京都大学 / 0048 / 新制・課程博士 / 博士(工学) / 甲第19722号 / 工博第4177号 / 新制||工||1644(附属図書館) / 32758 / 京都大学大学院工学研究科電子工学専攻 / (主査)教授 木本 恒暢, 教授 髙岡 義寛, 教授 山田 啓文 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DFAM

This work has examines the creation and use of chemical templates for nanocircuit and other nanodevice fabrication. Chemical templating can be useful in attachment, orientation and wiring of molecularly templated circuits. DNA origami provides a suitable method for creating molecularly templated circuits as DNA can be folded into complex shapes and functionalized with active circuit elements, such as semiconducting nanomaterials. Surface attachment of DNA origami structures can be accomplished by hybridization of dangling single-stranded DNA (ssDNA) on the origami structures with complementary surface-bound strands. Chemical templating provides a pathway for placing the patterned surface-bound attachment points needed for surface alignment of the molecular templates. Chemical templates can also be used to connect circuit elements on the surface by selectively metallizing the templates to form local wiring. AFM tip-directed nano-oxidation was selected as the method for patterning to create chemical templates. This project demonstrates new techniques for creating, continuous metallization of, and DNA attachment to nanochemical templates. Selective-continuous metallization of nanochemical templates is needed for wiring of circuit templates. To improve the metallization density and enable the continuous nano-scale metallization of amine-coated surfaces, the treatment of amine-coated surfaces with a plating additive prior to metallization was studied. The additive treatment resulted in a 73% increase in seed material, enabling continuous nano-scale metallization. A new method was developed to create amine nanotemplates by selective attachment of a polymer to surface oxide patterns created by nano-oxidation. The treatment of the templates with the additive enabled a five-fold reduction in feasible width for continuous metallization. Nano-oxidation was also used in the nanometer-scale patterning of a thiol-coated surface. Metallization of the background thiols but not the oxidized patterns resulted in a metal film that was a negative of the patterns. The resulting metal film may be useful for nanometer-scale pattern transfer. DNA-coated gold nanoparticles (AuNPs) were selectively attached to amine templates by an ionic interaction between the template and ssDNA attached to the particles. Only the ssDNA on the bottom of the AuNPs interacted with the template, leaving the top strands free to bind with complementary ssDNA. Attempts to attach origami structures to these particles were only marginally successful, and may have been hindered by the presence of complementary ssDNA in solution but not attached to the origami, or the by the low density of DNA-AuNPs attached to the templates. The formation of patterned binding sites by direct, covalent attachment of ssDNA to chemical templates was also explored. Initial results indicated that ssDNA was chemically bound to the templates and able to selectively bind to complementary strands; however, the observed attachment density was low and further optimization is required. Methods such as these are needed to enable nano-scale, site-specific alignment of nanomaterials.

Mucopolysaccharidosis VI (MPS VI) is a hereditary lysosomal storage disease caused by the absence of the enzyme arylsulfatase B (ARSB). Craniofacial defects are common in MPS VI patients and manifest as abnormalities of the facial bones, teeth, and temporomandibular joints. Although enzyme replacement therapy (ERT) is the treatment of choice for MPS VI, the effects on the craniofacial and dental structures are still poorly understood. In this study, we used an Arsb-deficient mouse model (Arsb m/m ) that mimics MPS VI to investigate the effects of ERT on dental and craniofacial structures and compared these results with clinical and radiological observations from three MPS VI patients. Using micro-computed tomography, we found that the craniofacial phenotype of the Arsb m/m mice was characterized by bone exostoses at the insertion points of the masseter muscles and an overall increased volume of the jaw bone. An early start of ERT (at 4 weeks of age for 20 weeks) resulted in a moderate improvement of these jaw anomalies, while a late start of ERT (at 12 weeks of age for 12 weeks) showed no effect on the craniofacial skeleton. While teeth typically developed in Arsb m/m mice, we observed a pronounced loss of tooth-bearing alveolar bone. This alveolar bone loss, which has not been described before in MPS VI, was also observed in one of the MPS VI patients. Interestingly, only an early start of ERT led to a complete normalization of the alveolar bone in Arsb m/m mice. The temporomandibular joints in Arsb m/m mice were deformed and had a porous articular surface. Histological analysis revealed a loss of physiological cartilage layering, which was also reflected in an altered proteoglycan content in the cartilage of Arsb m/m mice. These abnormalities could only be partially corrected by an early start of ERT. In conclusion, our results show that an early start of ERT in Arsb m/m mice achieves the best therapeutic effects for tooth, bone, and temporomandibular joint development. As the MPS VI mouse model in this study resembles the clinical findings in MPS VI patients, our results suggest enzyme replacement therapy should be started as early as possible.

Background Timing and quantity of protein (PRO) consumption are important considerations for muscle protein synthesis (MPS), fat-free mass (FFM) accretion, and body fat % (BF%) reduction. The effect of PRO ingestion on changes in FFM is mediated by many variables. Past studies have focused on specific composition of carbohydrate (CHO) and PRO consumption (CHO vs. PRO + CHO), and have also investigated PRO intake timing at pre-exercise, post-exercise, or both. Other studies have investigated FFM maintenance and growth with increased PRO consumption during catabolic or anabolic phases of energy balance (EB). These mechanisms have been studied in various populations, including healthy untrained individuals, overweight and obese people, and endurance athletes. However, studies have not explored relationships between the amount and timing of PRO ingested, and the state of EB, as it relates to FFM%. Method/Design A retrospective analysis design was used to assess relationships between PRO ingestion, timing, and EB on FFM in collegiate football players. Subjects were members of an intercollegiate Division 1 football team, had completed a one-day food and activity record, and had body composition assessed as part of a regular team screening procedure. Data acquisition was supervised by a PhD/Registered Dietitian. Food and activity records were analyzed using NutriTiming®, which predicts RMR via the Harris-Benedict equation, uses a MET-based relative intensity activity scale, and accesses the USDA Nutrient Database for Standard Reference, Release 26 to predict hourly EB and PRO consumption. EB was assessed as ±400 kcal EB (EBR), < 0 kcal EB (NEGEB), and > 0 kcal EB (POSEB). Total useable PRO (TUP) was defined as the sum of PRO consumed in units up to 30g max/meal, a value also assessed relative to EB at the time of ingestion. The goal was to assess the amount and timing of PRO intake with EB as these factors relate to FFM. Results Pearson's correlations found that BF% was negatively associated with TUP while in EBR (r=-.253; p=0.049), and FFM% was positively associated TUP in EBR (r=0.279; p=0.030) and in POSEB (r=0.282; p=0.028). NEGEB was positively associated with BF% (r=0.325; p=0.011), and negatively associated with FFM% (r=-0.322; p=0.011). Conclusions Results elucidate that players who ingest PRO in a relatively good energy-balanced state had higher FFM% and a lower BF%. Further, those players consuming TUP while in POSEB had an even stronger positive association with FFM% and a stronger inverse association with BF%. These data reject the null hypothesis that football players who consume PRO in POSEB have less FFM% than those who consume PRO in NEGEB.

By manipulating constraints and goals, this study had generated some ill-posed problems in "Fractions" which were packed into 2 mathematical tasks for teacher uses in an intended exploration of their perceived effectiveness of teaching mathematical problem-solving against their student responses through the lens of the theory of formative assessment. Each ill-posed problem was characterized by certain descriptive "instability" that users would have to define own sets of mathematical assumptions for problem-solving inquiries. 3 highly qualified, experienced, and trained mathematics teachers were purposefully recruited, and instructed to acquire and mark student responses without any prior teaching and intervention. Each of these teachers' perceptions of ill-posed problems was acquired through a semi-structured clinical case-interview. All teachers in common demonstrated only individual singular mathematical problem-solving inquiries as major instructional adjustments during evaluation, even though individuals had ample opportunities in manipulating the described intention of each problem. Although some could realize inquiries from students being alternative to own used, not all would intend to change initial instructional plans of each problem and could design dedicated tasks in extending given problem-solving contexts for subsequent teaching and maintaining the described problem-solving intentions merely because of evaluation purposes. The resulting thick teacher perceptions were then analyzed by the Mayring's (2015) Qualitative Content Analysis (QCA) method for exploring particularly those who could intend to influence and get influenced by students' used mathematical assumptions in interviews. Certain unanticipated uses of assumptions of student individuals and groups were evidently found to have influenced cognitively some teachers' further problem-solving inquiries at some interview instants and stimulated their perception changes. In the lack of subject implementation in mathematics education for the theory of "formative" assessment (Black & Wiliam, 2009), based on its definition, these instants should be put as their potential creations of and/or capitalizations upon certain asynchronous moments of contingency according to their planning of instructional adjustments for more comprehensive learning and definite growths of mathematical inquiries of students according to individuals' needs of problem-solving. Due to QCA, these perception changes might be characterized by four certain inductively formed categories of scenarios of perceptions, which were summarized as 1) Evaluation Perception, 2) Assumption Expansion Perception, 3) Assumption Collection Perception, and 4) Intention Indecision Perception. These scenarios of perceptions might be used to explore teachers' intentions, actions, and coherency in accounting for students' used assumptions in mathematical inquiries for given problem-solving contexts and extensions of given intentions of mathematical inquiries, particularly in their designs of mathematical tasks. Teacher uses of ill-posed problems were shown to have provided certain evidences in implementing formative assessments which should substantiate a subject implementation of its theory in the discipline of mathematics education. Methodologically, the current study also substantiate how theory-guided designs of ill-posed problems as well as generic plain text analysis through QCA have facilitate effectiveness comparisons of instructional adjustments within a teacher, across different teachers, decided prior knowledge, students of prior mathematical learning experiences, and students in different levels of schooling and class size.

Submitted by camilla martins (camillasmmartins@gmail.com) on 2017-03-06T15:50:14Z No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Tese_JogoSerioApoio.pdf: 3507711 bytes, checksum: f0f6f5973828281a59494c4f4bf96013 (MD5) / Approved for entry into archive by Edisangela Bastos (edisangela@ufpa.br) on 2017-03-22T12:46:23Z (GMT) No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Tese_JogoSerioApoio.pdf: 3507711 bytes, checksum: f0f6f5973828281a59494c4f4bf96013 (MD5) / Made available in DSpace on 2017-03-22T12:46:23Z (GMT). No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Tese_JogoSerioApoio.pdf: 3507711 bytes, checksum: f0f6f5973828281a59494c4f4bf96013 (MD5) Previous issue date: 2015-09-08 / A Modelagem de Processo de Software (MPS) é um importante tópico na engenharia de software, pois fornece subsídios para gerenciar, automatizar e apoiar a Melhoria de Processo de Software. Seu ensino é um desafio, principalmente em consequência da grande ênfase teórica e de poucos exercícios práticos. Além disso, ainda são poucas as abordagens de ensino que visam o MPS por meio da introdução de recursos inovadores, tais como jogos. O uso de jogos é principalmente focado em outras áreas da engenharia de software, por exemplo, gerência de projetos de software. Visando contemplar esta lacuna, este trabalho relata o desenvolvimento de um jogo (DesigMPS – que apoia o ensino da MPS) e um experimento formal para avaliar a sua eficácia no ensino de MPS, bem como compará-lo com o método instrucional de aprendizagem baseada em projetos (ABP) (project-based learning). Neste jogo, o aluno é desafiado a modelar um processo de software no contexto do Modelo de Melhoria de Processos do Software Brasileiro (MPS.BR). Também foram analisadas características como: adequação em relação ao conteúdo, suficiência, grau de dificuldade, sequência e método de ensino; atratividade; pontos fortes e fracos do jogo. Os resultados indicaram que o DesigMPS tem eficácia de aprendizagem positiva (diferença estatisticamente significativa) nos níveis de compreensão e aplicação na taxonomia revisada de objetivos educacionais de Bloom, mesmo havendo alguns pontos fracos como: a falta um de help sobre o uso de jogo e de um feedback instrucional mais claro com explicação das causas dos erros. O jogo também tem uma eficácia de aprendizagem positiva (diferença estatisticamente significativa) comparada ao ABP no nível de aplicação, mas igual no nível de compreensão. A maioria dos alunos considerou que o jogo é atrativo e relevante em respeito ao conteúdo da disciplina de Qualidade de Processos de Software, e assim pode ser considerado uma alternativa para ensinar MPS. / Software process modeling (SPM) is an important area of software engineering because it provides a basis for managing, automating, and supporting software process improvement (SPI). Teaching SPM is a challenging task, mainly because it lays great emphasis on theory and offers few practical exercises. Furthermore, as yet few teaching approaches have aimed at teaching SPM by introducing innovative features, such as games. The use of games has mainly been focused on other areas of software engineering, for example software project management. In an attempt to fill this gap, this paper describes a formal experiment carried out to assess the learning effectiveness of a serious game (DesigMPS), designed to support the teaching of SPM, and to compare game-based learning with a project-based learning method. In the DesigMPS game, the student models a software process from an SPI perspective, based on the Brazilian SPI model (MPS.BR). Also features of the game were analyzed as: appropriateness in terms of content relevance, sufficiency, degree of difficulty, sequence, teaching method; engagement; strengths and weakness. The results indicate that playing the game can have a positive learning effectiveness (statistically significant difference) on the cognitive levels of understanding and applying, according to the revised version of Bloom's taxonomy of educational objectives, despite some weaknesses as: the lack of “help” on the use of the game and the lack of clearer instructional feedback with explanations regarding the causes of errors. Also, there is positive learning effectiveness (statistically significant difference) when compared to the PBL on the applying level, but no significant difference on the understanding level. Most students considered that the game is engaging and relevant concerning the content of Software Quality course. Based on the results the game could be an option to teach SPM.

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Το παράδειγμα του Service Oriented computing αναφέρεται σε ένα σύνολο από έννοιες, αρχές και μεθόδους οι οποίες αξιοποιούν την Service Oriented αρχιτεκτονική, σύμφωνα με την οποία οι εφαρμογές λογισμικού κατασκευάζονται από ανεξάρτητες συνιστώσες υπηρεσιών με πρότυπες διεπαφές. Η υπηρεσιοστρεφής (Service Oriented) αρχιτεκτονική είναι ένα σύνολο από κανόνες και μεθοδολογίες για το σχεδιασμό και την ανάπτυξη λογισμικού με τη μορφή διαλειτουργικών υπηρεσιών. Μία από τις σημαντικότερες τεχνολογίες για την αξιοποίηση αυτής της αρχιτεκτονικής είναι τα Web Services. Τα Web Services είναι μία τεχνολογία σχεδιασμένη για την υποστήριξη διαλειτουργικών αλληλεπίδρασης σταθμών πάνω από το διαδίκτυο. Τα συστήματα βιομηχανικών αυτοματισμών είναι συστήματα τα οποία χρησιμοποιούνται για την αύξηση της απόδοσης των βιομηχανικών καθώς και των διαδικασιών παραγωγής. Οι παραδοσιακές τεχνικές ανάπτυξης των συστημάτων αυτών δεν ικανοποιούν πλέον τις απαιτήσεις των σύνθετων βιομηχανικών συστημάτων και υπάρχει μια τάση για αξιοποίηση τεχνολογιών αιχμής από την περιοχή του Software Engineering. Στην κατεύθυνση αυτή η παρούσα εργασία μελετά τα πλεονεκτήματα αλλά και τα μειονεκτήματα που προσφέρει η αξιοποίηση του SOC παραδείγματος στην ανάπτυξη βιομηχανικών συστημάτων. Μελετήθηκε η DPWS τεχνολογία η οποία αποτελεί μια επέκταση της τεχνολογίας των Web Services με σκοπό την ικανοποίηση των αναγκών που παρουσιάζουν οι εφαρμογές βιομηχανικού αυτοματισμού. Ως μελέτη περίπτωσης χρησιμοποιήθηκε το εργαστηριακό σύστημα Festo MPS. Σχεδιάστηκε και υλοποιήθηκε ένας εξομοιωτής του συστήματος αυτού, ο οποίος στη συνέχεια επεκτάθηκε για να είναι συμβατός με την DPWS Τεχνολογία. Με βάση αυτόν σχεδιάστηκε και υλοποιήθηκε ένας ελεγκτής του συστήματος ο οποίος αξιοποιώντας τις υπηρεσίες που προσφέρει η DPWS τεχνολογία υλοποίει την διαδικασία ελέγχου του συστήματος Festo MPS. Στη συνέχεια με βάση τα αποτελέσματα των δοκιμών προχωρήσαμε σε μια συνολική αξιολόγηση της τεχνολογίας. / The Service-Oriented Computing (SOC) paradigm refers to the set of concepts, principles, and methods that represent computing in Service-Oriented Architecture (SOA), in which software applications are constructed based on independent component services with standard interfaces. In software engineering, a Service-Oriented Architecture (SOA) is a set of principles and methodologies for designing and developing software in the form of interoperable services. One of the most important technologies used utilize this architecture is Web Services technology. Web service technology, is designed to support interoperable machine-to-machine interaction over a network. Industrial automation systems are the systems used for the enhancement of industrial and manufacturing processes. Traditional techniques to develop these systems, no longer satisfy the requirements of the complex industrial systems and there is a tendency to utilize state of the art technologies of software engineering area. The current thesis discusses the advantages and disadvantages as a result of utilizing the Service-Oriented Computing (SOC) paradigm in the development of industrial Systems. The technology that was utilized was the Devices Profile for Web Services technology(DPWS). DPWS is the extension of the Web Services technology that was designed in order to satisfy the requirements of the industrial systems applications. As a case study we used Festo Modular Production System. We designed and implemented a simulator of this system. This simulator was then redesigned and implemented in order to be compatible with DPWS technology. Based on the redesigned Simulator we designed and implemented a system Controller which utilizes the DPWS technology and implements the control process of Festo MPS. Then we proceeded with the evaluation of the technology based on the results of the tests.

Mucopolissacaridoses (MPS) são erros inatos do metabolismo, fazem parte das doenças lisossômicas de depósito e ocorrem devido à deficiência na atividade de enzimas que catalisam a degradação de glicosaminoglicanos (GAGs). São doenças crônicas e progressivas causadas pelo acúmulo de um ou mais GAGs nos lisossomos das células. A MPS do tipo IV (síndrome de Morquio) ocorre pelo acúmulo de queratan sulfato e condoitin-6-sulfato, causado pela deficiência de duas diferentes enzimas, que distinguem essa MPS em dois subtipos, deficiência de N-acetilgalactosamina-6-sulfatase (MPS IV tipo A) ou de β-galactosidase (MPS IV tipo B). Na MPS IV A as características clínicas predominantes são relacionadas ao sistema esquelético e na maioria das vezes o paciente tem inteligência normal; não há uma terapia efetiva para a doença, deste modo o diagnóstico precoce direciona para o início de tratamentos paliativos. A investigação inicial dessa MPS se baseia em avaliação clínica, radiografias, quantificação e identificação de GAGs urinários e o diagnóstico definitivo pela medida da atividade enzimática da N-acetilgalactosamina-6-sulfatase (GALNS) em leucócitos ou fibroblastos. O objetivo desse trabalho foi estudar alguns parâmetros bioquímicos da enzima GALNS em leucócitos de indivíduos normais e adaptar a técnica de medida dessa atividade enzimática para sangue impregnado em papel filtro. O Km e a Vmáx da GALNS em leucócitos de indivíduos normais foi de 7,16mM e 77,3nmol/17h/mg de proteína, respectivamente. Também adaptamos a técnica da medida da atividade enzimática dessa enzima utilizando menor concentração de substrato (3mM), esta concentração teve correlação positiva com a concentração 10 mM, que é empregada na técnica original. A partir disto, foram estabelecidos os valores de referência em leucócitos para indivíduos normais e indivíduos afetados com MPS IV A. Os mesmos foram, respectivamente: 11,0 a 101,4 e 0,1 a 0,2 nmol/17h/mg de proteína. Foi também observado que, com o passar do tempo, a temperatura de 70ºC causa uma inativação gradual da atividade enzimática. Por último, apesar de várias alterações na técnica original em leucócitos, não foi possível adaptá-la para ser utilizada na medida da atividade da GALNS em sangue impregnado em papel filtro. A determinação dos parâmetros bioquímicos da GALNS é conveniente devido ao avanço nos estudos clínicos de desenvolvimento da terapia de reposição enzimática aos indivíduos afetados com MPS IV A e na distinção de indivíduos saudáveis, afetados e heterozigotos. Desenvolver técnicas fluorimétricas em amostras de sangue impregnado em papel filtro é de grande importância para serem utilizadas em triagem de recém-nascidos e populações de alto risco para MPS. Devendo ser confirmado por testes de atividade da enzima em leucócitos ou fibroblastos cultivados. A partir dos nossos protocolos, não foi possível desenvolver e padronizar uma técnica para medida da atividade da enzima N-acetilgalactosamina-6-sulfatase em sangue impregnado em papel filtro de modo a triarmos indivíduos com suspeita de MPS IV A. / Mucopolysaccharidosis (MPS) are inborn errors of metabolism, are part of the lysosomal storage diseases and occur due to the deficiency in the activity of enzymes that catalyze the degradation of glycosaminoglycans (GAGs). They are chronic and progressive diseases caused by the accumulation of one or more GAGs in the lysosomes of cells. The MPS type IV (Morquio syndrome) occurs by the accumulation of keratan sulfate and condoitin-6-sulfate, caused by two different enzyme deficiencies, which distinguish this MPS into two subtypes, deficiency of N-acetylgalactosamine-6-sulfatase (MPS IV type A) or the enzyme β-galactosidase (MPS type IV B). In MPS IVA the predominant clinical features are related to the skeletal system and in most cases the patient has normal intelligence. There is no effective therapy for the disease, so early diagnosis directs for the beginning of palliative treatments. The initial investigation of this MPS is based on clinical evaluation, radiographs, quantification and identification of urinary GAGs and the definitive diagnosis by measure of N-acetylgalactosamine-6-sulfatase (GALNS) activity in leukocytes or fibroblasts. The aim of this work was to study some biochemical parameters of the GALNS in leukocytes of normal individuals and adapt the technique of measuring this enzyme activity to blood impregnated on filter paper. The Km and Vmax of GALNS in leukocytes from normal subjects was 7.16 mM and 77.3 nmol/17h/mg of protein, respectively. We also adapted the technique of measuring the enzymatic activity of this enzyme using lower substrate concentration (3mM). This concentration had a positive correlation with 10 mM concentration, which is used in the original technique. From this, the reference values for normal and individuals affected with MPS IVA in leukocytes were established. They were 11.0 to 101.4 and 0.1 to 0.2 of nmol/17h/mg of protein, respectively. It was also observed that over time the temperature of 70°C causes a gradual inactivation of enzyme activity. Finally, despite several changes to the original technique in leukocytes, it has not been possible to adapt it to be used in measuring the activity of GALNS blood impregnated on filter paper. The determination of biochemical parameters of GALNS is convenient due to the advancement in clinical studies for the development of enzyme replacement therapy for individuals affected with MPS IVA and to distinguish between healthy and affected heterozygous individuals. The development of fluorometric techniques in blood impregnated on filter paper is of great importance for use in newborn screening and in high risk populations to MPS. It should be confirmed by tests of enzyme activity in leukocytes or cultured fibroblasts. Unfortunately, from our protocols, it was not possible to develop and standardize a technique for measuring the activity of the enzyme N- acetylgalactosamine-6-sulfatase in blood impregnated on filter paper for to screen individuals suspected of MPS IVA.