Neste trabalho; estudamos a dinâmica das órbitas de uma partícula infinitesimal P contida no espaço euclidiano tridimensional; atraída unicamente pela força gravitacional induzida por um corpo maciço com densidade de massa constante na forma de anel ou disco circular. Este problema denominamos: Problema do anel ou disco circular homogêneo. Este problema apresenta alguns subproblemas: a linha vertical perpendicular ao plano que contém anel ou disco circular e passa pelo centro de massa; a qual denominamos de eixo-z ; o plano que contém o anel ou disco circular; que denominamos de plano horizontal e o plano perpendicular ao plano horizontal e que contém o eixo-z. Obtivemos resultados importantes da dinâmica em cada um destes subproblemas. Mostramos que o problema do anel ou disco circular é invariante por rotações em torno do eixo-z e desta forma podemos formular o problema em coordenadas giratórias. Escrevemos o problema como uma perturbação do problema de Kepler onde o parâmetro perturbador está associado a espessura do anel ou raio do disco. Utilizando a formulação do problema em coordenadas convenientes conseguimos obter uma grande quantidade de órbitas periódicas simétricas; como continuação de órbitas circulares e também elípticas no caso espacial e no caso dos subproblemas planares. A técnica empregada para conseguir tais órbitas foi o método de continuação analítica de Poincaré primeiramente aplicado a um problema geral que consiste em uma perturbação do problema de Kepler analítica e depois aplicamos ao nosso problema particular. Ainda estudamos as órbitas de escapes associadas a nosso problema; concentrando o escape nas direções dos eixos coordenados. _________________________________________________________________________________________ ABSTRACT: Our main concern, in this work, is describe the dynamics of the orbits of an in¯nitesimal particle moving in the space R3 under the in°uence of the gravitational force induced by a homogeneous annulus disk ¯xed on a plane. The aspects of the dynamics that we have interest are namely: Describe the di®erent ways the gravitational potential associated to the problem in each case; Characterize homogeneity properties of the potential; Describe the con¯guration space of these problems; Determine the symmetries of the vectorial ¯eld associate; Identify sub-problems associates according the dimension of the ambient space; In each sub-case,describe the dynamics and compares them to each other; Relate the potential singularities with the singularities of the vectorial ¯eld of each problem at issue; Introduce a convenient parameter; Determine a great diversity of families of periodic orbits in the di®erent sub-problems. Study the escape orbits in the di®erent cases; Compare the results obtained with the n-body problem in Celestial Mechanics.

En recherche et développement pharmaceutiques un candidat thérapeutique doit passer plusieurs barrières précliniques afin de déterminer certains paramètres pharmacocinétiques et pharmacodynamiques avant toute administration à l’homme. Malgré les efforts investis en R&D ces dernières années, l’industrie du médicament a souffert d’un ralentissement dans le développement de nouvelles molécules innovantes. Car avant sa mise sur le marché, tout candidat doit justifier de la sécurité liée à son utilisation mais aussi de sa balance bénéfice/ risque. Les modèles standards utilisés en développement en oncologie ne sont pas assez prédictifs et bien souvent non-adaptés, avec une niche tumorale inexistante. C’est pourquoi il est aujourd’hui essentiel de travailler sur des systèmes plus sensibles et mimant plus fidèlement la pathologie humaine afin d’obtenir des médicaments plus efficaces et moins toxiques pour une meilleure prise en charge. L’utilisation du modèle spontané de cancers comme approche prédictive en oncologie comparée a été rapportée par plusieurs équipes à travers le monde. En effet, les fortes similitudes au niveau histologique, moléculaire et clinique rapportées entre les tumeurs humaines et canines, font de ce modèle un allié essentiel pour l’optimisation du développement pharmaceutique chez l’homme ayant un bénéfice réciproque à la fois à la médecine humaine et vétérinaire.Chez l’homme, les mélanomes constituent l’une des formes les plus agressives des cancers cutanés. Ils représentent 4 à 11% des néoplasies cutanées et seulement 2% des cancers de l’épiderme. Ce sont des tumeurs très immunogènes et de très mauvais pronostic au stade métastatique contribuant au développement d’une réponse immunitaire anti-tumorale bien souvent responsable d’échappements et de résistances au traitement. Et malgré l’amélioration de 50 à 80% de la survie globale à 5 ans ces vingt dernières années, son incidence ne cesse d’augmenter et environ 7000 cas sont rapportés chaque année en France avec plus de 75% de décès liés à ces tumeurs.Bien que rares, ces tumeurs représentent 7% des cancers diagnostiqués chez le chien et environ 160000 cas sont recensés chaque année au niveau mondial. Sa localisation est buccale dans plus de 50% des cas. C’est aussi l’un des cancers les plus agressifs chez le chien, avec une survie globale post-opératoire de 173 jours associé à des métastases ganglionnaires et pulmonaires le plus souvent.Le but de ce travail a été la validation préclinique et clinique du modèle tumoral spontané canin dans la compréhension des mécanismes de cancérogenèse, de dormance tumorale et de développement thérapeutique. Validation préclinique, dans un premier temps via le développement et la caractérisation de modèles cellulaires et murins de mélanomes canins. Puis, dans un second temps, la validation clinique par le biais d’essais thérapeutiques chez le patient chien.A partir de prélèvements issus de deux profils cliniques distincts, deux lignées cellulaires de mélanome canin ont été développées et caractérisées sur le plan pharmacologique, génomique et fonctionnel. Une liste d’altérations génétiques a été établie sur ces deux profils en accord avec la littérature et présentant des points communs avec la pathologie humaine. De plus, il est bien établi que l’hétérogénéité tumorale est responsable de résistances au traitements conduisant aux rechutes, c’est pourquoi nous nous sommes par la suite intéressés à l’étude des populations souches tumorales au sein de notre modèle et à l’identification de marqueur permettant le ciblage de ces cellules pouvant contribuer ainsi à l’avancement de l’enrichissement de l’arsenal thérapeutique oncologique.En conclusion, le patient chien est doté d’un système immunitaire intact et d’une niche tumorale complète, constituant ainsi un système in-vivo très intéressant pour l’homme, pouvant contribuer à avancer la recherche et améliorer grandement nos connaissances sur cette pathologie. / Pharmaceutical development is a long and fastidious process. In fact, each drug candidate has to meet with a certain safety criteria list, pharmacokinetic and pharmacodynamics profiles need to be determined prior to first use in humans and market approval.For years, the pharmaceutical industry has been suffering from a lack of innovative molecules and thus despite the efforts and cost increases in R&D programs. And most novel drug candidates entering clinical trials fail to reach approval, largely because preclinical models used in development do not provide adequate information about their efficacy or toxicity. That’s why; more predictive models of efficiency in oncology, shaping more precisely the human pathology are needed.The study of novel drug candidates in dogs with naturally occurring tumors allows drug assessment in neoplasms sharing many fundamental features with its human counterparts, and thus provides an opportunity to answer questions guiding the cancer drug development path in ways not possible in more conventional models. Moreover, the strong homologies in clinical presentation, morphology, and overall biology between dogs and their human counterparts make companion animals a good model to investigate tumor process from ætiology to tailored treatments.The aim of this project was to validate the canine spontaneous tumor model, by combining preclinical and clinical approaches, in the comprehension of the underlying mechanisms of cancer from carcinogenesis to drug resistance and tumor dormancy and also the discovery of new tools essential for the prediction, diagnosis clinical follow-up and treatment.Metastatic melanoma is one of the most aggressive forms of cutaneous tumors in humans. It constitutes 4 to 11% of skin malignancies and only 2% of the cancers of the epidermis. These highly immunogenic tumors hold a severe prognosis when metastasized and contribute to an immune anti-tumor reaction which could potentially lead to immune escape and resistance to most standard treatment protocols. And even if the 5-year survival has been improved to 50 – 80% over the past decades, its incidence is still in the rise with 7000 cases and 75% related deaths reported every year in France.In dogs, melanomas are one of the most frequently diagnosed malignancies of the oral cavity. These cancers account for 7% of all malignant tumors in dogs and 160000 reported every year worldwide. It also constitutes one of the most aggressive metastasizing tumors with a median post-surgery survival rate of 173 days.We developed and characterized immunucytochemically, pharmacologically and genomically two canine melanoma cell lines from naturally occurring dog tumors with distinct clinical profiles. A list of genetic alterations of these two profiles has also been established and is in accordance with the published literature, presenting same features as human tumors. And because tumor heterogeneity is responsible of resistance to treatment and relapse, we isolated and investigated cancer stem cell populations in our cell line models in order to identify the linked biomarkers which may constitute future potential targets for the expansion of the oncological therapeutic panel.In conclusion, due to its intact immune system, tumor niche and also because it shares the same environment as we do, the canine patient represent a promising opportunity in the advancement of cancer research, the acceleration of translation process and the setting up of more effective and less toxic molecules with dual benefits for the human and veterinary medicine toward better patient care.

La Región Metropolitana es el área más densamente poblada del país. Se encuentra geográficamente rodeada de cerros y montañas lo que dificulta la ventilación de la cuenca donde se encuentra emplazada. La gran actividad humana la ha contaminado, siendo actualmente zona saturada de Ozono y Material Particulado Respirable, y mantiene zona de latencia de Monóxido de Carbono. Es por esto que se necesita conocer las fuentes que provocan estas emisiones de la forma más certera posible. Dentro de esos agentes que provocan la contaminación están las fuentes móviles. Es difícil determinar exactamente la emisión que estas fuentes generan porque se mueven por la ciudad y no están sometidas a un régimen constante de funcionamiento. Uno de los métodos para estimar emisiones es la metodología propuesta por Michel André sobre el desarrollo de ciclos de conducción. Un ciclo de conducción es una secuencia acotada de velocidad/tiempo estadísticamente representativa de la actividad de las fuentes móviles en la ciudad. Posteriormente a los ciclos obtenidos se les aplica metodología de estimación de factores de emisiones, tal como la metodología IVE, que permite caracterizar las situaciones temporales del vehículo con tasas de emisión. Dada la importancia de los vehículos livianos en el parque automotriz de Santiago, se realizó el siguiente trabajo de memoria para desarrollar y analizar los factores de emisión de vehículos livianos desagregándolos en tipo de vía y horario. Esto permitió establecer la caracterización de las dinámicas de conducción de cada vía en cada horario, permitiendo conocer tanto las velocidades medias de desplazamiento como las aceleraciones y frenadas como así los tiempos en que los vehículos están detenidos en el tráfico. Además, se estableció para cada vía en distintos horarios los factores de emisión de monóxido de carbono CO, dióxido de carbono CO2, NOx, hidrocarburos en suspensión HC y material particulado respirable MP10. Los resultados vinculan las emisiones vehiculares fuertemente con el tipo de vía donde se mueven las fuentes móviles. Además, se pudo establecer relaciones actualizadas entre velocidades medias presentes en las vías y factores de emisión. Para NOx y algunos casos CO, no se pudo establecer una buena relación. Estos gases son de importancia para la ciudad de Santiago, pues son generadores de Ozono troposférico. Por lo tanto, se valida la confección de factores de emisión para estos gases, de modo que queden determinados para cada tipo de vía y no por la velocidad media.

Francisella tularensis, l’agent étiologique de la tularémie, est une bactérie à multiplication intracellulaire facultative capable d’infecter de nombreux types cellulaires avec un tropisme particulier pour les macrophages. Cette bactérie est responsable d’infections graves chez de nombreuses espèces animales mais aussi chez l'homme. En particulier, la sous-espèce F. tularensis ssp tularensis a été classée comme agent de bioterrorisme de type A du fait de son pouvoir pathogène extrêmement élevé avec une faible dose infectieuse. Des approches de mutagénèse aléatoire et de criblage de banques de mutants ont suggéré l’importance des gènes impliqués dans les fonctions métaboliques et nutritionnelles dans le cycle intracellulaire de Francisella. Parmi ces gènes, on retrouve de très nombreux systèmes de transport d’acides aminés dont la sous-famille de transporteurs amino-polyamine-organocation (APC). Dans un premier temps, nous nous sommes intéressés à un transporteur APC codé par le gène FTN_0571, que nous avons appelé GadC. Pour comprendre l’importance de GadC dans la virulence de F. tularensis, nous avons réalisé un mutant chromosomique, délété du gène gadC, chez la sous-espèce novicida. Nous avons démontré que GadC est un importeur de glutamate et qu’il est nécessaire à la multiplication intracellulaire et à la virulence de Francisella, en assurant une sortie normale de la bactérie du phagosome. Ce phénomène s’explique par l’implication de GadC dans la résistance au stress oxydant généré dans le phagosome. De façon remarquable, la multiplication du mutant gadC est restaurée dans un contexte gp91phox-/-, incapable de générer des espèces réactives de l’oxygène, aussi bien in vitro qu’in vivo. Enfin, nous avons montré que l’activité de GadC modifie la production de certains intermédiaires du cycle de Krebs, et la transcription de l’enzyme qui leur est associée, démontrant un lien étroit entre la résistance au stress oxydant, le métabolisme du glutamate et la virulence de F. tularensis. Ces résultats nous ont conduits à nous intéresser à un autre transporteur appartenant à la sous-famille APC, présentant une homologie de 33% avec GadC, et que nous avons nommé ArgP. Nous montrons qu’un mutant argP présente un défaut de multiplication intracellulaire et de virulence résultant d’un retard sévère de sortie du phagosome. Ce phénotype s’explique par un défaut d’import d’arginine. L’inactivation du gène argP dans la sous-espèce holarctica LVS provoque des défauts de multiplication intracellulaire similaires à ceux observés dans la sous-espèce novicida, suggérant un rôle conservé du transporteur ArgP dans les différentes sous-espèces de F. tularensis. Comme l’arginine constitue un acide aminé essentiel pour la bactérie, nous nous sommes posés la question de l’importance de cet acide aminé durant la phase phagosomale. Une analyse du protéome bactérien du mutant argP de F. novicida, dans des conditions mimant les conditions nutritionnelles phagosomales, révèle que l’arginine joue un rôle prépondérant dans la traduction des protéines en affectant la synthèse des protéines ribosomales. L’ensemble des travaux réalisés au cours de cette thèse constitue la première démonstration de l’importance de l’acquisition d’acides aminés durant la phase phagosomale du cycle intracellulaire de F. tularensis. / Francisella tularensis, the etiologic agent of the zoonotic disease tularemia, is a facultative intracellular bacterium which can infect multiple cell types with specific tropism for macrophages. This bacterium is responsible for severe infections in numerous animal species and in humans. Of note, F. tularensis subsp. tularensis has been classified as a type A bioterrorism agent because of its high infectivity and very low infectious dose. Genome sequence analyses and genome-scale genetic studies have revealed the importance of genes involved in metabolic functions throughout the bacterial intracellular cycle. Among these genes, several amino acid transporter where found to belong to the amino-acid-polyamine organocation subfamily (APC), prompting us to address the role of these transporters in bacterial virulence. We first focused on the APC transporter encoded by gene FTN_0571 in F. tularensis subsp. novicida and named GadC. We showed that GadC was a genuine glutamate importer, necessary for Francisella intracellular multiplication and virulence. gadC inactivation completely blocked bacterial phagosomal escape. Remarkably, multiplication of a gadC mutant was restored in gp91phox-/- macrophages that are unable to generate reactive oxygen species. Altogether, our study revealed that glutamate uptake was critical in bacterial oxidative stress resistance in the phagosomal compartment and highlighted possible links between glutamate utilization and the tricarboxylic acid (TCA) cycle. These results prompted us to address the role of a second APC transporter sharing 33 % amino acid identity with GadC and named ArgP. argP inactivation severely delayed bacterial phagosomal escape, thus impairing intracellular multiplication and virulence. We demonstrated that ArgP was a high affinity arginine transporter, suggesting that impaired phagosomal escape might be directly linked to an arginine import defect. argP inactivation in the F. tularensis subsp. holarctica Live vaccine strain also leads to a severe intracellular multiplication defect, consistent with a conserved role among all F. tularensis subspecies. Arginine is an essential amino acid for F. tularensis. To understand the importance of this amino acid during the phagosomal phase of the Francisella intracellular life cycle, a proteomic analysis of the bacteria, in conditions of arginine limitation, was carried out. This analysis revealed that arginine limitation affected in the argP mutant the expression of a series of proteins and in particular of all the ribosomal proteins. One may imagine that intracellular bacteria could also sense nutrient limitations in the phagosome as a subcellular localization signal. Altogether, these studies constitute the first demonstration of the importance of amino acid acquisition during F. tularensis phagosomal escape.

The purpose of this study was to evaluate the effectiveness of video modeling of contingencies alone and/or combined with direct exposure to the contingencies in the treatment of food selectivity. Treatment procedures included sequentially introducing videos in which models consumed nonpreferred food, were exposed to differential reinforcement, or exposed to escape extinction and differential reinforcement. In addition, participants were exposed to differential reinforcement. Results indicated video modeling of differential reinforcement plus differential reinforcement may be effective at increasing consumption of some nonpreferred foods, but the results were not replicated across all foods. For one participant, consumption of one food increased with video modeling alone.

During the normalization period, the topic of countryside life in literature started to reappear. Many prosaic works depicted character's departure from the city to the countryside and his/her beginning of their new life in unknown surroundings. This thesis focuses on such works of art, published between the 1970s and 1980s. It compares four officially published examples of countryside novels containing any mark of escapism (in novels written by Jan Otčenášek, Bohumil Říha, Jiří Medek, Jan Kostrhun) with examples of prose published in samizdat or exile (Mojmír Klánský, Milan Kundera). Through intertextual as well as thematic and compositional analysis, the thesis investigates common features contained in this "escapist" literature. The analysis is inspired by the poetics of space and by the concept of the countryside as an idyllic space.

Present-day Mars is a cold and dry planet with a thin CO2-dominated atmosphere comprising only a few ­­­mbar pressure at low altitudes. However, the Martian surface is marked with valley networks, hydrated mineral clays, carbonates and the remains of deltas and meandering rivers, i.e. traces of an active hydrological cycle present early in the planet's geological history. A strong greenhouse effect, and thus a thicker atmosphere, would have been required to sustain a sufficiently warm environment, particularly under the weaker luminosity of the early Sun. The fate of this early atmosphere is currently unknown. While several mechanisms can remove atmospheric mass over time, a prominent hypothesis suggests that the lack of an intrinsic Earth-like global magnetic dipole has allowed the solar wind to erode the early Martian atmosphere by imparting energy to the planet's ionosphere which subsequently flows out as ion escape, over time depleting the greenhouse gasses and collapsing the ancient hydrological cycle. Previous studies have found insignificant ion escape rates under present-day conditions, however, the young Sun emitted significantly stronger solar wind and photoionizing radiation flux compared to the present. The geological record establishes the time of collapse of the hydrological cycle, estimated to have occurred in the mid-late Hesperian period (~3.3 billion years ago) at latest. To constrain the amount of atmosphere lost through ion escape since, we use the extensive database of ion flux measurements from the Analyzer of Space Plasmas and Energetic Atoms (ASPERA-3) particles package on the Mars Express orbiter (2004-present) to quantify the ion escape rate dependence on upstream solar wind and solar radiation conditions. The Martian ion escape rate is shown to be insensitive to solar wind parameters with a weak inverse dependence on solar wind dynamic pressure, and linearly dependent on solar ionizing photon flux, indicating efficient screening of the bulk ionosphere by the induced magnetic fields. The impact of an extreme coronal mass ejection is studied and found to have no significant effect on the ion escape rate. Instead, intense solar wind is shown to only increase the escaping energy flux, i.e. total power of escaping ions, without increasing the rate by accelerating already escaping ions. The orientation of the strongest magnetized crustal fields are shown to modulate the ion escape rate, though to have no significant time-averaged effect. We also study the influence of solar wind and solar radiation on the major Martian plasma boundaries and discuss factors that might limit the ion escape rate, including solar wind-ion escape coupling, which is found to be ≲1% and decreasing with increased solar wind dynamic pressure. The significant escape rate dependencies found are extrapolated back in time, considering the evolution of solar wind and ionizing radiation, and shown to account for only 4.8 ± 1.1 mbar equivalent surface pressure loss since the time of collapse of the Martian hydrosphere in the Hesperian, with ~6 mbar as an upper estimate. Extended to the late Noachian period (3.9 billion years ago), the found dependencies can only account for ≲10 mbar removed through ion escape, an insignificant amount compared to the ≳1 bar surface pressure required to sustain a warm climate on early Mars.

We consider the motion of a Brownian particle trapped in an arbitrary bounded two or three-dimensional domain, whose boundary is reflecting except for a small absorbing window through which the particle can escape. We use the method of matched asymptotic expansions to calculate the mean first passage time, defined as the time taken for the Brownian particle to escape from the domain through the absorbing window. This is known as the narrow escape problem. Since the mean escape time diverges as the window shrinks, the calculation is a singular perturbation problem. We extend our results to include N absorbing windows of varying length in two dimensions and varying radius in three dimensions. We present findings in two dimensions for the unit disk, unit square and ellipse and in three dimensions for the unit sphere. The narrow escape problem has various applications in many fields including finance, biology, and statistical mechanics. / Science, Faculty of / Mathematics, Department of / Graduate

The thesis disserts about marketing strategy of the corporation TheRoom. The aim of this thesis is to analyze the company marketing strategy, its marketing activities on the internet, evaluation and to create a list of opportunities, suggestions and recommendation. The theoretical part is dedicated to general meaning of marketing and other specifications of the classical and internet marketing. Practical part deals with corporate environment, including market and competition analyses. The thesis contexts also analysis of marketing communication, SWOT analysis and analysis of database of TheRooms clients. The contribution of the thesis lies in the complex view on the company, its marketing communication and whole market of escape games, which allows to create a comprehensive opinion about the current position and future develop of the company and this sector.

This thesis focuses on strategic analysis of the company Adventure World s. r. o. operating escape games in Prague. The goal of the thesis is to suggest strategic recommendations for further company development. The theoretical part deals with defining basic terminology and describing process of strategy formulation. In the practical part analytical tools described earlier are applied to analysis. In order to analyze external environment, the PEST framework is used. To illustrate the industry environment, 5 competitive forces analysis, map of strategic groups is used. In examining the internal firms conditions, the strategic resources and capabilities are identified through the value chain framework. Analyses findings are summarized in SWOT matrix, then strategy alternatives are generated. In conclusion, the author suggests the wording of the organization mission and updated vision, strategic goals, then author specifies actions, that are meant to fulfill those goals.