This thesis aimed to establish how different HLA genotypes correlate to MS severity and disease progression and whether they could be used as additional disease biomarkers and to a large extent the work has succeeded in this task. Association of MS with the alleles HLA-DRB1*15 and HLA-DQB1*06 and haplotype DRB1*15-DQB1*06 was identified, and under representation of other alleles, such as the HLA-DRB1*07 and HLA-A*02 alleles, showed a potentially protective role against the disease. HLA-A*02 was shown to be a marker of a better prognosis and, in contrast, HLA-B*07, B*08 and B*44 seem to be associated to with a worse prognosis. / Doctorat en Sciences médicales (Médecine) / info:eu-repo/semantics/nonPublished

京都大学 / 0048 / 新制・論文博士 / 博士(医学) / 乙第12815号 / 論医博第2077号 / 新制||医||1004(附属図書館) / 31302 / 京都大学大学院医学研究科医学専攻 / (主査)教授 山田 亮, 教授 小川 誠司, 教授 竹内 理 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20258号 / 医博第4217号 / 新制||医||1020(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 小西 靖彦, 教授 平家 俊男, 教授 中畑 龍俊 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21688号 / 医博第4494号 / 新制||医||1036(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 河本 宏, 教授 生田 宏一, 教授 江藤 浩之 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

The aim of this thesis is to exploit the technological capabilities of computer supported collaborative work (CSCW) in the field of collaborative Modelling and Simulation (M&S). The thesis focuses on addressing two main problems: (i) providing flexible means of consistency management in collaborative M&S, and (ii) the ability of providing platform and application independent services for collaborative M&S. In this work, some CSCW technologies and how some of the concepts can be incorporated in a distributed collaborative M&S environment, have been studied. An environment for component based simulation development and visualization, which provides support for collaborative M&S, has been designed. Some consistency policies that can be used in conjunction with distributed simulation and the High Level Architecture (HLA) have been investigated. Furthermore, the efficient utilization of HLA and XML in combination, as the foundation of a CSCW infrastructure has been proved. Two consistency policies were implemented utilizing HLA, a strict and an optimistic, in the distributed collaborative environment. Their performance was compared to the performance of a totally relaxed policy, in various collaboration situations. / QC 20101222

京都大学 / 新制・課程博士 / 博士(生命科学) / 甲第24759号 / 生博第500号 / 新制||生||66(附属図書館) / 京都大学大学院生命科学研究科高次生命科学専攻 / (主査)教授 杉田 昌彦, 教授 井垣 達吏, 教授 野田 岳志 / 学位規則第4条第1項該当 / Doctor of Philosophy in Life Sciences / Kyoto University / DFAM

Background Cancer immunotherapy has yielded many successes. Yet to some hard-to-treat brain tumors, such as glioblastoma multiforme (GBM) and diffuse intrinsic pontine glioma (DIPG), it still lacks substantial improvement. Neoantigens resulting from mutations in malignant cells are the key targets for employing adoptive cell therapies. A novel therapeutical strategy may be developed based on the identification of T cell receptors (TCRs) targeting specific neoantigens. Methods Previous work had been done to provide essential materials, including candidate neoantigen peptides, human leukocyte antigen (HLA) genotypes, and peripheral blood mononuclear cell (PBMCs) from patients and healthy donors (HDs). Autologous antigen-presenting cells (APCs) and T cells were isolated from PBMCs for in vitro assays. The activation of T cells against peptides was evaluated by the upregulation of 41BB utilizing flow cytometry (FACS). The cell populations with positive signals were sorted through FACS for TCR sequencing directly or after rapid cell expansion. Results T cells and APCs from 12 HDs were isolated. T cells from 10 HDs were analyzed after in vitro stimulation. T cells from HD30 showed reactions to several public neoantigens; while T cells from HD49 and HD53 showed reactions also to private neoantigens restricted in GBM patient C6. Conclusion The upregulation of 41BB indicated the activation of T cells and the existence of reactive TCRs against either public or private neoantigens in some HDs. Those reactive TCRs and their encoding sequences were the fundamentals of future works. Due to practical reasons, TCR sequencing cannot be done within this project. In future works, wildtype peptides will be included to further validate the results, ensuring identified TCRs recognize neoantigens specifically. Furthermore, the identified TCRs will be cloned and transferred to freshly isolated T cells to confirm their functionality. Keywords Cancer immunotherapy, brain cancer, neoantigen, MHC/HLA, TCR

INCOSE defines Model-Based Systems Engineering (MBSE) as "the formalized application of modeling to support system requirements, design, analysis, verification, and validation activities beginning in the conceptual design phase and continuing throughout development and later life cycle phases." One very important development is the utilization of MBSE to develop distributed and hybrid (discrete-continuous) simulation modeling systems. MBSE can help to describe the systems to be modeled and help make the right decisions and partitions to tame complexity. The ability to embrace conceptual modeling and interoperability techniques during systems specification and design presents a great advantage in distributed and hybrid simulation systems development efforts. Our research is aimed at the definition of a methodological framework that uses MBSE languages, methods and tools for the development of these simulation systems. A model-based composition approach is defined at the initial steps to identify distributed systems interoperability requirements and hybrid simulation systems characteristics. Guidelines are developed to adopt simulation interoperability standards and conceptual modeling techniques using MBSE methods and tools. Domain specific system complexity and behavior can be captured with model-based approaches during the system architecture and functional design requirements definition. MBSE can allow simulation engineers to formally model different aspects of a problem ranging from architectures to corresponding behavioral analysis, to functional decompositions and user requirements (Jobe, 2008).

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

In this thesis, a method for encoding and decoding arrays in systems based on the standard High Level Architecture is presented. High Level Architecture is a standard in the simulation industry, which enables interoperability between different simulation systems. When simulations share specific data with other simulations, they always send all parts of the data. This can become quite inefficient when the data is of an array type and only one or a few of its elements' values have changed. The whole array is always transmitted regardless whether the other simulations in the system need all elements or just the ones that have been modified since the last transmission. Therefore there might be more traffic on the network than needed in these cases. The proposed method, named Temporal Sparse Encoding, only encodes the modified elements when it needs to, plus some additional bytes as overhead, that allows for only sending updated elements. The method is based on the concept of sparse arrays and matrices, and is inspired by the Coordinate format, which uses extra arrays with indices referring to specific elements of interest. In a small simulation system, acting as a testing environment, it is shown how Temporal Sparse Encoding can save both time and above all, bandwidth, when sharing updates. Each test was carried out 10 times and in each test case 1 000 updates were transmitted. In each test case the transmission time was measured and the compression ratio was calculated by dividing the number of bytes in the encoding containing all elements by number of bytes in the encoding containing just the updated ones. The biggest compression ratio was calculated to be 750.13 and came from when 1 out of 1 000 elements were updated and transmitted. The smallest compression ratio was 1.00 and came from all the cases where all the array's elements were updated and transmitted. Some of the conclusions that were made was that the Temporal Sparse Encoding can save up to 33% of the time compared to the standard encoding and that a lot of the transmission time is spent on extracting elements once they have been decoded. These findings suggest that endeavors in optimization should be focused at the language level, specifically on management of data, rather than the transmission of data when there is not a lot of traffic occurring on the network.