Le corégulateur transcriptionnel RIP140 est un facteur ubiquitaire majeur impliqué dans la régulation de nombreux processus physiopathologiques, qui possède la capacité d’être un coactivateur ou un corépresseur des voies de signalisation selon son recrutement sur les gènes cible. Des résultats du laboratoire ont montré que RIP140 est un facteur de bon pronostic de la tumorigenèse intestinale sporadique. Ce travail s’intéresse à l’implication de ce facteur de transcription dans les cancers colorectaux familiaux et, plus particulièrement, en lien avec le syndrome de Lynch (LS). Le syndrome de Lynch est une prédisposition héréditaire aux cancers, majoritairement colorectaux, caractérisés par un défaut du système de réparation des mésappariements de l’ADN (Mismatch Repair, MMR), dû à une première mutation germinale d’un des gènes de ce système. La perte de fonctionnalité MMR est responsable du phénotype d’instabilité microsatellitaire (MSI). Cependant, il existe des formes familiales de cancers colorectaux, avec MSI, où il n’est pas retrouvé d’atteinte germinale ou somatique de l’un des gènes du système MMR. Ce sont les syndromes apparentés au syndrome de Lynch (Lynch Like Syndrome, LLS) dont la prise en charge est identique à celle du LS. L’utilisation de modèles murins et de lignées cellulaires colorectales, présentant des modulations d’expression de RIP140 ont permis de mettre en évidence l’effet positif de ce corégulateur sur la régulation transcriptionnelle de l’expression des gènes du système MMR, MSH2 et MSH6. La validité fonctionnelle de cette régulation a été explorée par des analyses d’instabilité microsatellitaire et de sensibilité à différentes molécules cytotoxiques. Des cohortes de tumeurs ont permis de confirmer la corrélation d’expression entre RIP140 et les gènes MSH2 et MSH6 chez les patients. En outre, la régulation de l’expression par RIP140 d’une polymérase translésionnelle particulière, la polymérase Polκ, a été étudiée. Cette polymérase assure la réplication des séquences microsatellitaires du génome. Nous avons démontré que RIP140 stimule l’expression du gène POLK dans nos modèles cellulaires et que son expression est corrélée à celle de RIP140 au sein des tumeurs colorectales humaines. Enfin, par séquençage de différentes lignées cellulaires, nous avons mis en évidence une mutation de RIP140 qui entraîne un décalage du cadre de lecture et génère une protéine tronquée avec perte de deux domaines répresseurs de la protéine. Un séquençage à très haut débit nous a permis de rechercher cette mutation parmi des échantillons de tumeurs colorectales avec MSI. Cette mutation est retrouvée dans 19% des tumeurs, notamment LLS (16,2%), où elle est associée à une moins bonne survie globale. Elle affecte les propriétés antiprolifératives et transrépressives de RIP140 ainsi que les régulations positives des gènes MSH2, MSH6 et POLK. Le développement d’un outil anticorps spécifique de cette mutation serait extrêmement utile pour suivre l’expression de la forme mutée au sein des tumeurs et des premiers essais ont été réalisés en ce sens. En conclusion de ce travail, RIP140 contrôle l’expression de gènes majeurs impliqués dans le maintien de l’intégrité du génome et une mutation de ce corégulateur transcriptionnel pourrait être responsable de l’instabilité microsatellitaire de certaines tumeurs où des altérations des gènes MMR ne sont pas retrouvées. Des études cliniques sur des cohortes plus conséquentes seront nécessaires pour valider son intérêt en tant que marqueur utilisable dans la prise en charge des patients. / The transcriptional coregulator RIP140 is an ubiquitous cofactor playing a major role in the regulation of many physiopathological processes. It can either act as a coactivator or as a corepressor of signaling pathways depending on its recruitment on target genes. It has been shown that RIP140 is a good prognostic marker in sporadic intestinal tumorigenesis. This work focuses on its role in familial colorectal cancers and particularly in relation to the Lynch syndrome (LS). Lynch syndrome is a hereditary cancer predisposition, mostly colorectal, characterized by a defect in the Mismatch Repair (MMR) system, due to a first germline mutation of one gene of this system. Loss of MMR function induces a microsatellite instability (MSI) phenotype. However, there are some MSI familial colorectal cancers, where neither germinal nor somatic alteration of one MMR gene is found. They are referred to as Lynch like Syndrome (LLS) and their overall management is identical to that of LS. Murine models and colorectal cell lines, harboring modulations of RIP140 expression, allowed us to demonstrate the positive transcriptional regulation of the MMR genes, MSH2 and MSH6 by RIP140. Functional validation of this regulation was explored by microsatellite instability and sensitivity to various cytotoxic drugs analyses. A positive correlation has been confirmed between RIP140 and MSH2 and MSH6 gene expression in a cohort of 396 patients. Moreover, the transcriptional regulation by RIP140 of a specialized translesional DNA polymerase, the Polκ polymerase, has been investigated. Polκ ensures microsatellite sequences replication. We have demonstrated that RIP140 positively stimulates the expression of the POLK gene in our cell models and which appears correlated with that of RIP140 in human colorectal tumors. Finally, by sequencing different cell lines, we found a frameshift mutation of RIP140, generating a truncated protein with loss of the last two repression domains. High-throughput sequencing allowed us to look for this mutation in patient MSI colorectal tumor samples. This mutation was found in 19% of these tumors, especially LLS (16,2%), where it has been associated with lower overall survival. This mutation affects the antiproliferative and transrepressive properties of RIP140, as well as the positive regulation of the MSH2, MSH6 and POLK gene. Development of a specific antibody for this mutation would be extremely useful in following the expression of this mutated form within tumors and first tests have been already carried out. In conclusion, RIP140 controls expression of major genes involved in genome integrity maintenance and a mutation of this transcriptional coregulator could be responsible for microsatellite instability of some tumors where alterations of MMR genes are not found. Clinical studies on larger cohorts will be necessary to validate its interest as a marker usable in patient management.

Common fragile sites are a set of genomic locations with a propensity to form lesions, breaks and gaps on mitotic chromosomes upon induction of replication stress. While the exact reasons for their fragility are unknown, CFS display instability in a cell-type specific manner, suggesting a substantial contribution from an epigenetic component. CFSs also overlap with sites of increased breakage and deletions in tumour cells, as well as evolutionary breakpoints, implying that their features shape genome stability in vivo. Previously, factors such as delays in replication timing, low origin density and transcription of long genes have been implicated in instability at CFS locations but comprehensive molecular studies are lacking. Chromatin structure, an important factor that fits the profile of cell-type specific contributor, has also not been investigated yet. Throughout their efforts to determine the factors that lead to the appearance of CFS lesions, investigators have focused on a single component at a time, potentially missing out complex interactions between cellular processes that could underlie fragility. Additional difficulties come from the cell-type specificity of CFS breakage: it indicates that only cell type-matched data would be informative, limiting the scope for studies using publicly available data. To perform a comprehensive study defining the role of different factors in determining CFS fragility, I explored replication timing, transcriptional landscapes and chromatin environment across a number of CFSs in two cell types exhibiting differential CFS breakage. Initially, I characterised the patterns of CFS fragility in the two cell types on both the cytogenetic and the molecular level. I then used a FISH-based technique to investigate the process of mitotic compaction at active CFS sites and found that the cytogenetically fragile core of these sites sits within larger regions which display a tendency to mis-fold in mitosis. The aberrant compaction of these regions could be observed on cytogenetically normal metaphase chromosomes, suggesting that finer scale abnormalities in chromosome structure underlie the cytogenetically visible breaks at fragile sites. I also investigated the links between transcription of long genes and CFS fragility using two approaches: I quantified levels of expression across all fragile sites using RNA-seq and modified transcription at a single active CFS using the CRISPR genome engineering methodology. My results indicate a complex interplay between transcription and CFS fragility: no simple linear correlation can be observed, but an increase of transcriptional levels at the active CFS led to a corresponding increase in fragility. To investigate the influence of the cell type specific replication programme and replication stress on CFS instability, I mapped replication timing genome-wide in unperturbed cells and under conditions of replication stress in both cell types. I found that replication stress induces bi-directional changes in replication timing throughout the genome as well as at CFS regions. Surprisingly, the genomic regions showing the most extreme replication timing alterations under replication stress do not overlap with CFS, implying that CFS instability is not fully explained by replication delays as previously suggested. Instead, I observed a range of replication-stress induced timing changes across CFS regions: while some CFSs appear under-replicated, others display switches to both earlier and later replication as well as differential recruitment of both early and late origins, implying that dis-regulation of replication timing and origin firing, rather than simply delays, underlie the sensitivity to CFS regions to replication stress. Finally, I investigated large-scale chromatin states at two active CFSs throughout S phase and into G2, the cell cycle stages most relevant stage for CFS breakage. I found that changes in large-scale chromatin architecture accompany the replication timing shifts triggered by replication stress, raising the possibility that such alterations contribute to instability. In conclusion, I assessed the influence of multiple relevant factors on CFS fragility. I found that bi-directional replication timing changes and alterations in interphase chromatin structure are likely to play a role, converging to promote mitotic folding problems which ultimately result in the well-described cytogenetic lesions on metaphase chromosomes and genomic instability.

abstract: Understanding the temperature structure of protoplanetary disks (PPDs) is paramount to modeling disk evolution and future planet formation. PPDs around T Tauri stars have two primary heating sources, protostellar irradiation, which depends on the flaring of the disk, and accretional heating as viscous coupling between annuli dissipate energy. I have written a "1.5-D" radiative transfer code to calculate disk temperatures assuming hydrostatic and radiative equilibrium. The model solves for the temperature at all locations simultaneously using Rybicki's method, converges rapidly at high optical depth, and retains full frequency dependence. The likely cause of accretional heating in PPDs is the magnetorotational instability (MRI), which acts where gas ionization is sufficiently high for gas to couple to the magnetic field. This will occur in surface layers of the disk, leaving the interior portions of the disk inactive ("dead zone"). I calculate temperatures in PPDs undergoing such "layered accretion." Since the accretional heating is concentrated far from the midplane, temperatures in the disk's interior are lower than in PPDs modeled with vertically uniform accretion. The method is used to study for the first time disks evolving via the magnetorotational instability, which operates primarily in surface layers. I find that temperatures in layered accretion disks do not significantly differ from those of "passive disks," where no accretional heating exists. Emergent spectra are insensitive to active layer thickness, making it difficult to observationally identify disks undergoing layered vs. uniform accretion. I also calculate the ionization chemistry in PPDs, using an ionization network including multiple charge states of dust grains. Combined with a criterion for the onset of the MRI, I calculate where the MRI can be initiated and the extent of dead zones in PPDs. After accounting for feedback between temperature and active layer thickness, I find the surface density of the actively accreting layers falls rapidly with distance from the protostar, leading to a net outward flow of mass from ~0.1 to 3 AU. The clearing out of the innermost zones is possibly consistent with the observed behavior of recently discovered "transition disks." / Dissertation/Thesis / Ph.D. Physics 2012

L'instabilité de Rayleigh-Plateau est utilisée dans les dispositifs d'impression à jet continu (CIJ) afin de piloter la dynamique de brisure des jets d'encre. Son étude dans ce cas de figure s'inscrit dans un cadre pluridisciplinaire relevant de la mécanique des fluides, de la rhéologie, ou encore de la physique des polymères. Le travail effectué se focalise sur l'influence des propriétés du fluide ainsi que de la géométrie de la buse d'impression sur cette dynamique. Ainsi, la caractérisation expérimentale des propriétés physicochimiques et rhéométriques des encres fait l'objet d'une attention particulière. La dynamique de brisure est ensuite modélisée à l'aide de différents logiciels de simulation numérique puis comparée aux expériences effectuées par ailleurs. Ces simulations prennent en compte lorsque c'est le cas les comportements non newtoniens des encres étudiées telles que leur propriétés rhéofluidifiantes ou viscoélastiques. Un lien étroit entre la dynamique de brisure et la forme du profil de vitesse en sortie de la buse est mis en évidence. Ce lien semble constituer une piste d'investigation particulièrement intéressante dans le cadre de la prédiction des dynamiques de jets obtenues par les dispositifs d'impression industriels. / Rayleigh-Plateau instability is used in continuous ink jet (CIJ) printers in order to drive ink jets breakup. Studies of such mechanisms are based on pluri-disciplinary concepts dealing with fluid mechanics, rheology and polymer sciences. The present work focuses on fluid properties and nozzles designs influences onto breakup dynamics. In this context, the experimental characterization of ink physical and rheological properties are of particular interest. Thereafter, jet dynamics computations are performed using several software and compared with experiences. Potential non Newtonian behaviours such as shear-thinning or viscoelasticity are modelled by computations. A close link between breakup dynamics and velocity profile at the nozzle exit is highlighted. This link is believed to bring crucial information for the prediction of jet dynamics observed in industrial printers.

Les instabilités inertielles sont des instabilités fluides excitées au sein de modèles physiques simplifiés de planètes ou d'étoiles. Elles peuvent générer un champ magnétique dynamo. Ce sont donc des alternatives aux écoulements forcés par la convection thermo-chimique pour générer les champs magnétiques dans les noyaux liquides des planètes et les enveloppes fluides des étoiles. Cependant, ces modèles simplifiés questionnent la pertinence des résultats, qui sont ensuite extrapolés aux contextes géo- et astrophysique. D'un point de vue fondamental, de récentes études numériques et expérimentales, réalisées à grande ellipticité pour compenser l'importance des effets visqueux dans les modèles, semblent en désaccord avec les prédictions théoriques (valides dans la limite asymptotique d'une diffusion négligeable et à faible déformation). De plus, de nombreux effets physiques sont négligés dans les modèles. Par exemple, seules les orbites circulaires ont été considérées. Bien que généralement de faible amplitude, l'excentricité induit une dépendance temporelle dans le forçage orbital, ce qui pourrait générer de nouveaux phénomènes. Enfin, l'existence des instabilités inertielles dans les enveloppes fluides stablement stratifiées en densité, comme les zones radiatives des étoiles chaudes de masse intermédiaire (dont la masse est comprise entre une et huit masses solaires), reste incertaine. La génération de champs magnétiques dynamos dans ces enveloppes stratifiées permettrait de réconcilier les modèles avec les observations astronomiques. Lors de cette thèse, nous nous sommes attachés à rapprocher les modèles (théoriques, numériques ou expérimentaux) des contextes géo et astrophysique. Nous avons combiné les approches théoriques (analyses de stabilité locale et globale) et numériques (simulations non linéaires) afin d'étudier les effets des forc cages mécaniques de rotation dans un ellipsoïde fluide. Nous montrons que la dissipation en volume n'est en fait pas négligeable dans les expériences de laboratoire et les simulations numériques, contrairement aux régimes planétaires et stellaires. Nous montrons aussi que l’excentricité orbitale peut, via la variation temporelle des axes de l’ellipsoïde, générer des instabilités fluides pour dans une gamme de paramètres où elles n’étaient pas attendues. Enfin nous avons étudié la capacité dynamo de l'instabilité de marée, dans les enveloppes stablement stratifiées en densité des étoiles chaudes de masse intermédiaire. Environ 10~% de ces étoiles ont un champ magnétique de surface, dont l’origine reste énigmatique. Nous montrons que l’instabilité de marée peut générer des dynamos de grande échelle dans les enveloppes fluides stablement stratifiées. En particulier, ce mécanisme serait susceptible d’expliquer le champ magnétique de faible intensité des étoiles en rotation rapide similaires à Vega et déformées par un compagnon orbital. / Inertial instabilities are fluid instabilities excited by mechanical forcings (e.g. tides, precession) in fluid bodies (e.g. planetary liquid cores or stellar envelopes) orbited by celestial companions. The nonlinear outcome of these instabilities can drive self-sustained, dynamo magnetic fields. Thus they could be an alternative to thermo-chemical convection to generate magnetic fields in geophysics and astrophysics. These instabilities have only been studied in idealised models, which challenges the extrapolation towards the relevant regimes in geophysics and astrophysics. Recent laboratory and numerical studies, performed in the achievable range of parameters (i.e. large deformations and overestimated diffusive effects), seem apparently not in agreement with theoretical predictions representative of celestial fluid bodies (i.e. extremely small deformations and vanishing diffusive effects). Several physical ingredients have been also neglected, such as the orbital eccentricity. This could drive additional tidal effects, as a result of the time-dependent forcing. Similarly, density variations have been largely neglected in these models. However, rotationally powered magnetic fields in stably stratified stellar envelopes could reconcile astronomical observations with dynamo models. In this thesis we have adopted more realistic models, by combining theoretical tools (linear stability analyses in unbounded and bounded fluids enclosed in ellipsoids) and numerical ones (direct numerical simulations) to study rotationally driven inertial instabilities. We show, with a linear stability analysis in bounded ellipsoidal geometry, that bulk diffusion cannot be neglected emph{a priori} compared to the boundary layer diffusion in laboratory experiments and simulations. This phenomena is not expected in celestial fluid bodies. We also show that an orbital eccentricity could generate additional instabilities in deformed bodies, for orbital configurations which were believed to be linearly stable. Finally, we have studied the dynamo capability of tidal flows in stably stratified fluid envelopes. These are idealised models of hot, intermediate-mass stars (i.e. with a mass ranging from one to eight solar masses). Approximatively 10~% of hot stars exhibit observable magnetic fields. We show that the tidal instability can drive dynamo magnetic fields of large wavelength in stably stratified fluids. Predictions obtained with this tidal model seem consistent with the ultra-weak magnetism of rapidly rotating, tidally deformed Vega-like stars.

Results are presented from a series of simulations undertaken to determine the effect of a novel form of molecular biaxiality upon the phase behaviour of the well established Gay-Berne (GB) liquid crystal model. Firstly, the simulation of a bulk system interacting via the Internally-Rotated Gay-Berne (IRGB) potential, which offers a single-site representation of a molecule rigidly constrained into a zig-zag conformation, is presented. The results of simulations performed for systems of IRGB particles with an aspect ratio of 3:1 confirm that the introduction of biaxiality into the model results in the destabilisation of the orientationally ordered phases. For particles with a sufficiently pronounced zig-zag conformation, this results in the complete destabilisation of the smectic A phase and the smectic B phase being replaced by the tilted smectic J phase. Following these observations, the effect upon the phase behaviour of increasing molecular elongation is also considered, with an increase in the aspect ratio from 3:1 to 4:1 resulting in the nematic and smectic J phases being replaced by smectic A and smectic G phases respectively. Secondly, a version of the IRGB potential modified to include a degree of molecular flexibility is considered. Results obtained from bulk systems interacting via the flexible IRGB for 3:1 and 4:1 molecules show that the introduction of flexibility results in the destabilisation of the smectic A phase and the stabilisation of the nematic and tilted hexatic phases. Finally, the effect upon the phase behaviour of the rigid IRGB model of the inclusion of a longitudinal linear quadrupole is examined. These results show that increasing quadrupole moment results in the destabilisation of the tilted hexatic phase, although the biaxial order parameter is increased with increasing quadrupole moment. There is no clear correlation between quadrupole magnitude and the other observed phase transitions, with the nematic and smectic A phases being variously stabilised and destabilised with increasing quadrupole magnitude. For the 4:1 molecules with large quadrupole moments, buckled smectic layers are observed where some molecules are tilted with respect to a local layer normal. Of all the systems considered here, this buckled structure is the one which most closely resembles the elusive smectic C phase.

[pt] Esta tese tem por objetivo investigar numérica e experimentalmente a mecânica da formação dos aneurismas na aorta abdominal. A parte experimental foi realizada no Laboratório de Membranas e Biomembranas utilizando-se tubos de silicone com a geometria aproximada da aorta sob pressão hidrostática. Foi investigada a pressão necessária à formação dos aneurismas e o comportamento do material ensaiado. A parte numérica foi realizada por meio do método dos elementos finitos através do programa ABAQUS (6.8.1). Com a análise numérica foi validada a análise experimental. Foram estudados casos de imperfeição geométrica e física do material, usando equações constitutivas propostas para o material da aorta. / [en] The aim of this work is to investigate numerically and experimentally the mechanics of aortic aneurisms. The experimental part was performed at the Laboratory of Membranes and Biomembranes using silicone tubes with the geometry of the aorta under hydrostatic pressure. We investigate the behavior of the material tested and the critical pressure, this is the pressure necessary for the formation of aneurysms. The numerical analysis is done using the finite element code ABAQUS (6.8.1), and is validated by the experimental analysis. Some studies of geometrical and physical imperfections are performed, as well as the ones with constitutive equations for the material of the aorta.

Esta pesquisa tem como objetivo analisar a existência de condições econômicas e institucionais no que diz respeito a integração de mercado, convergência de políticas macroeconômicas e simetria a choques que possibilitem um processo mais robusto de cooperação e integração monetária e financeira no Mercosul Ampliado. O aprofundamento desse processo nessa região é importante pela elevada necessidade de financiamento de longo prazo que esses países possuem e pela significativa vulnerabilidade e fragilidade as quais eles são expostos. Por meio de análises histórico-institucionais e empíricas, observa-se que: (a) os países desse bloco regional têm avançado a passos lentos rumo a um processo mais robusto de cooperação e integração monetária e financeira regional; e, (b) embora o Mercosul Ampliado apresente diversos aspectos que favoreçam o aprofundamento desse processo, outros fatores fundamentais, tais como integração comercial e financeira intrarregional e simetria a choques no bloco, indicam desafios para o avanço dessa estratégia. Assim, o aprofundamento da cooperação e integração monetária e financeira regional no Mercosul Ampliado apresenta obstáculos que não são desprezíveis, mas que podem ser superados por meio da vontade política dos países envolvidos para realizar os esforços necessários para implementar essa estratégia. / This research aims to analyze the existence of economic and institutional conditions with respect to market integration, convergence of macroeconomic politics and symmetry to shocks that allow a more robust process of monetary and financial cooperation and integration in the Amplified Mercosur. The deepening of this process in this region is important for the high need for long-term financing that these countries have and for the significant vulnerability and fragility which they are exposed. Through historical-institutional and empirical analysis, it is observed that: (a) countries of this region have advanced at a slow pace towards a more robust process of regional monetary and financial cooperation and integration; and, (b) although the Amplified Mercosur presents several aspects that favor the deepening of this process, other key factors, such as intrarregional trade and financial integration and symmetry to shocks in the block, indicate challenges to the advance of this strategy. Thus the deepening of regional monetary and financial cooperation and integration in the Amplified Mercosur presents obstacles that are not negligible, but that can be overcome through political will of the countries involved to make the necessary efforts to implement this strategy.

Introdução: A Doença de Parkinson (DP) é uma desordem neurodegenerativa, progressiva, patologicamente caracterizada pela perda neuronal de dopamina na via nigro-estriatal e pela presença de inclusões intraneuronais de corpos de Lewy. De etiologia desconhecida é consensualmente aceita como uma doença multifatorial com determinantes genéticos, ambientais e relacionados ao envelhecimento. Constitui-se na segunda doença neurodegenerativa mais comum em idosos. Caracteriza-se clinicamente pela tríade tremor, rigidez e bradicinesia. Juntam-se a esses sinais clássicos as alterações posturais, que levam a DP a ser considerada fator de risco independente para quedas. Apesar disso, a avaliação da estabilidade postural na DP ainda permanece imprecisa e com tratamento difícil. Objetivos e métodos: O principal foco desta dissertação é a compreensão dos mecanismos envolvidos nas alterações do equilíbrio na DP. Neste sentido realizamos uma avaliação da atividade elétrica muscular através da Eletromiografia (EMG) de superfície durante a realização do Pull Test (PT), em português teste de retropulsão. Padrões de latência e amplitude de ativação dos músculos tibial anterior, gastrocnêmio e bíceps femoral foram comparados durante a realização do PT entre pacientes com DP e indivíduos hígidos. Os padrões neurofisiológicos dos pacientes com DP foram comparados com escores no PT, tendência a quedas e administração de levodopa (períodos on e off). Resultados e conclusões: Foram encontradas diferenças significantes na atividade muscular entre DP e controles durante PT. Pacientes com DP apresentaram uma menor latência de ativação muscular. Além disso, após uma repetição em sequência de 10 PT, indivíduos controles apresentaram aumento progressivo das latências, sugerindo habituação. Já os pacientes com DP mantiveram uma latência de ativação constante, ou seja não apresentaram habituação. Não foram observadas diferenças relevantes de atividade muscular entre os DPs com PT positivo e negativo, entre caidores e não caidores e após a ingestão de Levodopa o que sugere a interferência de outros fatores relacionados à estabilidade postural, que levam a quedas na DP, em virtude da natureza heterogênea desses eventos. / Background: Parkinson's disease (PD) is a neurodegenerative disorder, progressive, pathologically characterized by neuronal loss of dopamine in the nigrostriatal pathway and the presence of intraneuronal inclusions of Lewy bodies. Of unknown etiology is widely accepted as a multifactorial disease with genetical, environmental and aging determinants. It constitutes the second most common neurodegenerative disease in the elderly. It is clinically characterized by a triad of tremor, rigidity and bradykinesia. Besides these classic signs we can add postural changes, leading PD to be considered an independent risk factor to falls. Despite this, the assessment of postural stability in PD remains unclear and difficult to treat. Objective and Methods: The main focus of this dissertation is understanding the mechanisms involved in balance disorders in PD. We undertook an assessment of muscle electrical activity through surface electromyography (EMG) while performing a Pull Test (PT). Patterns of latency and amplitude of muscle activation of the tibialis anterior, gastrocnemius and biceps femoris muscles were compared during the course of PT between PD patients and healthy individuals. Neurophysiological patterns of PD patients were compared with scores on the PT, the tendency to fall and administration of levodopa (on and off periods). Results and Conclusion: Significant differences were found in muscle activity between PD and controls during PT. PD patients had a lower latency of muscle activation. Furthermore, after a repetition in sequence of 10 PT, control subjects showed a progressive increase in latency, suggesting habituation. Patients with PD a latency of activation remained constant or showed no habituation. However, there were no significant differences in muscle activity between the PDs with positive and negative PT, between fallers and non fallers and after administration of L-dopa suggesting the influence of other factors related to postural stability, leading to falls in PD, due to the heterogeneous nature of these events.

This dissertation thesis is focused on the empirical analysis of monetary and fiscal policy using nonlinear models. In the first part, I examine the evolution of monetary policy rules in a group of inflation targeting countries. I apply a moment-based estimator in a time-varying parameter model with endogenous regressors. The main findings are twofold. First, with adoption of inflation targeting, coefficients in the monetary policy rules changed rather gradually. Second, the response of interest rates to inflation is particularly strong during periods when central bankers want to break a record of high inflation. Contrary to common view, the response of interest rates to inflation becomes less aggressive after the adoption of inflation targeting, suggesting a positive anchoring effect of this regime on inflation expectations. The second part discusses whether and how the selected central banks responded to episodes of financial stress over the last three decades. The time-varying monetary policy rule is extended for an indicator of financial stress, in order to show the departures of policy rules under financial instability. The findings suggest that central banks often decrease policy rates in the face of high financial stress. However, the size of the policy response varies substantially over time as well...