The importance of interactions between transmembrane domains of integral membrane proteins has been well-established in a range of essential cellular functions. Most integral membrane proteins also possess regions that lie on the exterior of the membrane that may influence the ability of these transmembrane domains to interact. We sought to test this hypothesis by quantifying the energetics of transmembrane helix self-association in the absence and presence of an amphipathic helix that can bind to the membrane surface. The model chosen for this study was the major coat protein (MCP) of M13 bacteriophage, which has an N-terminal amphipathic helix linked to its single transmembrane segment via a flexible linker. Dimerization of both full-length MCP and a peptide containing only the transmembrane domain (MCPTM) was studied by solution NMR in SDS micelles. We found that there was an increase in the apparent dimerization affinity in the absence of the N-terminal helix. However, this increase in apparent affinity could be attributed to differences in detergent-binding properties of the two polypeptides in monomeric versus dimeric states when the empty micelle was considered to be a participant in the dimer dissociation. Preliminary results from the integral membrane protein, p7 of the hepatitis C virus are also presented in this thesis. It has been demonstrated that p7 enhances viral infectivity and accumulation, and that this function may require oligomerization in the membrane. While we encountered limitations due to challenges in the generation of sufficient quantities of pure p7 samples, we were able to perform circular dichroism spectroscopy under conditions that may favor different oligomeric states. These studies suggest that there is a change in the degree of helicity upon oligomerization, and suggest that SDS could be a suitable system to characterize the interactions of the p7 oligomer in the future.

abstract: The cell is a dense environment composes of proteins, nucleic acids, as well as other small molecules, which are constantly bombarding each other and interacting. These interactions and the diffusive motions are driven by internal thermal fluctuations. Upon collision, molecules can interact and form complexes. It is of interest to learn kinetic parameters such as reaction rates of one molecule converting to different species or two molecules colliding and form a new species as well as to learn diffusion coefficients. Several experimental measurements can probe diffusion coefficients at the single-molecule and bulk level. The target of this thesis is on single-molecule methods, which can assess diffusion coefficients at the individual molecular level. For instance, super resolution methods like stochastic optical reconstruction microscopy (STORM) and photo activated localization microscopy (PALM), have a high spatial resolution with the cost of lower temporal resolution. Also, there is a different group of methods, such as MINFLUX, multi-detector tracking, which can track a single molecule with high spatio-temporal resolution. The problem with these methods is that they are only applicable to very diluted samples since they need to ensure existence of a single molecule in the region of interest (ROI). In this thesis, the goal is to have the best of both worlds by achieving high spatio-temporal resolutions without being limited to a few molecules. To do so, one needs to refocus on fluorescence correlation spectroscopy (FCS) as a method that applies to both in vivo and in vitro systems with a high temporal resolution and relies on multiple molecules traversing a confocal volume for an extended period of time. The difficulty here is that the interpretation of the signal leads to different estimates for the kinetic parameters such as diffusion coefficients based on a different number of molecules we consider in the model. It is for this reason that the focus of this thesis is now on using Bayesian nonparametrics (BNPs) as a way to solve this model selection problem and extract kinetic parameters such as diffusion coefficients at the single-molecule level from a few photons, and thus with the highest temporal resolution as possible. / Dissertation/Thesis / Source code related to chapter 3 / Source code related to chapter 4 / Doctoral Dissertation Physics 2020

Vitamin K is a fat soluble compound which is synthesized by the gut microbiota and produced in many tissues within the body. Considering its role in the liver as a cofactor for gamma carboxylase enzymes, treatment of dark circles and pigments under the eye among others. It is clear that is some circumstances vitamin K has to cross biological barriers, particularly, when the vitamin is produced by microbiota in the intestine or applied topically on skin. Thus it is important to develop methods that allow studies of vitamin K permeability through the skin including its participation in redox reactions and transdermal permeability. Taking into account that transdermal permeability is strongly limited for high molecular weight compounds, i.e., compounds with higher than 500Da, the study was conducted with vitamin K of  lower molecular weight. Specifically vitamin K4 model, i.e., 1,4-dihydroxy-2 naphthoic acid, with molecular weight of 204g/mol. Vitamin K4 is suitable for this kind of study , because it can work as reducing (antioxidant) compound as well as has relatively beneficial physicochemical characteristics for transdermal permeability. Permeability studies were conducted with skin covered oxygen electrode and franz diffusion cell. Data from measurements were analyzed to estimate diffusion coefficients, apparent Michaelis-Menten constants and flux of a vitamin K4 model whilst contribution of different permeability pathways was determined theoretically.

The report deals with the study of the resistence of the nonporous polymer materiále against permeation of the selected TICs, with the analysis of the running difussion processes and utilization of the acquired results for the selection of suitable barrier materials for the protective means.

Dans le cadre de la gestion des déchets nucléaires, les coques et embouts des gaines de combustibles sont coupées, compactées et empilés dans les colis CSD-C (Colis Standards de Déchets Compactés). Actuellement entreposés à la Hague, ces déchets seront stockés en milieu géologique profond dans des alvéoles en béton. Ces déchets MA-VL contiennent des RN d’intérêts dont le carbone-14 qui provient de l’activation neutronique de l’azote-14 et de l’oxygène-17 présents dans le Zircaloy. L’objectif de cette thèse, qui est menée en collaboration avec EDF et AREVA, est de répondre à la question du devenir et du comportement du carbone-14 dans ZrO₂ et Zr-métal. Cette thèse consistera à utiliser la simulation numérique, au moyen de la Théorie de la Fonctionnelle de la Densité (DFT), afin demodéliser le comportement du carbone-14 dans les CSD-C. Les simulations sont effectuées avec une approche multi-échelles : 1) Échelle atomique, optimisation de modèles atomiques permettant de représenter les différentes phases de ZrO₂ ; identification des différents sites d’insertion possibles pour l’atome de carbone en sites interstitiels et en substitutions à un atome d’oxygène ou de zirconium ; modélisation des différentes chemins d’énergie minimum associées à la migration d’un atome de carbone d’un site à un autre par mécanismes interstitiels et lacunaires. 2) Échelle macroscopique, détermination des coefficients de diffusion par la méthode Monte-Carlo dans ZrO₂ monoclinique pure et Zr pure. / As part of the nuclear waste management, hulls and ends of fuel claddings are cut, compacted and put in CSD-C containers (compacted standard waste containers). Currently stored at La Hague, the waste will be stored in deep geological environment. The MA-VL waste contains RN including carbon-14, which comes from the neutron activation of nitrogen-14 and oxygen-17 present in the oxide Zircaloy. The objective of this thesis, which is taken in collaboration with EDF and AREVA, is to answer the question of the carbon-14 behavior in ZrO₂ and Zr metal. This thesis is to perform numerical simulations, using the Theory of Density Functional (DFT) to model the behavior of carbon-14 in the CSD-C. The simulations are performed with multi-scale approach: 1) At atomic scale, optimization of atomic models to represent the different phases of ZrO₂; identification of the insertion sites for the carbon atom in interstitial sites and substitutions of an oxygen or zirconium atom; modeling different minimum energy path for the migration of a carbon atom from one site to another by interstitial and vacancye mechanisms. 2) At macroscopic scale, determination of diffusion coefficients in pure bulk monoclinic ZrO₂ and pure bulk Zr by the Monte Carlo method.

The dynamic of cavitation in hydraulic components cannot be computed accurately yet and therefore cavitation is hard to predict. The cavitation phenomenon can be divided in three sub-phenomenona: Pseudo-cavitation, Gas-cavitation and Vapour-cavitation. Pseudo-cavitation discribes the enlargement of an air bubble due to a pressure drop. Gas-cavitation refers to bubble growth which is driven by diffusion of dissolved air from the surrounding fluid into the bubble, when the solubility of air in the fluid is lowered by a pressure drop. Vapor-cavitation is the evaporation of the liquid phase on the bubble surface. Usually all three sub-phenomenona occur simultaneously when the pressure decreases and are summarised as cavitation in general. To implement the physics of gas-cavitation in a dynamic mathematical model it is necessary to know the diffusion coefficient of air in the hydraulic liquid and the maximum amount of air which can be dissolved in the liquid. The calculation can be accomplished by using the Bunsen coefficient. In this paper both coefficients for three different hydraulic oils are calculated based on experimental results.

The production and control of antihydrogen at very low temperatures provided a key tool to test the validity for the antimaterial of the fundamental principles of the interactions of nature such as the weak principle of equivalence (WEP), and CPT symmetry (Charge, Parity, and Time reversal). The work presented in this dissertation studies the collisions of electrons and positrons in strong magnetic fields that generate magnetobound positronium (positron-electron system temporarily bound due to the presence of a magnetic field) and its possible role in the generation of antihydrogen.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18128号 / 医博第3848号 / 新制||医||1001(附属図書館) / 30986 / 京都大学大学院医学研究科医学専攻 / (主査)教授 福山 秀直, 教授 戸井 雅和, 教授 平岡 眞寛 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DGAM

京都大学 / 0048 / 新制・論文博士 / 博士(医学) / 乙第12945号 / 論医博第2097号 / 新制||医||1010(附属図書館) / 32204 / (主査)教授 髙橋 良輔, 教授 富樫 かおり, 教授 髙橋 淳 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

This is a non-final version of an article published in final form in International Journal of Gynecological Cancer. Final publication is available at http://journals.lww.com/ijgc/Pages/default.aspx / 京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19557号 / 医博第4064号 / 新制||医||1013(附属図書館) / 32593 / 京都大学大学院医学研究科医学専攻 / (主査)教授 武藤 学, 教授 平岡 眞寛, 教授 古川 壽亮 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM