Reconcile Liminality

This thesis explores the concept of liminal space as a metaphor for the current transition to the digital era. We are not fully prepared for what the future holds. Fears and worries surrounding rapid development are amplified by the potential for social problems. However, by examining human development in history, we can gain insight into our current situation and start a discussion about where we are headed. The objective of this proposal is to create a space that eases concerns about the arrival of the new digital age. This is particularly relevant to Japan, which is now at a digital threshold. Despite ranking highly in fields such as microelectronics and computer hardware, Japan still uses outdated operating models, systems, and technologies. Such digital dysfunction indicates a palpable fear of the advent of digitization, as evidenced by the government’s use of fax machines to report infection numbers during the COVID-19 pandemic. This study thesis seeks to investigate how the concept of liminal space can be applied to design a solution that addresses the anxieties associated with the digital age transition anxieties over transition to the digital age in Japan and beyond. 本论文提出了一种设计解决方案来解决日本对数字化转型的恐惧和不情愿，这源于他们对技术的保守态度和生活在平成时代的历史门槛内。使用代表两种存在状态之间过渡的阈限空间的概念，本文旨在创造一个身心空间，以减轻围绕新数字时代到来的担忧和恐惧。设计灵感来源于日本平成时期首次引领世界的新陈代谢运动，利用新陈代谢建筑运动最具代表性的代表作——被拆除的中银胶囊塔。通过使用一个胶囊作为设计策略，这篇论文希望鼓励日本重拾平成时代的精神，无所畏惧地迎接新的变化。拟议的设计旨在促进从旧到新的平稳过渡，从而减少数字化转型的阻力，使日本能够在数字时代蓬勃发展

Targeted protein degradation and multicomponent reactions in drug discovery

Multicomponent reaction (MCR) chemistry is a promising and useful tool for building the chemical library in a manner of high-efficiency, low-cost and mild conditions. Targeted protein degradation (TPD) as a hopeful technology has attracted much attention from academia and industry. TPD could be utilized to regulate the specific protein, which is an amazing tool for drug discovery. There are many concepts in TPD, such as molecular glues, PROTACs, and hydrophobic tagging. In the first part of my thesis, the MCR was utilized and integrated with automated, miniaturized synthesis to build a chemical library about the molecular glues and accelerate drug discovery. Cell-based phenotypic screening was performed to evaluate the chemical library in order to discover the active compounds. In the second part of my thesis, the application of PROTACs and hydrophobic tagging technology were introduced and discussed. PROTACs are heterobifunctional molecules, with two ligands that bind to the target protein and E3 ligase, respectively, and a connected linker in between. In contrast, hydrophobic tagging mimics the process of misfolded or unfold proteins, leading to the protein destabilized and subsequent degradation. In this part, the compounds inducing SOS1 and 3CLpro protein degradation were designed and tested. Overall, this dissertation shows that MCR chemistry leads to diverse biologically important scaffolds in a simple and efficient manner and targeted protein degradation therapy is a significant concept in drug design and discovery

ANALYSIS OF THE JOINT ANGULES OF THE THROWING ARM IN JAVELIN THROW

The purpose of this study was to explore the feasibility of using the panning method to analyze the joint angles of the throwing arm during the throwing of javelin. Two cameras (250 Hz) were set on the side and the back of the runway to analyze the athlete’s throwing arm movemen with a panning method. Besides the joint angles of the shoulder (horizontal abduction/ horizontal adduction, abduction/ adduction, internal rotation/external rotation) and the elbow (extension/ flexion), the pronation/supination angles of the forearm, the ulnar/ radial flexion and the palmar flexion/ dorsiflexion of the wrist were also calculated . For each angle of the joints of the same trail of an athlete, the ICC (Intravlass correlation coefficients) of the two results from two different analysisers was bigger than 0.95 (

特異応力場の強さに注目した異種材料接合軸対称体の構造強度評価に関する研究

The bonded axi-symmetric structures have been widely used in the steel and petroleum industries recent years. However, as is known that there is stress singularity at the end of interface for different materials, which may result in the failure of the joint. The intensity of singular stress field (ISSF) was discussed for bonded plate under arbitrary material combination, while few studies are available for the intensity of bonded structures in axi-symmetric problems, and no results with varying material combination. Thus this research focuses on the analysis of ISSF of different axisymmetric problems with arbitrary material combinations, which may contribute to evaluating the strength for axi-symmetric structures. And in addition, the analysis method in this study was applied in the analysis of a practical engineering problem to verify the significance of this study. This thesis is composed of total 6 chapters and organized as follows; Chapter 1 gives an introduction of composites and bonded structures applied to aviation industry, microelectronic packaging, and steel process equipment. Also the applications and importance of bonded axi-symmetric structure are investigated. For example the application in thermal spray coating roll used in continuous annealing furnace and bonded joint of riser pipe in offshore oil equipment. With the extensive application of the technology, structural failure problems are emerging, which requires further study. Then, the issues of the research on singularity in the bonded structures are reviewed, and it is found that there are only few papers focused on the ISSF for bonded axi-symmetric problems. Then, the research purpose of this thesis is introduced, focusing on the analysis of ISSF for bonded axi-symmetric structures. In chapter 2, the proportional method is discussed for axi-symmetric problems. It is known that FEM is not suitable for the solution of bimaterial problems due to the mesh dependence of singular stress near the end of interface. However, FEM is still useful in the analysis of singular stress problems since FEM error can be eliminated by applying the proportional method. This study extends the method to the bonded axisymmetric problems. However, the difference between bonded plane problems and axisymmetric problems makes the application of proportional method quite difficult. This is because non-singular stress appears due to non-zero circumferential strain εθ. Then, non-singular terms are derived explicitly and eliminated from the stress components calculated by FEM to extend this method to axi-symmetric problems. Finally the method is verified by numerical analysis. In chapter 3, the ISSF for the bonded cylinder is first calculated by changing the material combination systematically after extending of the proportional method to axisymmetric problems. Then, the results are compared with that of plane strain problem and the differences are elaborated. It is found that the ISSF of axi-symmetric problem can not be governed by the Dundurs’ parameters, therefore, the maximum and minimum values of the SIFs are considered and shown in tables and charts in the space of Dundurs’ parameters. Chapter 4 mainly focuses on another type of axi-symmetric bonded structure, bonded pipe. The effect of inner radius on ISSF is also discussed. Generally, it is thought that the bonded pipe with an infinite inner diameter is equivalent to the plane strain problem, but it is found that they are quite different. Therefore, the results of bonded pipe with infinite inner diameter are compared with the plane strain problem. As is done in analysis of bonded cylinder in chapter 3, the maximum and minimum values of the ISSF are considered and shown in tables and charts in the space of Dundurs’ parameters. Chapter 5 shows an example of the proposed method applied to a practical engineering problem. By using the aforementioned analysis proposed for bonded axisymmetric structures, a pipe shaped hearth roll used in continuous annealing furnace for producing steel sheet is investigated. Spraying coating is commonly used in the hearth roll. However, after long-term use under high temperature and thermal shock, the spray coating, which is a sandwich bonded structure, will peel off. Thus, Chapter 5 discusses how to improve the strength of the spray coating under thermal shock. It is found that thinner top coating always has better thermal shock resistance. And under fixed top coating thickness, the ISSF takes a minimum value when the coating thickness ratio H/h≅2, which is in accord with the previous research for plane strain state and experimental results in engineering. Here, H and h represent the top coating thickness and bond coating thickness, respectively. In the last chapter of this thesis, chapter 6, main conclusions of this study are summarized for bonded cylinder and boded pipe, and for the optimum design of thermal spray coating.九州工業大学博士学位論文 学位記番号:工博甲第421号 学位授与年月日:平成28年9月23日1 Introduction|Chapter 2 Extended proportional method and the basic reference problem for the analysis of axisymmetric problems|3 Analysis on Intensity of Singular Stress for Cylinder in Comparison with Bonded Plate|4 Analysis on Intensity of Singular Stress for Bonded Pipe in Comparison with Bonded Plate|5 Analysis on singular stress intensity of ceramic spray coating on hearth roll|6 Conclusion九州工業大学平成28年

Systematical identification of splicing regulatory cis-elements and cognate trans-factors

The majority of human genes undergo alternative splicing to generate multiple isoforms with distinct functions. This process is generally controlled by cis-acting splicing regulatory elements (SREs) that recruit trans-acting factors to promote or inhibit the use of nearby splice sites. The growing interest in understanding the regulatory rules of splicing necessitates the systematic identification of these SREs and their cognate protein factors using experimental and computational approaches. Here we describe a strategy to identify and analyze both cis-acting SREs and trans-acting splicing factors. This strategy involves a cell-based screen to identify SREs from a random sequences library and a modified RNA affinity purification approach to unbiasedly identify the splicing factors. These methods can be adopted to identify splicing enhancers or silencers in both exons and introns, and can be extended to different cultured cells. The resulting SREs and splicing factors can be further analyzed with a series of computational and experimental approaches. This approach will help us to collect a molecular part-list for splicing regulation, providing a rich data source that enables a better understanding of the “splicing code”

Efficient backsplicing produces translatable circular mRNAs

While the human transcriptome contains a large number of circular RNAs (circRNAs), the functions of most circRNAs remain unclear. Sequence annotation suggests that most circRNAs are generated from splicing in reversed orders across exons. However, the mechanisms of this backsplicing are largely unknown. Here we constructed a single exon minigene containing split GFP, and found that the pre-mRNA indeed produces circRNA through efficient backsplicing in human and Drosophila cells. The backsplicing is enhanced by complementary introns that form double-stranded RNA structure to bring splice sites in proximity, but such structure is not required. Moreover, backsplicing is regulated by general splicing factors and cis-elements, but with regulatory rules distinct from canonical splicing. The resulting circRNA can be translated to generate functional proteins. Unlike linear mRNA, poly-adenosine or poly-thymidine in 3′ UTR can inhibit circular mRNA translation. This study revealed that backsplicing can occur efficiently in diverse eukaryotes to generate circular mRNAs

Splice site strength–dependent activity and genetic buffering by poly-G runs

Pre-mRNA splicing is regulated through the combinatorial activity of RNA motifs, including splice sites and splicing regulatory elements. Here we show that the activity of the G-run (polyguanine sequence) class of splicing enhancer elements is approx4-fold higher when adjacent to intermediate strength 5' splice sites (ss) than when adjacent to weak 5' ss, and approx1.3-fold higher relative to strong 5' ss. We observed this dependence on 5' ss strength in both splicing reporters and in global microarray and mRNA-Seq analyses of splicing changes following RNA interference against heterogeneous nuclear ribonucleoprotein (hnRNP) H, which cross-linked to G-runs adjacent to many regulated exons. An exon's responsiveness to changes in hnRNP H levels therefore depends in a complex way on G-run abundance and 5' ss strength. This pattern of activity enables G-runs and hnRNP H to buffer the effects of 5' ss mutations, augmenting both the frequency of 5' ss polymorphism and the evolution of new splicing patterns. Certain other splicing factors may function similarly.American Heart AssociationHuman Frontier Science Program (Strasbourg, France)National Institutes of Health (U.S.)National Science Foundation (U.S.) (equipment grant DBI-0821391