary space after irradiation. G-CSF is involved in cellular mobilization and may possibly be harmful to engraftment. We evaluated the therapeutical potential of MSC genetically-engineered to secrete a soluble G-CSF decoy receptor that would transiently sequester G-CSF. Results obtained show that G-CSF blocking improved hematopoietic homing. Overall, the findings presented in this thesis indicate that bone marrow microenvironment and G-CSF levels are important in hematopoietic homing process, and that the decline in hematopoietic tissue regeneration potential following irradiation can be reversed by cellular therapy using MSC genetically modified or not.

<div>Hydrocephalus is a debilitating disease characterized by an increase in cerebrospinal fluid (CSF) in the brain, leading to increases in pressure that can ultimately result in death. Current treatments for hydrocephalus include only invasive brain surgery. Therefore, the need for a pharmaceutical therapy is great. In order to develop a suitable treatment, we first must be able to study the disease and the mechanisms by which it develops. By characterizing appropriate in vivo and in vitro models, we are better able to study this disease. In this thesis, the Wpk rat model and the PCP-R cell line are described as such appropriate models. In addition to suitable models, we also require a target for drug treatment. Transient Receptor Potential Vanilloid 4 (TRPV4) is a non-selective cation ion channel present in the main CSF-producing organ in the brain, the choroid plexus (CP). Preliminary data suggest this channel plays a role in the development of hydrocephalus. In the following work, some of the mechanisms by which TRPV4 functions in the brain are also described, including through calcium-sensitive potassium channels and inflammation. From this research, we are able to achieve a better understanding of the function of TRPV4 and how it can affect the development and progression of hydrocephalus.</div>

O presente trabalho, inserido em uma proposta interdisciplinar de pesquisa entre sistemas complexos e políticas públicas, teve como intuito prover subsídios para a avaliação do programa Ciência sem Fronteiras (CsF), especialmente no contexto de políticas públicas de internacionalização e de Ciência, Tecnologia e Inovação (CT&I). O programa visa promover a consolidação, expansão e internacionalização da ciência e tecnologia, da inovação e da competitividade brasileira por meio do intercâmbio e da mobilidade internacional. A pesquisa examinou o ciclo de formulação, implementação e avaliação do programa para investigar se o investimento em mobilidade acadêmica internacional pode ser um mecanismo efetivo para fomentar a colaboração científica internacional. Inicialmente, foi entendido que o Brasil possui dois problemas fundamentais no campo de CT&I: i) déficit na formação de recursos humanos qualificados; e ii) baixa inserção científica e tecnológica no cenário internacional. Visto o problema, a formulação do CsF insere-se como parte da solução dentro de uma agenda estratégica nacional elaborada pelo Ministério de Ciência, Tecnologia e Inovação. Após quatro anos de implementação, em 2015 o programa atingiu a meta de conceder 101 mil bolsas de intercâmbio acadêmico, mas extrapolou em mais de três vezes o orçamento previsto. Entretanto, teve um efeito positivo para o aumento da oferta de bolsas no exterior em todas as áreas (inclusive as não contempladas pelo programa) e não interferiu nos recursos financeiros das bolsas de formação no país. Com o uso de dados bibliométricos, foram encontrados indícios de que o programa foi capaz de estimular e manter a colaboração internacional entre pesquisadores. Todavia, ainda não é possível afirmar se os efeitos são significativos ou não, por isso se faz necessário avaliações futuras sobre a influência do programa nas mais diversas disciplinas científicas e nas respectivas redes de coautorias, além de estudos sobre outras questões que derivam do trabalho. Devido a dificuldades específicas com coleta e uso de dados durante o processo avaliativo, o trabalho recomenda: i) que bancas de especialistas compilem grupos de palavras-chave que caracterizem as áreas científicas; ii) que dados sobre o Ciência sem Fronteiras disponíveis para visualização sejam também disponíveis para download; e iii) que a Plataforma Lattes inclua no currículo dos pesquisadores a opção de registro sobre o programa de bolsas a que foram vinculados. Por fim, o trabalho ressalta o entendimento de que o programa Ciência sem Fronteiras foi positivo no sentido de aumentar a visibilidade internacional da educação superior brasileira e inseriu as universidades e outras instituições brasileiras em programas de cooperação internacional no campo da pesquisa. Neste sentido, recomenda-se que o Brasil deve envidar esforços para manter uma política pública de mobilidade acadêmica internacional, mesmo que em dimensões menores e de maneira reformulada / This work, as part of an interdisciplinary proposal of research between complex systems and public policies, intends to provide subsidies for the evaluation of the Brazil Science without Borders (SwB) program, especially in the context of Science, Technology and Innovation (ST&I) and internationalization public policies. The program sought to promote the consolidation, expansion and internationalization of Brazilian science and technology, innovation and competitiveness through exchange and international mobility. The research examined the program\'s formulation, implementation and evaluation cycle to investigate whether investment in international academic mobility could be an effective mechanism to foster international scientific collaboration. Firstly, Brazil has two fundamental problems in the field of ST&I: i) deficits in the formation of qualified human resources; and ii) low scientific and technological insertion in the international scenario. Given these problems, the creation of the SwB was part of a solution within a national strategic agenda of improving Brazils standing within the fields of ST&I. From its inception to its conclusion four years later, the program achieved the goal of granting 101,000 exchange scholarships, but went three times over budget. However, SwB had a positive effect by increasing overseas scholarship offerings in all areas (even those not explicitly covered by the program) and did not interfere with the financial resources of the scholarship grants in the country. The use of bibliometric data has shown that the program was able to stimulate and maintain international collaboration among researchers. However, it is not yet possible to state whether the effects are significant or not, so it is necessary to evaluate the influence of the program in different scientific disciplines and in their respective co-authorship networks, as well as other issues derived from the work. Because of specific difficulties in collecting and using data during the evaluation process, this dissertation recommends: i) that expert panels compile groups of keywords that characterize the scientific disciplines; ii) that data on Science without Borders available for visualization also become available for download; and iii) that the Lattes Platform includes in the researchers\' curriculum the option of registering the scholarship program they were linked to. Finally, the paper acknowledges that the Science without Borders program improved the international visibility of Brazils higher education and inserted universities and other Brazilian institutions into international research cooperation programs. In this sense, the author recommends that Brazil should make efforts to maintain such a public policy of international academic mobility, even in a reduced or reformed format

The Pulse Couple Neural Network (PCNN) was developed by Eckhorn to model the observed synchronization of neural assemblies in the visual cortex of small mammals such as a cat. In this dissertation, three novel PCNN based automatic segmentation algorithms were developed to segment Magnetic Resonance Imaging (MRI) data: (a) PCNN image 'signature' based single region cropping; (b) PCNN - Kittler Illingworth minimum error thresholding and (c) PCNN -Gaussian Mixture Model - Expectation Maximization (GMM-EM) based multiple material segmentation. Among other control tests, the proposed algorithms were tested on three T2 weighted acquisition configurations comprising a total of 42 rat brain volumes, 20 T1 weighted MR human brain volumes from Harvard's Internet Brain Segmentation Repository and 5 human MR breast volumes. The results were compared against manually segmented gold standards, Brain Extraction Tool (BET) V2.1 results, published results and single threshold methods. The Jaccard similarity index was used for numerical evaluation of the proposed algorithms. Our quantitative results demonstrate conclusively that PCNN based multiple material segmentation strategies can approach a human eye's intensity delineation capability in grayscale image segmentation tasks.

O presente trabalho, inserido em uma proposta interdisciplinar de pesquisa entre sistemas complexos e políticas públicas, teve como intuito prover subsídios para a avaliação do programa Ciência sem Fronteiras (CsF), especialmente no contexto de políticas públicas de internacionalização e de Ciência, Tecnologia e Inovação (CT&I). O programa visa promover a consolidação, expansão e internacionalização da ciência e tecnologia, da inovação e da competitividade brasileira por meio do intercâmbio e da mobilidade internacional. A pesquisa examinou o ciclo de formulação, implementação e avaliação do programa para investigar se o investimento em mobilidade acadêmica internacional pode ser um mecanismo efetivo para fomentar a colaboração científica internacional. Inicialmente, foi entendido que o Brasil possui dois problemas fundamentais no campo de CT&I: i) déficit na formação de recursos humanos qualificados; e ii) baixa inserção científica e tecnológica no cenário internacional. Visto o problema, a formulação do CsF insere-se como parte da solução dentro de uma agenda estratégica nacional elaborada pelo Ministério de Ciência, Tecnologia e Inovação. Após quatro anos de implementação, em 2015 o programa atingiu a meta de conceder 101 mil bolsas de intercâmbio acadêmico, mas extrapolou em mais de três vezes o orçamento previsto. Entretanto, teve um efeito positivo para o aumento da oferta de bolsas no exterior em todas as áreas (inclusive as não contempladas pelo programa) e não interferiu nos recursos financeiros das bolsas de formação no país. Com o uso de dados bibliométricos, foram encontrados indícios de que o programa foi capaz de estimular e manter a colaboração internacional entre pesquisadores. Todavia, ainda não é possível afirmar se os efeitos são significativos ou não, por isso se faz necessário avaliações futuras sobre a influência do programa nas mais diversas disciplinas científicas e nas respectivas redes de coautorias, além de estudos sobre outras questões que derivam do trabalho. Devido a dificuldades específicas com coleta e uso de dados durante o processo avaliativo, o trabalho recomenda: i) que bancas de especialistas compilem grupos de palavras-chave que caracterizem as áreas científicas; ii) que dados sobre o Ciência sem Fronteiras disponíveis para visualização sejam também disponíveis para download; e iii) que a Plataforma Lattes inclua no currículo dos pesquisadores a opção de registro sobre o programa de bolsas a que foram vinculados. Por fim, o trabalho ressalta o entendimento de que o programa Ciência sem Fronteiras foi positivo no sentido de aumentar a visibilidade internacional da educação superior brasileira e inseriu as universidades e outras instituições brasileiras em programas de cooperação internacional no campo da pesquisa. Neste sentido, recomenda-se que o Brasil deve envidar esforços para manter uma política pública de mobilidade acadêmica internacional, mesmo que em dimensões menores e de maneira reformulada / This work, as part of an interdisciplinary proposal of research between complex systems and public policies, intends to provide subsidies for the evaluation of the Brazil Science without Borders (SwB) program, especially in the context of Science, Technology and Innovation (ST&I) and internationalization public policies. The program sought to promote the consolidation, expansion and internationalization of Brazilian science and technology, innovation and competitiveness through exchange and international mobility. The research examined the program\'s formulation, implementation and evaluation cycle to investigate whether investment in international academic mobility could be an effective mechanism to foster international scientific collaboration. Firstly, Brazil has two fundamental problems in the field of ST&I: i) deficits in the formation of qualified human resources; and ii) low scientific and technological insertion in the international scenario. Given these problems, the creation of the SwB was part of a solution within a national strategic agenda of improving Brazils standing within the fields of ST&I. From its inception to its conclusion four years later, the program achieved the goal of granting 101,000 exchange scholarships, but went three times over budget. However, SwB had a positive effect by increasing overseas scholarship offerings in all areas (even those not explicitly covered by the program) and did not interfere with the financial resources of the scholarship grants in the country. The use of bibliometric data has shown that the program was able to stimulate and maintain international collaboration among researchers. However, it is not yet possible to state whether the effects are significant or not, so it is necessary to evaluate the influence of the program in different scientific disciplines and in their respective co-authorship networks, as well as other issues derived from the work. Because of specific difficulties in collecting and using data during the evaluation process, this dissertation recommends: i) that expert panels compile groups of keywords that characterize the scientific disciplines; ii) that data on Science without Borders available for visualization also become available for download; and iii) that the Lattes Platform includes in the researchers\' curriculum the option of registering the scholarship program they were linked to. Finally, the paper acknowledges that the Science without Borders program improved the international visibility of Brazils higher education and inserted universities and other Brazilian institutions into international research cooperation programs. In this sense, the author recommends that Brazil should make efforts to maintain such a public policy of international academic mobility, even in a reduced or reformed format

Allergic asthma is an immunological disease, mediated by CD4+ Th2 cells, and its prevalence has increased over recent decades. Features of allergic asthma include airway hyperresponsiveness (AHR), airway eosinophilia, excessive airway mucus production, and increased IgE and Th2 cytokine levels. Airway remodeling with pulmonary fibrosis is noted in the progress of asthma. In this thesis, a murine model of allergic asthma was used to investigate the effect of cyclophosphamide (CY) on asthma and the involvement of regulatory T cells (Treg), and the role of Granulocyte-macrophage colony stimulating-factor (GM-CSF) in allergic asthma by using GM-CSF knockout mice. CY is a cytotoxic agent, which paradoxically augments several immune responses. The first part of this thesis was aimed to study the effects of CY in a murine model of allergic airway inflammation. BALB/c mice were immunized with ovalbumin (OVA) on days 0 and 14, and challenged with aerosolized OVA from days 21 to 27. Some mice additionally received CY on days -2 and 12. In the CY-treated animals, pronounced worsening of inflammatory features was noted, including increases in eosinophil infiltration, epithelial thickness, mucus occlusion and eosinophil numbers in bronchoalveolar lavage fluid (BALF). Increased total and OVA-specific serum IgE were also noted in the CY-treated animals. In cell cultures from peritracheal lymph nodes, the Th2 cytokines IL-4 and IL-5 were elevated in animals treated with CY. It was hypothesized that the effects of CY could be caused by reduced immunosuppression mediated by Treg. mRNA expression of the immunosuppressive cytokines IL-10 and TGF-beta was reduced in the lungs of CY-treated mice. The expression of FoxP3, a marker of naturally occurring Treg, was significantly reduced in spleens, thymuses and peritracheal lymph nodes after the second injection of CY, and in the lung tissue after allergen challenge in CY-treated mice. Furthermore, lung IL-10-producing CD4+ T cells and CTLA-4+-bearing CD4+ T cells were reduced after allergen aerosol challenge in CY-treated mice. Thus CY worsened the features of allergic pulmonary inflammation in this model, in association with increased production of IgE and Th2 cytokines. The reduction in expression of FoxP3 and immunosuppressive cytokines by CY suggests that toxicity to Treg may contribute to the increased inflammation. GM-CSF plays a role in the growth, development, and maturation of bone marrow hemopoietic cells into mature blood cells, and has been proposed to be involved in potentiating the function of inflammatory cells in allergic inflammation. In the second part of this thesis, GM-CSF knockout (KO) mice were used to investigate the role of GM-CSF. In allergic KO mice, airway eosinophils were only shown in the perivascular, but not peribronchial areas in the lung, compared to the allergic wild-type (WT) mice in which eosinophil infiltration appeared in both areas. Eosinophil numbers were drastically reduced in the bronchoalveolar lavage fluid (BALF) of KO mice. IL-5 production in the lung tissue and BALF in allergic KO mice was reduced; similar results were also found in peritracheal draining lymph nodes after in vitro stimulation assays. However, IL-4 and IL-13 production, airway hyperresponsiveness (AHR), and serum IgE production were not affected in allergic KO mice. Surprisingly, lung IFN-gamma mRNA and BALF levels were increased in allergic KO mice. Lung mRNA levels of CCR3, a key chemokine receptor on eosinophils, were significantly reduced in allergic KO mice, whereas expression of the chemokines eotaxin and RANTES were at similar levels in allergic KO and WT mice. Lung mRNA levels of the IFN-gamma-inducible chemokines Mig (CXCL9) and IP-10 (CXCL10), which are antagonists of CCR3, and their receptor CXCR3 were increased in allergic KO mice, compared with allergic WT mice. Data obtained from flow cytometry showed more eosinophils survived in the lung of WT mice than KO mice. Another allergy model, a peritoneal allergy model was performed to investigate inflammation in a different model. Leukocyte subpopulations such as neutrophils, eosinophils, macrophages, and lymphocytes were reduced in the peritoneal lavage fluid of allergic KO mice. The findings revealed that GM-CSF is essential for IL-5 production, pulmonary airway eosinophilia and eosinophil survival. In the absence of GM-CSF, over-production of IFN-???? may induce chemokines, including Mig and IP-10, which are antagonists for CCR3 and may reduce airway eosinophil infiltration. In this thesis, a murine model of allergic asthma has been used to obtain novel findings on the regulation of allergic inflammation. The results with CY are relevant to the treatment of asthma patients with CY and other cytotoxic agents. The findings in the GM-CSF KO mice suggest that GM-CSF is a potential therapeutic target in asthma, and that in assessment of new therapeutic agents for asthma, effects on GM-CSF should be considered.