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High-throughput sequencing technologies have changed the way we identify, study and understand the role of rare variation in Mendelian diseases. Sequencing in complex diseases have proven to be more challenging to interpret, but methods and approaches are being developed to aid in our understanding of variation in these diseases.

China’s behavior as a near-monopolist of rare earths has come under increasing scrutiny in recent years. This thesis first examines the underlying causes behind China’s rise to the status of rare-earths near-monopolist, including government support; lax environmental controls; unregulated production; and relatively low costs compared to the rest of the world. Second, the thesis also examines the preeminent international and domestic factors influencing China’s behavior as a near-monopolist of rare earths. International factors include international demand; international trade pressure; international price-setting authority issues; and geopolitical factors. I next identify domestic factors that exert influence over China’s rare earths-related behavior: environmental protection; rare earth resource protection; rare earths industry regulation; and protecting and aiding China’s domestic rare earths industry. The study concludes with a synthesis of the factors influencing China’s rare-earths-related behavior in the overall context of support and direction by China’s Central Government.

Retinoic acid (RA) has been recognized as a chemotherapeutic agent for various malignances such as lung, skin as well as cervical cancers. It binds to retinoid receptors heterodimers and consequently activates several RA-responsive genes which are involved in many biological processes including vertebrate development, bone growth, vision, haematopoiesis, cell growth, differentiation and apoptosis. These genes are under the control of numerous regulators to ensure their timely ordered activities. Among these regulators, we focused here on the 26S proteasome and ubiquitination. It has been reported that the activity of the ubiquitin/proteasome system (UPS) plays a fundamental role in retinoic acid receptor (RAR)-regulated transactivation. The mechanisms underlying this role, however, remain to be established. Chromatin immunoprecipitation (ChIP) assays in our study demonstrated that the 26S proteasome activity is important for preserving the occupancy of a TATA box-containing RA-responsive promoters by liganded retinoid receptors and thus by their coactivators. Additionally, by using coimmunoprecipitation assays and by measuring the half-life of retinoid receptors, we found that the non-proteolytic function of the proteasome is required for ligand-dependent association between DNA-free RAR-α and both DNA-free RXR-α and coactivators. Moreover, using immunofluorescent staining and in vivo ubiquitination assays, a proteasome inhibition-dependent cytoplasmic localization of RAR-α as well as ligand-enhanced ubiquitination and stabilization of RAR-α were shown. Our findings therefore, define novel mechanisms by which the UPS controls RAR-regulated genes. Furthermore, we shed new light on the regulators of retinoid receptors ubiquitination and subcellular localization.

Simulation of rare events can be costly with respect to time and computational resources. For certain processes it may be more efficient to begin at the rare event and simulate a kind of reversal of the process. This approach is particularly well suited to reversible Markov processes, but holds much more generally. This more general result is formulated precisely in the language of stationary point processes, proven, and applied to some examples. An interesting question is whether this technique can be applied to Markov processes which are substochastic, i.e. processes which may die if a graveyard state is ever reached. First, some of the theory of substochastic processes is developed; in particular a slightly surprising result about the rate of convergence of the distribution pi(n) at time n of the process conditioned to stay alive to the quasi-stationary distribution, or Yaglom limit, is proved. This result is then verified with some illustrative examples. Next, it is demonstrated with an explicit example that on infinite state spaces the reversal approach to analyzing both the rate of convergence to the Yaglom limit and the likely path of rare events can fail due to transience.

The number of known monogenic rare diseases (~7000) exceeds the number of effective treatments (~500) by more than an order of magnitude underlining the pressing need for generalizable therapeutic approaches for this class of conditions. In this regard, the majority of recessive and x-linked recessive disorders are caused by missense mutations encoding proteins that frequently have residual function but are rapidly degraded by the 26S proteasome. Bortezomib is a small molecule that inhibits the 26S proteasome and has been approved for use in patients for an unrelated condition; multiple myeloma. Previous work has shown that, for a small number of disorders, bortezomib can inhibit the degradation of the mutant protein, thereby increasing the protein level and activity, holding out the promise of a beneficial therapeutic effect by the repurposing of this agent. We present here a high level western blot based survey of nine recessive disorders to characterize the general effectiveness of such an approach. Thirteen patient fibroblast cell lines comprising 9 different diseases with 19 known mutations were selected on the basis of missense mutations protein expression data when available. The cell lines were incubated with bortezomib (10 nM and 50 nM; 24 hrs) and levels of the mutated protein were quantified by western blot. Unfortunately, no consistent, appreciable increase was observed for any of the conditions tested. The general therapeutic value of re-purposing bortezomib for recessive and x-linked diseases appears limited at best. The few reported cases of bortezomib successfully working in increasing mutated protein levels appear to be the exceptions and not the norm. Moreover successes are more often limited to cell lines carrying a transgene expressing the mutated protein rather than endogenous mutated protein in patient cell lines.

Ces dernières années, l'analyse de systèmes complexes critiques est devenue de plus en plus importante. En particulier, l'analyse quantitative de tels systèmes est nécessaire afin de pouvoir garantir que leur probabilité d'échec est très faible. La difficulté de l'analyse de ces systèmes réside dans le fait que leur espace d’état est très grand et que la probabilité recherchée est extrêmement petite, de l'ordre d'une chance sur un milliard, ce qui rend les méthodes usuelles inopérantes. Les algorithmes de Model Checking quantitatif sont les algorithmes classiques pour l'analyse de systèmes probabilistes. Ils prennent en entrée le système et son comportement attendu et calculent la probabilité avec laquelle les trajectoires du système correspondent à ce comportement. Ces algorithmes de Model Checking ont été largement étudié depuis leurs créations. Deux familles d'algorithme existent : - le Model Checking numérique qui réduit le problème à la résolution d'un système d'équations. Il permet de calculer précisément des petites probabilités mais soufre du problème d'explosion combinatoire- - le Model Checking statistique basé sur la méthode de Monte-Carlo qui se prête bien à l'analyse de très gros systèmes mais qui ne permet pas de calculer de petite probabilités. La contribution principale de cette thèse est le développement d'une méthode combinant les avantages des deux approches et qui renvoie un résultat sous forme d'intervalles de confiance. Cette méthode s'applique à la fois aux systèmes discrets et continus pour des propriétés bornées ou non bornées temporellement. Cette méthode est basée sur une abstraction du modèle qui est analysée à l'aide de méthodes numériques, puis le résultat de cette analyse est utilisé pour guider une simulation du modèle initial. Ce modèle abstrait doit à la fois être suffisamment petit pour être analysé par des méthodes numériques et suffisamment précis pour guider efficacement la simulation. Dans le cas général, cette abstraction doit être construite par le modélisateur. Cependant, une classe de systèmes probabilistes a été identifiée dans laquelle le modèle abstrait peut être calculé automatiquement. Cette approche a été implémentée dans l'outil Cosmos et des expériences sur des modèles de référence ainsi que sur une étude de cas ont été effectuées, qui montrent l'efficacité de la méthode. Cette approche à été implanté dans l'outils Cosmos et des expériences sur des modèles de référence ainsi que sur une étude de cas on été effectué, qui montre l'efficacité de la méthode. / In the past decades, the analysis of complex critical systems subject to uncertainty has become more and more important. In particular the quantitative analysis of these systems is necessary to guarantee that their probability of failure is very small. As their state space is extremly large and the probability of interest is very small, typically less than one in a billion, classical methods do not apply for such systems. Model Checking algorithms are used for the analysis of probabilistic systems, they take as input the system and its expected behaviour, and compute the probability with which the system behaves as expected. These algorithms have been broadly studied. They can be divided into two main families: Numerical Model Checking and Statistical Model Checking. The former computes small probabilities accurately by solving linear equation systems, but does not scale to very large systems due to the space size explosion problem. The latter is based on Monte Carlo Simulation and scales well to big systems, but cannot deal with small probabilities. The main contribution of this thesis is the design and implementation of a method combining the two approaches and returning a confidence interval of the probability of interest. This method applies to systems with both continuous and discrete time settings for time-bounded and time-unbounded properties. All the variants of this method rely on an abstraction of the model, this abstraction is analysed by a numerical model checker and the result is used to steer Monte Carlo simulations on the initial model. This abstraction should be small enough to be analysed by numerical methods and precise enough to improve the simulation. This abstraction can be build by the modeller, or alternatively a class of systems can be identified in which an abstraction can be automatically computed. This approach has been implemented in the tool Cosmos, and this method was successfully applied on classical benchmarks and a case study.

The present study concerns the application of LSM using an excimer laser to enhance the corrosion resistance of rare-earth Elektron 21 magnesium alloy. The alloy has been treated by an excimer laser to produce a highly homogeneous and refined microstructure for improvement of corrosion resistance. The laser surface treatment was applied on two different prepared surfaces of the alloy; i) a ground surface up to 1200 SiC grit; ii) a chemically cleaned surface using CrO3 +AgNO3 boiling solution. The intermetallic phases within the α-matrix that are believed to initiate corrosion have been dissolved by two methods. The first is by the excimer laser, where they were dissolved in the melted layers. The second is by a chemical dissolution prior LSM. Variation of the laser parameters such as changed laser influence (low, medium and high) and increased number of pulses, resulted in formation of thicker melted layers, but promoted the formation of porosity and micro-cracks particularly at overlap regions. The initial stage of this study was aimed at optimising the laser conditions for production of a uniform microstructure, with an increase in the corrosion resistance of the alloy being determined by potentiodynamic polarization measurements in sodium chloride solution. A laser fluence of 6 and 7 J/cm2 with 10, 20, 25, 40 and 50 pulses with a different overlap ratio of 7%, 20% and 50% were subsequently selected as the optimum condition to treat the surface of the alloy. After laser treatment, the top surfaces and the cross-sections of the alloy showed a relatively homogenous melted layer and a significant reduction in the number of large intergranular Mg-Zn-RE phase was achieved resulting in a significant improvement of the corrosion resistance of the alloy. This work also investigated the mechanism of corrosion and the interaction between the intergranular Mg-Zn-RE phase, the Zr-rich regions within the grains and the bulk Mg-rich matrix. The results obtained by scanning electron microscopy (SEM) / energy-dispersive X-ray (EDX) and scanning Kelvin prop forced microscopy (SKPFM) potential map measurements as well as transmission electron microscopy (TEM) / energy-dispersive X-ray (EDX) have shown the importance of the microstructure in the initiation of corrosion in 3.5 wt% NaCl solution, where the Zr-rich regions played a distinct role in the early stages of corrosion in this alloy. However, the obtained results have demonstrated that such laser melted layers improved the corrosion resistance of the alloy, but further work is still needed to obtain the fully understanding of such behaviour which can better the research results, particularly the selectively chemical dissolution of the second phases prior LSM.

The notion of rare continuity was introduced by Popa {15} as a new generalization of weak continuity {7}. In this paper, we introduce a new class of functions called rarely pre- θ -continuous functions as a new generalization of the class of strongly θ -precontinuous functions and investigate some of its fundamental properties.

Orientador: Pascoal José Giglio Pagliuso / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Física Gleb Wataghin / Made available in DSpace on 2018-08-31T09:11:43Z (GMT). No. of bitstreams: 1 Jesus_CamiloBrunoRamosde_D.pdf: 5302284 bytes, checksum: 324e3103dff95287aa0b4d19f9ce5a4a (MD5) Previous issue date: 2016 / Resumo: Neste trabalho investigamos as propriedades estruturais e magnéticas da família de compostos intermetálicos RTBi2 (R = Ce, Pr, Nd, Sm, Gd; T = Cu, Au) além do composto CeCd0,7Sb2. As amostras foram crescidas pelo método de fluxo metálico, a maioria delas de forma inédita. Medidas macroscópicas de resistividade elétrica, susceptibilidade magnética e calor específico foram realizadas, além de medidas de espectroscopia de raios X de energia dispersiva ¿ EDS e difração de raios X. Medidas microscópicas de difração magnética de raios X e ressonância magnética nuclear (RMN) foram realizadas, com ajuda de colaboradores, no composto CeCuBi2. Um modelo de campo médio que inclui uma interação de troca isotrópica entre primeiros vizinhos e efeitos de campo cristalino tetragonal foi utilizado para ajustar as medidas de magnetização e calor específico. Esses ajustes forneceram os parâmetros e esquemas de campo cristalino e os valores das constantes da interação de troca. A partir dessas análises encontramos como que efeitos de campo cristalino e a competição entre interações magnéticas, ferromagnética e antiferromagnética, governam as propriedades magnéticas desses compostos / Abstract: In this work we have investigated the structural and magnetic properties of the family of intermetallic compounds RTBi2 (R = Ce, Pr, Nd, Sm, Gd, T = Cu, Au) and, additionally, the CeCd0.7Sb2 compound. The samples were grown by Bi metallic flux method, most of them for the first time. Macroscopic measurements of electrical resistivity, magnetic susceptibility, specific heat were carried out with supplementary measurements of Energy-dispersive X-ray spectroscopy (EDS) and X-ray diffraction. Microscopic measurements of magnetic X-ray diffraction and nuclear magnetic resonance (NMR) were carried out with the help of collaborators in the CeCuBi2 compound. A mean-field model that includes an anisotropic exchange interaction between nearest neighbors and tetragonal crystal field effects was used to fit the magnetization and specific heat data. The best fits yield the crystal field parameters and schemes of level and the values of the constants of exchange interaction for each compound in the RTBi2 series. From these analyzes, we have described how the crystal field effects and the competition between magnetic interactions, ferromagnetic and antiferromagnetic, govern the magnetic properties of these compounds / Doutorado / Física / Doutor em Ciências / 1141235/2012 / CAPES