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Um einen besseren Zugang zum Verständnis struktureller Eigenschaften von den ternären Verbindungen des Systems Yb–Pd–Ga zu bekommen, wurden zunächst die Ordnungs- und Unordnungsbeziehungen sowie die chemische Bindung in den Kristallstrukturen binärer Pd–Ga- bzw. Yb–Ga-Verbindungen analysiert. Im Rahmen der phasenanalytischen Untersuchungen des binären Systems Yb–Ga konnte eine neue Verbindung charakterisiert werden (Ytterbiumpentagallid). Für den galliumreichen Teil des ternären Phasendiagramms Yb–Pd–Ga wurde ein isothermer Schnitt bei 600 °C erstellt (> 50 At.-% Ga). Die Homogenitätsbereiche der untersuchten Verbindungen wurden metallographisch bzw. röntgenographisch bestimmt. Die Kristallstrukturen wurden aus Röntgen-Einkristalldaten bestimmt. In den Kristallstrukturen wurden drei unterschiedliche Arten von Unordnung beobachtet (Substitutionsunordnung, Symmetrie-Brechung, Positionsunordnung). Für eine Reihe von Verbindungen des Systems Yb–Pd–Ga wurde der elektronische Zustand von Yb bestimmt. Dies gelang mit Hilfe von Messungen der magnetischen Suszeptibilität bzw. mit der Röntgen-Absorptionsnahkantenspektroskopie.

Um einen besseren Zugang zum Verständnis struktureller Eigenschaften von den ternären Verbindungen des Systems Yb–Pd–Ga zu bekommen, wurden zunächst die Ordnungs- und Unordnungsbeziehungen sowie die chemische Bindung in den Kristallstrukturen binärer Pd–Ga- bzw. Yb–Ga-Verbindungen analysiert. Im Rahmen der phasenanalytischen Untersuchungen des binären Systems Yb–Ga konnte eine neue Verbindung charakterisiert werden (Ytterbiumpentagallid). Für den galliumreichen Teil des ternären Phasendiagramms Yb–Pd–Ga wurde ein isothermer Schnitt bei 600 °C erstellt (> 50 At.-% Ga). Die Homogenitätsbereiche der untersuchten Verbindungen wurden metallographisch bzw. röntgenographisch bestimmt. Die Kristallstrukturen wurden aus Röntgen-Einkristalldaten bestimmt. In den Kristallstrukturen wurden drei unterschiedliche Arten von Unordnung beobachtet (Substitutionsunordnung, Symmetrie-Brechung, Positionsunordnung). Für eine Reihe von Verbindungen des Systems Yb–Pd–Ga wurde der elektronische Zustand von Yb bestimmt. Dies gelang mit Hilfe von Messungen der magnetischen Suszeptibilität bzw. mit der Röntgen-Absorptionsnahkantenspektroskopie.

Os Procedimentos de Manifestação de Interesse (PMI) e Propostas Não Solicitadas (PNS) são mecanismos para a viabilização de projetos de Parcerias Público-Privadas (PPP/PFIs). Contudo, a ausência de critérios claros para avaliação e priorização de parceiros, de forma transparente e técnica, leva à seleção adversa de propostas, contribuindo para o insucesso dos projetos. O principal instrumento utilizado na avaliação PPP/PFIs é uma análise quantitativa baseada no Value For Money (VfM). O propósito deste trabalho foi investigar os problemas relacionados com os processos de avaliação das propostas dos PMI submetidas aos órgãos demandantes dos serviços. Iniciou-se com a análise do Fatores Críticos para o Sucesso (FCSs) das PPP/PFIs, dos PMI e PNS, identificadas na literatura. Os Fatores Críticos foram apresentados a um conjunto de 78 especialistas que responderam também sobre a processo de análise das propostas. No questionário os autores foram confrontados também com as propriedades da visão. O resultado indica que a análise com o VfM seria incompleta e insuficiente para capturar a complexidade do escopo destes projetos. A pesquisa possibilitou ainda organizar os fatores críticos em 7 dimensões a serem consideradas na avaliação destes projetos. Essas dimensões podem ser utilizadas para a criação de instrumentos de avaliação e um exemplo foi proposto, um indicador nomeado de índice \"T\", avaliado por um grupo de 12 especialistas em projetos de PPP/PFIs. A pesquisa contribui, portanto, para apoiar a criação de instrumentos de avaliação de PPP/PFIs que considerem uma análise mais ampla, considerando aspectos qualitativos e quantitativos. / Unsolicited Proposals (UNPs) are one of the main mechanisms for verifying the feasibility of Public-Private Partnerships (PPP/PFIs/PFIs) projects. However, the lack of clear criteria to evaluate and to prioritize the partner, in a transparent and technical way, has led to adverse selection of proposals increasing the level of failure of these projects. The main instrument used in the PPP/PFIs evaluation is a quantitative analysis based on Value for Money. The purpose of this research was to investigate the problems related with the processes of evaluation of the Unsolicited Proposals (UNPs) that are submitted to the respective government offices. The study compiles the analysis of Critical Success Factors (CSFs) for Public-Private Partnerships (PPP/PFI) and the Unsolicited Proposals (UNPs), identified in the literature, and synthetized by the evaluation of a group of 78 specialists, resulting in the organization of 7 (seven) dimensions to be considered in the evaluation of these projects. This study also demonstrated that, according to these experts, the analysis with VfM would be incomplete and insufficient to capture the complexity of the scope of these projects. As an alternative a set of 7 (seven) indicators where created related to each dimension and a general index that synthetize the performance in the dimensions, considering qualitative and quantitative aspects. The index was labeled as \"T\" index and evaluated by a group of 12 (twelve) experts on PPP/PFI projects. The results from the analyses indicate that the index allows a linear comparative analysis between the proposals received by the public entity requesting the Public- Private Partnership (PPP/PFI) services. The model of indicators decreases the subjectivity of the choices made by public managers, resulting in greater transparency for the process of proposal qualification and security to the market.

Les études d'associations en génome entier ("GWAS") ont récemment permis la découverte de nombreux polymorphismes génétiques impliqués dans la susceptibilité aux maladies multifactorielles. Cependant, ces polymorphismes n'expliquent qu'une faible part de l'héritabilité génétique de ces maladies, nous poussant ainsi à explorer de nouvelles pistes de recherche. Une des hypothèses envisagées serait qu'une partie de cette héritabilité manquante fasse intervenir des phénomènes d'interactions entre polymorphismes génétiques. L'objectif de cette thèse est d'explorer cette hypothèse en adoptant une stratégie de recherche d'interactions basée sur des critères statistiques et biologiques à partir de données issues de différentes études "GWAS". Ainsi, en utilisant différentes méthodes statistiques, nous avons commencé par rechercher des interactions entre polymorphismes qui pourraient influencer le risque de thrombose veineuse. Cette recherche n'a malheureusement pas abouti à l'identification de résultats robustes vis à vis du problème des tests multiples. Dans un deuxième temps, à partir d'hypothèses "plus biologiques", nous avons tenté de mettre en évidence des interactions entre polymorphismes impliqués dans les mécanismes de régulation de l'expression génique associés aux microARNs. Nous avons pu ainsi montrer de manière robuste dans deux populations indépendantes qu'un polymorphisme au sein de la séquence du microARN hsa-mir-219-1 interagissait avec un polymorphisme du gène HLA-DPB1 pour en moduler l'expression monocytaire. Nous avons également montré que l'expression monocytaire du gène H1F0 était influencée par un phénomène d'interaction impliquant un polymorphisme du microARN hsa-mir-659. En apportant sa propre contribution à l'engouement récent que suscite la recherche d'interactions entre polymorphismes dans les maladies dites complexes, ce travail de thèse illustre clairement la difficulté d'une telle tâche et l'importance de réfléchir à de nouvelles stratégies de recherches. / Recently, Genome-Wide Association Studies (GWAS) have led to the discovery of numerous genetic polymorphisms involved in complex human diseases. However, these polymorphisms contribute only a little to the overall genetic variability of these diseases, suggesting the need for new kind of investigations in order to disentangle the so-called "missing heritability". The purpose of my PhD project was to investigate how different research strategies relying on statistical and biological considerations could help in determining whether part of this missing heritability could reside in interaction phenomena between genetic polymorphisms. Firstly, we applied different statistical methodologies and looked for interactions between polymorphisms that could influence the risk of venous thrombosis (VT). Even though this study was based on two large GWAS datasets, we were not able to identify pairwise interactions that survive multiple testing. This work suggests that strong interactive phenomena between common SNPs are unlikely to contribute much to the risk of VT. Second, by adopting a hypothesis-driven approach relying on biological arguments, we sought for interactions between microRNA related polymorphisms that could alter genetic expression. Using two large GWAS datasets in which genome-wide monocyte expression was also available, we were able to demonstrate the existence of two pairwise interaction phenomena on monocyte expression involving miRNAs polymorphisms: 1/ the expression of HLA-DPB1 was modulated by a polymorphism in its 3'UTR region with a polymorphism in the hsa-mir-219-1 microRNA sequence; 2/ similarly, the expression of H1F0 was influenced by a polymorphism in its 3'UTR region interacting with a polymorphism in the microRNA hsa-mir-659. Altogether, this project supports for the role of gene x gene interactions in the interindividual variability of biological processes but their identifications remain a tedious task requiring large samples and the development of new research strategies and methodologies.

Os Procedimentos de Manifestação de Interesse (PMI) e Propostas Não Solicitadas (PNS) são mecanismos para a viabilização de projetos de Parcerias Público-Privadas (PPP/PFIs). Contudo, a ausência de critérios claros para avaliação e priorização de parceiros, de forma transparente e técnica, leva à seleção adversa de propostas, contribuindo para o insucesso dos projetos. O principal instrumento utilizado na avaliação PPP/PFIs é uma análise quantitativa baseada no Value For Money (VfM). O propósito deste trabalho foi investigar os problemas relacionados com os processos de avaliação das propostas dos PMI submetidas aos órgãos demandantes dos serviços. Iniciou-se com a análise do Fatores Críticos para o Sucesso (FCSs) das PPP/PFIs, dos PMI e PNS, identificadas na literatura. Os Fatores Críticos foram apresentados a um conjunto de 78 especialistas que responderam também sobre a processo de análise das propostas. No questionário os autores foram confrontados também com as propriedades da visão. O resultado indica que a análise com o VfM seria incompleta e insuficiente para capturar a complexidade do escopo destes projetos. A pesquisa possibilitou ainda organizar os fatores críticos em 7 dimensões a serem consideradas na avaliação destes projetos. Essas dimensões podem ser utilizadas para a criação de instrumentos de avaliação e um exemplo foi proposto, um indicador nomeado de índice \"T\", avaliado por um grupo de 12 especialistas em projetos de PPP/PFIs. A pesquisa contribui, portanto, para apoiar a criação de instrumentos de avaliação de PPP/PFIs que considerem uma análise mais ampla, considerando aspectos qualitativos e quantitativos. / Unsolicited Proposals (UNPs) are one of the main mechanisms for verifying the feasibility of Public-Private Partnerships (PPP/PFIs/PFIs) projects. However, the lack of clear criteria to evaluate and to prioritize the partner, in a transparent and technical way, has led to adverse selection of proposals increasing the level of failure of these projects. The main instrument used in the PPP/PFIs evaluation is a quantitative analysis based on Value for Money. The purpose of this research was to investigate the problems related with the processes of evaluation of the Unsolicited Proposals (UNPs) that are submitted to the respective government offices. The study compiles the analysis of Critical Success Factors (CSFs) for Public-Private Partnerships (PPP/PFI) and the Unsolicited Proposals (UNPs), identified in the literature, and synthetized by the evaluation of a group of 78 specialists, resulting in the organization of 7 (seven) dimensions to be considered in the evaluation of these projects. This study also demonstrated that, according to these experts, the analysis with VfM would be incomplete and insufficient to capture the complexity of the scope of these projects. As an alternative a set of 7 (seven) indicators where created related to each dimension and a general index that synthetize the performance in the dimensions, considering qualitative and quantitative aspects. The index was labeled as \"T\" index and evaluated by a group of 12 (twelve) experts on PPP/PFI projects. The results from the analyses indicate that the index allows a linear comparative analysis between the proposals received by the public entity requesting the Public- Private Partnership (PPP/PFI) services. The model of indicators decreases the subjectivity of the choices made by public managers, resulting in greater transparency for the process of proposal qualification and security to the market.

Les études d'associations en génome entier ("GWAS") ont récemment permis la découverte de nombreux polymorphismes génétiques impliqués dans la susceptibilité aux maladies multifactorielles. Cependant, ces polymorphismes n'expliquent qu'une faible part de l'héritabilité génétique de ces maladies, nous poussant ainsi à explorer de nouvelles pistes de recherche. Une des hypothèses envisagées serait qu'une partie de cette héritabilité manquante fasse intervenir des phénomènes d'interactions entre polymorphismes génétiques. L'objectif de cette thèse est d'explorer cette hypothèse en adoptant une stratégie de recherche d'interactions basée sur des critères statistiques et biologiques à partir de données issues de différentes études "GWAS". Ainsi, en utilisant différentes méthodes statistiques, nous avons commencé par rechercher des interactions entre polymorphismes qui pourraient influencer le risque de thrombose veineuse. Cette recherche n'a malheureusement pas abouti à l'identification de résultats robustes vis à vis du problème des tests multiples. Dans un deuxième temps, à partir d'hypothèses "plus biologiques", nous avons tenté de mettre en évidence des interactions entre polymorphismes impliqués dans les mécanismes de régulation de l'expression génique associés aux microARNs. Nous avons pu ainsi montrer de manière robuste dans deux populations indépendantes qu'un polymorphisme au sein de la séquence du microARN hsa-mir-219-1 interagissait avec un polymorphisme du gène HLA-DPB1 pour en moduler l'expression monocytaire. Nous avons également montré que l'expression monocytaire du gène H1F0 était influencée par un phénomène d'interaction impliquant un polymorphisme du microARN hsa-mir-659. En apportant sa propre contribution à l'engouement récent que suscite la recherche d'interactions entre polymorphismes dans les maladies dites complexes, ce travail de thèse illustre clairement la difficulté d'une telle tâche et l'importance de réfléchir à de nouvelles stratégies de recherches.

Dans ce projet nous nous intéresserons à la création d’un nouveau modèle permettant de simuler des enregistrements extracellulaires de l’activité électrique neurale dans le système nerveux périphérique. Ce modèle fut développé pour permettre une meilleure compréhension de l’impact des différentes propriétés des interfaces sur la qualité des signaux recueillis. Ce projet fut en particulier conduit pour répondre au contexte actuel qui voit le développement de nombreuses applications dans le domaine des neuro-prothèses et autres interfaces neurales à but biomédical. Nos intentions étaient de fournir un nouvel outil permettant de mieux comprendre les particularités des interfaces existantes ou d’aider à leur amélioration et à la planification de futures innovations. Ce modèle est construit comme la synthèse de la compréhension actuelle des différents rouages biophysiques impactant les enregistrements. Sa structure peut être perçue comme l’assemblage de différents sous-systèmes interconnectés et représentant chacun une dimension du processus. Il s’avère particulièrement efficace pour l’analyse comparative des performances entre diffèrent types/géométries d’électrodes invasives. Dans ce document, nous nous efforcerons d’expliquer en détail la structure et les paramètres de notre modèle. Nous décrirons ensuite les différents tests que nous avons entrepris pour sa validation expérimentale, ainsi que les différentes voies d’applications que nous avons commencé à explorer. Nous finirons par décrire les améliorations qui nous sont apparues comme nécessaires ou possibles et par une discussion sur les ouvertures futures offerte à ce domaine de recherche. / Neural interfaces are becoming a newly dynamic and promising field especially thanks to the numerous applications they could have in the biomedical domain. A great deal of these applications requires a monitoring of targeted neural activity. Among the different technologies available for such recording practice, chronic electrodes implanted in the peripheral nervous system offer a good compromise on the resolution versus invasiveness technological constraint. A large array of electrodes has been developed in this intention but there is still only a limited comprehension of their recording principles and weakness. This makes difficult any targeted improvement of the electrodes and led this field to be mainly dominated by a trial and error empirical approach simultaneously costly in funds, animal lives and time. In particular, intrafascicular electrodes, while providing exiting results for stimulation, have often failed in recordings. These electrodes typically show interesting recording performance right after implantation but have rapid decline of their efficacy up to the points that they often become useless after a few weeks. Such performance proves problematic as they drastically limit the transfer of experimental results to human applications. The extent of our work has been the development of a theoretical framework for the study of implantable electrodes. Our goal here has been to construct a model that could be used as a platform to better understand implanted electrode and compare their performance and possible improvement. We focused our work on intrafascicular electrode for the peripheral nervous system. However, our procedure could easily be applied to other type of interface. During this project we first constructed a detailed model of the recording biophysical process happening at the peripheral nerve electrical interface. This model encompasses all the mechanism known to influence the quality and shape of neural activity recordings. We have then recreated within our model specific controlled experiments and by comparing the properties of the simulated recording with their experimental counterparts demonstrated the potency of our approach to produce bio-plausible signals. This validated our model as an in silico alternative to compare and test electrodes. We then further developed this model to also simulate some of the changes happening in the nerve post implantation. In particular, we found that the growth of the fibrotic scar could already explain a large part of the signal degradation happening in the first weeks. Then to demonstrate the adaptability of this model we used it to compare the performance of the main type of electrodes implanted nowadays peripherally. Finally, as the main weakness of our model relied in its relative complexity and the related long computing time, we started to analyze how this model could be simplified without losing the precision necessary for the intended applications. In conclusion, this project led to the creation of a model which in its current form can be used as an in silico platform to test and compare electrodes. This will facilitate the planning and development of future peripheral neural interface by proving both more economical and informative that current strategies. Conjointly, we opened the way to future improvement of our model, leading to more practicality.

No description available.

A estimulação elétrica periférica (PES), que abrange diversas técnicas com respostas fisiológicas diversas, tem apresentado em alguns casos resultados clínicos promissores para o tratamento da dor e reabilitação clínica. No entanto, as respostas encontradas são heterogêneas, principalmente porque há uma falta de compreensão em relação ao seu mecanismo de ação. Neste estudo, buscamos avaliar os efeitos da PES através da medição da ativação cortical cerebral utilizando a espectroscopia funcional por infravermelho (fNIRS). A fNIRS é um método de imagem óptica funcional que avalia mudanças hemodinâmicas nas concentrações de hemoglobina oxigenada (HbO) e desoxigenada (HbR), relacionadas à atividade cortical. Nós hipotetizamos que a PES do nervo acessório espinal (ASN) pode promover a ativação do córtex motor (MC) e do córtex pré-frontal dorsolateral (DLPFC), relacionados ao processamento da dor. Quinze voluntários saudáveis receberam estimulação elétrica ativa e sham em um ensaio clínico randomizado cruzado. A resposta hemodinâmica à estimulação elétrica unilateral direita do nervo acessório com 10 Hz foi medida pela espectroscopia funcional por um sistema de 40 canais. A variação de HbO nas áreas corticais de interesse mostrou ativação do DLPFC direito (p=0,025) e do MOTOR esquerdo (p=0,042) no grupo ativo comparado com sham. Em relação ao DLPFC esquerdo (p=0,610) e ao MOTOR direito (p=0,154), não houve diferença estatística entre os grupos. Como na modulação top-down, a estimulação bottom-up do nervo acessório parece ativar as mesmas áreas corticais, relacionadas às dimensões sensório-discriminativas e afetivo-motivacionais da dor. Esses resultados fornecem evidência adicional para desenvolver e otimizar o uso clínico da estimulação elétrica periférica. / Peripheral electrical stimulation (PES), which encompasses several techniques with heterogeneous physiological responses, has shown in some cases remarkable outcomes for pain treatment and clinical rehabilitation. However, results are still mixed, mainly because there is a lack of understanding regarding its neural mechanisms of action. In this study, we aimed to assess its effects by measuring cortical activation as indexed by functional near infrared spectroscopy (fNIRS). fNIRS is a functional optical imaging method to evaluate hemodynamic changes in oxygenated (HbO) and de-oxygenated (HbR) blood hemoglobin concentrations in cortical capillary networks that can be related to cortical activity. We hypothesized that PES of accessory spinal nerve (ASN) can promote cortical activation of motor cortex (MC) and dorsolateral prefrontal cortex (DLPFC) pain processing cortical areas. Fifteen healthy volunteers received both active and sham ASN electrical stimulation in a crossover design. The hemodynamic response to unilateral right ASN burst electrical stimulation with 10 Hz was measured by a 40- channel fNIRS system. The effect of ASN electrical stimulation over HbO concentration in cortical areas of interest was observed through the activation of right- DLPFC (p=0.025) and left-MOTOR (p=0.042) in the active group but not in sham group. Regarding left-DLPFC (p=0.610) and right-MOTOR (p=0.174) there was no statistical difference between groups. As in non-invasive brain stimulation (NIBS) topdown modulation, bottom-up electrical stimulation to the accessory spinal nerve seems to activate the same critical cortical areas on pain pathways related to sensorydiscriminative and affective-motivational pain dimensions. These results provide additional mechanistic evidence to develop and optimize the effects of peripheral neural electrical stimulation.