Cancer is a complex and deadly disease that is caused by genetic lesions in somatic cells. Further research in computational methodology for detecting and characterizing somatic mutations is necessary in order to understand the comprehensive systems level model of the roles of those lesions in cancer development. In the first project, I trained a list of supervised machine learning classifiers that classify false positive versus true positive somatic single nucleotide variants (SNVs). I was able to show an improvement of somatic SNV detection on the data set over the reported classifier. In the second project, we developed PhyloSub model that uses a nonparametric Bayesian prior over a set of trees to cluster SNVs, and infer the subclonal phylogenetic structure of tumors with uncertainty from SNV sequencing data. Experiments showed that PhyloSub model could infer the subclonal phylogenetic structure from both single and multiple tumor samples.

Game designers spend a great deal of time developing balanced game experiences. However, differences in player ability, hardware capacity (e.g. network connections) or real-world elements (as in mixed-reality games), make it difficult to balance games for different players in different conditions. In this research, adaptive time-variant minigames have been introduced as a method of addressing the challenges in time balancing as a part of balancing players of games. These minigames were parameterized to allow both a guaranteed minimum play time (the minimum time to complete a minigames to address the fixed temporal constraints) and dynamic adaptability (the ability of adapting the game during the game play to address temporal variations caused by individual differences). Three time adaptation algorithms have been introduced in this research and the interaction between adaptive algorithm, game mechanic, and game difficulty were analyzed in controlled experiments. The studies showed that there are significant effects and interactions for all three factors, confirming the initial hypothesis that these processes were important and linked to each other. Furthermore, the studies revealed that finer temporal granularity leads to less-perceptible adaptation and smaller deviations in game completion times. The results also provided evidence that adaptation mechanisms allow accurate prediction of play time. The designed minigames were valuable in helping to balance temporal asymmetries in a real mixed-reality game. It was also found that these adaptation algorithms did not interrupt the overall play experience.

Lehmer's conjecture asserts that $\tau(p) \neq 0$, where $\tau$ is the Ramanujan $\tau$-function. This is equivalent to the assertion that $\tau(n) \neq 0$ for any $n$. A related problem is to find the distribution of primes $p$ for which $\tau(p) \equiv 0 \text{ } (\text{mod } p)$. These are open problems. However, the variant of estimating the number of integers $n$ for which $n$ and $\tau(n)$ do not have a non-trivial common factor is more amenable to study. More generally, let $f$ be a normalized eigenform for the Hecke operators of weight $k \geq 2$ and having rational integer Fourier coefficients $\{a(n)\}$. It is interesting to study the quantity $(n,a(n))$. It was proved by S. Gun and V. K. Murty (2009) that for Hecke eigenforms $f$ of weight $2$ with CM and integer coefficients $a(n)$ \begin{equation} \{ n \leq x \text { } | \text{ } (n,a(n))=1\} = \displaystyle\frac{(1+o(1)) U_f x}{\sqrt{\log x \log \log \log x}} \end{equation} for some constant $U_f$. We extend this result to higher weight forms. \\ We also show that \begin{equation} \{ n \leq x \ | (n,a(n)) \text{ \emph{is a prime}}\} \ll \displaystyle\frac{ x \log \log \log \log x}{\sqrt{\log x \log \log \log x}}. \end{equation}

Lehmer's conjecture asserts that $\tau(p) \neq 0$, where $\tau$ is the Ramanujan $\tau$-function. This is equivalent to the assertion that $\tau(n) \neq 0$ for any $n$. A related problem is to find the distribution of primes $p$ for which $\tau(p) \equiv 0 \text{ } (\text{mod } p)$. These are open problems. However, the variant of estimating the number of integers $n$ for which $n$ and $\tau(n)$ do not have a non-trivial common factor is more amenable to study. More generally, let $f$ be a normalized eigenform for the Hecke operators of weight $k \geq 2$ and having rational integer Fourier coefficients $\{a(n)\}$. It is interesting to study the quantity $(n,a(n))$. It was proved by S. Gun and V. K. Murty (2009) that for Hecke eigenforms $f$ of weight $2$ with CM and integer coefficients $a(n)$ \begin{equation} \{ n \leq x \text { } | \text{ } (n,a(n))=1\} = \displaystyle\frac{(1+o(1)) U_f x}{\sqrt{\log x \log \log \log x}} \end{equation} for some constant $U_f$. We extend this result to higher weight forms. \\ We also show that \begin{equation} \{ n \leq x \ | (n,a(n)) \text{ \emph{is a prime}}\} \ll \displaystyle\frac{ x \log \log \log \log x}{\sqrt{\log x \log \log \log x}}. \end{equation}

The thesis deals with the revitalisation of military brownfields located within the city Cheb. The objective of the thesis is to find the possible variants of the new use of the locality and evaluate them by using the multiple-criteria decision analysis. In the theoretical part of the thesis there is characterized the term of brownfields and the area characterized. Methodical part includes the description of the process of multiple-criteria decision analysis. In the final practical part there are the variants of the new use of the locality suggested, as well as defined there are the criteria for decision making including determination of the importance defined and on the basis of mathematical model there is the most suitable variant chosen.

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For many companies, design related information mainly exists as rooms of paper-based archives, typically in the form of manufacturing drawings and technical specifications. This 'static' information cannot be easily reused. The work presented in this thesis proposes a methodology to ease this problem. It defines and implements a computer-based design tool that will enable existing design families to be transformed into 'dynamic' CAD-based models for the Conceptual, Embodiment and Detailed stages of the design process. Two novel concepts are proposed here, i) the use of a Function Means Tree to store Conceptual and Embodiment design and ii) a Variant Method to represent Detailed design. In this way a definite link between the more abstract conceptual and the concrete detailed design stages is realised by linking individual detailed designs to means in the Function Means Tree. The use of the Variant Method, incorporating 'state-of-the-art' developments in Solid Modelling, Feature-Based Design and Parametric Design, allows an entire family of designs to be represented by a single Master Model. Therefore, instances of this Master Model need only be stored as a set of design parameters. This enables current design families and new design cases to be more created more efficiently. Industrial Case Studies, including a Lathe Chuck family, a Drive-End casting and a family of Filtration Systems are given to prove the methodology.

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.

Staphylococcus aureus est un pathogène opportuniste au potentiel de virulence élevé et particulièrement diversifié. Responsable d'intoxications alimentaires, d'infections localisées suppurées et, dans certains cas extrêmes, d’infections systémiques graves, celui-ci est pleinement capable de causer la mortalité chez des patients immunodéprimés. Pourtant, S. aureus est également la cause de divers types d’infections à fort caractère chronique et de persistance chez l’homme et les animaux, infections qui sont difficiles à traiter par antibiothérapie, et qui le plus souvent échappent au contrôle du système immunitaire. Les mammites à S. aureus sont considérées comme l’une des maladies majeures chez les bovins d’élevage, causant de lourdes pertes économiques pour l’industrie laitière. Elles se caractérisent fréquemment par des formes sous-cliniques et chroniques, rendant leur diagnostic et contrôle difficiles. La vaccination contre les infections intramammaires à S. aureus pourrait permettre de protéger les animaux contre les nouvelles infections, diminuant la propagation contagieuse du pathogène lors de la traite, et permettre ainsi de réduire la prévalence de celui-ci dans les troupeaux. Pourtant, aucune formulation n’a pu montrer de réelle efficacité de protection à ce jour. Puisque le déploiement d’une immunité adaptative strictement basée sur la réponse en anticorps n’est pas adéquat pour protéger contre un pathogène chronique tel que S. aureus, le besoin criant de développer de nouvelles méthodes et formulations de vaccin se penche maintenant sur l’amélioration de la réponse à médiation cellulaire, considérée indispensable pour une meilleure protection. Les vaccins vivants atténués, basés sur leur capacité à imiter une infection naturelle, ont su prouver leur efficacité dans le développement d’immunités spécifiques et fortes contre de nombreux microorganismes, en particulier les pathogènes intracellulaires et chroniques. On a démontré que ces souches atténuées pouvait être utilisées comme vecteurs antigéniques et aider à balancer la réponse vers des fonctions effectrices de l’immunité qui permettent de combattre plus adéquatement ce type d’infections. Cette étude a eu pour objectif principal la construction d’une souche atténuée de S. aureus pour l’utilisation à titre de vaccin vivant contre les infections intramammaires. Cette souche vaccinale atténuée est fondée sur la stabilisation génétique du phénotype small-colony variant, à la fois comme base d’atténuation de la virulence et comme facteur permettant l’internalisation temporaire et non destructive dans les cellules de l’hôte. Cette souche a été caractérisée et évaluée dans un modèle d’infection de cellules en culture et dans un modèle in vivo de mammite chez la souris, qui ont tous deux pu confirmer sa robuste atténuation et établir un première preuve de son innocuité comme vaccin.

Zirconium alloys are widely used by the nuclear industry as fuel cladding and structural materials. Many physical and metallurgical properties of zirconium alloys, that are important for their performance in nuclear reactors, are affected by crystallographic texture due to the strong anisotropy of individual crystals. Irradiation assisted growth is one example. Zirconium crystals deform anisotropically under irradiation, which in the presence of strong textures (like the ones observed in cold-rolled sheet) causes undesirable deformation of components during service. For this reason, the nuclear industry is interested in developing thermomechanical processes that produce random textures, taking advantage of the allotropic phase transformation undergone by zirconium, from the low temperature hcp alpha-phase to the high temperature bcc beta-phase. One of these processes is beta-quenching, which has showed certain success in weakening strong rolling textures. However, there is no consensus about the fundamental mechanisms involved.The aim of this work is to study the evolution of the texture of the zirconium alloy Zircaloy-2 during beta-quenching, in order to gain understanding on the mechanisms involved on texture development and evolution during the alpha-to-beta and beta-to-alpha phase transformations. Firstly industrially beta-quenched samples were characterised using well known techniques such as laboratory X-ray diffraction (LXRD) and electron backscatter diffraction (EBSD), which revealed a relationship between peak temperature and the inherited alpha texture. An in situ synchrotron X-ray diffraction (SXRD) experiment provided, for the first time, information of texture evolution of zirconium during rapid changes and at non-ambient conditions. Different peak temperatures and stress/strain conditions were tested. Detailed post mortem EBSD characterisation of samples studied in situ provided insight on the relationship between the microstructure and the texture. Finally, laboratory furnaces were used to beta-quench samples at very high temperature. It was found that there is selection of orientation variants during beta-quenching of zirconium, but while the selection during the alpha-to-beta transformation is almost negligible, depending on the texture evolution of the beta-phase (affected by grain growth and/or plastic deformation), diverse mechanisms of variant selection act during the beta-to-alpha phase transformation. The inherited textures observed result from the combination of these mechanisms. Some of the results of this work can be transferred to other systems such as titanium and the alpha-gamma-alpha phase transformation in steel.