L'étude de l'impact des facteurs environnementaux sur les effets à long-terme des psychostimulants a montré que des facteurs négatifs, comme le stress, augmentent le risque de développer une addiction, alors que des facteurs positifs, comme l'exposition à des conditions stimulantes, le réduisent. Une partie de cette thèse a consisté à rechercher les mécanismes neurobiologiques et cellulaires qui sous-tendent cette influence environnementale. Ainsi, l'exposition d'animaux à un environnement enrichi (EE), qui procure des conditions stimulantes, diminue leur niveau d'anxiété, un effet qui serait en partie lié à la régulation de gènes appartenant au système cannabinoïde endogène (SCE) dans des régions impliquées dans la réactivité au stress (article 1). Par ailleurs, nos travaux ont mis en évidence des limites de l'exposition à l'EE : quand celle-ci est interrompue, ses effets bénéfiques sont perdus et la vulnérabilité à la cocaïne est même augmentée. Ceci s'expliquerait par l'apparition d'un état émotionnel négatif, associé à une activation du facteur CREB dans l'amygdale étendue, une région carrefour entre la récompense et le stress (article 2). Nous nous sommes aussi intéressés à la toxicité de la méthamphétamine et à sa modulation par le SCE, pour lequel des propriétés neuroprotectives avaient déjà été suggérées. Ainsi, une stimulation pharmacologique du SCE permet de prévenir la neurotoxicité dopaminergique induite par la méthamphétamine (article 3). Nos résultats soulignent la complexité d'utilisation des manipulations environnementales et mettent en lumière les capacités protectives du SCE contre la dépendance et la neurotoxicité engendrées par les psychostimulants. / Studies of the impact of environmental factors on the long-term effects of psychostimulants have shown that negative factors, such as stress, increase the risk of developing drug addiction, while positive factors, such as exposure to stimulating conditions, reduce it. The first aim of this thesis work was to look for the neurobiological and cellular mechanisms that underlie this environmental influence. We found that exposure of animals to stimulating enriched environments (EE) reduces anxiety levels, an effect that may be partly related to the regulation of genes belonging to the endogenous cannabinoid system (ECS) in regions involved in stress reactivity (Article 1). In addition, our work has highlighted some limitations of the exposure to EE since discontinuation of enrichment results not only in the loss of its beneficial effects but also in increased vulnerability to cocaine. This effect is associated with emotional distress associated and changes in the activity of the transcription factor CREB in the extended amygdala, an interface region between reward and stress processes (Article 2). We also investigated whether ECS, for which neuroprotective properties have already been suggested, could reduce the brain toxicity induced by methamphetamine. We found that pharmacological stimulation of ECS provides protection against the methamphetamine-induced dopaminergic neurotoxicity (Article 3). Our results highlight the complex consequences of environmental conditions on brain and behavior and highlight the protective role of ECS against both addiction and neurotoxicity induced by psychostimulants.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / The equine protozoal mieloencefalite (EPM) is caused mainly by Sarcocystis neurona. It s definitive host is the opossum (Didelphis spp.), which becomes infected by ingesting sporocysts from tissues of intermediate hosts, that belong to different species. Clinical manifestations occur with neurologic signs, which vary according to the area of the nervous system affected. Clinical disease is not common, however cases of immunosuppression as senility, stress, use of corticosteroids may lead to development of clinical signs. From an epidemiological standpoint, it is interesting to determine the distribution of the protozoa in order to know the areas where animals were exposed to S. neurona through serological tests, in order to consider EPM in differential diagnosis of neurological diseases and guide the treatment. In the U.S. it is estimated that half of the horses are reagents for S. neurona, in Brazil there are not many reports about prevalence of seropositive horses. The transplacental infection has been described for other species of Sarcocystis, however there is no evidence of intrauterine infection by S. neurona, only some studies suggesting the vertical transmission as another way of agent maintenance, which could be confirmed by detecting antibodies in sera from neonates before colostrum ingestion. While S. neurona is the primary agent of equine mieloencefalite, S. cruzi is related to losses in cattle. Although parasites present similar life cycle, but with different definitive hosts, horses were exposed to both species of Sarcocystis, and these two species may infect horses and spread concurrently in herds. Therefore, this study aimed to detect the occurrence of transplacental transmission by S. neurona in horses and compare the prevalence of flocks against S. neurona and S. cruzi. Results were arranged in two chapters. In chapter one, we investigated the occurrence of transplacental infection of S. neurona in horses. For this, blood was collected from mares and their newborns for antibodies against S. neurona. In the second chapter, we compared, by indirect immunofluorescence, serum samples from 189 mares for the presence of antibodies against Sarcocystis spp. using as antigen S. neurona and S. cruzi. The analysis of the results revealed the majority of animals responding to antigens of S. cruzi and a third of seropositive animals reacted to antigens of both species. / A mieloencefalite equina por protozoário (MEP) é causada principalmente por Sarcocystis neurona. O hospedeiro definitivo de S. neurona é o gambá (Didelphis spp.), que se infecta ingerindo esporocistos dos tecidos dos hospedeiros intermediários, que pertencem a diversas espécies. Os sinais clínicos cursam com sinais neurológicos, que variam conforme a área do sistema nervoso afetada. A doença clínica não é comum, porém casos de imunossupressão como senilidade, estresse, uso de corticoides podem levar ao desenvolvimento dos sinais clínicos. Do ponto de vista epidemiológico, é interessante determinar a distribuição geográfica do protozoário a fim de se conhecer as áreas onde os animais foram expostos a S. neurona por meio de testes sorológicos, a fim considerar a MEP no diagnóstico diferencial de doenças neurológicas e direcionar o tratamento. Nos EUA estima-se que metade dos equinos seja reagentes para S. neurona, no Brasil não há muitos relatos sobre prevalência de equinos soropositivos. A infecção transplacentária já foi descrita para outras espécies de Sarcocystis, porem ainda não há evidências da infecção intrauterina pelo S. neurona, somente alguns estudos que sugerem a transmissão vertical como outra forma de manutenção do agente, o que poderia ser confirmada pela detecção de anticorpos no soro do neonato antes da ingestão do colostro. Enquanto o S. neurona é o principal agente da mieloencefalite equina, a infecção por S. cruzi está relacionada a prejuízos em bovinos. Apesar dos parasitas apresentarem ciclo de vida distintos, com hospedeiros definitivos diferentes, equinos estão expostos a ambas espécies de Sarcocystis, sendo que as duas espécies podem infectar equinos e se disseminar concomitantemente nos planteis. Assim sendo, este trabalho teve por objetivo detectar a ocorrência da transmissão transplacentária por S. neurona em equinos e comparar a soroprevalência dos plantéis frente a S. neurona e S. cruzi. Os resultados encontrados foram dispostos em dois capítulos. No capítulo um, investigou-se a ocorrência de infecção transplacentária de S. neurona em éguas. Para tal foi coletado sangue desses animais e seus neonatos para a pesquisa de anticorpos contra S. neurona. No segundo capítulo, comparou-se, por imunofluorescência indireta, amostras sorológicas de 189 éguas quanto a presença de anticorpos contra Sarcocystis spp. utilizando como antígeno S. neurona e S. cruzi. Na análise dos resultados revelou a maioria dos animais reagindo a antígenos de S. cruzi e um terço dos animais soropositivos reagiu a antígenos das duas espécies.

Le cancer est l'une des principales causes de morbidité et de mortalité dans le monde avec environ 14 millions de nouveaux cas et 8,2 millions de décès liés aux cancers selon l'OMS (Organisation Mondiale de la Santé). Le cancer du poumon est le premier cancer diagnostiqué chez l'homme et compte pour 20% du nombre de mort par cancer par an dans le monde. Parmi les cancers pulmonaires, on distingue les cancers à petites cellules et les cancers non à petites cellules. Ce travail a porté sur l'étude des adénocarcinomes pulmonaires lépidiques, un type de cancer non à petites cellules, chez l'homme et l'animal. Chez l'homme, il fait partie des tumeurs pulmonaires rares, pas ou peu lié au tabagisme. Il est similaire cliniquement, radiologiquement et histologiquement à l'adénocarcinome pulmonaire ovin, un cancer du poumon induit par le β-rétrovirus JSRV (Jaagsiekte Sheep RetroVirus) affectant les petits ruminants domestiques. JSRV transforme les cellules épithéliales du parenchyme via son enveloppe oncogénique. Ces tumeurs humaines et animales ne sont pas associées au développement de métastases extra-thoraciques ou pleurales. Le but de notre travail a été d'étudier les évènements moléculaires spécifiques des adénocarcinomes lépidiques humains et animaux par i. l'analyse transcriptomique de l'expression des gènes dans ces deux cancers, ii. la caractérisation de l'adénocarcinome pulmonaire ovin par l'expression des mucines et iii. l'étude d'un rôle putatif des séquences rétrovirales endogènes dans l'induction de l'adénocarcinome lépidique humain. Premièrement, notre étude a porté sur l'analyse en parallèle des mécanismes moléculaires spécifiques des adénocarcinomes lépidiques prédominants par l'analyse des profils d'expression des gènes impliqués dans les voies de signalisation BMI1, NOTCH, Hedgehog et WNT importantes dans le développement du poumon normal et au cours des cancers pulmonaires et dans la voie de l'angiogenèse, permettant la dissémination des cellules tumorales. L'augmentation de l'expression de CDH1 (E-cadherin), acteur crucial de la voie BMI1, et la diminution de l'expression des ligands et récepteurs activateurs de l'angiogenèse VEGF/VEGFR (Vascular Growth Factor), PDGF/PDGFR (Platelet-derived Growth Factor) et ANGPT/TIE (Angiopoietin/Tyrosine kinase with immunoglobulin like and EGF like domains) ont été observées dans ces deux cancers. Lors de l'analyse de l'expression des ARNm et des protéines, nous avons mis en évidence le blocage de la voie principale de l'angiogenèse dans les cancers lépidiques. En effet, l'absence d'expression du ligand VEGFA (Vascular Endothelial Growth Factor A) et de son récepteur VEGFR2 (Vascular Endothelial Growth Factor Receptor 2) a été observée. Ce blocage n'était pas compensé par la surexpression de gènes impliqués dans les voies alternatives d'angiogenèse. Le blocage de la voie de l'angiogenèse explique l'absence de métastases extrathoraciques dans les adénocarcinomes lépidiques chez l'homme et l'animal. Deuxièmement, les adénocarcinomes pulmonaires lépidiques chez l'homme sont subdivisés en deux entités majoritaires : les adénocarcinomes lépidiques prédominants non mucineux et les adénocarcinomes mucineux invasifs. Dans le contexte des analogies entre ces cancers humains et l'adénocarcinome induit par le virus JSRV, nous avons analysé l'expression des mucines dans les cancers animaux. Nous avons montré que sur 37 cancers pulmonaires induits par JSRV, 62% étaient non mucineux, qu'ils sur exprimaient MUC1 (mucin 1, cell surface associated) et que 50% exprimaient MUC5B (mucin 5B, oligomeric mucus/gel-forming). Par ces résultats, nous avons montré que les adénocarcinomes pulmonaires ovins se rapprochaient principalement des adénocarcinomes lépidiques prédominants / Cancer is the main cause of morbidity and mortality worldwide with 14 million new cases and approximately 8.2 million deaths according to the WHO (World Health Organization). Lung cancer is the most diagnosed cancer in men and account for 20% of cancer death in the world annually. Among lung cancers, there are small cell lung cancers and non-small cell lung cancers. My work focused on the lepidic adenocarcinoma, a subtype of nonsmall cell lung cancer, in humans and animals. In humans, it is a rare lung cancer and it is not or rarely linked to tobacco smoking. Lepidic adenocarcinomas share striking clinical, radiological and histopathological similarities with ovine pulmonary adenocarcinomas induced by the β-retrovirus JSRV (Jaagsiekte Sheep RetroVirus) affecting sheep and goats. JSRV transforms epithelial cells of the distal lung through its oncogenic envelope. These human and animal tumors are not associated with pleural or extra thoracic metastases. My work was to study specific molecular events in human and animal lepidic adenocarcinomas by i. a transcriptomic analysis of the gene expression in these two lung cancers, ii. ovine pulmonary adenocarcinoma characterization by mucin expression and iii. the study of a potential role for endogenous retroviral sequences in the induction of human lepidic adenocarcinomas. First, my work focused on the parallel analysis of expression patterns in genes implicated in BMI1, NOTCH, Hedgehog and WNT pathways important for lung development and for lung cancer development and the angiogenesis pathway whose activation leads to cancer cell dissemination. CDH1 (E-cadherin) up regulation and the down regulation of main angiogenic ligand and receptors VEGF/VEGFR (Vascular Endothelial Growth Factor), PDGF/PDGFR (Platelet-derived Growth Factor) and ANGPT/TIE (Angiopoietin/Tyrosine kinase with immunoglobulin like and EGF like domains) were observed. Then, when analyzing lepidic adenocarcinomas mRNA and protein expression, we highlighted the blockade of the main angiogenesis pathway. Indeed, the VEGFA ligand and its receptor VEGFR2 were absent in lepidic adenocarcinomas. Moreover, this blockade was not compensated with angiogenic alternative pathways. These results correlate with the absence of extra thoracic metastases in human and animal lepidic adenocarcinomas. Secondly, human lepidic predominant adenocarcinomas are divided in two groups, non-mucinous lepidic adenocarcinomas and invasive mucinous adenocarcinomas. To characterize ovine pulmonary adenocarcinomas and determine to which one of these two human lepidic adenocarcinomas they are close to, we analyzed mucine expression in animal lung cancer. On 37 JSRV-induced lung cancer, 62% were nonmucinous, 100% expressed MUC1 (mucin 1, cell surface associated) and 50% expressed MUC5B (mucin 5B, oligomeric mucus/gel-forming). These results highlighted that ovine pulmonary adenocarcinomas are closer to non-mucinous lepidic adenocarcinomas

In this paper, we analyze, estimate and compare five prototypic models of innovation, from a simple learning-by-doing model to an elaborated model that includes financial, organizational and technological determinants of innovation. From the comparison of the five models we conclude that institutions - in particular the national system of innovation - and organizations matter. The importance of networks and the importance of information flows from different economic actors add to the explanatory power and gives the best model fit among all models specified. / Series: Department of Economics Working Paper Series

Research macroeconomists have witnessed remarkable methodological developments in mathematical, statistical, and computational tools during the last two decades. The three essays in this dissertation took advantage of these advances to analyze important macroeconomic issues. The first essay, “ Habit Formation, Adjustments Costs, and International Business Cycle Puzzles” analyzes the extent to which incorporating habit formation and adjustment costs in investment in a one-good two-country general equilibrium model would help overcome some of the international business cycle puzzles. Unlike standard results in the literature, the model generates persistent, cyclical adjustment paths in response to shocks. It also yields positive cross-country correlations in consumption, employment, investment, and output. Cross-country correlations in output are higher than the ones in consumption. This is qualitatively consistent with the stylized facts. These results are particularly striking given the predicted negative correlations in investment, employment, and output that are typically found in the literature. The second essay, “Comparison Utility, Endogenous Time Preference, and Economic Growth,” uses World War II as a natural experiment to analyze the degree to which a model where consumers' preferences exhibit comparison-based utility and endogenous discounting is able to improve upon existing models in mimicking the transitional dynamics of an economy after a shock that destroys part of its capital stock. The model outperforms existing ones in replicating the behavior of the saving rate (both on impact and along the transient paths) after this historical event. This result brings additional support to the endogenous rate of time preference being a crucial element in growth models. The last essay, “Monetary Policy under Fear of Floating: Modeling the Dominican Economy,” presents a small scale macroeconomic model for a country (Dominican Republic) characterized by a strong presence of fear of floating (reluctance to have a flexible exchange rate regime) in the conduct of monetary policy. The dynamic responses of this economy to external shocks that are of interest for monetary policy purposes are analyzed under two alternative interest rate policy rules: One being the standard Taylor rule and another that responds explicitly to deviations of the exchange rate with respect to its long-term trend.

The diploma thesis deals with Europe 2020 strategy and its targets in the context of growth theories. The thesis aims at relating the measures suggested by the strategy to the implications of the growth theories. First, the targets are compared with the current situation in EU member states and problem areas of European competitiveness are identified. Growth models described in the first chapter yield some normative recommendations with respect to growth policies. Based on these conclusions, the thesis discusses the policies designed in the Europe 2020 strategy and their implications for economic growth in the EU.

In this thesis, the effects that state sector relocations have on regional development in Sweden are investigated. In January 2017, a government report was released, suggesting the relocation of 10 000 state sector jobs from the capital of Stockholm to other parts of Sweden in order to enhance the preconditions for regional development in the destination localities. This thesis aims to investigate which effects that state sector relocations and state sector jobs have on regional development. Three determinants were used to find these effects: the share of state sector employees, the state sector employee growth rate and a dummy variable which denoted four separate occasions of larger relocations. Three of those relocations were executed as a compensation for military base closures. With a fixed effect panel data analysis, it was possible to investigate the effects of these three determinants and a number of control variables on two regional development variables: average income growth and net migration rate. The data used consists of panel data for the years 2006-2015 on a municipality level, with 264 included municipalities, in Sweden and derived from Statistics Sweden. The results showed that the state sector employee growth rate-variable had a positive effect on average income growth. However, the state sector relocation dummy had a negative effect on average income growth. These contradictory results, might be due to the military base closures which occurred a couple of years before the relocations, blurring the positive effects from the relocations. The state sector job-variables had no significant effect on net migration rate, and no obvious long-term effects were found as the share of state sector employees did not show any significant effects on average income growth.

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The purpose of this research was to determine if the introduction of a competitive and collaborative computer-based gaming software system into middle school classrooms would result in improved attendance and grades, and motivate students to have a greater interest in their studies. This study was conducted over a 6 week period, with attendance and performance data being collected from 284 students. Two quantitative surveys were used to measure course interest and motivation: (a) the Course Interest Survey (CIS), and (b) the Instructional Materials Motivation Survey (IMMS). Participation in these surveys consisted of 84 students taking the CIS and 40 students taking the IMMS. The results indicated that the experimental group showed statistically better scores than the comparison group in attendance and performance. Students participating in the experimental group had significantly lower mean ranks of absenteeism compared to students in the comparison group. Results also revealed significant differences on grades. Students that were in the experimental group had significantly higher grades compared to students that were in the comparison group. Results of the CIS suggest that a statistically significant difference does not exist on Attention, Relevance, Confidence, and Satisfaction between the experimental and comparison groups. Results of the means and standard deviations for the IMMS Motivation Scores fell somewhere between Moderately true and Mostly true. This research study suggests that student's attendance and performance can be improved when quiz based gaming software that is both collaborative and competitive is used regularly in the classroom. However, for student's that participated in the gaming software, their interest in studying the subject doesn't appear to be significantly different from students that did not participate.

Chez les mammifères, les lymphocytes T CD4 sont essentiels à la défense de l’organisme contre des infections par des pathogènes ou le développement de tumeurs. Après activation, les lymphocytes T CD4 naïfs ont la capacité de se différencier en divers lymphocytes T helper (Th1, Th2, Th17…) en fonction des signaux reçus. Le choix du lignage permet d’adapter le phénotype et la fonction des cellules au type de danger détecté. Le processus de différenciation des lymphocytes T helper implique l’établissement de programmes d’expression des gènes distincts. La dynamique et la stabilité de ces programmes sont notamment régulées par l’activité d’éléments cis-régulateurs. Le but de ma thèse était de comprendre les mécanismes épigénétiques qui contrôlent la programmation des lymphocytes T CD4. Dans cet objectif, nous avons étudié le rôle de la H3K9 méthyl-transférase SETDB1 dans la différenciation des lymphocytes T CD4 en Th1 et Th2, deux lignages T helper fortement antagonistes. Nous avons découvert que SETDB1 réprime de manière critique le programme d’expression des gènes Th1. En effet, en l’absence d’expression de Setdb1, la différenciation Th1 est exacerbée. De plus, lorsqu’elles sont exposées à un signal pro-Th1, les cellules Th2 franchissent les barrières de lignage et se transdifférencient en Th1. De manière surprenante, SETDB1 ne cible pas directement les enhancers Th1. Au contraire, l’enzyme dépose de manière type cellulaire spécifique la marque répressive H3K9me3 au niveau d’un set restreint de rétrovirus endogènes (ERVs). Des analyses bio-informatiques ont indiqué que les rétrotransposons ciblés sont fortement associés à des gènes impliqués dans les processus immunitaires. La suite de ces analyses a indiqué que ces ERVs flanquent et répriment l’activité d’éléments cis-régulateurs des gènes Th1, ou agissent eux même comme des enhancers du lignage. En conclusion, la déposition de H3K9me3 par SETDB1 garantit l’intégrité des lymphocytes T helper en réprimant un panel d’ERVs qui ont été exaptés en modules cis-régulateurs pour façonner et contrôler le réseau de gènes Th1. / CD4 T lymphocytes play a central role in the defense of mammal organisms against infections by pathogens and the development of tumors. Upon activation, naïve CD4 T cells differentiate into distinct helper cell subsets depending on environmental cues. T helper cells are key players of the immune system as they finely orchestrate immune responses in a danger-adapted manner. The process of T helper differentiation relies on the establishment of complex and lineage-specific gene expression programs. The dynamics and stability of these programs are regulated at the chromatin level through epigenetic control of cis-regulatory elements. My thesis objective was to investigate the epigenetic pathways involved in the regulation of enhancer activity in CD4 T cells. In this purpose, we studied the role of the H3K9 specific methyltransferase SETDB1 in the differentiation of Th1 and Th2 cells, which are strongly antagonistic. We report that SETDB1 critically represses the Th1 gene expression program. Indeed, Setdb1-deficient naïve T cells show exacerbated Th1 priming. Moreover, when exposed to a Th1-instructive signal, SETDB1-deficient Th2 cells cross lineage boundaries and transdifferentiate into Th1 cells. Surprisingly, SETDB1 does not directly target Th1 enhancers to heterochromatin. Instead, SETDB1 deposits the repressive H3K9me3 mark at a restricted and cell type specific set of endogenous retroviruses, strongly associated with genes involved in immune processes. Further bioinformatic analyses indicated that these retrotransposons flank and repress Th1 gene cis-regulatory elements or behave themselves as Th1 gene enhancers. Thus, H3K9me3 deposition by SETDB1 ensures T cell lineage integrity by repressing a repertoire of ERVs that have been exapted into cis-regulatory modules to shape and control the Th1 gene network.