<p>Low-dose ionizing radiation (LDIR) exposure (under 10.0 centigray (cGy)) from man-made sources, such as diagnostic imaging, predominates in the US population and comprises nearly 50% of an average individual's yearly radiation exposure (Ullrich, Brooks et al. 2009). The increase in such exposures has led to public and government alarm about the impact of LDIR on human health (Ullrich, Brooks et al. 2009). Besides the mutational effects of radiation exposure, there is concern it might also result in modifications of the epigenome. Such aberrations can disrupt normal development and are involved in the progression of numerous diseases, including cancer (Gasser and Li 2011). High doses of radiation (>100.0 cGy) have been shown to cause epigenetic disruption (Kaup, Grandjean et al. 2006; Tamminga, Koturbash et al. 2008; Ilnytskyy, Koturbash et al. 2009), which is necessary for the persistence of radiation-induced genomic instability (Rugo, Mutamba et al. 2011); however, it is presently unclear to what extent LDIR in vivo alters the epigenome. </p><p>The viable yellow agouti (Avy) mouse was used here to characterize the dose-dependent epigenetic response to LDIR. The Avy mouse is a unique biological model that functions as a biosensor for environmentally induced epigenetic changes and disease susceptibility due to the presence of a metastable epiallele that modulates coat color (Waterland and Jirtle 2003). Pregnant dams were whole-body exposed to one of five doses of X-ray radiation ranging from 0-10.0 cGy on gestational day 4.5. Using a phantom mouse model, the intrauterine doses were estimated to be 0.0 cGy, 0.4 cGy, 0.7 cGy, 1.4 cGy, 3.0 cGy, and 7.6 cGy, respectively. At weaning, offspring coat colors were assessed and tissues were collected for methylation analysis. First, methylation changes at CpG sites in the Avy and Cdk activator binding protein (CabpIAP) metastable epialleles and at intracisternal a particle (IAP) elements across the genome were quantified using Sequenom technology. Second, three imprinted genes, Peg3, Nnat, and H19, were assessed for methylation changes in differentially methylated regions (DMRs) that regulate their parent-of-origin monoallelic expression using Sequenom technology. Lastly, it was postulated that the epigenetic changes at the Avy locus could be counteracted with dietary alterations. To test this hypothesis, female mice were placed on an antioxidant-supplemented diet prior to pregnancy and throughout gestation and lactation. Pregnant dams were irradiated with 3.0 cGy of whole-body X-rays. Offspring coat colors were assessed and methylation changes at the Avy allele were measured with the Sequenom platform. </p><p>Herein, I demonstrate that in utero LDIR exposure induced epigenetic changes in the Avy mouse in a dose-dependent and sex-specific manner. Acute, whole-body exposure to 0.7 cGy, 1.4 cGy, 3.0 cGy or 7.6 cGy X-rays significantly shifted offspring coat color distribution toward pseudoagouti. Acute exposure to 1.4 cGy, 3.0 cGy, and 7.6 cGy significantly increased methylation at multiple CpG sites in the Avy metastable epiallele in male offspring, but not female offspring. Methylation changes at DMRs in Nnat, Peg3, and H19 also occurred in a dose-dependent manner. Furthermore, inhibition of the phenotypic and Avy methylation changes with an antioxidant-supplemented diet suggests that the mechanisms to induce epigenetic changes are mediated by oxidative stress. These results demonstrate that relevant, low doses of radiation can elicit epigenetic changes that lead to a persistent phenotype, but can be mitigated with dietary supplementation. The successful completion of this project has resulted in the first in vivo epigenetic characterization of LDIR exposure and will contribute to the development of more relevant risk assessment strategies for protecting human populations.</p> / Dissertation

Alzheimer’s disease (AD) is the most common cause of dementia, affecting almost 40 million people worldwide, and it is predicted that this number will rise to nearly 150 million by 2050. It results not only in enormous distress for affected individuals and carers but also a substantial economic burden on society. Although more than 100 years have passed since its discovery, no cure for AD exists, despite enormous efforts in basic and clinical research over the past few decades, due to limited understanding of its underlying mechanisms. Neurodegenerative disorders, of which AD is an example, are highly complex disorders characterized by extensive neuronal dysfunction associated with the misfolding and aggregation of a specific set of proteins, including amyloid plaques and neurofibrillary tangles in AD. One promising avenue for progress in the field is to improve our understanding of the mechanisms by which cellular dysfunction arises from the initial protein aggregation events. The studies described in the thesis are based on the recent finding that a large number of proteins are inherently supersaturated, being expressed at concentrations higher than their solubilities, and constituting a metastable subproteome potentially susceptible to aggregation. These studies illustrate the dependence of aggregation prone metastable proteins on the cellular degradation machineries. They also study the role of metastable proteins and their homeostasis complement in the vulnerability of various body and brain tissues to protein aggregation diseases. Using extensive sequencing data and network based systems biology approaches, they elucidate how fundamental physicochemical properties of an individual or group of proteins relate to their biological function or dysfunction.

! ! Dissertation Abstract ! ! This research presents examination of the figural theory as established by Jean-François Lyotard in his work Discourse, figure (1971). Figural theory groundwork proved to be underpinned within the psychoanalytical framework as in the classical dreamwork and concept of transitional space as elaborated by D. Winnicott. We argue that the specific figural intermediary space defines a type of space that allows the image and the viewer to explore the individuation processes, as established by G. Simondon (1992) and thus create potential new series of the image which instigate and challenge new perceptive patterns of the viewer. Figural backdrop has been detected within the work of Gilles Deleuze, precisely in Logic of Sensation (1981) where Deleuze examines the diagrammatic system. As a result of the in-depth exploration of Lyotardian poetic transgressions as we have applied on the film intertitles we have proved a presence of a specific mobile integral title. This type of inter title brings forth the coalescence of text-image that resurfaces the image's resources. The pictorial transgression was examined on the example of Nicolas Roeg's color- events in Don't Look Now 1973 and the cinematic transgression was explored on the example of William Kentridge' s video work Automatic...

abstract: In many natural systems aqueous geochemical conditions dictate the reaction pathways of organic compounds. Geologic settings that span wide ranges in temperature, pressure, and composition vastly alter relative reaction rates and resulting organic abundances. The dependence of organic reactions on these variables contributes to planetary-scale nutrient cycling, and suggests that relative abundances of organic compounds can reveal information about inaccessible geologic environments, whether from the terrestrial subsurface, remote planetary settings, or even the distant past (if organic abundances are well preserved). Despite their relevance to planetary modeling and exploration, organic reactions remain poorly characterized under geochemically relevant conditions, especially in terms of their reaction kinetics, mechanisms, and equilibria. In order to better understand organic transformations in natural systems, the reactivities of oxygen- and nitrogen-bearing organic functional groups were investigated under experimental hydrothermal conditions, at 250°C and 40 bar. The model compounds benzylamine and α-methylbenzylamine were used as analogs to environmentally relevant amines, ultimately elucidating two dominant deamination mechanisms for benzylamine, SN1 and SN2, and a single SN1 mechanism for deamination of α-methylbenzylamine. The presence of unimolecular and bimolecular mechanisms has implications for temperature dependent kinetics, indicating that Arrhenius rate extrapolation is currently unreliable for deamination. Hydrothermal experiments with benzyl alcohol, benzylamine, dibenzylamine, or tribenzylamine as the starting material indicate that substitution reactions between these compounds (and others) are reversible and approach metastable equilibrium after 72 hours. These findings suggest that relative ratios of organic compounds capable of substitution reactions could be targeted as tracers of inaccessible geochemical conditions. Metastable equilibria for organic reactions were investigated in a natural low-temperature serpentinizing continental system. Serpentinization is a water-rock reaction which generates hyperalkaline, reducing conditions. Thermodynamic calculations were performed for reactions between dissolved inorganic carbon and hydrogen to produce methane, formate, and acetate. Quantifying conditions that satisfy equilibrium for these reactions allows subsurface conditions to be predicted. These calculations also lead to hypotheses regarding active microbial processes during serpentinization. / Dissertation/Thesis / Doctoral Dissertation Biochemistry 2017

京都大学 / 0048 / 新制・課程博士 / 博士(工学) / 甲第19727号 / 工博第4182号 / 新制||工||1645(附属図書館) / 32763 / 京都大学大学院工学研究科材料化学専攻 / (主査)教授 田中 勝久, 教授 平尾 一之, 教授 三浦 清貴 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DGAM

This dissertation presents an assortment of research aimed at understanding the composition-dependence of deformation behavior and the response to thermomechanical processing, to enable efficient design and processing of low stacking fault energy (SFE) high entropy alloy (HEAs). The deformation behavior and SFE of four low SFE HEAs were predicted and experimentally verified using electron microscopy and in-situ neutron diffraction. A new approach of employing a minimization function to refine and improve the accuracy of a semi-empirically derived expression relating composition with SFE is demonstrated. Ultimately, by employing the minimization function, the average difference between experimental and predicted SFE was found to be 2.64 mJ m-2. Benchmarking with currently available approaches suggests that integrating minimization functions can substantially improve prediction accuracy and promote efficient HEA design with expansion of databases. Additionally, in-situ neutron diffraction was used to present the first in-situ measurement of the interspacing between stacking faults (SFs) which were correlated with work hardening behavior. Electron transparent specimens (< ~100 nm thick) were used in order to resolve nanoscale planar faults instead of the thicker sub-sized specimens (on the order of millimeters in thickness) which exhibit the classical stages III work hardening behavior characteristic of low SFE metals and alloys. The present study demonstrates these characteristic dimensions of SFs can be tracked in real-time using neutrons or high-energy x-rays. SFs have also been shown to act as barriers to dislocation motion and thus contribute to strengthening and sustained work hardening during deformation.

No description available.

Le processus de contact est l'un des systèmes de particules en interaction les plus étudiés. Il peut s'interpréter comme un modèlepour la propagation d'un virus dans une population ou sur un réseau. L'objectif de cette thèse est d'étudier la relation entre la structure locale du réseau et le comportement global du processus sur le réseau tout entier.Le cadre typique dans lequel on se place est celui d’une suite de graphes aléatoires $(G_n)$ convergeant localement vers un graphe limite $G$.On étudie alors le comportement asymptotique du temps d’extinction $tau_n$ du processussur $G_n$; lorsqu’initialement tous les individus sont infectés. Nous montrons sur plusieurs exemples qu’il existe unetransition de phase lorsque $lambda$ - le taux d'infection du processus - traverse une valeur critique $ lambda_c (G)$, qui ne dépend que de $G$.Plus précisément, pour certains modèles de graphes aléatoires comme le modèle de configuration, le graphe d'attachement préférentiel, le graphe géométrique aléatoire, le graphe inhomogène, nous montrons que $ tau_n $ est d'ordre soit logarithmique soit exponentiel; selon que $ lambda$ est soit inférieur ou supérieur à $lambda_c (G) $.De plus, dans certains cas, nous montrons des résultats de métastablité: en régime sur-critique, $ tau_n $ divisé par son espérance converge en loi vers une variable aléatoire exponentielle de moyenne $1$, et la densité des sites infectés reste stable (et non nulle) sur une période de temps d’ordre typiquement $tau_n$. / The contact process is one of the most studied interacting particle systems and is also often interpreted as a model for the spread of a virus in a population or a network. The aim of this thesis is to study the relationship of the local structure of the network and the global behavior of the contact process (the virus) on the whole network. Let $(G_n)$ be a sequence of random graphs converging weakly to a graph $G$. Then we study $tau_n$, the extinction time of the contact process on $G_n$ starting from full occupancy. We prove in some examples that there is a phase transition of $tau_n$ when $lambda$ - the infection rate of the contact process crosses a critical value $lambda_c(G)$ depending only on $G$. More precisely, for some models of random graphs, such as the configuration model, preferential attachment graph, random geometric graph, inhomogeneous graph, we show that $tau_n$ is of logarithmic (resp. exponential) order when $lambda < lambda_c(G)$ (resp. $lambda < lambda_c(G)$). Moreover, in some cases we also prove metastable results: in the super-critical regime, $tau_n$ divided by its expectation converges in law to an exponential random variable with mean $1$, and the density of the infected sites is stable for a long time.

Le but de ce travail de thèse est de mieux comprendre les mécanismes de déformation à température ambiante dans les alliages de titane bêta-métastable Ti17 et Ti5553. Les microstructures étudiées sont composées de grains bêta transformé, dans lesquels la phase alpha peut précipiter, selon les relations de Burgers, sous la forme de douze variants différents. Une approche multi-échelles est donc préconisée avec trois niveaux représentatifs: macroscopique, mésoscopique (ex-grains bêta), et microscopique (variants alpha et matrice bêta de chaque grain). Différents modèles à champs moyens sont adaptés pour reproduire le comportement mécanique du Ti17 et du Ti5553. Ces modèles impliquent deux transitions d'échelle, et sont basés sur l'homogénéisation des comportements locaux, avec plusieurs manières de représenter les interactions intergranulaires. Les relations entre microstructures et propriétés mécaniques sont également considérées. Les modèles les plus complexes développés dans cette étude vont permettre de simuler l'anisotropie élastique et l'écoulement visqueux de chaque variant alpha (hcp) et de chaque matrice bêta (bcc), en employant la plasticité cristalline avec des écrouissages de type cinématique et isotrope. L'identification des paramètres matériaux est faite à partir d'une vaste base de données expérimentale provenant du projet PROMITI. Pour comprendre le rôle de chaque phase dans le processus de déformation, un calcul EF a également été fait afin de reproduire l'essai de traction sur une très fine éprouvette plate. Dans cette étude, le niveau mésoscopique est explicitement représenté en reprenant fidèlement la géométrie et l'orientation cristallographique de chaque grain bêta transformé. Des comparaisons entre expérience et simulation sont faites à l'échelle macroscopique pour les courbes contrainte - déformation, ainsi qu'au niveau mésoscopique, en considérant les champs de déplacement hors-plan et les champs de déformation. / The purpose of this PhD work is to investigate deformation mechanisms at room temperature in beta-metastable titanium alloys Ti17 and Ti5553. Studied microstructures are composed of beta-grains, in which alpha phase can precipitate under twelve different variants according to Burgers relationship. A multiscale approach is then proposed with three levels to consider: macroscopic, mesoscopic (prior beta grains) and microscopic (alpha variants and beta matrix of each grain). Different mean field models are adapted to depict Ti17 and Ti5553 mechanical behaviors. These models are based on the two scale-transition homogenization of local behaviors, with various ways of representing intergranular interactions. Relationships between microstructures and mechanical properties are also considered. The most advanced micromechanical models developed in this work depict elastic anisotropy and viscoplastic flow of each hcp alpha variant and each bcc beta matrix, using crystal plasticity with kinematic and isotropic hardening. Identification of material parameters is done using a large experimental database from PROMITI project. To understand the role of each phase in the deformation process, a FE computation was also made to reproduce the uniaxial tensile test of a very thick micro-specimen. In this study, the mesoscopic scale is explicitly represented: each beta grain has a real geometry and crystallographic orientation, according to a measured EBSD map in SEM. Comparisons between experiment and the numerical simulation are made on macroscopic stress - strain curves as well as on the mesoscopic scale, by considering out-of-plane displacement and strain fields.

No description available.