京都大学 / 0048 / 新制・課程博士 / 博士(社会健康医学) / 甲第19275号 / 社医博第66号 / 新制||社医||9(附属図書館) / 32277 / 京都大学大学院医学研究科社会健康医学系専攻 / (主査)教授 古川 壽亮, 教授 佐藤 俊哉, 教授 髙橋 良輔 / 学位規則第4条第1項該当 / Doctor of Public Health / Kyoto University / DFAM

Indiana University-Purdue University Indianapolis (IUPUI) / Non-coding RNAs across the genome have been associated with various biological processes, ranging from regulation of splicing to remodeling of chromatin. Amongst the repertoire of non-coding sequences lies a critical species of RNAs called long non-coding RNAs (lncRNAs). LncRNAs significantly contribute to a large spectrum of human phenotypes, including cancers, Heart failure, Diabetes, and Alzheimer’s disease. This dissertation emphasizes the need to characterize the functional role of lncRNAs to improve our understanding of human diseases. This work consolidates a resource from multiple computational genomics and natural language processing-based approaches to advance our ability to functionally annotate hundreds of lncRNAs and their interactions, providing a one-stop lncRNA functional annotation and dynamic interaction network and multi-facet omics data visualization platform. RNA interactions are vital in various cellular processes, from transcription to RNA processing. These interactions dictate the functional scope of the RNA. However, the multifaceted functional nature of RNA stems from its ability to form secondary structures. Therefore, this work establishes a computational method to characterize RNA secondary structure by integrating SHAPE-seq and long-read sequencing to enhance further our understanding of RNA structure in modulating the post-transcriptional regulatory processes and deciphering the influence at several layers of biological features, ranging from structure composition to consequent protein occupancy. This study will potentially impact the research community by providing methods, web interfaces, and computational pipelines, improving our functional understanding of long non-coding RNAs. This work also provides novel integration methods of technologies like Oxford Nanopore-based long-read sequencing, RNA structure-probing methods, and machine learning. The approaches developed in this dissertation are scalable and adaptable to investigate further the functional and regulatory role of RNA and its structure. Overall, this study accelerates the development of RNA-based diagnostics and the identification of therapeutic targets in human disease.

Climate change poses a significant challenge to economies throughout the world; understanding its potential economic impacts at the regional level is important for making informed policy decisions and mapping out effective adaptation strategies. This thesis examines the long-run effect of climate change in Sweden, an environmentally diverse, developed country with ambitious sustainability goals. By using a half-panel Jackknife Fixed Effect (HPJ-FE) method that estimates the effect of deviations in temperature and precipitation from long-run historical norms on the growth of different county-level economic performance indicators between 1968 and 2021. The study suggests that deviations in temperature have a positive effect on the growth rates of real GRP, real GRP per capita, and employment in Sweden, while productivity sees a negative effect. The results are compared to the United States and suggest that Sweden is seeing fewer negative effects and adapting faster to climate change than the United States.

Indiana University-Purdue University Indianapolis (IUPUI) / The cardiac voltage-gated sodium channel α subunit Nav1.5 generates the cardiac sodium current, which is essential for the initiation and propagation of the cardiac action potentials. Mutations of SCN5A, the gene that encodes Nav1.5, have been well documented to cause long-QT syndrome (LQTs) by disrupting channel inactivation and increasing late sodium current. Previous studies have revealed the importance of the intracellular loop region between transmembrane domain III and IV of sodium channel α subunit in regulating the fast inactivation. A recent clinical case study reported an infant patient with LQTs carrying a phenylalanine (F) deletion at amino acid 1486 of the Nav1.5 channel. This study reported that the patient showed severe cardiac arrhythmia reflected as LQTs and subsequent ventricular tachycardia, which was refractory to antiarrhythmic drug lidocaine treatment. Therefore, it was hypothesized that the deletion of F1486 on Nav1.5 would substantially alter electrophysiological properties of the channel and reduce the potency of lidocaine on sodium channel. Using HEK293 cells and neonatal rat cardiomyocytes, the F1486del channel was functionally characterized by whole-cell patch clamp techniques. Studies revealed that the deletion of F1486 causes a combination of changes including a loss-of-function alteration reflected as a substantial reduction of peak current density and a number of gain-of-function alterations including reduced channel inactivation, substantial augmentation of late sodium current, and an increase in ramp current. In addition, lidocaine sensitivity was dramatically reduced. By contrast, the voltage for half maximal activation (V1/2) and the time constant for channel deactivation for the F1486del channel were identical to the wild type channels. Using neonatal rat cardiomyocytes, we were able to study the functional consequence of F1484del on action potential duration (APD). Cardiomyocytes expressing F1486del channel have substantial APD prolongation and prominent spontaneous early afterdepolarizations, which likely underlie the subsequent LQTs in the patient. Taken together, despite the reduction in peak current density, the substantial gain-of-function changes are sufficient to cause the APD prolongation, which is a prominent characteristic of LQTs. These findings provide knowledge for understanding the relationships between sodium channel structure, pharmacology and the physiological consequence of sodium channel mutations that underlie LQT3.

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<p>Transition metals such as manganese (Mn), iron (Fe) and zinc (Zn) are some of the essential metals for normal CNS development and function. Each must be present at specific levels to avoid deficiencies or toxic excess. The research in this thesis investigates the role of transition metals in diseases in which myelin is lost in the central nervous system (CNS). A loss of myelin is termed demyelination, and an example of a disease with prominent demyelination is multiple sclerosis. An incomplete formation of myelin sheaths is termed dysmyelination. This thesis focused on the measurements of manganese, iron and zinc concentrations in a rodent model of dysmyelination; the Long Evans Shaker (<em>les</em>) rat.<strong></strong></p> <p>The Long Evans Shaker (<em>les</em>) rat is a fragile, severely dysmyelinated rodent model with body tremors at a young age and severe ataxia in older rats. The mutation causing the severe dysmyelination in these rats is transmitted as an autosomal recessive trait. With a lifespan of 4 to 5 months, the <em>les</em> rat is markedly deficient in myelin in the CNS, where most axons are entirely naked and the remaining ones are surrounded by a loosely woven, thin myelin sheath.</p> <p>In this thesis we studied alterations in manganese, iron and zinc transition metal levels in 3 and 16-week-old <em>les</em> rats and their age-matched control counterparts. Using neutron activation analysis (NAA), manganese measurements were made in the brain, spinal cord and visceral organs using an existing protocol, while a new assay was developed for iron and zinc measurements that were made in the spinal cord tissues. The higher trend in manganese concentration observed within the 3 and 16 week old <em>les</em> rats in comparison to the controls, where there was a significant increase (ples cerebellum, supports evidence suggesting that manganese levels are associated with astrogliosis. Whereas for iron and zinc, which were measured in the spinal cord tissues, there was also an overall increase in the levels of these metals in the <em>les</em> mutant strain when compared to the controls; however, only significant increases in zinc concentration within the 16 week old <em>les </em>spinal cords were observed.</p> <p>The characterization of the <em>les</em> rodent model mutation and its biochemical abnormality will advance our understanding of not only the process of myelination, but also diseases related to aberrant myelination or the maintenance of myelin sheaths.</p> / Master of Science (MSc)

Precaldera volcanism between 3.2-2.6 M.a. produced a basalt -trachybasalt -trachyandesite -quartz latite suite peripheral to the present Long Valley caldera from a heterogeneous, interactive, deep crustal magmatic -system. The suite consists of ( 1) widespread, predominately porphyritic olivine-augite basalt / trachybasalt / trachyandesite flow sequences (> 24 km³), (2) local orthopyroxene -phyric silicic trachyandesite flows (> I km³), and (3) sparsely -phyric orthopyroxene -hornblende -plagioclase quartz latite dome-flows and coarsely -phyric biotite -hornblende -plagioclase quartz latite dome-flows ( > 4 km³) erupted in that general sequence. Field, petrographic, and major-, minor-, and trace-element, as well as Sr isotopic studies of representative precaldera lavas on the northwest periphery of the caldera suggest that: (I) the basaltic magmas were generated from a lherzolite partial melt modified by minor crystal fractionation (limited fractionation due to their high incompatible element content) and contamination by older sialic rocks or their derivatives (represented by granitic inclusions, quartz xenocrysts, and progressively higher ⁸⁷Sr/⁸⁶Sr, 0.7062 to 0.7067), (2) the silicic trachyandesite was probably the result of intimate mixing of basaltic and quartz latite magmas (reflected in compositional gaps in progressively more silicic bulk compositional trends and the similarity of the quartz latite and silicic trachyandesite initial ⁸⁷Sr/⁸⁶Sr ratios, 0.7070-0.7074), and (3) the quartz latite was derived by crustal melting at different depths (as reflected in the variable ⁸⁷Sr/⁸⁶Sr, 0.7072-0.7095) and underwent radically changing crystallization conditions and contamination by trachyandesite (represented by heterogeneous mineral assemblages, chemistry, and textures indicating changing equilibrium conditions most evident in the trachyandesite enclave-rich quartz latite). The basaltic magmas provided the heat and mass to the crust promoting partial melting and generation of quartz latitic magmas. Synchronous basaltic intrusion and generation of crustal melts interacted and hybridized to yield trachyandesite. The isolated occurrence of trachyandesite enclaves in the youngest quartz latite dome-flows, suggests the disruption of a quartz latite-trachyandesite interface during late stages of the eruptive drawdown of a small volume magmatic system. Heat from continued basaltic input and coalesence of initially separate quartz latite bodies could possibly have resulted in development of the larger silicic magma chamber from which the younger rhyolitic (Glass Mountain-Bishop Tuft) magmas erupted. / M.S.