Limited resources are currently available to assist engineers in implementing compliant members into mechanical designs. As a result, engineers often have little to no direction incorporating compliant mechanisms. This thesis develops a conceptual design framework and process that utilizes a proposed classification scheme and a library of mechanisms to help engineers incorporate compliant mechanisms into their applications. As the knowledge related to the synthesis and analysis of compliant mechanisms continues to grow and mature, and through the classification scheme established in this thesis, compliant mechanisms may become more extensively used in commercial mechanical designs. This thesis also demonstrates a design approach engineers can use to convert an existing rigid-body mechanism into a compliant mechanism by using the established classification scheme and a library of compliant mechanisms. This approach proposes two possible techniques that use rigid-body replacement synthesis in conjunction with a compliant mechanism classification scheme. One technique replaces rigid-body elements with a respective compliant element. The other technique replaces a complex rigid-body mechanism by decomposing the mechanism into simpler functions and then replacing a respective rigid-body mechanism with a compliant mechanism that has a similar functionality. These techniques are then demonstrated by developing and designing a competitive and feasible compliant road bicycle brake system.

Lamina emergent mechanisms (LEMs) can provide a way to meet the demand for more compact and inexpensive mechanisms. Previous research has developed LEM designs and identified applications for them, but many applications would benefit from suitable actuation techniques. This thesis presents the design considerations and a variety of applicable methods for internal and external LEM actuation in the macro scale. Integrated LEM actuator possibilities have been identified, each with its advantages and disadvantages depending on the application. Shape memory alloys are especially compatible with LEMs. Traditional actuators have also been discussed as a way of actuating a LEM from the outside for cases in which space constraints allow it. The feasibility of new internal actuators using basic actuation principles, especially flat solenoids, has been explored. The magnetic field distribution along the axis of a high-aspect-ratio solenoid has been derived. Analytical and experimental results show that the output force of a high-aspect-ratio solenoid is suitable for LEMs. A pseudo-solenoid conceptual prototype was manufactured and evaluated, revealing challenges for which solutions have been recommended.

Origami-inspired design is an emerging field capable of producing compact and efficient designs. The object of a surrogate fold is to provide a fold-like motion in a non-paper material without undergoing yielding. Compliant mechanisms provide a means to achieve these objectives as large deflections are achieved. The purpose of this thesis is to present a summary of existing compliant joints suitable for use as surrogate folds. In doing so, motions are characterized which no existing compliant joint provides. A series of compliant joints is proposed which provides many of these motions. The possibility of patterning compliant joints to form an array is discussed. Arrays capable of producing interesting motions are noted.

Cardiovascular disease (CVD) is the leading cause of death due to its prevalence in tandem with the propensity of atherosclerosis to worsen and cause myocardial infarction and stroke. The greatest risk factor for CVD development is age. The multifactorial etiology of atherosclerosis has made CVD difficult to model and consequently little is known about CVD onset and progression. Hutchinson-Gilford Progeria Syndrome (HGPS) is a severe human premature aging disorder caused by a mutation in Lamin A that leads to the accumulation of an aberrant Lamin A protein termed progerin. Patients who harbour this mutation develop atherosclerosis and die from myocardial infarction or stroke at an average age of 13 years old. Autopsies reveal deterioration of vascular smooth muscle cells (VSMCs) in HGPS patients, underlining a strong connection between VSMC loss and predisposition to CVD development. The major aim of this thesis was to model normative vascular aging and disease using HGPS induced pluripotent stem cell (iPSC)-derived VSMCs and monitor the onset of defective epigenetic inheritance in vitro. My results indicate reprogramming of patient fibroblasts to restores a normal nuclear phenotype. Patient derived iPSC lines generated from fibroblasts are nearly indistinguishable from healthy controls in terms of pluripotency, nuclear membrane integrity, as well as transcriptional and epigenetic profiles. However, differentiation of HGPS iPSCs to generate HGPS VSMCs recapitulates many aspects of normative vascular aging exemplified by increased ROS, DNA damage and transcriptomic aberrations. Furthermore, using a multi-omic approach including RNA-sequencing, and accelerated native isolation of protein on nascent DNA, HGPS VSMCs demonstrate loss of histone acetylation due to defective MOF abundance that contributed to impaired engagement with DNA damage repair pathway. This dissertation provides insights on the mechanisms that drive the epigenetic and transcriptomic changes in HGPS vasculature, illuminating druggable pathways that may also drive CVD in the general population.

京都大学 / 新制・論文博士 / 博士(医学) / 乙第13566号 / 論医博第2293号 / 新制||医||1068(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 柊, 卓志, 教授 篠原, 隆司, 教授 後藤, 慎平 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

Tow-placement machines have made it possible to manufacture curved-fiber composite tow paths. A composite structure with curved-fiber tow paths can be formed in a manner similar to filament winding. The result is a laminate with spatially varying stiffness and response. This manufacturing method can also result in overlap regions between adjacent tow paths. In previous research, a closed-form solution was developed to determine the response of these variable-stiffness laminates, but the overlap regions were not included in this model. Additionally, the fiber-orientation angle throughout the panel was based on individual fiber path definitions and not tow path definitions. In this thesis, a method of creating a finite element model of tow-placed variable-stiffness composite panels is presented. This method provides a representation of the overlap regions and an accurate model of the fiber-orientation angle change throughout the laminate. The GENESIS finite element analysis and design package is used to solve for the static response of the models created. The results of these analyses compare favorably with the results of the previous research and give some insight into the interaction of the thickness and fiber-orientation variation. Additionally, some of the advanced design capabilities of the finite element modeling method, and some results of those designs are demonstrated. / Master of Science

Macrophages are leukocytes of the innate immune system that display great phenotypic plasticity to mediate diverse functions. The ontogeny of tissue resident macrophages has been debated in recent decades. It is now recognised that tissue macrophages can be replenished from embryonically-derived precursors, and/or monocyte intermediates in a tissue specific manner. Interferon Regulatory Factor 5 (IRF5) is a transcription factor that promotes a pro-inflammatory phenotype in macrophages in vitro and in vivo. Indeed, IRF5 contributes to the pathogenesis of experimental inflammatory arthritis, lupus, and obesity via recruitment and activation of effector cells. Research described here as part of this thesis, involves the profiling of the intestinal Mononuclear Phagocyte system to investigate the role of IRF5 in the development of monocyte-derived macrophages in the Colonic Lamina Propria (cLP) which are exclusively replenished by adult Ly6C^hi monocytes. Using Mixed Bone Marrow Chimaeras (MBMCs) we showed that in shared environment Wild-Type (WT) cLP macrophages dominated IRF5-deficient (Irf5^-/-) cLP macrophages in both steady state and inflammation. The development of in vitro bone marrow derived macrophages, and the reconstitution of the haematopoietic compartment in bone marrow of MBMCs were not significantly affected by IRF5 deficiency. IRF5 promoted the accumulation of WT monocytes in the cLP of MBMCs in a process possibly dependent on the CCL2/CCR2 axis. Furthermore, IRF5 expression committed Ly6C^hi monocytes to a pro-inflammatory macrophage fate in the inflamed cLP, characterised by protein expression of the cytokines IL1β, and TNFα, and the expression of Ccl4 and Ccl8 transcripts, whilst loss of IRF5 favoured accumulation of CD11b⁺ IRF4-dependent Dendritic Cells. Of significance, IRF5 expression might have prevented further differentiation of inflammatory macrophages into tissue-resident macrophages, thus supporting an inflammatory state. Irf5-/- mice were protected from Helicobacter hepaticus + αIL10R colitis. Intriguingly, protection from colitis may also be conferred by the presence of Irf5-/- haematopoietic cells, evidenced by WT:Irf5-/- MBMCs . Modulation of IRF5 activity may therefore be a viable therapeutic strategy. RNA sequencing identified that C1q, Cd81, and Ccl8 were upregulated in WT macrophages from MBMC, which may prove therapeutic targets.

京都大学 / 0048 / 新制・課程博士 / 博士(理学) / 甲第18496号 / 理博第4011号 / 新制||理||1578(附属図書館) / 31382 / 京都大学大学院理学研究科生物科学専攻 / (主査)教授 西村 いくこ, 教授 鹿内 利治, 教授 長谷 あきら / 学位規則第4条第1項該当 / Doctor of Science / Kyoto University / DGAM

Lamina emergent mechanisms (LEMs) are a maturing technology that is prepared for commercial implementation into new products. LEMs are defined by three functional characteristics; they (1) are compliant, (2) are fabricated from planar materials, and (3) emerge from a flat initial state. Advantages, design challenges, and design tools are described for each of the functional characteristics. Opportunities for LEMs are discussed, namely disposable LEMs, novel arrays of LEMs, scaled LEMs, LEMs with surprising motion, shock absorbing LEMs, and deployable LEMs. Technology push product development processes were employed to select applications for LEMs. LEM technology was characterized. In a LEM workshop, eighteen industry professionals then helped identify over 200 potential applications for the technology. The applications were evaluated, and the most promising ideas that were identified for each LEM opportunity are described with graphics of possible product embodiments. Of the various product opportunities enabled by LEMs, deployable mechanisms – particularly in the credit card size – are among the most viable. The compactness and portability of credit-card-sized products create a strong motivation for their development. Expanding the capabilities of credit-card-sized mechanisms to include more sophisticated motions and a broader range of tasks may dramatically increase their market potential. A review of the current state-of-the-art in credit-card-sized mechanisms reveals two primary classes of mechanisms most commonly used in this form factor: rigid-body mechanisms and in-plane compliant mechanisms. The limitations of each and corresponding LEM advantages are described. Criteria for determining whether a product is a suitable candidate for using LEM technology to create or improve a credit-card-sized product are established. The advantages of LEMs in credit-card-sized products are illustrated through an example product: a compact lancing device that could be used as a main component for a highly portable epinephrine syringe.

Introdução: As Distrofias Musculares Congênitas (DMCs) são um grupo clínica e geneticamente heterogêneo de doenças musculares que se manifestam ao nascimento ou no primeiro ano de vida, sendo caracterizadas por hipotonia, fraqueza muscular, retardo do desenvolvimento motor e retrações fibrotendíneas. O músculo esquelético apresenta-se distrófico, mas sem alterações estruturais específicas. Em quase metade dos casos a doença é causada pela deficiência da laminina alfa;-2 (merosina). Outras deficiências proteicas descritas incluem: colágeno VI, selenoproteína N1, várias glicosiltransferases responsáveis pela glicosilação da alfa- distroglicana e lamina A/C. Vários genes já foram identificados. Objetivo: o objetivo deste estudo foi a caracterização clínica, histológica e molecular das crianças com DMC por deficiência de lamina A/C. Método: Foram incluídos 13 pacientes com diagnóstico clínico e histológico de DMC, com expressão muscular normal para distrofina, sarcoglicanas, merosina, colágeno 6 e disferlina. Os pacientes foram reavaliados segundo protocolo clínico e neurológico. As biópsias musculares realizadas previamente foram revisadas e o estudo das mutações no gene da lamina A/C foi realizado através de sequenciamento de toda região codificadora do gene. Resultados: Identificamos mutações em 30,7% dos pacientes (quatro casos) com fenótipo clínico de DMC por deficiência de lamina A/C. Todas as mutações encontradas (p.E358K, p.R249W, e p.N39S) ocorreram em heterozigose e de novo e já haviam sido descritas na literatura em pacientes com distrofias musculares. Em geral, estes pacientes apresentavam um grave comprometimento motor com o característico aspecto de cabeça caída, com início dos sintomas nos primeiros dois anos de vida. A CPK estava elevada entre 2 a 6 vezes o padrão superior da normalidade. O padrão histológico variou desde um músculo levemente até gravemente distrófico. Curiosamente, no estudo histológico do músculo, um dos pacientes apresentou agregados intracitoplasmáticos. Um outro paciente apresentava associadamente alterações neurogênicas ao estudo eletroneuromiográfico. Em todos os casos observamos complicações respiratórias, cardíacas e distúrbios de deglutição. Houve um caso de morte súbita, provavelmente em decorrência de arritmia cardíaca. Conclusões: A correlação genótipo-fenótipo permanece difícil, mas todos os casos apresentaram sinal da cabeça caída, comprometimento respiratório, cardíaco e biópsia muscular distrófica. A ampliação do conhecimento clínico e histológico pode orientar o diagnóstico e direcionar para o estudo molecular adequado, além de permitir o diagnóstico precoce das complicações, tão frequentes na DMC por deficiência de lamina A/C. Os exons 1, 4 e 6 são os mais frequentemente mutados e devem ser pesquisados inicialmente. Esta série de casos contribui também por demonstrar a distribuição universal da doença / Background: The Congenital Muscular Dystrophies (CMD) are a clinically and genetically heterogeneous group of myopathies characterized by muscle hypotonia, delayed motor development and early onset of progressive muscle weakness with dystrophic pattern on muscle biopsy. The clinical course is broadly variable and can comprise the involvement of the brain and eyes. Almost half of the cases is caused by deficiency of laminin-alfa 2 (merosin). Other protein deficiencies described include: collagen VI, selenoprotein N1, several glycosyltransferases responsible for glycosylation of alfa-dystroglycan and lamin A/C. Several genes have been identified and the increased knowledge of new clinical and histological forms of CMD can guide diagnosis and direct appropriate molecular studies. LMNA-related CMD is often characterized by muscle weakness and a dropped head developed in the early years of life. Regarding lamin A/C deficiency, the immunohistochemical findings can be normal, probably because the protein change is functional only; this makes diagnosis using muscle samples more difficult. Objectives: The aim of this study was to characterize the clinical, histological and molecular aspects in patients with CMD related to deficiency of lamin A/C. Methods: thirteen children with clinical and histological diagnosis of CMD with normal muscle expression for dystrophin, merosin, collagen 6, sarcoglycans and dysferlin were included in this study. The LMNA gene was sequenced after amplification of all coding exons. In addition, the muscle biopsies were revised. Results: In 30.7% (four cases) of our patients with typical clinical phenotype of lamin A/C deficiency were detected mutations on LMNA gene and all of them presented dropped-head syndrome, restrictive ventilator insufficiency, cardiac changes, increased serum CPK level and myopathic/dystrophic aspect on muscle biopsy. Two of the patients had normal motor development milestones in the first months of life and subsequently developed cervical and limb weakness. The other two patients presented a more severe motor involvement and failure to walk. One patient showed associated peripheral neuropathy. Curiously one case had myofibrillar aggregates on muscle biopsy. All mutations (p.E358K, p.R249W and p.N39S) were heterozygous and de novo and had been previously described in patients with muscular dystrophy. Conclusion: Genotype/phenotype correlation in CMD remains difficult. However patients with LMNA mutation and CMD seems to have a more homogeneous phenotype characterized by dropped head, severe motor disability, and cardiac and pulmonary involvement. Mutations on exons 1, 4 and 6 should be tested first. This case series also contributes for showing the universal distribution of the disease