京都大学 / 0048 / 新制・課程博士 / 博士(農学) / 甲第19243号 / 農博第2140号 / 新制||農||1036(附属図書館) / 学位論文||H27||N4947(農学部図書室) / 32242 / 京都大学大学院農学研究科応用生物科学専攻 / (主査)教授 今井 裕, 教授 祝前 博明, 教授 松井 徹 / 学位規則第4条第1項該当 / Doctor of Agricultural Science / Kyoto University / DFAM

We present a novel platform for testing the effects of interventions on the life- and healthspan of a short-lived freshwater organism with complex behavior and physiology-the planktonic crustacean Daphnia magna. Within this platform, dozens of complex behavioral features of both routine motion and response to stimuli are continuously quantified over large synchronized cohorts via an automated phenotyping pipeline. We build predictive machine-learning models calibrated using chronological age and extrapolate onto phenotypic age. We further apply the model to estimate the phenotypic age under pharmacological perturbation. Our platform provides a scalable framework for drug screening and characterization in both life-long and instant assays as illustrated using a long-term dose-response profile of metformin and a short-term assay of well-studied substances such as caffeine and alcohol.

Made available in DSpace on 2016-04-26T20:48:55Z (GMT). No. of bitstreams: 1 Joao Paulo Pieroni.pdf: 521209 bytes, checksum: a399a879f7342b37382038cb88316ecc (MD5) Previous issue date: 2009-05-25 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / The price stabilization that occurred in Brazil since 1994, after a long period of macroeconomic volatility, seemed to be sufficient to extend the terms and improve the internal public debt compound from the country. However, in spite of some advances, the debt compound is still in short term and with high participation of interest index bonds. The aim of this work is to show structural factors that still inhibits the effective extension and improvement of the internal public debt. In order to achieve this goal, some characteristic of primary and secondary market of public bonds and its close relation to the monetary policy through yield curve are shown. It emphasizes that the structure format of this curve, together with low liquidity on secondary market, makes it difficult for the long term bonds demand. It discusses the small benefits of the improvement of the debt extension in relation to the high financial costs given by this strategy. From the descriptive analyses of primary auction of public bonds and the relation between monetary policy and the public debt administration in Brazil, after 1999, we can see that the efforts made to extend the term and improve the exposure of the brazilian debt are, in great part, removed from eventual internal or external uncertain crisis. The work concludes that as long as the interest index bonds, the incentive to short term culture of the agents and the high level of interest rates were maintained, there will be limits to effective extension and improvement the compound of the internal public debt in Brazil / A estabilização de preços ocorrida no Brasil a partir de 1994, após um longo período marcado pela volatilidade macroeconômica, parecia ser condição suficiente para o alongamento e melhora do perfil da dívida pública mobiliária interna (DPMFi) do país. Entretanto, a despeito de alguns avanços, a composição da dívida continua a ser de curto prazo e com elevada participação de títulos indexados a taxa de juros. O objetivo desta dissertação é apontar os fatores estruturais que continuam inibindo o efetivo alongamento e melhora do perfil da DPMFi no país. Para isso, são apresentadas as características dos mercados primário e secundário de títulos públicos e sua estreita relação com a política monetária, por meio da estrutura a termo da taxa de juros. Enfatiza-se que o formato dessa estrutura, em conjunto com a baixa liquidez do mercado secundário, dificultam a demanda por títulos mais longos. Questiona-se os benefícios dos pequenos avanços no alongamento da dívida em relação aos elevados custos financeiros impostos por essa estratégia. A partir da análise descritiva dos leilões primários de títulos públicos e das relações entre política monetária e administração da dívida pública no Brasil, após 1999, constata-se que os esforços realizados para ampliar os prazos e melhorar a exposição da dívida brasileira são, em grande parte, eliminados por eventuais crises de confiança, internas e/ou externas. Conclui-se que enquanto forem mantidos, entre outros fatores, os títulos pós-fixados indexados a taxas de juros, o incentivo à cultura de curto prazo dos agentes financeiros e o elevado nível das taxas de juros, haverá limites para o efetivo alongamento e melhora do perfil da dívida pública no país

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Die Arbeit beschreibt das phänotypische Verhalten von kultivierten Langerhanszellen, antigenpräsentierenden Zellen der Epidermis, sowie die Art und Weise ihrer Elimination. Hierfür wurden Zellkulturen von Langerhanszellen durch Migration aus normaler menschlicher Haut gewonnen. Die Langerhanszellen durchlaufen dabei die gleiche funktionelle Entwicklung, wie nach Antigenpräsentation in situ. Ziel der Untersuchung war es, die funktionellen und zellulären Eigenschaften und die Elimination von Langerhanszellen in der Zellkultur zu ermitteln. Die Anzahl viabler Zellen wurde mittels Trypanblauausschluß zu verschiedenen Zeitpunkten der Kultur ermittelt. Außerdem wurden die Zellen mittels Elektronenmikroskopie und Immuncytochemie untersucht. Die Befunde zeigen, daß die Zellen in der Kultur eine Veränderung ihres Phänotyps sowie funktionelle Änderungen im Sinne einer Ausreifung zu antigenpräsentierenden, T-Zell stimulierenden Zellen erfahren. Das in-vitro-Verhalten entspricht dem von Langerhanszellen in vivo nach Kontaktsensibilisierung. Mit Hilfe von eines für Apoptose spezifischen ELISA (= Enzyme-linked immunosorbent assay: eine Nachweisreaktion für Antigene bzw. Antikörper mithilfe von Enzymen) und Elektronenmikroskopie wurde nachgewiesen, daß die Zellen in unseren Kulturen durch Apoptose starben. Es gibt keinen Anhaltspunkt dafür, daß sich die Zellen nicht auch in vivo apoptotisch eliminieren. Die Verlauf der Funktionsmarker weist darauf hin, daß vorwiegend die maturierten Zellen von Apoptose betroffen waren, und die Apoptose über das CD 95/CD 95 L- System gesteuert wurde. Die Versuche zeigten insgesamt, daß Langerhanszellen durch Apoptose aus der Kultur eliminiert werden. Da sich die Zellen nach Migration in vitro wie Langerhanszellen nach Antigenpräsentation in vivo verhalten, scheint die Apoptose ein biologisches Regulativ für die Elimination von funktionell ausgereiften Langerhanszellen darzustellen. / This work describes the phenotypic behavior of cultivated Langerhans-cells, epidermal cells presenting antigenes and how they are eliminated . Therefore cultures of Langerhans-cells won by migration from normal human skin were used. The migrated Langerhans-cells have the same phenotypic features as Langerhans-cells after presentation of antigenes in situ. The aim of this work was to show the functional and cellular features of Langerhans-cells in culture and the way of their elimination. The cells still alive were count at distinct times using the Trypan-blue-exclusion-method. Additionally the cells were examined by electron microscopy and immuncytochemical methods. The findings show, that the cells in culture have the same characteristics of the phenotype and change of their function in the direction of developing to antigen-presenting, T-cell-stimulating cells. The in vitro behaviour is the same as of Langerhans-cells in vivo after contact-sensitization. With the help of an elisa (=Enzyme-linked immunosorbent assay) specific for apoptosis ( Cell Death Detection Elisa = CDDE) and with electron microscopy was shown, that the cultivated cells died by apoptosis. There is no reference point, that the cells do not do the same in vivo. The process of the functional markers shows, that predominantly the matured cells die by apoptosis and that it was controled by the CD 95/CD 95-L -system The investigations showed, that the Langerhans-cells were eliminated by apoptosis of the culture. The cells after migration in vitro behave in the same manner as after presentation of antigen in vivo. This indicates apoptosis to be the biologic regulation for the elimination of functional matured Langerhans-cells.