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The basal ganglia are the key circuitry controlling movement and reward behavior. Both locomotion and reward-related behavior are also modified by dopaminergic input from the substantia nigra and the ventral tegmental area (VTA). If the basal ganglia are severed by lesion or in disease, such as in Parkinson’s disease, the affected individuals suffer from severe motor impairments and often of affective and reward-related symptoms. The subthalamic nucleus (STN) is a glutamatergic key area of the basal ganglia and a common target for deep brain stimulation in Parkinson’s disease to alleviate motor symptoms. The STN serves not only motoric, but also limbic and cognitive functions, which is often attributed to a tripartite anatomical subdivision. However, the functional output of both VTA and STN may rely more on intermingled subpopulations than on a strictly anatomical subdivision. In this doctoral thesis, the role of subpopulations within and associated with the basal ganglia is addressed from both a genetic and a behavioral angle. The identification of a genetically defined subpopulation within the STN, co-expressing Paired-like homeodomain transcription factor 2 (Pitx2) and Vesicular glutamate transport 2 (Vglut2), made it possible to conditionally reduce glutamatergic transmission from this subgroup of neurons and to investigate its influence on locomotion and motivational behavior, giving interesting insights into the mechanisms possibly underlying deep brain stimulation therapy and its side-effects. We address the strong influence of the Pitx2-Vglut2 subpopulation on movement, as well as the more subtle changes in reward-related behavior and the impact of the alterations on the reward-related dopaminergic circuitry. We also further elucidate the genetic composition of the STN by finding new markers for putative STN subpopulations, thereby opening up new possibilities to target those cells genetically and optogenetically. This will help in future to examine both STN development, function in the adult central nervous system and defects caused by specific deletion. Eventually identifying and characterizing subpopulations of the STN can contribute to the optimization of deep brain stimulation and help to reduce its side-effects, or even open up possibilities for genetic or optogenetic therapy approaches.

Under current investigation is the re-implementation of the Distorted-Wave Impulse Approximation (DWIA), originally formulated in FORTRAN by N.S. Chant and P.G. Roos, with the intention of developing it in a portable Python environment. This will be complimented by developing a GEANT4 detector simulation application. These two techniques will be used to model the (p,2p) proton knock-out reaction 40Ca(p; 2p)39K (2.52 MeV)1 2 + first excited state, at intermediate incident energies of 150 MeV. This study is a test-bed that lays the foundation and platform from which one may develop an interactive workbench and toolkit in GEANT4 which: (i.) accurately models an accelerator-detector experimental set-up, such as those found at iThemba Labs, and (ii.) incorporates the DWIA formalism as a built-in physics process within the framework of GEANT4. Furthermore the Python modules developed for the specific proton knock-out reaction studied here, can be generalized for an arbitrary set of nuclear scattering reactions and packaged as a suite of scientific Python codes. / Theoretical and Computational Nuclear Physics / M. Sc. (Theoretical and Computational Nuclear Physics)

本文的主要內容為評價JPMorgan Chase & Co.（美國摩根大通銀行）及UBS（瑞士銀行）所發行的兩檔結構型票券，共同的特色是票券為保本型且不付息，報酬條款中附有雙重界限觸及失效選擇權，其價值對於標的資產的波動程度相當敏感。一旦標的資產價格觸及任一界限，具有額外收益的選擇權將失效，投資人僅能拿回原始投資本金，相當於損失了原本可能獲得的無風險利息。 　　針對雙重界限觸及失效選擇權，我們使用顯式、隱式以及Crank-Nicolson三種有限差分法來進行評價，並比較蒙地卡羅模擬和封閉解的結果，藉以了解各種方法的準確性及效率。接著我們求算避險參數Greeks，分析發行商所面臨的風險。同時根據市場未來的情況，分析投資人的預期收益，進而了解這種商品在市場上廣為流通的原因，以及此類新奇結構型商品對於風險的重分配方式，如何締造買方賣方雙贏的局面。

Les levures Candida sont des pathogènes opportunistes responsables d’infections graves chez les patients immunodéprimés. Au cours de ce travail, nous avons développé un modèle cellulaire in vitro pour la caractérisation multiparamétrique des phénotypes d’interaction entre les levures Candida et les macrophages et les neutrophiles, principaux effecteurs de la défense anti-Candida. Il repose sur l’utilisation de marqueurs fluorescents pour le suivi quantitatif de l’interaction en cytométrie en flux et en fluorimétrie. Ce modèle a été validé par la comparaison de l’interaction de trois espèces de levures, C. albicans, C. glabrata et C. lusitaniae, avec des macrophages murins et des neutrophiles humains. Deux stratégies principales de survie des levures à la phagocytose ont été mises en évidence : par la résistance à la phagolyse et la multiplication des levures à l’intérieur des phagocytes jusqu’à leur éclatement, ou par l’évitement de la phagocytose et la multiplication des levures à l’extérieur des phagocytes. L’interprétation des données quantitatives a été confirmée par microscopie à fluorescence et vidéo-microscopie. Afin de mieux comprendre les interactions Candida-phagocytes, nous avons mis au point des outils pour l’analyse fonctionnelle de gènes chez C. lusitaniae. Une stratégie de PCR chevauchante a été développée pour l’obtention de mutants nuls de C. lusitaniae, sans étape de clonage. C’est ainsi que le gène OLE2, codant une Δ9 désaturase d’acides gras potentiellement impliquée dans la biosynthèse de la prostaglandine PGE2, a été invalidé. Le mutant ole2Δ présentait de très nets défauts de filamentation et de reproduction sexuée. Par rapport à une souche sauvage, le mutant ole2∆ était massivement phagocyté par les macrophages, et la survie des phagocytes était plus importante, ce qui suggère un rôle important des lipides insaturés et des oxylipides dans la signalisation cellulaire au cours de l’interaction Candida-phagocytes. Dans la dernière partie de notre travail, nous avons construit une banque de 10 000 mutants de C. lusitaniae par l’intégration aléatoire d’un marqueur dans le génome. Le criblage de cette banque à travers notre modèle cellulaire d’interaction permettra d’identifier de nouveaux gènes impliqués dans l’interaction avec les phagocytes afin de mieux comprendre la physiopathologie des candidoses et de trouver de nouvelles pistes thérapeutiques. / Candida species are opportunistic pathogens causing severe infectious diseases in immunocompromised patients. In this work, we developed a tool for a multi-parameter characterization of the cell interactions between the yeasts Candida and both macrophages and neutrophils, which constitute the main defense against candidiasis. It relies on the labelling of each population with specific fluorescent markers, and on the use of fluorimetry and flow cytometry to assess interactions. The tool has been validated by comparing the interactions of three yeast species C. albicans, C. glabrata and C. lusitaniae, with murine macrophages and human neutrophils. We found that yeasts use two main ways for escaping phagocytosis, which has been confirmed using video-microscopy: either (1) by surviving to phagolysis and dividing into the phagosome until phagocytes burst, or (2) by avoiding phagocytosis and dividing outside phagocytes. In order to better understand the cellular and molecular mechanisms involved in Candida-phagocytes interactions, we developed new molecular tools for the functional analysis of genes in C. lusitaniae, notably a two-step cloning-free PCR-based method for the deletion of genes. This method was successfully used for the deletion of OLE2, a gene encoding a Δ9-desaturase of fatty acids, possibly implicated in prostaglandin PGE2 biosynthesis. The ole2Δ mutant exhibited strong defects in both pseudofilamention and sexual mating. During macrophages infection, ole2Δ yeast cells were massively internalized and triggered less phagocytes cell death than the wild type strain, suggesting that unsaturated fatty acids and/or oxylipids could play a role during interaction with phagocytes. Lastly, a bank of 10,000 mutants was constructed in C. lusitaniae by the random integration of a genetic marker in the genome. The screening of this bank through our tool to analyse cellular interactions will be undertaken to gain insights into understanding of the early stages of the infectious process.

Under current investigation is the re-implementation of the Distorted-Wave Impulse Approximation (DWIA), originally formulated in FORTRAN by N.S. Chant and P.G. Roos, with the intention of developing it in a portable Python environment. This will be complimented by developing a GEANT4 detector simulation application. These two techniques will be used to model the (p,2p) proton knock-out reaction 40Ca(p; 2p)39K (2.52 MeV)1 2 + first excited state, at intermediate incident energies of 150 MeV. This study is a test-bed that lays the foundation and platform from which one may develop an interactive workbench and toolkit in GEANT4 which: (i.) accurately models an accelerator-detector experimental set-up, such as those found at iThemba Labs, and (ii.) incorporates the DWIA formalism as a built-in physics process within the framework of GEANT4. Furthermore the Python modules developed for the specific proton knock-out reaction studied here, can be generalized for an arbitrary set of nuclear scattering reactions and packaged as a suite of scientific Python codes. / Theoretical and Computational Nuclear Physics / M. Sc. (Theoretical and Computational Nuclear Physics)

目前全球的金融衍生性商品市場中，利率衍生性商品占了全球衍生性商品交易量的一半以上，其次為匯率衍生性商品。市場上的結構型商品，有的連結數個標的，有的報酬型態複雜，不易為一般投資人所了解，且投資人容易被商品條款上的高配息或最高報酬率吸引，而忽略了對投資人不利的條款。 本文針對目前金融市場上已發行的利率及匯率連結金融商品，進行個案評價與分析，希望能讓一般投資人更了解市面上結構型商品的報酬型態，以及潛在的投資風險，並站在發行商的角度，進行商品利潤分析及發行策略的探討。 本文所評價的兩個商品為英國勞埃德銀行(Lloyds TSB Bank Plc.)所發行的「每日計息雙區間可贖回債券」和中國農民銀行所發行的「觸及失效匯率連結債券」，分別以LIBOR Market Model (Brace, Gatarek and Musiela,1997，也稱為BGM模型)和三元樹模型(Ritchken,1995)對其進行評價。最後針對評價結果分析發行商的發行策略以及投資人需注意的投資陷阱。

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