京都大学 / 新制・課程博士 / 博士(農学) / 甲第24656号 / 農博第2539号 / 新制||農||1097(附属図書館) / 学位論文||R5||N5437(農学部図書室) / 京都大学大学院農学研究科森林科学専攻 / (主査)教授 北山 兼弘, 教授 田中 千尋, 教授 松浦 健二 / 学位規則第4条第1項該当 / Doctor of Agricultural Science / Kyoto University / DGAM

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Fungal infections of animals have become an increasingly important global issue. White-Nose Syndrome is an ongoing fungal epizootic of North American hibernating bats, caused by epidermal infections of the fungus, Pseudogymnoascus destructans. Infections emerged early in 2006 in New York State and have since spread to 35 US States and seven Canadian Provinces, with rates of mortality exceeding 90% in some bat colonies. As an emerging outbreak in North America, the transmission of P. destructans is assumed to occur in a radial fashion outwards from the point of origin. In addition, the factors that may influence P. destructans transmission have been postulated, but not tested before. Lastly, as reproduction is assumed to be strictly clonal in North America, invasive populations should have low genetic diversity, and may even accumulate deleterious mutations over time. The aim of my PhD research is to test these assumptions regarding the spread, evolution, and adaptation of P. destructans using combination of genotyping methods. My results showed how P. destructans isolates have shifted in terms of phenotypes and physiological capabilities since being introduced. In addition, I describe patterns of connectivity across the landscape, which are more consist with the level of anthropogenic activity than variation in climate. The mutations common to all invasive strains of P. destructans are associated with adaptations that have occurred since being introduced from Europe, some with relevant metabolic functions that fit their pathogenic lifestyle. Together, my results revealed significant phenotypic and genotypic changes during the spread of P. destructans in North America. The factors identified here that influence the phenotypic and genotypic changes should help developing better management strategies against the White-Nose Syndrome pathogen. / Thesis / Doctor of Philosophy (PhD)

As complementary metal-oxide semiconductor (CMOS) technology faces more and more severe physical barriers down the path of continuously feature size scaling, innovative nano-scale devices and other post-CMOS technologies have been developed to enhance future circuit design and computation. These nanotechnologies have shown promising potentials to achieve magnitude improvement in performance and integration density. The substitution of CMOS transistors with nano-devices is expected to not only continue along the exponential projection of Moore's Law, but also raise significant challenges and opportunities, especially in the field of electronic design automation. The major obstacles that the designers are experiencing with emerging nanotechnology design include: i) the existing computer-aided design (CAD) approaches in the context of conventional CMOS Boolean design cannot be directly employed in the nanoelectronic design process, because the intrinsic electrical characteristics of many nano-devices are not best suited for Boolean implementations but demonstrate strong capability for implementing non-conventional logic such as threshold logic and reversible logic; ii) due to the density and size factors of nano-devices, the defect rate of nanoelectronic system is much higher than conventional CMOS systems, therefore existing design paradigms cannot guarantee design quality and lead to even worse result in high failure ratio. Motivated by the compelling potentials and design challenges of emerging post-CMOS technologies, this dissertation work focuses on fundamental design methodologies to effectively and efficiently achieve high quality nanoscale design. A novel programmable logic element (PLE) is first proposed to explore the versatile functionalities of threshold gates (TGs) and multi-threshold threshold gates (MTTGs). This PLE structure can realize all three- or four-variable logic functions through configuring binary control bits. This is the first single threshold logic structure that provides complete Boolean logic implementation. Based on the PLEs, a reconfigurable architecture is constructed to offer dynamic reconfigurability with little or no reconfiguration overhead, due to the intrinsic self-latching property of nanopipelining. Our reconfiguration data generation algorithm can further reduce the reconfiguration cost. To fully take advantage of such threshold logic design using emerging nanotechnologies, we also developed a combinational equivalence checking (CEC) framework for threshold logic design. Based on the features of threshold logic gates and circuits, different techniques of formulating a given threshold logic in conjunctive normal form (CNF) are introduced to facilitate efficient SAT-based verification. Evaluated with mainstream benchmarks, our hybrid algorithm, which takes into account both input symmetry and input weight order of threshold gates, can efficiently generate CNF formulas in terms of both SAT solving time and CNF generating time. Then the reversible logic synthesis problem is considered as we focus on efficient synthesis heuristics which can provide high quality synthesis results within a reasonable computation time. We have developed a weighted directed graph model for function representation and complexity measurement. An atomic transformation is constructed to associate the function complexity variation with reversible gates. The efficiency of our heuristic lies in maximally decreasing the function complexity during synthesis steps as well as the capability to climb out of local optimums. Thereafter, swarm intelligence, one of the machine learning techniques is employed in the space searching for reversible logic synthesis, which achieves further performance improvement. To tackle the high defect-rate during the emerging nanotechnology manufacturing process, we have developed a novel defect-aware logic mapping framework for nanowire-based PLA architecture via Boolean satisfiability (SAT). The PLA defects of various types are formulated as covering and closure constraints. The defect-aware logic mapping is then solved efficiently by using available SAT solvers. This approach can generate valid logic mapping with a defect rate as high as 20%. The proposed method is universally suitable for various nanoscale PLAs, including AND/OR, NOR/NOR structures, etc. In summary, this work provides some initial attempts to address two major problems confronting future nanoelectronic system designs: the development of electronic design automation tools and the reliability issues. However, there are still a lot of challenging open questions remain in this emerging and promising area. We hope our work can lay down stepstones on nano-scale circuit design optimization through exploiting the distinctive characteristics of emerging nanotechnologies. / Ph. D.

This thesis presents a new ant-optimized biclustering technique known as SNAP biclustering, which runs faster and produces results of superior quality to previous techniques. Biclustering techniques have been designed to compensate for the weaknesses of classical clustering algorithms by allowing cluster overlap, and allowing vectors to be grouped for a subset of their defined features. These techniques have performed well in many problem domains, particularly DNA microarray analysis and collaborative filtering. A motivation for this work has been the biclustering technique known as bicACO, which was the first to use ant colony optimization. As bicACO is time intensive, much emphasis was placed on decreasing SNAP's runtime. The superior speed and biclustering results of SNAP are due to its improved initialization and solution construction procedures. In experimental studies involving the Yeast Cell Cycle DNA microarray dataset and the MovieLens collaborative filtering dataset, SNAP has run at least 22 times faster than bicACO while generating superior results. Thus, SNAP is an effective choice of technique for microarray analysis and collaborative filtering applications. / Master of Science

Bakgrund: Postoperativa sårinfektioner orsakar lidande för den drabbade patienten och kostnader för patienten, vården och samhället. Intraoperativ kontamination av operationsinstrumenten är en av källorna till dessa infektioner. Operationssjuksköterskan är ansvarig för aseptiken och operationsinstrumenten.   Syfte: Syftet med denna pilotstudie var att mäta graden av bakteriell kontamination över tid på operationsinstrument som används vid öppen neurokirurgi samt observera utvalda källor till kontamination under samma tid. Metod: Denna studie designades som en kvantitativ icke-experimentell observationsstudie. Datainsamlingen skedde under hösten 2015 och bestod av omhändertagandet av specifika instrument som använts av operatören under operationen efter förutbestämd åtgången knivtid. Bakterieodlingar på dessa instrument skedde sedan på laboratorium enligt en förutbestämd metod och graden av kontamination mättes genom observation av mängden colony forming units (CFU). Resultaten presenteras i form av förändringar av mängden CFU. Resultat: Fem operationer observerades och tio odlingar utfördes på tio instrument. Totalt tio CFU registrerades under samtliga observationer. Ingen signifikant ökning av antal CFU kunde observeras från en till två timmars knivtid (P=0,156). Antal dörröppningar ökade från 3,4 till 9,0 och antal personer på operationssalen ökade från 5,4 till 5,8. Slutsats: Trots det ringa antal observationer som ingick i denna studie tyder resultaten på god aseptik och minimal bakteriell kontamination på operationsinstrumenten under operationens två första timmar. Ytterligare forskning med längre observationer, fler observationer och observationer kring annan typ av kirurgi behövs. / Background: Post-operative surgical site infections (SSI) cause suffering for the afflicted patient and is a great cost for the patient, the health care system and society. Intra-operative contamination of surgical instruments is one of the sources of these infections. The operating room nurse is responsible for preventing infections. Purpose: The purpose of this pilot-study was to measure the degree of bacterial contamination over time on surgical instruments used in open neurosurgery as well as to observe specific sources of contamination during this time. Method: The design was a quantitative nonexperimental observational study. The data collection took place during autumn 2015 and consisted of the sampling of specific instruments used by the surgeon during surgery after preset elapsed operating times. Bacterial culturing on these instruments was then carried out at a laboratory according to a preset routine and the degree of contamination was measured by observing the amount of colony forming units (CFU). The results are presented as changes in CFU. Results: Five operations were observed and ten bacterial culturings were conducted on ten instruments. A total of ten CFU was registered during all observations. No significant increase in the number of CFU could be observed from one to two hours of elapsed surgery (P=0,156). The amount of door openings increased from 3,4 to 9,0 and the number of personnel in the operating room increased from 5,4 to 5,8. Conclusion: Despite the small number of observations included in this study the results indicate good aseptics and minimal bacterial contamination on the surgical instruments during the first two hours of surgery. Further research with longer observations, more observations and observations on other forms of surgery is needed.

Une des stratégies pour limiter les neutropénies induites par la chimiothérapie est l’utilisation de granulocyte-colony stimulating factor (G-CSF). Nous avons développé, par une approche de population, un nouveau modèle pharmacocinétique/pharmacodynamique capable de décrire la cinétique des neutrophiles des patients traités au carboplatine, qu’ils aient ou non reçu du G-CSF. Les simulations réalisées à partir de ce modèle ont montré que le G-CSF n’était pas bénéfique chez tous les patients et que la formulation à action longue semblerait plus efficace que les autres formulations. Nous avons également établi des règles de décision permettant d’une part de prédire le risque de neutropénie sévère, et d’autre part d’identifier précocement les patients pour lesquels le G-CSF peut avoir un effet bénéfique. / Granulocyte colony-stimulating factor (G-CSF) is often used in cancer patients receiving cytotoxic drugs to prevent or reduce high grade neutropenia. We developed a new population pharmacokinetic/pharmacodynamic model to describe neutrophil time-course in carboplatin-treated patients, whether or not they received G-CSF. Model simulations showed that G-CSF was not as beneficial as expected in some patients and that the onceper- cycle formulation was more efficient than other formulations. Model-based decision rules were also built to anticipate prolonged high grade neutropenia and early identify patients for whom G-CSF was beneficial.