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The presence of self-assembled protein aggregates known as Amyloid fibrils are associated with an increasing number of human conditions such as type-II Diabetes, Parkinson’s, Huntington’s and Alzheimer’s disease. A link has been made between the fragility of these normally robust structures and an enhancement of their toxic effects. This highlights a need for a firm understanding of the factors that govern their mechanical properties if effective therapeutic strategies are to be developed. The main aims of this thesis are to probe, at a molecular level, the key interactions that contribute to the mechanical stability generically exhibited by amyloid fibril systems and then explore ways in which these may be modulated. A variety of atomistic detailed fibrils are computationally mod- elled and then subjected to molecular dynamics steering forces from a variety of directions that characterise their fragmentation through disruption of the stabilising interactions. This work focuses on models of proto-fibrils associated with type-II Diabetes and mature fibres linked with Alzheimer’s disease. Three separate investigations were undertaken to examine firstly the role played by the peptide sequence in mechanical resistance, then ways of modulating mechanical failure in polymorphic fibril arrangements and finally the mechanical effects of heterologous cross-seed interfaces. The presence of structural defects in the otherwise highly ordered protein aggregates were consistently found to be able to dominate the overall mechanical characteristics of the fibrils. The results of the simulations give further insights into the fracture mechanisms as well as have wider implications for both therapeutic and potential nano-technological applications.

The LHCb detector at the LHC collider has been very successfully operated over the past years, providing new and profound insights into the Standard Model, in particular through study of b-hadrons to achieve a better understanding of CP violation. One of the key components of LHCb is its particle identification system, comprised of two RICH detectors, which allow for high precision separation of particle species over a large momentum range. In order to retain and improve the performance of the particle identification system in light of the LHCb upgrade, the TORCH detector has been proposed to supplement the RlCH system at low momentum (2-10 GeV Ic). The TORCH detector provides (charged) particle identification through precision timing of particles passing through it. Assuming a known momentum from the tracking, it is possible to derive the species of a particle from the time of flight from its primary vertex. This measurement is achieved by timing and combining photons generated in a solid radiator. The geometry of the detector (composed of large plates of fused silica) is such that the generated Cherenkov photons are trapped inside the plate by total internal reflection, and propagate to the periphery of the radiator. Here they are projected onto a plane of photodetectors, comprised of purpose designed MCP-PMTs. The photons detected for a track are combined into a time stamp for each particle, finally resulting in the time of flight being measured so that the particle identity can be derived. The final goal of the TORCH project is to prove the feasibility and desirability of the TORCH detector as an addition to the LHCb particle identification system. This thesis will describe the progress that has been made towards the key objectives of the TORCH project; in particular the development of optics, detectors and electronics.

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Notre connaissance actuelle de l'Univers repose sur l'existence de quatre interactions fondamentales, qui sont la gravitation, l'électromagnétisme, l'interaction forte et l'interaction faible. Je m'intéresse dans ma thèse à l'aspect classique des théories physiques sous-jacentes, appelées « théories de jauge ». Dans un premier temps, ma démarche consiste à étudier la formulation mathématiques de ces théories de jauge afin de mettre en lumière certaines structures géométrico-algébriques sous-jacentes. Dans un second temps, on propose de nouveaux cadres mathématiques possibles pour formuler des théories de jauge. On a exploré pour cela la géométrie conforme et les théories de jauge de la gravitation conforme associées, le tout formulé dans le langage de la géométrie de Cartan. En appliquant la méthode de l'habillage, qui consiste à réduire la symétrie de jauge d'une théorie par un simple changement de variable, on retrouve les objets habituellement définis dans une telle géométrie, comme les Tractors et les Twistors, avec en prime une meilleure compréhension de leur nature géométrique. On présente également le cadre des algébroïdes de Lie transitifs, et différentes façons de formuler des théories de jauge unifiées en son sein, où différents secteurs des théories fondamentales émergent naturellement d'un même lagrangien. Finalement, nous présentons un travail récent consistant à combiner géométrie de Cartan et algébroïdes de Lie transitifs, donnant une définition d'une connexion de Cartan dans ce langage, en nous attachant à démontrer l'équivalence de cette définition avec la définition usuelle en termes de fibrés principaux. / Our current knowledge about Universe rests on the existence of four fundamental interactions. These are : gravitation, electromagnetism, weak interaction and strong interaction. They have formed the conceptual basis of modern physics since half a century. I am interested in the classical aspect of the underlying physical theories : « gauge theories ». First, my approach consists in studying gauge theories in their mathematical formulation, in order to enlighten some underlying geometrico-algebraic structures. Second, generalized mathematical frameworks are proposed to formulate gauge theories. We explored conformal geometry and its associated conformal gauge theories, formulated in the language of Cartan geometry. Applying the dressing field method, which consists in reducing the gauge symmetry of a theory by a mere change of variables, we recover some objects usually defined in this geometry, as Tractors and Twistors. The bonus is that we get a deeper understanding of their geometric nature. We also present the theory of transitive Lie algebroids, and different ways of formulating unified gauge theories in this framework, where different sectors of fundamental theories emerge together in a same lagrangian. Finally, we present a recent work which consists in combining Cartan geometry and transitive Lie algebroids, given a definition of a Cartan connection in this framework. We show the equivalence of this definition with the usual one on principal fibre bundles.