En nous invitant à considérer son œuvre d’un point de vue esthétique, André Gide souhaite dépasser les considérations morales et psychanalytiques plaçant un pan de la sexualité en dehors de la norme. L’auteur s’attache à présenter les défauts de tout ce qui est défini a priori comme étant la normale. Ainsi, le paraître auquel ont recours certains personnages de L’Immoraliste, des Caves du Vatican ou des Faux-monnayeurs permet de repenser le modèle représenté par la famille bourgeoise. Il ne convient plus de traiter certaines perversions comme de simples déviances. En jouant avec les apparences, les personnages oscillent entre le monde du spectacle et le travestissement. Tous ces jeux rhétoriques et esthétiques incitent à une redéfinition de la perversion. Ajoutons enfin que cette volonté de dépasser l’idée selon laquelle l’homosexuel se trouve en dehors de la normale permet à Gide de proposer une véritable réflexion sur l’homosexualité et la place de l’homosexuel dans notre société. C’est notamment grâce à cette réflexion que va émerger dans les pays anglo-saxons et plus tardivement en France une nouvelle approche de la sexualité appelée : Gender Studies / By asking to look at his work from an aesthetical point of view, André Gide wishes to go beyond the moral and psychological standards which tend to consider some parts of sexuality outside of the norm. Gide shows all the flaws of what is considered normal. In doing so, the family has to face its own flaws. The appearance that is shown by some characters of L'Immoraliste, Les Caves du Vatican or Les Faux-monnayeurs, gives the author the opportunity to reconsider the model that embodies the bourgeois family. Hence, it appears that the principles on which are based the norm and what is normal aren’t enough to claim that some perversions are just deviances. Playing with appearances, the characters range from simple acting to complete disguise; therefore, no one can rely on what they have shown. Through rhetorical and aesthetical games, Gide invites us to redefine perversion. Moving the boundaries that place the homosexual outside of the norm, Gide goes in depth about homosexuality and its standing in our society. Thanks to this new definition, it will emerge first in Anglo-Saxon countries and later in France a new approach to sexuality called "Gender Studies".

Orientador: Marcos Roberto de Mattos Fontes / Resumo: Acidentes ofídicos são considerados um problema de saúde pública global, dada sua alta ocorrência de mortes, onde alguns casos resultam em sequelas irreparáveis, deixando o indivíduo desabilitado por toda a vida. Somente no Brasil, em média 20 mil mortes ao ano são registradas. Desta forma, alguns pesquisadores têm buscado estudar a estrutura-função de componentes dos venenos de serpentes peçonhentas à fim de desenvolver alternativas terapêuticas para esse problema de grande interesse médico. Um dos componentes que tem recebido atenção nas últimas décadas é a BthTX-I, uma proteína PLA2s-homóloga não catalítica, devido seu efeitos farmacológico notadamente miotóxico. Embora diversas técnicas tenham sido empregadas na compreensão do mecanismo de ação dessas proteínas, o conhecimento nessa área permanece controverso, tornando-se necessário a continuidade de estudos. O estudo estrutural e computacional de proteínas constitui uma alternativa viável para identificar as várias conformações de uma dada proteína, bem como seu comportamento dinâmico. Sendo assim, o presente trabalho buscou aplicar métodos computacionais, como simulação de MD, análise de Modos Normais (NM) e Dinâmica Molecular excitada por Modos Normais (MDeNM) à BthTX-I em pH ácido ou básico e nativa ou em complexo com o α-tocoferol – molécula tida como ativadora alostérica – na descrição do seu espaço conformacional, buscando compreender os aspectos estruturais do seu mecanismo de ação. Além disso, foram empregadas té... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Ophidian accidents constitute a global public health problem due its high mortality, with some cases leading to permanent sequels. In Brazil, around 20 thousand deaths are registered. Therefore, researchers have been studying the snake venom composition in order to develop therapeutic alternatives to this medical problem. Some components from snake venom are highlighted in the past decades, as BthTX-I, a non-catalytic PLA2s-homologous protein, due its many pharmacological effects, notably myotoxic. Although many techniques have been employed to better understand the molecular mechanism of action for these proteins, this knowledge remains controversial, emphasizing the need to progress this field. The structural and computational study of proteins is a valuable tool to access the various conformations of a given protein, as well its dynamical behavior. Thus, the present work applied computational methods as MD, Normal Modes (NM) analysis and Molecular Dynamics with excited Normal Modes (MDeNM) to BthTX-I in acidic or basic pH and unbound or bound to α-tocopherol – a molecule identified as an allosteric activator – in order to describe the conformational space of this protein and determine the structural aspects of its mechanism of action. Further, biophysical experiments as Dynamic Light Scattering (DLS) were employed in order to comprehend the oligomeric form of BthTX-I with or without α-tocopherol. MD simulations showed that dimeric form of BthTX-I is stable when in neutral/... (Complete abstract click electronic access below) / Doutor

PhD / When modeling a system as complex as the brain, considerable simplifications are inevitable. The nature of these simplifications depends on the available experimental evidence, and the desired form of model predictions. A focus on the former often inspires models of networks of individual neurons, since properties of single cells are more easily measured than those of entire populations. However, if the goal is to describe the processes responsible for the electroencephalogram (EEG), such models can become unmanageable due to the large numbers of neurons involved. Mean-field models in which assemblies of neurons are represented by their average properties allow activity underlying the EEG to be captured in a tractable manner. The starting point of the results presented here is a recent physiologically-based mean-field model of the corticothalamic system, which includes populations of excitatory and inhibitory cortical neurons, and an excitatory population representing the thalamic relay nuclei, reciprocally connected with the cortex and the inhibitory thalamic reticular nucleus. The average firing rates of these populations depend nonlinearly on their membrane potentials, which are determined by afferent inputs after axonal propagation and dendritic and synaptic delays. It has been found that neuronal activity spreads in an approximately wavelike fashion across the cortex, which is modeled as a two-dimensional surface. On the basis of the literature, the EEG signal is assumed to be roughly proportional to the activity of cortical excitatory neurons, allowing physiological parameters to be extracted by inverse modeling of empirical EEG spectra. One objective of the present work is to characterize the statistical distributions of fitted model parameters in the healthy population. Variability of model parameters within and between individuals is assessed over time scales of minutes to more than a year, and compared with the variability of classical quantitative EEG (qEEG) parameters. These parameters are generally not normally distributed, and transformations toward the normal distribution are often used to facilitate statistical analysis. However, no single optimal transformation exists to render data distributions approximately normal. A uniformly applicable solution that not only yields data following the normal distribution as closely as possible, but also increases test-retest reliability, is described in Chapter 2. Specialized versions of this transformation have been known for some time in the statistical literature, but it has not previously found its way to the empirical sciences. Chapter 3 contains the study of intra-individual and inter-individual variability in model parameters, also providing a comparison of test-retest reliability with that of commonly used EEG spectral measures such as band powers and the frequency of the alpha peak. It is found that the combined model parameters provide a reliable characterization of an individual's EEG spectrum, where some parameters are more informative than others. Classical quantitative EEG measures are found to be somewhat more reproducible than model parameters. However, the latter have the advantage of providing direct connections with the underlying physiology. In addition, model parameters are complementary to classical measures in that they capture more information about spectral structure. Another conclusion from this work was that a few minutes of alert eyes-closed EEG already contain most of the individual variability likely to occur in this state on the scale of years. In Chapter 4, age trends in model parameters are investigated for a large sample of healthy subjects aged 6-86 years. Sex differences in parameter distributions and trends are considered in three age ranges, and related to the relevant literature. We also look at changes in inter-individual variance across age, and find that subjects are in many respects maximally different around adolescence. This study forms the basis for prospective comparisons with age trends in evoked response potentials (ERPs) and alpha peak morphology, besides providing a standard for the assessment of clinical data. It is the first study to report physiologically-based parameters for such a large sample of EEG data. The second main thrust of this work is toward incorporating the thalamocortical system and the basal ganglia in a unified framework. The basal ganglia are a group of gray matter structures reciprocally connected with the thalamus and cortex, both significantly influencing, and influenced by, their activity. Abnormalities in the basal ganglia are associated with various disorders, including schizophrenia, Huntington's disease, and Parkinson's disease. A model of the basal ganglia-thalamocortical system is presented in Chapter 5, and used to investigate changes in average firing rates often measured in parkinsonian patients and animal models of Parkinson's disease. Modeling results support the hypothesis that two pathways through the basal ganglia (the so-called direct and indirect pathways) are differentially affected by the dopamine depletion that is the hallmark of Parkinson's disease. However, alterations in other components of the system are also suggested by matching model predictions to experimental data. The dynamics of the model are explored in detail in Chapter 6. Electrophysiological aspects of Parkinson's disease include frequency reduction of the alpha peak, increased relative power at lower frequencies, and abnormal synchronized fluctuations in firing rates. It is shown that the same parameter variations that reproduce realistic changes in mean firing rates can also account for EEG frequency reduction by increasing the strength of the indirect pathway, which exerts an inhibitory effect on the cortex. Furthermore, even more strongly connected subcircuits in the indirect pathway can sustain limit cycle oscillations around 5 Hz, in accord with oscillations at this frequency often observed in tremulous patients. Additionally, oscillations around 20 Hz that are normally present in corticothalamic circuits can spread to the basal ganglia when both corticothalamic and indirect circuits have large gains. The model also accounts for changes in the responsiveness of the components of the basal ganglia-thalamocortical system, and increased synchronization upon dopamine depletion, which plausibly reflect the loss of specificity of neuronal signaling pathways in the parkinsonian basal ganglia. Thus, a parsimonious explanation is provided for many electrophysiological correlates of Parkinson's disease using a single set of parameter changes with respect to the healthy state. Overall, we conclude that mean-field models of brain electrophysiology possess a versatility that allows them to be usefully applied in a variety of scenarios. Such models allow information about underlying physiology to be extracted from the experimental EEG, complementing traditional measures that may be more statistically robust but do not provide a direct link with physiology. Furthermore, there is ample opportunity for future developments, extending the basic model to encompass different neuronal systems, connections, and mechanisms. The basal ganglia are an important addition, not only leading to unified explanations for many hitherto disparate phenomena, but also contributing to the validation of this form of modeling.

Recent research has shown that it is often preferable to encode real-world problems as propositional satisfiability (SAT) problems and then solve using a general purpose SAT solver. However, much of the valuable information and structure of these realistic problems is flattened out and hidden inside the corresponding Conjunctive Normal Form (CNF) encodings of the SAT domain. Recently, systematic SAT solvers have been progressively improved and are now able to solve many highly structured practical problems containing millions of clauses. In contrast, state-of-the-art Stochastic Local Search (SLS) solvers still have difficulty in solving structured problems, apparently because they are unable to exploit hidden structure as well as the systematic solvers. In this thesis, we study and evaluate different ways to effectively recognise, model and efficiently exploit useful structures hidden in realistic problems. A summary of the main contributions is as follows: 1. We first investigate an off-line processing phase that applies resolution-based pre-processors to input formulas before running SLS solvers on these problems. We report an extensive empirical examination of the impact of SAT pre-processing on the performance of contemporary SLS techniques. It emerges that while all the solvers examined do indeed benefit from pre-processing, the effects of different pre-processors are far from uniform across solvers and across problems. Our results suggest that SLS solvers need to be equipped with multiple pre-processors if they are ever to match the performance of systematic solvers on highly structured problems. [Part of this study was published at the AAAI-05 conference]. 2. We then look at potential approaches to bridging the gap between SAT and constraint satisfaction problem (CSP) formalisms. One approach has been to develop a many-valued SAT formalism (MV-SAT) as an intermediate paradigm between SAT and CSP, and then to translate existing highly efficient SAT solvers to the MV-SAT domain. In this study, we follow a different route, developing SAT solvers that can automatically recognise CSP structure hidden in SAT encodings. This allows us to look more closely at how constraint weighting can be implemented in the SAT and CSP domains. Our experimental results show that a SAT-based mechanism to handle weights, together with a CSP-based method to instantiate variables, is superior to other combinations of SAT and CSP-based approaches. In addition, SLS solvers based on this many-valued weighting approach outperform other existing approaches to handle many-valued CSP structures. [Part of this study was published at the AAAI-05 conference]. 3. Finally, we propose and evaluate six different schemes to encode temporal reasoning problems, in particular the Interval Algebra (IA) networks, into SAT CNF formulas. We then empirically examine the performance of local search as well as systematic solvers on the new temporal SAT representations, in comparison with solvers that operate on native IA representations. Our empirical results show that zChaff (a state-of-the-art complete SAT solver) together with the best IA-to-SAT encoding scheme, can solve temporal problems significantly faster than existing IA solvers working on the equivalent native IA networks. [Part of this study was published at the CP-05 workshop].

關於二維之變數，Arnold and Press (1989) 首先提出檢驗兩個條件分配是否滿足相容性的理論。本研究嘗試對n維之變數，探討n個條件分配滿足相容性的檢驗方式；並提出在三維聯合分配下，給定三個條件分配為常態(normal) 時，檢驗此三個條件分配滿足相容性的充分必要條件；最後，並推導出此三個條件分配滿足相容性時，其所對應的聯合機率密度函數之公式。若此三個條件分配其所對應的聯合機率密度函數進一步假設為常態時，檢驗其相容性的充分必要條件可更加以簡化。 / Arnold and Press (1989) first provide the theory about the compatibility of two conditional distributions in two dimensions. In this research, we extend the two dimensional cases to the high dimensional cases. In particular, we find the necessary and sufficient conditions of the compatibility of three conditional normal distributions in three dimensions. Furthermore, we also provide a formula to find the joint probability density function when three dimensional conditional normal distributions are compatible. Finally, simple sufficient and necessary conditions are also given when the joint distribution is further assumed to be normal.

Normal pressure hydrocephalus (NPH), a CSF circulation disorder, is important as a reversible cause of gait and cognitive disturbance in an aging population. The inconsistent response to CSF shunting is usually attributed to difficulties in differential diagnosis or co-morbidity. Improving outcome depends on an increased understanding of the pathophysiology of NPH. Specifically, this thesis examines the contribution of, and inter-relationship between, the brain parenchyma and CSF circulation in the pathophysiology of NPH. Of the four core studies of the thesis, the first quantifies the characteristics of the CSF circulation and parenchyma in NPH using CSF infusion studies to measure the resistance to CSF absorption and brain compliance. The second study assesses cerebral blood flow (CBF) was using O15-labelled positron emission tomography (PET) with MR co-registration. By performing CSF infusion studies in the PET scanner, CBF at baseline CSF pressure and at a higher equilibrium pressure is measured. Regional changes and autoregulatory capacity are assessed. The final study examines the microstructural integrity of the parenchyma using MR diffusion tensor imaging. These studies confirm the importance of the inter-relationship of the brain parenchyma and CSF circulation. NPH symptomatology and its relationship to the observed regional CBF reductions in the basal ganglia and thalamus are discussed. Regional CBF reductions with increased CSF pressure and the implications for autoregulatory capacity in NPH are considered. The reduction in CBF when CSF was increased was most striking in the periventricular regions. In addition, periventricular structures demonstrated increased diffusivity and decreased anisotropy. The relationship between these changes and mechanisms such as transependymal CSF passage are reviewed. The findings of this thesis support a role of both the CSF circulation and the brain parenchyma in the pathophysiology of NPH. The results have implications for the approach to the management of patients with NPH.

Le contexte général dans lequel s'inscrivent les travaux développés dans ce mémoire est le contrôle des processus industriels complexes. Ces travaux proposent des nouvelles techniques d'amélioration du contrôle statistique des processus non gaussiens : la carte de contrôle avec des paramètres variables et la carte de contrôle théorique pour la loi de distribution de Rayleigh. Un modèle d'intégration des outils des domaines de l'APC (Automatic Process Control) et de la MSP est proposée et ensuite analysé par le biais des deux modèles de processus réel.

Le domaine valaisan dessine la suture majeure qui marque la limite entre les zones internes et externes des Alpes occidentales et dont l'interprétation géodynamique était controversée. Cette suture est constituée d'une série de flysch (le flysch valaisan) et d'un complexe magmatique et sédimentaire (le complexe du Versoyen). Suivant les auteurs, les roches magmatiques d'affinité tholéïtique pourraient représenter: 1) une klippe d'origine piémontaise (suture d'hyper-collision), 2) une écaille ophiolitique située au front d'un prisme d'accrétion (suture océanique), 3) un complexe magmatique lié à un amincissement crustal (inversion structurale). Le but de ce travail était de trouver des arguments qui permettaient de résoudre cette controverse. Ainsi les résultats de ce travail montrent que : - Dans la région du col du Petit-Saint-Bernard (frontière franco-italienne), certaines tholéïtes sont recoupées par des filons leucocrates qui correspondent à des liquides différenciés, cogénétiques du magmatisme. Les datations UlPb sur les zircons contenus dans l'un de ces filons indiquent un âge Carbonifère supérieur- Permien inférieur pour le magmatisme du Versoyen. - Ce magmatisme présente des caractères géochimiques et isotopiques, intermédiaires entre ceux des N-MORB et des T-MORB, dans les régions du col du Petit-Saint-Bernard et de Visp (Suisse). Ces tholéïtes dériveraient de la fusion partielle d'un manteau appauvri (de type N-MORB), avec probablement la participation d'une source enrichie (de type OIB), ce qui est en accord avec une mise en place dans un domaine en cours d'océanisation. - Le complexe du Versoyen est affecté par un métamorphisme polyphasé éclogitique, puis schiste bleu et enfin schiste vert. La paragénèse éclogitique correspond à des conditions de Haute-Pression et Basse-Température (P > 13Kb, 425 < T < 475°C) qui traduisent un enfouissement à grande profondeur, lié à une subduction. Les datations Ar/Ar réalisées sur les phengites donnent des âges de refroidissement proches de 33 Ma et permettent d'établir le chemin P-T-t de ce complexe au cours de l'exhumation des éclogites. - Le complexe du Versoyen est affecté par une déformation syn-schiste vert qui correspond à un jeu normal vers le SE. La comparaison entre les données de terrain et les données sismiques ECORS suggère que les failles normales se prolongent en profondeur et s'applatissent vers 10-15 km. Cette déformation postérieure à 38 Ma explique en partie l'exhumation des éclogites. Ce jeu normal est contemporain de chevauchements dans la zone externe et pourrait accommoder un réamincissement crustal au cours de la collision alpine. Ces données montrent que l'individualisation du substratum du domaine valaisan est liée au cycle hercynien et que ses relations complexes avec le flysch sus-jacent sont liées à une inversion structurale anté-flysch, alors que son évolution tectono-métamorphique est controlée par une extension succèdant aux phases compressives.

Il s'agit d'une thèse d'habilitation à diriger des recherches portant sur les invariants additifs en géométrie réelle, complexe et p-adique.

<p>The present thesis is focused on the development and application of dose response models for radiation therapy. Radiobiological models of tissue response to radiation are an integral part of the radiotherapeutic process and a powerful tool to optimize tumor control and minimize damage to healthy tissues for use in clinical trials. Ideally, the models could work as a historical control arm of a clinical trial eliminating the need to randomize patents to suboptimal therapies. In the thesis overview part, some of the basic properties of the dose response relation are reviewed and the most common radiobiological dose-response models are compared with regard to their ability to describe experimental dose response data for rat spinal cord using the maximum likelihood method. For vascular damage the relative seriality model was clearly superior to the other models, whereas for white matter necrosis all models were quite good except possibly the inverse tumor and critical element models. The radiation sensitivity, seriality and steepness of the dose-response relation of the spinal cord is found to vary considerably along its length. The cervical region is more radiation sensitive, more parallel, expressing much steeper dose-response relation and more volume dependent probability of inducing radiation myelitis than the thoracic part. The higher number of functional subunits (FSUs) consistent with a higher amount of white matter close to the brain may be responsible for these phenomena. With strongly heterogeneous dose delivery and due to the random location of FSUs, the effective size of the FSU and the mean dose deposited in it are of key importance and the radiation sensitivity distribution of the FSU may be an even better descriptor for the response of the organ. An individual optimization of a radiation treatment has the potential to increase the therapeutic window and improve cure for a subgroup of patients.</p>