Le médulloblastome (MB), une tumeur formée à partir du cervelet en développement, est l’un des cancers pédiatriques malins les plus fréquents. Des profils d’expression géniques ont montré l’existence de quatre groupes distincts de MB qui présentent des profils moléculaires et des pronostics différents. Parmi ces groupes, l’un d’entre eux est caractérisé par une activation de la voie de signalisation Sonic Hedgehog (SHH). Ce groupe de MB provient des précurseurs de neurones en grain lors du développement cérébelleux. Les traitements actuels comprennent la chirurgie, la chimiothérapie ainsi que la radiothérapie, ce qui a pour effet d’altérer les capacités cognitives et sociales des survivants. Ainsi, des efforts considérables ont été mis en œuvre dans le but de trouver des cibles thérapeutiques afin de bloquer spécifiquement les mécanismes tumorigéniques sans affecter le développement normal. De récentes analyses à grande échelle ont révélé le rôle crucial de mécanismes épigénétiques, et en particulier dans le groupe SHH, dans lequel la perte de fonction d’un certain nombre de modificateurs chromatiniens a été identifiée. Ainsi, l'objectif principal de ma thèse est d'étudier l'implication de potentiels candidats modificateur chromatinien, à la fois au cours du développement cérébelleux et lors du MB SHH. Nous avons concentré notre étude sur plusieurs modificateurs de la chromatine qui ont été trouvés mutés dans les MB SHH humains. Nous avons commencé l’étude avec trois modificateurs chromatiniens sélectionnés selon (i) leur impact sur la survie, (ii) leur expression au cours du développement du cervelet, (iii) leur expression dans les MB SHH humains et nous sommes finalement concentré sur un.Afin d'étudier ce candidat, un objectif important de ma thèse a été de développer des outils fiables. Dans ce contexte, nous avons développé des modèles de souris knock-out conditionnelles et le système CRISPR-cas9 dans le développement cérébelleux postnatal afin d'étudier l'impact de la perte du candidat à la fois dans le développement du cervelet et dans le MB SHH. Ensuite, nous nous sommes intéressés aux mécanismes moléculaires contrôlés par ce modificateur de la chromatine. Plus précisément, nous avons défini (i) l’interactome, et (ii) des cibles transcriptionnelles spécifiques qui nous ont aidé à comprendre comment une protéine impliquée dans la modification de la chromatine peut favoriser l’état tumoral. En conclusion, ces travaux permettent de mettre en évidence comment la perte de la fonction de modificateur chromatinien spécifique peut différemment affecter le destin cellulaire dans le développement normal cérébelleux et dans le MB SHH et soulève la question d’une prise en charge plus personnalisée des patients atteints de MB SHH. / Medulloblastoma (MB), a tumor arising from the developing cerebellum, is one of the most common malignant pediatric brain tumors. Gene expression profiling showed the existence of four groups of MB with distinct molecular profiles and patient outcomes. Among these groups, one of them is associated with an activation of the Sonic Hedgehog (SHH) pathway.This specific group is thought to arise from cerebellar Granule Neuron Progenitors (GNPs) during cerebellar development. The actual treatment is heavy and consists of surgery, chemotherapy as well as radiotherapy impairing social and cognitive ability of survivors. Thus, considerable effort has been made in order to find drug targets that would specifically block tumorigenic mechanisms without affecting normal development.Recent large scale analysis revealed the crucial role of epigenetic mechanisms, and especially in the SHH group of MB in which loss of function mutation of several chromatin modifiers has been identified. Thus, the main goal of my PhD is to study the involvement of potential candidate chromatin modifiers both during cerebellar development and in SHH MB.We focused our study on several chromatin modifiers that were found mutated in human SHH MB. We began to study three chromatin modifiers that were selected according to (i) their impact on survival, (ii) their expression during cerebellar development, (iii) their expression in human SHH MB and finally we selected one for further functional validation.In order to study this candidate, one important goal of my PhD has been to develop reliable tools. In that context, we developed conditional knock-out mice models and the CRISPR-Cas9 system in postnatal cerebellar development in order to study the impact of the loss of this chromatin modifier both in cerebellar development and SHH MB initiation. Then, we investigated the molecular mechanisms controlled by this chromatin modifier. In particular, we defined (i) the interactome, and (ii) specific target genes that helped us understanding how a protein implicated in chromatin modification can favor tumors. In conclusion, this work provides insights into how the loss of function of a specific chromatin modifier can differentially affect cell fate in the context of normal cerebellar development and in SHH MB, stressing the question of a more personalized patient care.

Interference effects of co-generated hydrides of arsenic, antimony, bismuth and selenium on trapping behavior of selenium or antimony hydrides (analytes) within iridium modified, transversely heated graphite tube atomizer (THGA) was investigated. A twin-channel hydride generation system was used for independent separate generation and introduction of analyte and interferent hydrides, i.e. in simultaneous and/or sequential analyte-interferent and interferent-analyte mode of operation. Influence of the analyte and modifier mass, interferent amount, trapping temperature and composition of the gaseous phase was studied. A simple approach for elimination of mutual interference effects by modification of the gaseous phase with oxygen in substoichiometric ratio to chemically generated hydrogen is proposed and suppression of these interference effects is demonstrated. A hypothesis on mechanism of trapping and mutual interference effects is drawn.

京都大学 / 0048 / 新制・課程博士 / 博士(工学) / 甲第21062号 / 工博第4426号 / 新制||工||1688(附属図書館) / 京都大学大学院工学研究科都市社会工学専攻 / (主査)教授 河野 広隆, 准教授 服部 篤史, 准教授 山本 貴士 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DFAM

Asphalt binder modification is a common method of improving Hot-mix Asphalt (HMA) performance by enhancing mix properties and reducing or delaying three general HMA distress types: deformation (rutting and shoving), cracking (from repeated loads and low temperatures) and general deterioration (raveling and stripping). Since the early 1960’s, a common modified asphalt alternative has employed reclaimed rubber as an economical and environmental friendly method of recycling waste tires while improving asphalt physical and mechanical properties. Pavement network deterioration combined with increasing material costs makes polymer modification of asphalt binder desirable, with reclaimed rubber from waste tires being an attractive alternative which addresses performance, economics and environmental issues. The primary objective of this dissertation is to demonstrate the importance of proper processing of all types of modified bituminous binders, whether they be virgin (e.g. styrene-butadiene-styrene (SBS) or styrene-butadiene rubber (SBR)), post-consumer polymers (e.g. ground tire rubber (GTR)) or a combination (GTR plus SBS). To achieve this four secondary objectives were identified: 1) characterize GTR using thermo-gravimetric analysis (TGA), 2) improve processing of GTR modified binders, 3) improve testing and specifications of GTR modified binders and 4) evaluate mixes containing GTR modified binders. A simple efficient instrumental, TGA, method to analyze polymers in binary rubber compounds was developed to quantify the functional polymer content available in GTR. TGA analysis provides a better understanding of the general chemical characteristics of GTR used in modification of asphalt binders for production of asphalt paving mixtures. Results are presented from efforts to optimize GTR modified binder formulations with respect to how GTR loading, GTR particle size, processing temperature and asphalt cement source affect modified binder properties and ability to meet performance graded binder specifications. These results are the basis to establish recommended processing parameters for formulation and preparation of GTR modified asphalt binders. GTR modified binders were used in: dense graded asphalt (DGA), stone matrix asphalt (SMA) and open graded friction courses (OGFC) and compared to conventional asphalt cement and styrene-butadiene-styrene (SBS) modified asphalt binders. Mixture performance evaluation with respect to binder effectiveness as it relates to the three general HMA distress types.

京都大学 / 新制・課程博士 / 博士(工学) / 甲第24605号 / 工博第5111号 / 新制||工||1978(附属図書館) / 京都大学大学院工学研究科機械理工学専攻 / (主査)教授 平山 朋子, 教授 松原 厚, 教授 小森 雅晴 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DFAM

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During World War II, it was discovered that when lead was added to double-base propellants, it produced beneficial burn rate phenomena. Specifically, the propellant burn rate first increased unexpectedly at low pressures, then the burn rate became independent of pressure, followed lastly by “mesa burning” where the burn rate actually decreased with increasing pressure. This results in a beneficial negative feedback mechanism. Over the past 75 years, researchers have explored different lead complexes to achieve better propellant performance. However, over the last decade, research has shifted to finding an alternative to using lead as an additive to reduce toxicity. Until the attempts detailed herein, researchers had not, to our knowledge attempted to combine double-base propellant stabilizers with various metals to achieve these desired results. In doing so, we prepared two lead complexes, Tetrakis (µ3-(4-methyl-3-nitrophenyl imido lead (II))) 1, and Bis(dinitrophenyl imido lead(II)) 2, that were synthesized by reacting lead bis(trimethylsilyl)amide with a common double-base propellant stabilizer 2-nitrodiphenylamine (NDPA) and 4-methyl-3-nitroaniline. Both complexes formed from protolysis of the trimethylsilylamide ligand by the acidic proton of the amine, and crystallized from tetrahydrofuran (THF). Bomb calorimetry coupled with crystal density structure determined that 1 has a very high energy density of 74.1 MJ/L, more than three times the energy density of conventional nitroamine explosives, whereas 2 was lower at 38.2 MJ/L. The structure, charge and characterization of 1 and 2 are discussed. However, each complex is air sensitive making burn rate experimentation infeasible, so any possible changes to the propellant as an additive remained undetermined. Attempts to use of tin, zinc, or bismuth bis(trimethyl)amides in place of lead, were unsuccessfully characterized, although reactions were likely observed. / Chemistry

The examination of the application and accuracy of optical sensors for the purpose of determining rail lubricity of top-of-rail friction modifier is investigated in this research. A literature review of optical sensors as they relate to detecting thin layers is presented, as well as a literature review of the significant aspect of surface roughness on optical signature. Both commercially available optical sensors and optical devices, such as independent lasers and detectors, are examined in a comprehensive parametric study to determine the most suitable configuration for a prototype with adequate third-body detection. A prototype is constructed considering parameters such as sunlight contamination, vibrations, and angle of detection. The prototype is evaluated in a series of laboratory tests with known lubricity conditions for its accuracy of measurements and susceptibility to environmental conditions, in preparation for field testing. Upon field testing the prototype, the data indicates that it is capable of providing subjective measurements that can help with determining whether a rail is highly lubricated or unlubricated, or it is moderately lubricated. It is anticipated that the device could be used to provide a rail lubricity index. The investigation of the optical response of a rail in various conditions, including top-of-rail friction modifier presence and underlying surface roughness, reveals the behavior of friction modifying material on rail/wheel interactions. It is determined that surface roughness is imperative for distinguishing between scattering due to surface condition and scattering due to third-body layers. Additionally it is revealed that friction modifying materials become entrapped within the surface roughness of the rail, effectively causing a "seasoning" effect instead of a simple third body layer. This provides some explanation on the inadequacy of determining lubricity conditions using contacting methods since they cannot detect the entrapped material that are revealed only when the top of rail undergoes a micro deformation due to a passing wheel. Furthermore, the fluorescent signature of flange grease can be utilized to detect any flange grease contamination on top of rail. The results of the study indicate that it is possible to have practical optical sensors for top-of-rail third body layer detection and any contamination that may exist, initially through spot checking the rail and eventually through in-motion surveying. / Master of Science / Top-of-rail friction modifiers are used in the railway industry for a variety of reasons, including, but not limited to, reduction in wear and fuel savings; although their use has been widely accepted, methods of detection of such materials have not been adequately developed. Presently, methods of measurement of physical aspects of a rail are used in order to deduce the presence or lack of friction modifier on top-of-rail. However, no direct method of measurement exists in the published literature today. This study examines the use of optical sensors for the purpose of determining rail lubricity conditions. The literature is reviewed in this study for all applicable topics pertaining to the optical detection of top-of-rail friction modifier, including the optical theory used and the importance of surface roughness on an optical signature. Different characteristics of optical sensors are examined and a configuration is determined for the construction of a prototype device. This device utilizes laser reflective detectors and a fluorescence sensor in order to distinguish friction modifier presence or other third-body layers. This prototype was tested and evaluated in a series of laboratory tests with known lubricity conditions in preparation for field testing. Additionally, metrics were developed using optical theory in order to quantify the differences between different lubricity conditions. It was seen that this prototype was able to determine the presence of friction modifier by its laser reflective properties, and the presence of flange grease contamination through its fluorescence signature. Field testing with this prototype confirmed the prototype’s ability to distinguish adequate lubricity conditions using these metrics. It is anticipated that the device could be used to provide a rail lubricity index that is able to aid railway professionals in maintenance practices regarding rail lubricity.