Fra-1 appartient à la famille des facteurs de transcription AP-1. Son expression est particulièrement élevée dans les cellules de cancer du sein qui n'expriment pas le récepteur aux œstrogènes (RE-), c'est-à-dire les cellules les plus agressives. L'inhibition de Fra-1 dans ces cellules entraîne une diminution de la motilité, de l'invasion et de la prolifération, mais elle entraîne aussi de profonds changements de morphologie. Les cellules RE-, qui présentent un phénotype mésenchymateux s'arrondissent et établissent un plus grand nombre de contacts cellule-cellule après l'inhibition de Fra-1. Dans les cellules RE-, la β-caténine est localisée au noyau ou dans le cytoplasme, ce qui est un marqueur de mauvais pronostic. Au cours de cette thèse, j'ai montré que Fra-1 régule la localisation nucléaire de la β-caténine et ainsi régule son activité transcriptionelle en agissant très tardivement sur la voie Wnt. J'ai également mis en évidence une interaction physique directe entre Fra-1 et la β-caténine qui pourrait être responsable de cet effet. De plus, l'analyse de microarrays par RT-QPCR a révélé la régulation d'autres gènes comme la mœsine, la fibronectine et l'extracellular matrix protein 1, qui pourraient également jouer un rôle dans la régulation de l'agressivité tumorale par Fra-1. Par ailleurs, Fra-1 est une protéine instable et nous avons montré qu'elle est phosphorylée et stabilisée par PKCθ. Fra-1 est d'ailleurs nécessaire à l'effet de la kinase sur la motilité cellulaire. / Fra-1 is a member of the AP-1 transcription factor family. It is aberrantly expressed in breast cancer cells lacking Estrogen Receptor (ER-) expression, which are the most aggressive ones. Fra-1 inhibition in these cells leads to a decreased in motility, invasion and proliferation, but also to deep morphologic changes. ER- cells, which present a mesenchymal phenotype, become rounder and establish a greater number of cell-cell contacts after Fra-1 inhibition. In ER- cells, β-catenin is nuclear or cytoplasmic, which is considering as a poor prognosis marker. During this PhD, I demonstrate that Fra-1, which acts very downstream in the Wnt/β-catenin signaling pathway, regulates the nuclear localization of β-catenin leading to up-regulation transcriptional activity of β-catenin. I also found that Fra-1 directly interacts with β-catenin. In addition, RT-QPCR microarrays analysis has revealed the regulation of other genes such as mœsin, fibronectin and extracellular matrix protein 1, which might also take part in the tumoral aggressiveness regulated by Fra-1. Moreover, we show that Fra-1, which is an unstable protein, is phosphorylated and stabilized by PKCθ. Furthermore, Fra-1 is necessary to mediate the kinase effect on cell motility.

This thesis deals with optical design of f-theta lens for purposes of precision micromachining using a laser beam. Optical design consists of creating a nominal design according to specifications given by Meopta – optika s.r.o company and a tolerance analysis, which describes manufacturability of given design. Specifications given are most importantly diffraction limited image quality, correction of distortion throughout the field and telecentricity of systém in image space. F-theta lens in this thesis was created using an optical design software called Zemax.

The ability to inhibit a prepotent response is a crucial prerequisite of goal-directed behavior. So far, research on response inhibition has mainly examined these processes when there is little to no cognitive control during the decision to respond. We manipulated the “context” in which response inhibition has to be exerted (i.e., a controlled or an automated context) by combining a Simon task with a go/no-go task and focused on theta band activity. To investigate the role of “context” in response inhibition, we also examined how far theta band activity in the pretrial period modulates context-dependent variations of theta band activity during response inhibition. This was done in an EEG study applying beamforming methods. Here, we examined n = 43 individuals. We show that an automated context, as opposed to a controlled context, compromises response inhibition performance and increases the need for cognitive control. This was also related to context-dependent modulations of theta band activity in superior frontal and middle frontal regions. Of note, results showed that theta band activity in the pretrial period, associated with the right inferior frontal cortex, was substantially correlated with context-dependent modulations of theta band activity during response inhibition. The direction of the obtained correlation provides insights into the functional relevance of a pretrial theta band activity. The data suggest that pretrial theta band activity reflects some form of attentional sampling to inform possible upcoming processes signaling the need for cognitive control.

Le courant cationique activé par l'hyperpolarisation (courant H) est impliqué dans l'organisation temporelle de l'activité neuronale. Nous montrons que le courant H améliore la synchronisation et la régularité des oscillations thêta dans l'hippocampe et dans le néocortex in vitro. Il détermine les oscillations thêta par la définition de résonnance intrinsèque de membrane, la fidélité de décharge et le couplage entre potentiels postsynaptiques et décharge. Les cinétiques du courant H sont modulés par l'AMPc. Nous montrons que l'augmentation de l'activité synaptique provoque une augmentation de la concentration en AMPc intracellulaire qui pourrait réguler les oscillations de l'activité de réseau. Ces résultats illustrent le rôle clef d'un courant intrinsèque dans l'organisation temporelle de l'activité des neurones en réseau. La modulation des propriétés cinétiques du courant H peut agir comme un régulateur de fréquence.

INTRODUÇÃO: O Transtorno do Espectro Autista tem incidência precoce e causas genéticas e ambientais multifatoriais. Gera disfunção no desenvolvimento da linguagem e da sociabilidade e um padrão de comportamento restrito e repetitivo. A formação e o desenvolvimento do sistema nervoso são afetados provocando impacto na arquitetura tecidual, desequilíbrio funcional entre os sistemas excitatórios e inibitórios, além de problemas na conectividade e consistência das redes neurais. O tratamento baseia-se em estimulação multiprofissional precoce e no uso de medicamentos que interferem na sintomatologia impactante do cotidiano. Os comportamentos restritos e repetitivos marcam o perfil funcional do paciente com Transtorno do Espectro Autista e podem interferir diretamente no desenvolvimento da linguagem e na sociabilidade. A mudança do espectro comportamental em razão do amadurecimento cognitivo não impede o desequilíbrio funcional nas atividades da vida diária. Existem indícios de que a função da flexibilidade cognitiva somada à capacidade para gerar novos conceitos e à velocidade de processamento das informações estão afetadas nesses pacientes e podem representar a base fisiopatológica dos Comportamentos Restritos e Repetitivos e suas repercussões no desenvolvimento desses indivíduos. O presente estudo visa avaliar os efeitos da facilitação da transmissão dos impulsos nervosos na função da flexibilidade cognitiva e no comportamento restrito e repetitivo dos pacientes com o diagnóstico de Transtorno do Espectro Autista de alto funcionamento através da Estimulação Magnética Transcraniana de pulsos pareados no Córtex Pré Frontal Ventro Lateral (CPFVL) direito em sua porção antero inferior. MÉTODOS: Trata-se de um estudo experimental com procedimento sistematizado e intervencional realizado com 11 pacientes de 9 a 17 anos, pareados por um perfil cognitivo dentro dos limites da normalidade, que foram submetidos ao protocolo de estimulação com a técnica de \"Theta Burst\" em CPFVL antero inferior à direita em 15 sessões divididas em três semanas. Os pacientes foram testados antes e depois do procedimento. A avaliação da flexibilidade cognitiva, da capacidade de formação de novos conceitos e do tempo cognitivo foram realizada através dos testes Wisconsin Sort Card Test (WSCT) e STROOP, aplicados aos pacientes. Os Comportamentos Restritos e Repetitivos foram avaliados pelos instrumentos Repetitive Behavior Scale - Revised (RBS-r) e Escala de Pensamentos Obsessivos e Comportamentos Compulsivos de Yale Brown (YBOCS) por meio de questionários aplicados aos pais e cuidadores desses pacientes. RESULTADOS: Encontraram-se evidências de mudanças no padrão de inflexibilidade cognitiva, representada pelo WSCT, nos itens Erros Perserverativos (p=0,028) e na Formação de Nível Conceitual (p=0,022). A alteração demonstrada pela Formação de Nível Conceitual pelo WSCT e pelo Total de Tempo para realizar o STROOP test (p=0,001) representam mudança na velocidade de processamento de informações. Constatou-se melhora do Comportamento Restrito e Repetitivo tanto pelo RBS-r (p=0,002) quanto no YBOCS Total de Compulsões (p=0,02). Todas as classes mostraram mudanças significativas: Ordem Inferior (p=0,05), Ordem superior (p=0,028) e Insistência na Mesmice (p=0,014). Houve correlação entre as curvas que representam as mudanças ocorridas no RBS-r e na flexibilidade cognitiva, representada pelo item Respostas Perseverativas (r=0,049). Por se tratar de um piloto, o presente estudo permite o aprofundamento das pesquisas que relacionam esta forma de intervenção descrita ao tratamento do Comportamento Restrito e Repetitivo em pacientes com Transtorno do Espectro Autista / INTRODUTION: The Autism Spectrum Disorder has an early incidence. It has genetic and environment multifactorial causes. Patients present language and social development disability and restricted and repetitive behavior. The maturation and development of the nervous system are damaged. Hence there is a disruption on the tissue architecture, functional imbalance between excitatory and inhibitory systems and connectivity and consistency of neural networks issues. The treatment is grounded on premature multiprofessional stimulation to improve cognition and the medication for mood instability, sleep problems, anxiety, hyperactivity and attention problems. The Restricted and Repetitive Behavior marks the functional profile of the Autism Spectrum Disorder and can hinder the communication and sociability development. The behavior changes with the cognitive maturation but does not prevent from the functional imbalance in daily activities. Evidence revel that the cognitive inflexibility added to the impairment to form new concepts and cognitive tempo can reflect the pathophysiology of these behaviors and its impact on development. The current study aims to valuate changes on cognitive flexibility and restricted and repetitive behavior after the facilitation of impulses through paired pulse Trascranial Magnetic Stimulation (EMT) on right anterior inferior Ventro Lateral Pre Frontal Cortex (VLPFC) in high function Autism Spectrum Disorder individuals. METHODS: It is an experimental study with systemic interventional procedure. Eleven subjects with nine to seventeen years old paired by normal cognitive profile were submitted to the protocol of Theta Burst stimulation on right anterior inferior VLPFC with fifteen sessions divided into three weeks. Subjects were tested before and after the procedure. They were tested for cognitive inflexibility, the ability to form new concepts and the cognitive tempo by the Wisconsin Sort Card (WSCT) test and STROOP test. The restricted and repetitive behaviors were evaluated by Restricted and Repetitive Behavior Scale revised (RBS-r) and Yale Brown Obsessive and Compulsive Scale applied for parents. RESULTS: Evidence of changes on cognitive inflexibility pattern were found items Perseverative Errors (p=0,028) and Conceptual level Response (p=0,022) of the WSCT test. Information processing speed changes were established by the Conceptual level Response of the WSCT and the Total Time to Finish the STROOP test (p=0,001). Improvement on restricted and repetitive behavior were found by changes on total score of RBS-r (p=0,002) and by YBOCS Total of Compulsions (p=0,02). There were changes on all aspects of the repetitive behaviors: Low-Order behavior (p=0,05), High-Order behavior (p=0,028) and Sameness behavior (0,014). Correlation were found between changing curves of cognitive inflexibility represented by Perseverative Response and total score of RBS-r (r=0,049). Since this is a pilot study, our data allows us to suggest that EMT-pp can be efficient for treating restricted and repetitive behavior on Autism Spectrum Disorder. Further controlled studies will be conducted to confirm this hypothesis

En 1998, R. Gompf a défini un invariant homotopique des champs de plans orientés des 3-variétés fermées orientées. Cet invariant est défini pour les champs de plans orientés xi; de toute 3-variété fermée orientée M dont la première classe de Chern c_1(xi) est un élément de torsion de H_2(M;Z). Dans le premier chapitre de la thèse, nous définissons une extension de l’invariant de Gompf pour toutes les 3-variétés compactes orientées à bord et nous étudions ses variations lors de chirurgies lagrangiennes. Il en résulte que l’invariant de Gompf étendu peut être vu comme un invariant de type fini de degré 2.L’invariant Théta est un invariant de variétés de dimension 3 parallélisées qui provient de la partie de degré 1 du développement perturbatif de la théorie de Chern-Simons. G. Kuperberg et D. Thurston ont identifié l’invariant Théta(M,tau) d’une sphère d’homologie entière M munie d’une parallélisation tau; à lambda_cw(M) + 1/4·p_1(tau) où lambda_cw désigne la généralisation de Walker de l’invariant de Casson et p_1 est un invariant de la parallélisation définie à partir d’une première classe de Pontrjagin. C. Lescop a étendu l’invariant Théta aux sphères d’homologie rationnelle munies d’une classe d’homotopie de combings et elle a montré que pour toute sphère d’homologie rationnelle M munie d’un combing X, la formule Théta(M,[X]) = 3·lambda_cw(M) + 1/4·p_1([X]) était encore valable pour une extension ad hoc des nombres de Pontrjagin aux combings. Elle a aussi donné une formule combinatoire pour l’invariant Théta d’une sphère d’homologie rationnelle présentée par un diagramme de Heegaard et munie d’un combing associé au diagramme, et elle a démontré combinatoirement que cette formule définit un invariant homotopique des couples (M,[X]). Dans le prolongement de ce travail, le deuxième chapitre de la thèse présente une preuve combinatoire de la décomposition de cet invariant combinatoire comme 3·lambda_cw(M) + 1/4·p_1([X]). Cette preuve repose sur la théorie des invariants de type fini des sphères d’homologie rationnelle relativement aux chirurgies lagrangiennes établie par D. Moussard en 2012 / In 1998, R. Gompf defined a homotopy invariant of oriented 2-plane fields in 3-manifolds. This invariant is defined for oriented 2-plane fields xi in a closed oriented 3-manifold M when the first Chern class c_1(xi) is a torsion element of H_2(M;Z). In Chapter I, we define an extension of the Gompf invariant for all compact oriented 3-manifolds with boundary and we study its iterated variations under Lagrangian-preserving surgeries. It follows that the extended Gompf invariant has degree two for a suitable finite type invariant theory.The Theta-invariant is an invariant of parallelized 3-manifolds constructed from the degree one part of the perturbative expansion of Chern–Simons theory. G. Kuperberg and D. Thurston identified the invariant Theta(M,tau) of a rational homology 3-sphere M equipped with a parallelization tau with 3·lambda_cw(M) + 1/4·p_1(tau) where lambda_cw denotes Walker’s generalization of the Casson invariant and where p_1 is an invariant of parallelizations defined using a first Pontrjagin class. C. Lescop extended the Theta-invariant to rational homology 3-spheres equipped with a homotopy class of combings and she showed that for all rational homology 3-sphere M equipped with a combing X, the relation Theta(M,[X]) = 3·lambda_cw(M) + 1/4·p_1([X]) still holds using an ad hoc extension of the Pontrjagin numbers for combings. She also gave a combinatorial formula for the Theta-invariant of a rational homology 3-sphere represented by a Heeagaard diagram and equipped with a combing associated to the diagram, and she proved that this formula defines a homotopy invariant of the pair (M,[X]), in a combinatorial way. Following this work, Chapter II presents a combinatorial proof of the decomposition of this combinatorial invariant as 3·lambda_cw(M) + 1/4·p_1([X]). This proof relies on the finite type invariant theory for rational homology 3-spheres with respect to Lagrangian-preserving surgeries established by D. Moussard in 2012

Made available in DSpace on 2016-06-02T20:06:07Z (GMT). No. of bitstreams: 1 4757.pdf: 552745 bytes, checksum: 4f9bf1ad04dfca4e80bbfdf36c909f6f (MD5) Previous issue date: 2012-12-06 / Financiadora de Estudos e Projetos / Time series forecasting is probably one of the most primordial interests on economics and econometrics, and the literature on this subject is extremely vast. Due to technological growth in recent decades, large amounts of time series are daily collected; which, in a first moment, it requires forecasts according a fixed horizon; and on the second moment the forecasts must be constantly updated, making it impractical to human interaction. Towards this direction, computational procedures that are able to model and return accurate forecasts are required in several research areas. The search for models with high predictive power is an issue that has resulted in a large number of publications in the area of forecasting models. We propose to do a theorical and applied study of forecasting methods applied to multiple univariate time series. The study was based on exponential smoothing via state space approach, automatic ARIMA methods and the generalized Theta method. Each model and method were applied in large data bases of univariate time series and the forecast errors were evaluated. We also propose an approach to estimate the Theta coefficients, as well as a redefinition of the method regarding the number of decomposition lines, extrapolation methods and a combining approach. / A previsão de séries temporais é provavelmente um dos interesses mais primordiais na área de economia e econometria, e a literatura referente a este assunto é extremamente vasta. Devido ao crescimento tecnológico nas últimas décadas, diariamente são geradas e disponibilizadas grandes quantidades de séries temporais; que em um primeiro momento, requerem previsões de acordo com um horizonte fixado; e no segundo momento as previsões precisam ser constantemente atualizadas, tornando pouco prática a interação humana. Desta forma, procedimentos computacionais que modelem e posteriormente retornem previsões acuradas são exigidos em diversas áreas do conhecimento. A busca por modelos com alto poder de preditivo é uma questão que tem resultado em grande quantidade de publicações na área de modelos para previsão. Neste trabalho, propõe-se um estudo teórico e aplicado de métodos de previsão aplicado à múltiplas séries temporais univariadas. O estudo foi baseado em modelos de alisamento exponencial via espaço de estados, método ARIMA automático e o método Theta generalizado. Cada modelo e método foi aplicado em grandes bases de séries temporais univariadas e avaliado o resultado em relação aos erros de previsão. Também foi proposta uma abordagem para estimação dos coeficientes Theta, assim como redefinição do método em relação a quantidade de linhas para decomposição, métodos de extrapolação e combinação das linhas para previsão.

INTRODUÇÃO: O Transtorno do Espectro Autista tem incidência precoce e causas genéticas e ambientais multifatoriais. Gera disfunção no desenvolvimento da linguagem e da sociabilidade e um padrão de comportamento restrito e repetitivo. A formação e o desenvolvimento do sistema nervoso são afetados provocando impacto na arquitetura tecidual, desequilíbrio funcional entre os sistemas excitatórios e inibitórios, além de problemas na conectividade e consistência das redes neurais. O tratamento baseia-se em estimulação multiprofissional precoce e no uso de medicamentos que interferem na sintomatologia impactante do cotidiano. Os comportamentos restritos e repetitivos marcam o perfil funcional do paciente com Transtorno do Espectro Autista e podem interferir diretamente no desenvolvimento da linguagem e na sociabilidade. A mudança do espectro comportamental em razão do amadurecimento cognitivo não impede o desequilíbrio funcional nas atividades da vida diária. Existem indícios de que a função da flexibilidade cognitiva somada à capacidade para gerar novos conceitos e à velocidade de processamento das informações estão afetadas nesses pacientes e podem representar a base fisiopatológica dos Comportamentos Restritos e Repetitivos e suas repercussões no desenvolvimento desses indivíduos. O presente estudo visa avaliar os efeitos da facilitação da transmissão dos impulsos nervosos na função da flexibilidade cognitiva e no comportamento restrito e repetitivo dos pacientes com o diagnóstico de Transtorno do Espectro Autista de alto funcionamento através da Estimulação Magnética Transcraniana de pulsos pareados no Córtex Pré Frontal Ventro Lateral (CPFVL) direito em sua porção antero inferior. MÉTODOS: Trata-se de um estudo experimental com procedimento sistematizado e intervencional realizado com 11 pacientes de 9 a 17 anos, pareados por um perfil cognitivo dentro dos limites da normalidade, que foram submetidos ao protocolo de estimulação com a técnica de \"Theta Burst\" em CPFVL antero inferior à direita em 15 sessões divididas em três semanas. Os pacientes foram testados antes e depois do procedimento. A avaliação da flexibilidade cognitiva, da capacidade de formação de novos conceitos e do tempo cognitivo foram realizada através dos testes Wisconsin Sort Card Test (WSCT) e STROOP, aplicados aos pacientes. Os Comportamentos Restritos e Repetitivos foram avaliados pelos instrumentos Repetitive Behavior Scale - Revised (RBS-r) e Escala de Pensamentos Obsessivos e Comportamentos Compulsivos de Yale Brown (YBOCS) por meio de questionários aplicados aos pais e cuidadores desses pacientes. RESULTADOS: Encontraram-se evidências de mudanças no padrão de inflexibilidade cognitiva, representada pelo WSCT, nos itens Erros Perserverativos (p=0,028) e na Formação de Nível Conceitual (p=0,022). A alteração demonstrada pela Formação de Nível Conceitual pelo WSCT e pelo Total de Tempo para realizar o STROOP test (p=0,001) representam mudança na velocidade de processamento de informações. Constatou-se melhora do Comportamento Restrito e Repetitivo tanto pelo RBS-r (p=0,002) quanto no YBOCS Total de Compulsões (p=0,02). Todas as classes mostraram mudanças significativas: Ordem Inferior (p=0,05), Ordem superior (p=0,028) e Insistência na Mesmice (p=0,014). Houve correlação entre as curvas que representam as mudanças ocorridas no RBS-r e na flexibilidade cognitiva, representada pelo item Respostas Perseverativas (r=0,049). Por se tratar de um piloto, o presente estudo permite o aprofundamento das pesquisas que relacionam esta forma de intervenção descrita ao tratamento do Comportamento Restrito e Repetitivo em pacientes com Transtorno do Espectro Autista / INTRODUTION: The Autism Spectrum Disorder has an early incidence. It has genetic and environment multifactorial causes. Patients present language and social development disability and restricted and repetitive behavior. The maturation and development of the nervous system are damaged. Hence there is a disruption on the tissue architecture, functional imbalance between excitatory and inhibitory systems and connectivity and consistency of neural networks issues. The treatment is grounded on premature multiprofessional stimulation to improve cognition and the medication for mood instability, sleep problems, anxiety, hyperactivity and attention problems. The Restricted and Repetitive Behavior marks the functional profile of the Autism Spectrum Disorder and can hinder the communication and sociability development. The behavior changes with the cognitive maturation but does not prevent from the functional imbalance in daily activities. Evidence revel that the cognitive inflexibility added to the impairment to form new concepts and cognitive tempo can reflect the pathophysiology of these behaviors and its impact on development. The current study aims to valuate changes on cognitive flexibility and restricted and repetitive behavior after the facilitation of impulses through paired pulse Trascranial Magnetic Stimulation (EMT) on right anterior inferior Ventro Lateral Pre Frontal Cortex (VLPFC) in high function Autism Spectrum Disorder individuals. METHODS: It is an experimental study with systemic interventional procedure. Eleven subjects with nine to seventeen years old paired by normal cognitive profile were submitted to the protocol of Theta Burst stimulation on right anterior inferior VLPFC with fifteen sessions divided into three weeks. Subjects were tested before and after the procedure. They were tested for cognitive inflexibility, the ability to form new concepts and the cognitive tempo by the Wisconsin Sort Card (WSCT) test and STROOP test. The restricted and repetitive behaviors were evaluated by Restricted and Repetitive Behavior Scale revised (RBS-r) and Yale Brown Obsessive and Compulsive Scale applied for parents. RESULTS: Evidence of changes on cognitive inflexibility pattern were found items Perseverative Errors (p=0,028) and Conceptual level Response (p=0,022) of the WSCT test. Information processing speed changes were established by the Conceptual level Response of the WSCT and the Total Time to Finish the STROOP test (p=0,001). Improvement on restricted and repetitive behavior were found by changes on total score of RBS-r (p=0,002) and by YBOCS Total of Compulsions (p=0,02). There were changes on all aspects of the repetitive behaviors: Low-Order behavior (p=0,05), High-Order behavior (p=0,028) and Sameness behavior (0,014). Correlation were found between changing curves of cognitive inflexibility represented by Perseverative Response and total score of RBS-r (r=0,049). Since this is a pilot study, our data allows us to suggest that EMT-pp can be efficient for treating restricted and repetitive behavior on Autism Spectrum Disorder. Further controlled studies will be conducted to confirm this hypothesis

No description available.

Disertační práce se zabývá vyšetřováním kvalitativních vlastností diferenčních rovnic se zpožděním, které vznikly diskretizací příslušných diferenciálních rovnic se zpožděním pomocí tzv. $\Theta$-metody. Cílem je analyzovat asymptotické vlastnosti numerického řešení těchto rovnic a formulovat jeho horní odhady. Studována je rovněž stabilita vybraných numerických diskretizací. Práce obsahuje také srovnání s dosud známými výsledky a několik příkladů ilustrujících hlavní dosažené výsledky.