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京都大学 / 新制・課程博士 / 博士(医学) / 甲第23793号 / 医博第4839号 / 新制||医||1057(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 大森 孝一, 教授 花川 隆, 教授 渡邊 直樹 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

The circulatory system is one of the first systems that develops during embryogenesis. Angiogenesis describes the formation of blood vessels as a part of the circulatory system and is essential for organ growth in embryogenesis as well as repair in adulthood. A dysregulation of vessel growth contributes to the pathogenesis of many disorders. Thus, an imbalance between pro- and antiangiogenic factors could be observed in infantile hemangioma (IH). IH is the most common benign tumor during infancy, which appears during the first month of life. These vascular tumors are characterized by rapid proliferation and subsequently slower involution. Most IHs regress spontaneously, but in some cases they cause disfigurement and systemic complications, which requires immediate treatment. Recently, a therapeutic effect of propranolol on IH has been demonstrated. Hence, this non-selective β-blocker became the first-line therapy for IH. Over the last years, our understanding of the underlying mechanisms of IH has been improved and possible mechanisms of action of propranolol in IH have postulated. Previous studies revealed that gap junction proteins, the connexins (Cx), might also play a role in the pathogenesis of IH. Therefore, affecting gap junctional intercellular communication is suggested as a novel therapeutic target of propranolol in IH. In this review we summarize the current knowledge of the molecular processes, leading to IH and provide new insights of how Cxs might be involved in the development of these vascular tumors

A comparative study is carried out to investigate the most promising route towardsthe lightweight construction of a retractable mast for a sailing cargo vessel.Four design families are developed and compared. The primary criteria forjudgment are the structural mass, strength, and stiffness in relation to a providedbenchmark design. Additional evaluation criteria are the capital costsfor raw materials and manufacturing.The design space includes isotropic materials as well as fiber-reinforced polymer(FRP) solutions and is navigated by employing analytical evaluation methodssupported by finite element analysis (FEA). Restrictions to the designspace are given by a general arrangement of the benchmark design. This includesthe limitation to the ULS loads and the overall mast geometry.A review of relevant Det Norske Veritas (DNV) rules for classification is performedand the guidelines for wind turbine blades and wind-powered units(WPU) are judged most suitable to the design challenge. Relevant design principlesare implemented in the structural analysis.It is concluded that pure metal constructions imply an unreasonably large weightpenalty. Local buckling is found to disqualify FRP single-skin solutions as successfulcandidates. Secondary to that, strength concerns are the major driversfor the structural mass.The report presents two designs that are judged fit for the purpose, one is ahybrid truss structure from high strength low alloy steel (HSLA steel) and carbonfiber-reinforced polymer (CFRP). The second design is a sandwich constructionwith CFRP face sheets, a PVC foam core, and additional stiffeningmembers in steel.

Stroke, a life-threatening condition, primarily resulting from ischemic events often caused by occlusion of the middle cerebral artery (MCA). Pre-existing leptomeningeal collateral (LMC) vessels connect MCA branches to anterior or posterior arteries, situated along the brain's cortical surface or meninges, under healthy conditions these vessels remain dormant due to their small diameters and relatively low flow velocity. LMCs serve as vascular redundancies that retrogradely re-supply blood to help salvage the penumbra following cerebral vascular occlusion. Their outward growth or remodeling (arteriogenesis) is essential for promoting cerebral reperfusion and preventing tissue damage after ischemic stroke. Increased fluid shear stress on collateral vessel wall activates arteriogenesis result in the activation of the endothelium and subsequent recruitment of peripheral-derived immune cells (PDICs), which have been shown to aid this unique adaptive process in other organ systems, however their role and mechanism(s) involved in LMC remodeling in stroke has not previously been evaluated. Initial findings suggest the EphA4, a well-established axonal growth and guidance receptors, plays a novel role in LMC arteriogenesis. This dissertation examined PDIC-specific functions of EphA4 using GFP labeled bone marrow chimeric mice subjected to permanent middle cerebral artery occlusion (pMCAO). We assessed immune cell population changes, infarct volume, functional recovery, characterized subtypes of infiltrated immune cell, and measured collateral vessel diameters. Additionally, we explored the Tie2-mediated PI3K signaling pathway in peripheral-derived monocyte/macrophages (PDM) treated with soluble Tie2-Fc and a PI3K p110α inhibitor. The results from this dissertation show that loss of PDIC-specific EphA4 led to increased collateral remodeling, associated with decreased infarct volume, improved cerebral blood flow, and functional recovery within 24 hours post-pMCAO. The crosstalk between EphA4-Tie2 signaling in PDMs, regulated through PI3K/Akt axis, inhibited pial collateral remodeling. In conclusion, our findings highlight the negative regulatory role of PDM-specific EphA4 in collateral growth and remodeling by inhibiting Tie2 function via the PI3K regulated pathway. Peripheral myeloid-derived EphA4 emerges as a new regulator of cerebral vascular injury and neuroinflammation following acute ischemic stroke. / Doctor of Philosophy / Stroke, a life-threatening condition, occurs when blood flow to part of the brain is disrupted due to the vascular occlusion of a major brain artery, such as the MCA. Within protective layers of our brain, there are pre-existing pial collateral vessels that act as backup connections. These vessels play an important role in increasing cerebral reperfusion and preventing tissue damage after stroke. One fascinating aspect of stroke recovery involves PDICs. These immune cells migrate into the blood hypo-perfused region of the brain and regulate the growth of collateral vessels. However, the specific functions of PDICs, particularly a receptor called EphA4, has remained unclear. Our research delved into the immune response following ischemic stroke using genetically modified mice. We examined immune cell populations, infarct volume (the damaged brain tissue), functional recovery, and collateral vessel diameters. Notably, we discovered that deletion of PDIC-specific EphA4 enhanced collateral vessel remodeling. This led to decreased infarct volume, better blood flow, and improved functional recovery within 24 hours after stroke. Furthermore, we explored a signaling pathway involving Tie2 and PI3K in PDM. This crosstalk between EphA4 and Tie2, mediated through PI3K regulation, played a critical role in suppressing collateral vessel remodeling. In summary, understanding how immune cells contribute to stroke recovery may pave the way for novel therapeutic approaches to enhance outcomes for stroke patients.

As the world's nuclear reactors approach the end of their originally planned lifetimes and seek license extensions, which would allow them to operate for another 20 years, accurate information regarding neutron radiation exposure is more important than ever. Structural components such as the reactor pressure vessel (RPV) become embrittled by neutron irradiation, reducing their capability to resist crack growth and increasing the risk of catastrophic failure. The current dosimetry approaches used in these high flux environments do not provide real-time information. Instead, radiation dose is calculated using computer simulations, which are checked against dose readings that are only available during refueling once every 1.5-2 years. These dose readings are also very expensive, requiring highly trained technicians to handle radioactive material and operate specialized characterization equipment. This dissertation describes the development of a novel neutron radiation dosimeter based on carbon nanotubes (CNTs) that not only provides accurate real-time dosimetry, but also does so at very low cost, without the need for complex instrumentation, highly trained operators, or handling of radioactive material. Furthermore, since this device is based on radiation damage rather than radioactivation, its readings are time-independent, which is beneficial for nuclear forensics. In addition to development of a novel dosimeter, this work also provides insight into the particularly under-investigated topic of the effects of neutron irradiation of carbon nanotubes. This work details the fabrication and characterization of carbon nanotube based neutron and gamma radiation dosimeters. They consist of a random network of CNTs, sealed under a layer of silicon dioxide, spanning the gap between two electrodes to form a conductive path. They were fabricated using conventional wafer processing techniques, making them intrinsically scalable and ready for mass production. Electrical properties were measured before and after irradiation at several doses, demonstrating a consistent repeatable trend that can be effectively used to measure dose. Changes to the microstructure were investigated using Raman spectroscopy, which confirmed that the changes to electrical properties are due to increasing defect concentration. The results outlined in this dissertation will have significant impacts on both the commercial nuclear industry and on the nanomaterials scientific community. The dosimeter design has been refined to the point where it is nearly ready to be deployed commercially. This device will significantly improve accuracy of RPV lifetime assessment while at the same time reducing costs. The insights into the behavior of CNTs in neutron and gamma radiation environments is of great interest to scientists and engineers studying these nanomaterials. / Ph. D.

In this dissertation, an approach for determining parameters for a nonlinear Lagrangian mechanical system model of a submerged vessel maneuvering near waves is presented. The nonlinear model with determined parameters is capable of capturing nonlinear effects neglected by other linear models, and therefore can be applied to improve maneuvering performance and expand the operating envelope for submerged vessels operating in elevated sea states. To begin, a first principles Lagrangian nonlinear maneuvering (LNM) model for a surface-affected submerged vessel derived by using Lagrangian mechanics cite{BattistaPhD2018} is reformulated to allow the application of data from a medium fidelity potential flow code. In the reformulation process, the order of integration and differentiation in the integro-differential parameters are switched and partial derivatives of the Lagrangian function are computed with readily available data from the panel code solution. As a result, all model parameters can be computed individually using the panel code, wherein the need for additional numerical discretization is circumvented in the computation process through use of solutions already performed by the basic panel code, enabling higher accuracy and lower computational cost. Furthermore, incident wave effects are incorporated into the reformulated LNM model to yield a Lagrangian nonlinear maneuvering and seakeeping (LNMS) model. The LNMS model is numerically validated by confirming the proposed methods and by comparing steady and unsteady hydrodynamic force calculations from the LNMS model against panel code computations for various vessel motions in calm water and in plane progressive waves. Finally, methods for computing physically intuitive components of the model parameters, as well as methods for making approximations of the terms accounting for memory effects are presented, leading to a model formulation amenable to control design. By applying the methods proposed in this dissertation, each and every parameter of the Lagrangian mechanical system model of a submerged vessel maneuvering in waves can be obtained accurately and with computational efficiency by using a potential flow panel code. The resulting nonlinear motion model provides higher model fidelity than existing unified maneuvering and seakeeping models, especially in applications such as nonlinear control design and simulation. / Doctor of Philosophy / A unified maneuvering and seakeeping model for a submerged vessel maneuvering near waves describes mathematically the relationship between input values to the dynamical system, such as thrust from the propulsors, and output values from the system, such as the position and orientation of the vessel. This unified model has a wide range of applications, ranging from vessel hull form optimization in the early design phase to motion controller tuning after the vessel has been constructed. In order for a unified model to make accurate predictions, for instance, for a submerged vessel making a rapid turn near large waves, nonlinear effects have to be included in the model formulation. To that end, a nonlinear motion model for a marine craft affected by a free surface has been developed using Lagrangian mechanics. This dissertation describes an approach for determining the parameters of the nonlinear motion model using a potential flow panel code, which is originally designed to determine flow velocity of the fluid and pressure distribution over marine vessels. The nonlinear motion model is reformulated and the software implementation is modified to support parameter computations. In addition, the methods are numerically validated by comparing computations using the model against solutions output by the panel code. Compared to traditional parameter estimation approaches, the proposed methods allow for a more accurate and efficient determination of parameters of the nonlinear potential flow model for a submerged vessel operating near waves. The resulting Lagrangian nonlinear maneuvering and seakeeping (LNMS) model with determined parameters is able to capture critical nonlinear effects and has applications such as nonlinear control design, rapid design optimization and training simulator development.

Rhododendron is a monophyletic group that inhabits many different climates. One clearly defined diversification was from temperate ancestors into tropical habitats. The focus of this work was to explore leaf and stem anatomical traits in relation to habitat (temperate and tropical) and elevation of the native range. A closely-related group of Rhododendron was selected to reduce variation in genetic history and reveal environment–associated adaptive traits. Vessel anatomical traits of Rhododendron accessions were assayed for the trade of between safety (protection against catastrophic failure) and efficiency (high theoretical conductivity). Rhododendron wood and vessels were found to be relatively safe. The metrics of wood efficiency were higher for the tropical species. Thus, a trade-off between safety and efficiency was found although the wood of Rhododendron is characterized as highly safe. Leaf anatomical traits of Rhododendron were assayed for habitat and elevation. Leaves on tropical species were thicker and denser compared with temperate species. Idioblasts were always found in tropical leaves but not in temperate species. Leaves of tropical species were more xeromorphic (drought tolerant) than those of temperate species. Increasing elevation of the native range did not influence leaf anatomical traits. Idioblast abundance and leaf water relations traits were assayed for tropical Rhododendron species. Idioblast expression varied from 5% to 28% and stomatal pore index varied from 0.08 to 3.3. Idioblast expression was highly correlated with leaf succulence, and water deficit at the turgor loss point. Idioblast expression was positively associated with leaf capacitance for thin (< 0.5 mm) leaves. Thus, idioblasts can serve as a water buffer for relatively thin leaves. Synthesis–Wood traits of evergreen Rhododendron shrubs reflect adaptation for safety. Although tropical species have significantly higher efficiency, wood safety is still the dominant feature. The implication of high wood safety is constrained water flow and a potential for low water potential. Both leaf succulence and the presence of idioblasts in thin leaves enhances leaf capacitance and provides some buffering against short-term drought. These leaf adaptations in tropical Rhododendron shrubs likely reflect the abundance of epiphytes in this group. / Ph. D. / <i>Rhododendron</i> is a very diverse genus that is found in many different habitats from arctic to tropical. However, most of the species are evergreen with a slow growth rate. The goal of this study was to explore the variation in wood and leaf anatomical traits in order to explain how these plants can succeed in so many different habitats. The vessels in wood of temperate species were found to be very small. Although the size of the vessels increased for tropical species, they were still small relative to many other species. Surprisingly, leaf traits suggested greater drought tolerance for tropical species compared with temperate species. A unique anatomical trait called idioblasts was found only in leaves of tropical species. Idioblasts were very large cells, found just below the upper epidermis, which occupied up to 30% of the leaf volume. Idioblasts were found to help buffer water loss for thin tropical leaves. In summary, <i>Rhododendron</i> wood constrains water flow for plants in all habitats, which will induce water stress in warm or dry areas. Consequently, leaves have drought tolerance traits in tropical regions. Therefore, anatomical traits of wood and leaf help explain how <i>Rhododendron</i> species can occupy a wide diversity of habitats.

Yes / Irton Moor was excavated by Derek Simpson in 1973 but remained unpublished at the time of his death in 2006. Material from the excavation including a skeletal report and some publication drawings were located in DDAS’s archives and brought back to Bradford for archiving. Sufficient work had been done by DDAS to bring the report to publication though clearly the archive had suffered over the years. Irton Moor represents a small structured round cairn of the Early Bronze Age producing evidence for long-term occupation of the site from the Early Neolithic though this occupation does not appear to have been continuous. The cairn was used for Food Vessel and Collared Urn-associated cremations.

This research deals with the phenomenon of anthropomorphic vessels between the 7th and the beginning of the 5th millennium BC in a vast area that includes the Italian peninsula with Sicily, Central Europe, the Balkans and the Near East. The survey concerned 927 specimens from 229 sites. The formal analysis of the artifacts belonging to the cultures attested between Mesopotamia and the Rhine river allowed to establish the times and vectors of diffusion of this tradition before its arrival in Italy, as well as to hypothesize the connections that have transmitted the tradition of the anthropomorphic vessel to the Neolithic farming communities in the south-east of southern Italy. The study of Italian finds has led to the recognition of four main areas affected by the phenomenon and has allowed us to define their styles. An important part of the study was the examination of the archaeological contexts of the finds, in order to understand the possible spheres of use. In particular, the research allowed us to highlight the frequent and widespread presence of the anthropomorphic vessel in waste pits together with a series of symbolic objects: a constant presence and therefore not random, which is a hint of deliberate deposition of selected materials. This circumstance suggests that the anthropomorphic vessel belongs to a set of objects of ritual use and that the Neolithic refuse pit, contrary to what is generally believed, should be interpreted also as places of performative activity.