京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22330号 / 医博第4571号 / 新制||医||1041(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 妹尾 浩, 教授 湊谷 謙司 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 新制・課程博士 / 博士(医学) / 甲第23374号 / 医博第4743号 / 新制||医||1051(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 藤田 恭之, 教授 椛島 健治, 教授 斎藤 通紀 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

In this thesis I will evaluate few discrete devices and their differences in structure, static and switching characteristics and also some structurall and manufacturing principles. After that I will follow up with their integration into power modules , where I will also aim on construction solutions and trends. These power moduls are today delivered as „stack“ or „system“, where for optimization and highest achievable efficiency of the whole unit the integration of protection, drive and cooloing stage is incorporated. Cooling and drive of some devices will be subject of a separate chapter. Also some of novel materials, which are very promissing, will be introduced. They show improvemnet in electrical and thermal properties. They have potential to replace the currently dominant Silicon in the near future.

Much research and experiments have gone into studying idealized wing-body junction flows and their impact on horseshoe vortex and wake formation.  The vortices have been found to generate regions of high surface pressure fluctuations and turbulence that are detrimental to structural components and acoustics.  With the focus in the military and commercial industry on reducing the acoustical impact of aircraft and their engines, very little research has been done to examine the potential impact wing-body junctions may have on acoustics, especially for high lifting bodies such as propellers.  Two similar tests were conducted in the Virginia Tech Open Jet Wind Tunnel where boundary layer measurements, oil flow visualizations, acoustic linear array and surface pressure fluctuation measurements of a baseline Rood airfoil model and two novel junction fairing designs were all taken.  Boundary layer measurements were taken at four locations along the front half of the flat plate and the profiles were shown to be all turbulent despite the low Reynolds number of the flow, (test 1: Re_"<1400, test 2: Re_"<550).  Oil flow visualizations were taken and compared to those of previous researchers and the location of separation and line of low shear along with the maximum width of the wake and width of wake at the trailing edge all scaled relatively well with the Momentum Deficit Factor, defined for wing-body junction flows [Fleming, J. L., Simpson, R. L., Cowling, J. E. & Devenport, W. J., 1993. An Experimental Study of a Turbulent Wing-Body Junction and Wake Flow. Experiments in Fluids, Volume 14, pp. 366-378. ].  A linear microphone array was used to estimate the directivity of the facility acoustic background noise to be used to improve background subtraction methods for surface pressure fluctuation measurements.  Surface pressure fluctuation spectra were taken ahead of the leading edge of the plate and along the surface of the models.  These showed that the fairings reduced pressure fluctuations along the plate upstream of the leading edge, with fairing 1 reducing them to clean tunnel flow levels.  On the surface of the models, the fairings tended to reduce low frequency (<1000Hz) pressure fluctuation peaks when compared to the baseline model and increase the pressure fluctuations in the high frequency range.  Simple scaling arguments indicate that this spectral change may be more beneficial than detrimental as low frequency acoustics especially those between 800 Hz and 1200 Hz are the frequencies that humans perceive as the loudest noise levels.  Scaling the frequencies measured to those of full scale applications using Strouhal numbers show that frequencies below 1000 Hz in this experiment result in frequencies at the upper limit of the human hearing frequency range.  Low frequency acoustic waves also tend to travel farther and high frequency acoustic waves are more apt to be absorbed by the surrounding atmosphere. / Master of Science

Cardiomyopathies represent a heterogeneous group of diseases of the heart muscle that often lead to progressive heart failure with high morbidity and mortality. In a significant and increasing percentage of the patient population, cardiomyopathies have been associated with hereditary mutations in genes encoding critical cellular components that make up the cytoarchitecture of cardiac muscle cells, or cardiomyocytes. While specific mutations have been linked to different classes of cardiomyopathies, it is however not well understood how these mutations cause cytostructural abnormalities that ultimately lead to dysfunction of cardiomyocytes. To gain insights into the pathogenesis of inherited cardiomyopathies, we focus in this thesis on a particular set of mutations in the cardiac cytoskeleton and desmosomes that are associated with dilated and arrhythmogenic cardiomyopathies, and probe their pathogenic mechanisms using cardiomyocytes derived from human induced pluripotent stem cells and bioengineered culture platforms. In part one, we describe the mechanical and molecular basis for the assembly of sarcomeres, the fundamental contractile units within cardiomyocytes, and reveal how mutations in titin (TTN) abolish this process by disrupting cell-matrix interaction and impairing diastolic force generation, a hallmark of dilated cardiomyopathy. In the second part of this thesis, we reveal that plakophilin-2 (PKP2) mutations that are associated with arrhythmogenic cardiomyopathy lead to impaired systolic function by destabilizing cell-cell junctions and in turn disrupting sarcomere stability and organization. Together, our studies establish a deeper understanding of how cell-matrix and cell-cell interactions contribute to the organization and function of cardiomyocytes and how disruption of these interactions by pathogenic mutations lead to cardiac dysfunction. / 2022-05-18T00:00:00Z

Die wichtigsten Barrieren des peripheren Nerven sind die Myelin-Barriere und die Blut-Nerven-Schranke. Sie übernehmen eine bedeutende Aufgabe beim Schutz des Nerven vor externen Einflüssen, dem Bewahren der nervalen Homöostase und der Aufrechterhaltung der Nervenleitungsgeschwindigkeit. Eine Öffnung der peripheren Barriere wird oft mit neuropathischen Schmerzen assoziiert. Im Rahmen dieser Dissertation habe ich mittels Immunfluoreszenzfärbung, Permeabilitätstest, Western Blot und Polymerase-Kettenreaktion die Barrierefunktion des peripheren Nervensystems bei weiblichen Cldn12-KO Mäusen untersucht. Sowohl bei den WT Mäusen als auch bei den Cldn12-KO Mäusen konnte eine intakte Barrierefunktion des peripheren Nerven nachgewiesen werden. / The most important barriers of the peripheral nerve are the myelin-barrier and the blood-nerve-barrier. They play an important role in protecting the nerve from external influences, maintaining nerve homeostasis and nerve conduction speed. Opening the peripheral barrier is often associated with neuropathic pain. In this thesis I examined the barrier function of the peripheral nervous system in female Cldn12-KO mice using immunofluorescence staining, permeability test, western blot, and polymerase chain reaction. An intact barrier function of the peripheral nerve could be demonstrated in both the WT mice and the Cldn12-KO mice.

The placenta of two Sphagnum species was examined by electron microscopy. In contrast to all mosses so far investigated, neither sporophyte nor gametophyte placental cells of Sphagnum develop wall ingrowths. The sporophyte cells are highly vacuolate and the gametophyte cells close to them degenerate to produce a system of spaces filled with mucilage. Whether this type of placenta represents a primitive or derived condition in mosses is discussed.

Nectin-1 is an adhesion protein implicated in the organization of adherens junctions and tight junctions in epithelial cells. Previous studies in our laboratory demonstrated that nectin-1 accumulation was significantly decreased in Chlamydia trachomatis-infected HeLa cells. In the present study, Western blot analyses indicated that nectin-1 down-regulation was C. trachomatis concentration-dependent. The half-life of nectin-1 was also greatly diminished in C. trachomatis-infected cells compared to that observed in mock-infected cells, indicating that nectin-1 was likely down-regulated post-translationally. The chlamydia-secreted protease CPAF is known to degrade several important host proteins; CPAF expression within infected cells correlated with the time-dependent cleavage of nectin-1. Notably, CPAF proteolytic activity is inhibited by lactacystin but not by the proteosome inhibitor MG132. In vivo inhibition experiments demonstrated that nectin-1 down-regulation was blocked by lactacystin exposure. In contrast, MG132 had no effect. Finally, cell-free cleavage assays demonstrated that functional recombinant GST-CPAFwt protein degrades nectin-1. This degradation was blocked by lactacystin, as previously observed in vivo. Collectively, these results indicate that nectin-1 is degraded by CPAF in C. trachomatis-infected cells, a novel strategy that chlamydiae may use to aid their dissemination.

Claudin-5 is a transmembrane cell junction protein that is a component of tight junctions in endothelial cell layers. We have previously shown that claudin-5 also localizes to lateral membranes of murine cardiomyocytes at their junction with the extracellular matrix. Claudin-5 levels are specifically reduced in myocytes from a mouse model of muscular dystrophy with cardiomyopathy. To establish whether claudin-5 is similarly specifically reduced in human cardiomyopathy, we compared the levels of claudin-5 with other cell junction proteins in 62 cardiomyopathic end-stage explant samples. We show that claudin-5 levels are reduced in at least 60% of patient samples compared with non-failing controls. Importantly, claudin-5 reductions can be independent of connexin-43, a gap junction protein previously reported to be reduced in failing heart samples. Other cell junction proteins including α-catenin, β-catenin, γ-catenin, desmoplakin, and N-cadherin are reduced in only a small number of failing samples and only in combination with reduced claudin-5 or connexin-43 levels. We also show that reduced claudin-5 levels can be present independently from dystrophin alterations, which are known to be capable of causing and resulting from cardiomyopathy. These data are the first to show alterations of a tight junction protein in human cardiomyopathy samples and suggest that claudin-5 may participate in novel mechanisms in the pathway to end-stage heart failure.

This study explores in detail design options and simulations of multi-junction solar cells that utilize silicon-germanium-tin (SixGe1-x-ySny or SiGeSn) to achieve high-efficiency solar power conversion devices. SixGe1-x-ySny is an emerging system of alloys that can lattice match with germanium and gallium arsenide and can provide a bandgap higher than that of germanium; useful in the development of multi-junction solar cells. The results herein include designs of four devices: a triple-junction, a quadruple-junction, a seven-junction, and a six-junction, with estimated efficiencies of 41.6%, 42.6%, 41.2%, and 39.2% respectively under 1000x concentrated AM1.5D illumination, where the seven- and six-junction devices relax the thickness requirement of the germanium layer, and have room for improvement via the development of an advanced tunnel-junction component. Visualizations of the potentially available SiGeSn bandgaps are developed. The documentation supports further work in modelling additional compositions of SiGeSn. Loss mechanisms of the devices are calculated and plotted, enabling the design of the device layer components. Tools and techniques are developed to determine and control the resultant output error, and a generalized simulation mesh definition is given that efficiently controls the primary source of error of the calculation, which is related to the optical interaction. Lateral currents and surface recombination effects are included. The software is modularized to enable the development of higher-order segmented devices.