Hepatitis B virus (HBV) vaccination is recommended for individuals with hepatitis C virus (HCV) infection given their shared risk factors and increased liver-related morbidity and mortality upon super-infection. Vaccine responses in this setting are often blunted, with poor response rates to HBV vaccinations in chronically HCV-infected individuals compared to healthy subjects. In this study, we investigated the role of T cell immunoglobulin mucin domain-3 (Tim-3)-mediated immune regulation in HBV vaccine responses during HCV infection. We found that Tim-3, a marker for T cell exhaustion, was over-expressed on monocytes, leading to a differential regulation of IL-12/IL-23 production which in turn TH17 cell accumulation, in HCV-infected HBV vaccine non-responders compared to HCV-infected HBV vaccine responders or healthy subjects (HS). Importantly, ex vivo blockade of Tim-3 signaling corrected the imbalance of IL-12/IL-23 as well as the IL-17 bias observed in HBV vaccine non-responders during HCV infection. These results suggest that Tim-3-mediated dysregulation of innate to adaptive immune responses is involved in HBV vaccine failure in individuals with chronic HCV infection, raising the possibility that blocking this negative signaling pathway might improve the success rate of HBV immunization in the setting of chronic viral infection.

Sequence divergence of orthologous proteins enables adaptation to a plethora of environmental stresses and promotes evolution of novel functions. As one of the most common motifs in biology capable of diverse enzymatic functions, the TIM barrel represents an ideal model system for mapping the phenotypic manifestations of protein sequence. Limits on evolution imposed by constraints on sequence and structure were investigated using a model TIM barrel protein, indole-3-glycerol phosphate synthase (IGPS). Exploration of fitness landscapes of phylogenetically distant orthologs provides a strategy for elucidating the complex interrelationship in the context of a protein fold. Fitness effects of point mutations in three phylogenetically divergent IGPS proteins during adaptation to temperature stress were probed by auxotrophic complementation of yeast with prokaryotic, thermophilic IGPS. Significant correlations between the fitness landscapes of distant orthologues implicate both sequence and structure as primary forces in defining the TIM barrel fitness landscape. These results suggest that fitness landscapes of point mutants can be successfully translocated in sequence space, where knowledge of one landscape may be predictive for the landscape of another ortholog. Analysis of a surprising class of beneficial mutations in all three IGPS orthologs pointed to a long-range allosteric pathway towards the active site of the protein. Biophysical and biochemical analyses provided insights into the molecular mechanism of these beneficial fitness effects. Epistatic interactions suggest that the helical shell may be involved in the observed allostery. Taken together, knowledge of the fundamental properties of the TIM protein architecture will provide new strategies for de novo protein design of a highly targeted protein fold.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20260号 / 医博第4219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 前川 平, 教授 木原 正博, 教授 河本 宏 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

A model that accurately describes the transient and steady-state response of thermal microactuators is desirable to provide guidance for design and operation. However, modeling the full response of thermal actuators is challenging due to the temperature-dependent material properties and nonlinear deformations that must be included to obtain accurate results. To meet these challenges a three-dimensional multi-physics nonlinear finite-element model was developed using commercial code. The Thermomechanical Inplane Microactuator (TIM) was chosen as a candidate application to validate the model. TIMs were fabricated using the SUMMiT V™ process and their response was measured using a high-speed camera. The TIMs were modeled and the model output was compared to the experimental data. The finite-element model predicts the steady-state response to within 0.74 percent and the transient response, as described by the time constant, to within 42 percent. The usefulness of the model was further demonstrated by its predicting that response time and energy consumption can be reduced by actuating thermal microactuators with short-duration high-voltage pulses. This behavior was verified through testing. Feedback control has proven useful in improving reliability and performance for a variety of systems. However there has been limited success implementing feedback control on surface micromachined MEMS devices. The inherent difficulties in sensing microscale phenomena complicate the development of an economical transducer that can accurately monitor the states of a surface micromachined system. We have demonstrated a simple and effective sensing strategy that uses the piezoresistive property of the polysilicon thin film of which surface micromachined MEMS devices are fabricated. The states of the device are monitored by measuring the change in resistance of flexible members which deflect as the device moves. Measurement of the output displacement of an in-plane thermal actuator is presented as a candidate application. The thermal actuator is constructed of angled pairs of expansion legs that are connected to a center shuttle. As current flows through the legs they heat up and expand. The expansion causes the center shuttle to displace in the direction the legs are angled. The center shuttle is also connected to a pair of sensing legs. Theses legs are identical to the expansion legs except that they are angled in the opposite direction. Three other leg pairs are electrically connected to the sensing legs in a Wheatstone bridge configuration. An excitation voltage is applied to the bridge, and as the sensing legs deflect with the center shuttle displacement, the resistance change across the legs can be determined by measuring the voltage across the bridge. While there still is a noise issue to be dealt with, this setup provides adequate signal strength to implement feedback control using off-chip analog circuitry. Implementation of proportional/integral control on the system is successfully demonstrated.

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Denna uppsats är en komparativ analys av Roald Dahls bok Kalle och chokladfabriken från 1964 med Mel Stuarts filmadaption från 1971 och Tim Burtons filmadaption från 2005. Syftet med uppsatsen är att se vilka möjliga likheter och skillnader som finns mellan karaktärerna och ifall de olika skillnaderna kan bero på tidsperioden verket skapades i. Analysen påvisar att det finns några tydliga skillnader som ändrar karaktärerna drastiskt och att detta bland annat kan kopplas till den tidsperiod som verket är gjord i. Således är det ingen stor skillnad i karaktärerna mellan Roald Dahls bok och Mel Stuarts filmadaption troligtvis då de skapats i samma tidsperiod. Budskapet i Burtons adaption har däremot blivit alternerat med mer fokus på tidens mer aktuella frågor såsom mental hälsa och familjerelationer och har därmed orsakat en stor förändring i karaktärerna Willy Wonka, Kalle Spann och Oompa-Loompianerna. Med dessa tre verk kan lärare didaktiskt undervisa eleverna om hur ett verk kan ändras när adaptioner sker för att passa samtiden. Dock får läraren påpeka att det inte alltid är självklart vad som är en produkt av tiden och vad som är en upphovsmans egen konststil.

Tim O'Brien, a contemporary author writing mostly about his combat experience in Vietnam, has written eight books to date. All involve Vietnam in some way—overtly, for the most part. He and his stories are well known stylistically for several traits including the blurred distinctions between what actually happened and "story truth," something that did not really happen, but is true nonetheless. Within the story, he also blurs the line between what actually happens and what is imagined by the narrator or one of the characters; and, although he sometimes makes the distinction, he often does not. To help shed some light on this, there are a number of published interviews and articles wherein he discusses the themes, forms, and methods of his writing as well as his experiences. Research and analysis of O'Brien and his works show that, although his stories overtly deal with a myriad of other issues and themes, the complex and specific theme of displacement caused by trauma is present in all of his work, and can even be considered the engine that drives his stories and how they work with the reader. Additionally, O'Brien's well-known method of writing is actually a subtle yet intensely effective performance and enactment of this underlying theme of displacement. When used as a reading strategy, the theme itself clarifies and unlocks several points of contention about his texts such as O'Brien's generally negative treatment of women. / Master of Arts