This thesis concerns residual stress modeling in soft living tissues. The word living means that the tissue interacts with surrounding organs and that it can change its internal properties to optimize its function. From the first day all tissues are under pressure, due, for example, to gravity, other surrounding organs that utilize pressure on the specific tissue, and the pressure from the blood that circulates within the body. This means that all organs grow and change properties under load, and an unloaded configuration is never present within the body. When a tissue is removed from the body, the obtained unloaded state is not naturally stress free. This stress within an unloaded body is called residual stress. It is believed that the residual stress helps the tissue to optimize its function by homogenizing the transmural stress distribution. The thesis is composed of two parts: in the first part an introduction to soft tissues and basic modeling is given and the second part consist of a collection of five manuscripts. The first four papers show how residual stress can be modeled. We also derive evolution equation for growth and remodeling and show how residual stress develops under constant pressure. The fifth paper deals with damage and viscosity in soft tissues.

The formation of the myelin sheath is a crucial step during development because it enables fast and efficient propagation of signals within the limited space of the mammalian central nervous system. During the process of myelination, oligodendrocytes actively interact with the extracellular matrix (ECM). These interactions are considered crucial for proper and timely completion of the myelin sheath. However, the exact regulatory circuits involved in the signaling events that occur between the ECM and oligodendrocytes are currently not fully understood. Therefore, in this dissertation we investigated the role of a known integrator of cell-ECM signaling, namely, focal adhesion kinase (FAK), during oligodendrocyte morphological maturation in vivo and in vitro. Conditional and inducible FAK-knockout mice (Fakflox/flox: PLP/CreERT mice) were generated to observe the effect of FAK loss on myelination in vivo. The role of FAK during post-migratory premyelinating oligodendrocyte morphological maturation was explored in vitro using primary rat oligodendrocyte cultures in combination with siRNA or inhibitor treatment. When inducing FAK knockout just prior to and during active myelination in vivo, we observed a significant reduction in the number of myelinated fibers following initial myelination. In addition, our data revealed a decreased number of primary processes extending from oligodendrocyte cell bodies at this stage of development under induction of FAK knockout. In contrast, myelination appeared normal on postnatal day 28. Our in vitro data demonstrated that reduction of FAK expression or activity affected the oligodendrocyte process network maturation in a way that is unique to the ECM substrate present. More specifically, our data suggest that FAK restrains the expansion of the oligodendrocyte process network in the presence of fibronectin and promotes expansion of the oligodendrocyte process network in the presence of laminin-2. We showed that the FAK-mediated restriction of oligodendrocyte morphological maturation is tightly developmentally regulated; being highly active during early stages of post-migratory premyelinating oligodendrocyte morphological maturation but greatly diminished at the later stages of oligodendrocyte development. Thus, our data suggest that FAK controls the efficiency and timing of CNS myelination during its initial stages, at least in part, by regulating oligodendrocyte process network morphological maturation.

The nucleosome remodeling factor (NURF) is an evolutionary conserved ATP-dependent chromatin remodeling factor. It was first isolated from Drosophila as a complex with enzymatic activity that once recruited to nucleosome, it slides the nucleosome to provide accessibility for transcription factors. Since then, numerous works from animal models and cell lines show the role of NURF as a regulator of gene expression. NURF interacts with H3K4me3 and sequence specific transcription factors that recruit the complex to promoter regions. Whether this is the only mechanism by which NURF regulates gene expression is not known. However, other ATP-dependent chromatin remodeling complexes are known to regulate gene expression independent from transcription initiation. In order to explore the role of NURF in regulating gene expression, we utilized two genome wide approaches to map NURF binding and NURF dependent changes in chromatin structure using ChIP-Seq and FAIRE-Seq, respectively. From these analyses, we discovered that NURF broadly localizes in the genome with preferences to gene bodies and 3’ends of genes. Also, we found that NURF maintains open chromatin regions at upstream, intron and downstream of genes. These novel findings shed light on new roles for NURF complex within genes, in addition to its classical role at promoter regions. Furthermore, we discovered the function of a previously uncharacterized domain in the NURF specific subunit BPTF. We show that the N-terminal the plant homeodomain (PHD) of BPTF directly interacts with THOC4, a protein associated with RNA-pol 2. Also, we show using ChIP analyses that this interaction recruits BPTF to gene bodies. Next, we investigated functional consequences for NURF recruitment to gene bodies using Cyclin D1 (Ccnd1) gene as a model. These analyses revealed that NURF is required for normal mRNA processing and loss of NURF induces intron retention, which results in unstable transcripts. Finally, we show that the defect in mRNA processing is not specific to the Ccnd1 gene, as we observe similar defects in four other BPTF dependent genes. Together, our work uncovered new role of mammalian NURF complex in regulating gene expression through mRNA processing.

A hipertensão arterial é uma condição clínica grave acompanhada por alterações estruturais do aparelho cardiovascular. Os antagonistas dos receptores 1-adrenérgicos são drogas usadas na terapêutica anti-hipertensiva. O nebivolol é um antagonista seletivo dos receptores 1 de terceira geração, que estimula a liberação endotelial de NO e diminui a ativação da -nicotinamida adenosina dinucleotído fosfato (NAD(P)H) oxidase. O metoprolol é um antagonista seletivo dos receptores 1de segunda geração, que não apresenta efeitos vasodilatadores. As metaloproteinases da matriz (MMPs), principalmente a MMP-2, são enzimas que participam ativamente do processo de remodelamento vascular. Elas passam de seu estado latente para seu estado ativo pela ação de proteases e espécies reativas de oxigênio (EROs). Como na hipertensão há aumento de EROs, de MMPs e remodelamento vascular, é possível que o nebivolol impeça o aumento dos níveis de MMPs vasculares e o remodelamento vascular hipertrófico associados à hipertensão, além do seu efeito de antagonismo do receptor 1. Primeiro, realizamos uma avaliação das alterações aórticas da hipertensão 2-rins,1-clipe (2R-1C), pois há poucas informações sobre essas alterações durante o desenvolvimento da hipertensão. Para isso, ratos hipertensos e controles foram estudados com 2, 4, 6 e 10 semanas após a indução da hipertensão. A pressão arterial sistólica foi monitorada semanalmente. As alterações na parede aórtica foram estudadas em hematoxilina/eosina (H&E), picrosirius e orceína. Foram avaliados também a atividade da NAD(P)H oxidase, a produção de ânion superóxido, a atividade gelatinolítica por zimografia in situ; os níveis e localização de MMP-2, MMP-14 e TIMP-2 por imunofluorescência zimografia e imunohistoquímica. No segundo protocolo, após 6 semanas de hipertensão foi iniciado o tratamento com metoprolol (Meto -20/mg/kg/dia) ou nebivolol (Nebi -10mg/kg/dia), realizado durante 4 semanas. Foram avaliados a pressão arterial sistólica, as alterações na parede aórtica por H&E, a atividade da NAD(P)H oxidase, produção de ânion superóxido, a atividade gelatinolítica, os níveis e localização de MMP-2 por imunofluorescência e zimografia em gel, e os níveis de nitrotirosina por imunohistoquímica. Observamos no protocolo temporal que a pressão foi gradualmente aumentada nos animais hipertensos quando comparado aos controles. Houve hiperplasia e hipertrofia da aorta, com aumento da deposição de colágeno e elastina. Observamos aumento nos níveis de estresse oxidativo, MMPs e atividade gelatinolítica em todas as semanas de estudo. Ao final do tratamento com metoprolol e nebivolol, observamos que a pressão diminuiu nos animais hipertensos, e que essa redução da pressão ocorreu de modo semelhante com os diferentes tratamentos. Os animais hipertensos apresentaram hipertrofia da aorta, aumento nos níveis de EROs, de MMP-2 e da atividade gelatinolítica. Essas alterações foram revertidas apenas pelo tratamento com nebivolol, mas não pelo metoprolol. Assim, o remodelamento da hipertensão 2R-1C parece estar estabelecido com duas semanas de hipertensão arterial, com elevados níveis de espécies reativas de oxigênio e MMPs, e o tratamento com nebivolol, mas não o metoprolol, atenuou o estresse oxidativo e o remodelamento vascular associado à hipertensão. / Hypertension is a serious clinical condition with structural changes in the cardiovascular system. Beta-adrenoreceptor antagonists are used in hypertension therapy. Nebivolol is a third-generation selective 1-adrenoreceptor antagonist that stimulates endothelial cell NO production and prevents vascular NAD(P)H oxidase activation. Metoprolol is a second-generation selective 1-adrenoreceptor antagonist, without vasodilatory effect. The matrix metalloproteinases (MMPs), especially MMP-2, participate actively in the vascular remodeling process, and are activated by reactive oxygen species (ROS). There are increases in ROS, of MMPs, and vascular remodeling in hypertension. Because of these, it´s possible that nebivolol prevent MMP increases and vascular remodeling associated with hypertension beyond its 1-receptorblocking properties. First, structural aortic changes in the development of two-kidney, one-clip hypertension (2K-1C) were evaluated. Sham or 2K1C hypertensive rats were studied after 2, 4, 6, and 10 weeks of hypertension. Systolic blood pressure (SBP) was monitored weekly. Morphometry of structural changes in the aortic wall was studied in hematoxylin/eosin, orcein and picrosirius red sections. Aortic NAD(P)H activity and superoxide production was evaluated. Aortic gelatinolytic activity was determined by in situ zymography, and MMP-2, MMP-14, and tissue inhibitor of MMPs (TIMP)-2 levels were determined by gelatin zymography, immunofluorescence and immunohistochemistry. Six weeks after surgery, hypertensive and sham rats were treated with metoprolol (20 mg/kg/ day) or nebivolol (10 mg/kg/day), for four weeks, in the second-protocol. Systolic blood pressure (SBP) was monitored weekly Aortic structural were studied in hematoxylin/eosin sections. NAD(P)H oxidase activity and ROS and nitrotyrosine production were evaluated. MMPs levels and activity were determined by zymography and in situ zymography. In the temporal study, 2K-1C hypertension was associated with increased aortic collagen and elastin content in the early phase of hypertension, which was associated with vascular hypertrophy, increased vascular MMPs levels, and increased gelatinolytic activity, possibly as a result of increased vascular NAD(P)H oxidase activity and oxidative stress. In the second-protocol, similar reductions in SBP were found with both metoprolol and nebivolol treatments. However, only Nebi reversed aortic hypertrophy, the increases in aortic NAD(P)H oxidase activity, in aortic ROS levels, in nitrotyrosine staining, in aortic MMP-2 levels and in aortic MMP activity. These results indicate that vascular remodeling of renovascular hypertension is an early process associated with increases in MMPs activities, enhanced matrix deposition and oxidative stress, and that treatment with Nebi attenuate the oxidative stress and the vascular remodeling associated with 2K-1C hypertension.

O reparo ósseo de alvéolos após exodontia dos molares superiores em um modelo animal em ratos Wistar (Rattus norvegicus, albinus) de osteonecrose dos maxilares associada ao uso de bisfosfonatos foi avaliado através de analise microscópica e molecular. Foram utilizados 48 ratos (Rattus norvegicus, albinus, Wistar) machos, com 12 semanas de vida e peso aproximado de 300 gramas, que foram dividos em 4 grupos. Cada grupo era composto por 12 animais, sendo 2 grupos experimentais AZ e AZ-Cirúrgico (AZ-C), que foram submetidos a administração de ácido zoledrônico, 0,6 mg/kg a cada 28 dias com um total de 5 doses e 2 grupos controles CO e CO-Cirúrgico (CO-C) com administração de cloreto de sódio 0,9% no mesmo volume e frequencia do ácido zoledrônico. Todas as soluções foram administradas por via intraperitoneal. O grupo AZ-C e o grupo CO-C foram submetidos a exodontia do primeiro, segundo e terceiro molares superiores 45 dias após a primeira aplicação das soluções. Todos os animais foram eutanasiados após 150 dias do início do experimento (105 dias após as exodontias). As maxilas dos animais foram avaliadas macroscopicamente para presença de lesões espontâneas e com uma sonda clinica número 5 as regiões das exodontias dos molares foram avaliadas para presença ou ausência de solução continua do epitélio. Após feita a avaliação macroscópica as regiões das exodontias dos molares superior esquerdo e do lado contralateral de cada animal foram submetidas a análises qualitativa e quantitativa para presença de sequestros ósseos, restos radiculares, área de osteonecrose, área de espaço trabecular, área de reação periosteal, através de estudos por microscopia óptica pela coloração Hematoxilina e Eosina. Análise quantitativa da expressão do RNAm de proteínas envolvidas no processo de reparo ósseo RANK, RANKL, OPG e VEGF, pelo método de reação em cadeia da polimerase em tempo real (RealTimePCR) também foi realizada. A avaliação macroscópica mostrou que 91,66% dos animais do grupo AZ-C e 41,66% do grupo CO-C apresentaram solução de continuidade do epitélio, sendo estatisticamente significante maior no grupo em terapia com ácido zoledrônico pelo este exato de Fischer (p<0,05). Todos animais do grupo AZ-C e nenhum do grupo CO-C apresentaram sequestros ósseos e todos os animais apresentaram presença de restos radiculares na análise microscópica. A área de osteonecrose foi maior nos animais do grupo AZ-C do que no grupo CO-C (p<0,005), não havendo diferença estatística entre as áreas de espaço trabecular, reação periosteal e osso total. Na análise molecular de RANK, RANKL, OPG e VEGF não houve diferença estatisticamente significante entre os grupos CO, AZ, COC e AZ-C, mesmo quando comparadas áreas de exodontia com áreas com dentes. Estes resultados levam a conclusão que o modelo animal utilizado no presente estudo é um modelo seguro, que o ácido zoledrônico interferiu no reparo ósseo dos alvéolos, causando um atraso na remodelação óssea da região e uma maior incidência de osteonecrose e sequestros ósseos. O ácido zoledrônico não afetou a expressão de RANK, RANKL, OPG e VEGF 105 dias após as exodontias. / The alveolar bone repair following extraction of maxillary molars in an animal model of bisphosphonate related osteonecrosis of the jaws in Wistar rats (Rattus norvegicus, Albinus) was assessed through microscopic and molecular analysis. A total of 48 rats (Rattus norvegicus, Albinus, Wistar rats) with 12 weeks old and weighing approximately 300 grams were used, they were divided into 4 groups. Each group consisted of 12 animals, with 2 experimental groups AZ and AZ-Cirúrgico (AZ-C), who underwent the administration of zoledronic acid, 0.6 mg / kg every 28 days with a total of 5 doses. And 2 control groups CO and CO-Cirúrgico (CO-C) with administration of sodium chloride at 0.9% in the same volume and frequency of zoledronic acid. All solutions were administered intraperitoneally. The group AZ-C and CO-C underwent to extraction of the first, second and third molars 45 days after the first application of the solutions. All animals were sacrificed after 150 days from the beginning of the experiment (105 days after extractions). The maxilla of the animals were assessed macroscopically for the presence of spontaneous lesions, and with a clinical probe number five the regions of the molar extractions were evaluated for the presence or absence of loss of continuity of the oral epithelium. After macroscopic evaluation, the upper left molar and contralateral side of the extraction regions of each animal were submitted to qualitative and quantitative analyzes for the presence of bone sequestrum, root fragments, osteonecrosis area, trabecular space area, area of periosteal reaction, through optical microscopic studies by hematoxylin and eosin staining. And quantitative analysis of mRNA expression of proteins involved in bone repair (RANK, RANKL, OPG and VEGF), by the method of RealTimePCR were carried out. Macroscopic evaluation showed that 91.66% of the AZ -C group and 41.66% of the CO-C group presented a loss of continuity of the epithelium, which was statistically significant higher in the zoledronic acid group according to the Fisher test (p<0.05). All animals in group AZ-C and none in CO-C group showed bone sequestrum and all animals in both groups had root fragments in microscopic analysis. The area of osteonecrosis was higher in the animals of AZ-C group than in CO-C (p<0.005), with no statistical difference between the areas of trabecular space, periosteal reaction and total bone. In the molecular analysis of RANK, RANKL, OPG e VEGF there was no statistically significant difference between the CO, AZ, CO-C e AZ-C groups, even when extraction regions were compared to non extractions areas. These results lead to the conclusion that the animal model described used in this study is a reliable model and zoledronic acid interferes with alveolar bone repair causing a delay in bone emodeling and a higher incidence of osteonecrosis and bone sequestrum. Zoledronic acid did not affect the expression of RANK, RANKL, OPG and VEGF 105 days after dental extractions.

Lui Ho Yin. / "Architecture Department, Chinese University of Hong Kong, Master of Architecture Programme 2001-2002, design report." / Content --- p.1 / Acknowledgement --- p.3 / Project Synopsis --- p.4 / Chapter i/ --- Introduction --- p.6 / Preface --- p.7 / Conservation of Cultural Heritage --- p.8 / Reason for conservation --- p.9 / Conservation and Urban Renewal --- p.11 / Conservation Modes Comparison --- p.13 / Chapter ii/ --- Initiation of Project --- p.15 / Magistrates' Court in Hong Kong --- p.16 / Type of Courts --- p.17 / Social Concern toward Legal System in Hong Kong --- p.20 / Comparison between Hong Kong and China Legal System --- p.22 / Chapter iii/ --- Exploring on Site / Urban --- p.26 / Methodology --- p.27 / District I: Sheung Wan / Central / District II: Tsim Sha Tsui / District III: Causeway Bay / My Choice / Site Location --- p.32 / Examine the characteristic of Site --- p.33 / Historical Background --- p.35 / Architectural Merits --- p.39 / Adjacent Special Areas --- p.40 / Chapter iv/ --- Site Analysis --- p.42 / Context Analysis --- p.43 / Characteristics of Central Police Station Buildings --- p.48 / Court of Final Appeal (Former French Mission Building) --- p.62 / Chapter vi/ --- Design Guideline --- p.64 / Building Users --- p.65 / Planning the layout of the magistrates' court --- p.67 / Schedule of Accommodation --- p.70 / Design Concept --- p.72 / Model Photo --- p.76 / Chapter vii/ --- Special Study --- p.79 / Block A --- p.80 / Block B and the other --- p.84

Thesis (M.Arch.)--Massachusetts Institute of Technology, Dept. of Architecture, 1980. / MICROFICHE COPY AVAILABLE IN ARCHIVES AND ROTCH. / Includes bibliographical references. / by Shepperson A. Wilbun, Jr. / M.Arch.

Thesis (M. Arch.)--Massachusetts Institute of Technology, Dept. of Architecture, 1981. / MICROFICHE COPY AVAILABLE IN ARCHIVES AND ROTCH. / Includes bibliographical references (p. 71). / The mill buildings of New England add a unique dimension to the heritage and identity of the region. Today some of these buildings continue to function as the site of industry, others have been converted to commercial or residential uses, and quite a few have been left to decompose. This thesis proposes some alternatives for converting 19th century mill buildings to residential use. It examines mills of brick bearing-wall construction with respect to their organization and materials, and looks critically at several contemporary mill conversions. It then concentrates specifically on showing how the exterior brick wall can be transformed in order to make decent places to live out of buildings designed for a very different purpose - industrial production. / Paul Pressman. / M.Arch.

Thesis (M. Arch.)--Massachusetts Institute of Technology, Dept. of Architecture, 1980. / MICROFICHE COPY AVAILABLE IN ARCHIVES AND ROTCH. / Includes bibliographical references. / Adaptability in this Thesis refers to the inherent capacity of a dwelling, to accommodate changing spatial and economic requirements over time. The adaptable dwelling is intended to respond to change as a fundamental condition of the human life-cycle, and offers choices to its inhabitants when changes occur. The adaptable dwelling is intended to provide an alternative to either moving as a result of change or to tolerating a space/need mis-match. Adaptability inevitably requires some overprovision of space and/or services within the dwelling which, in turn, requires increased expenditures. Thus, a major obstacle to providing adaptable housing - quite aside from strictly architectural concerns - is an economic one. A major contention of this Thesis is that adaptability will be realized only when it is built within an economic framework that will support/justify the necessary overprovision of space and/or services. The proposed economic framework in this Thesis is based on the notion of income-generation. The dwelling is conceived as a collection of areas that the inhabitants can combine - and continuously recombine - in a variety of ways such that the inhabitants can rent to others those areas which they do not need for themselves at any given time. In this way, overprovided space and/or services can generate operating income for the inhabitant which can offset the additional expenditures required for adaptability. The architectural intent of this Thesis is to design prototypical adaptable dwellings based on these social and economic notions. The adaptable dwelling is designed to function usefully as a residence for one, two or three families - at the option of the controlling inhabitant. A dwelling conceived and designed in this manner has a significant potential for adaptability within a supportive economic framework. / by John A. Winslow. / M.Arch.

A administração crônica de ouabaína (OUA) induz hipertensão arterial (HA) em ratos, alterações funcionais e remodelamento em artérias mesentéricas de resistência (AMR). A literatura sugere que a resposta pressórica da OUA pode ser bloqueada pelo antagonismo do receptor AT1 e pela inibição COX-2. No entanto, não se conhece a participação dessas vias no remodelamento arterial nesse modelo de HA. O presente estudo teve como objetivo investigar o papel do sistema renina-angiotensina (SRA) e da COX no remodelamento das AMR induzido pela OUA. Em AMR de ratos OUA, o SRA e a COX-2 participam da resposta pressórica, do remodelamento hipotrófico para dentro e da rigidez. Esses ajustes estão associados ao stress oxidativo e a deposição de colágeno na parede vascular estimulados pela capacidade da OUA em promover a ativação do receptor AT1 e da COX-2. / The chronic administration of ouabain (OUA) induces hypertension in rats, functional and structural alterations in mesenteric resistance arteries (MRA). It is well known that OUA-induced hypertension is blocked by AT1 receptor antagonism and the COX-2 inhibition. However, the participation of these pathways in MRA remodeling in this model of hypertension remains unknown. This study aimed to investigate the role of the renin angiotensin system (RAS) and COX pathways on MRA remodeling induced by OUA. In AMR from OUA rats, RAS and COX-2 participate in the pressor response, the inward hypotrophic remodeling and stiffness. These adjustments are the result of oxidative stressand increasing collagen deposition in the vascular wall stimulated by the OUA ability to stimulate the activation of AT1 receptor and COX-2.