The regulation of fluid (water) volume in the body is crucial for tissue homeostasis. The interstitial fluid, which comprises almost 20% of the body fluid, is stored in the loose connective tissue and its volume is actively regulated by components of this tissue. The loose connective tissue provides a path for fluid flow from capillaries to the tissue and lymphatics. This fluid is partially stored in the interstitium and the remainder is directed to the lymphatics. The fibroblasts in the loose connective tissue actively compact the fibrous extracellular matrix (ECM) through mechanotransduction via integrins. This in turn, maintains the interstitial fluid pressure and keeps the ground substance underhydrated. The interstitial fluid pressure is part of the forces that regulate the efflux of fluid from capillaries and keep the ground substance underhydrated. The underhydrated ground substance has a potential to take up fluid 3-fold the plasma volume. Therefore, the active contraction of the ECM via fibroblasts is crucial to prevent the risk of evacuation of fluid from capillaries. During pathologies, such as inflammation and carcinogenesis, the interstitial fluid pressure and hence the interstitial fluid volume is altered. The results presented in this thesis show that the signaling events downstream of αVβ3 integrin, collagen-binding β1 integrins, and platelet-derived growth factor receptor β, that induce cell-mediated matrix contraction, included paired function of PI3K and PLCγ, cofilin activation, actin turnover, and generation of actomyosin forces. Furthermore, the results highlight new potential roles for fibrin and αVβ3 integrins, for instance during clearance of edema. Notably, fibrin extravasation at inflammatory sites induced αVβ3 integrin-dependent matrix contraction, leading to normalization of the altered interstitial fluid volume. It also reprograms the expression of ECM-related genes and hence induces ECM turnover. Taken together, these results provide further insight into the regulatory mechanism through which the loose connective tissue actively regulates the interstitial fluid volume.

Orientador: Peter Christian Hackspacher / Banca: Luiz Sergio Amarante Simões / Banca: Nelson Angeli / Banca: Carlos José Archanjo / Banca: Marcos Egydio da Silva / Resumo: A zona de cisalhamento Itapetim (ZCI) desenvolveu foliação e lineação nos diferentes tipos de rochas, milonitos a ultramilonitos. Muitos dos tipos de microestruturas observadas na ZCI preservam evidências de condições metamórficas de alto grau e baixo grau de temperatura. O padrão das orientações preferenciais dos eixos [c] de quartzo, obtida a partir de agregados policristalinos deformados, mostra dois diferentes tipos de simetrias, guirlandas do tipo I e simples. A análise da textura sugere partição da deformação com cisalhamento coaxial e não coaxial na ZCI. Um veio de quartzo mineralizado em ouro encaixado em rocha ultramilonítica, constitui a zona de precipitação hidrotermal. O veio é bandado por segmentos de turmalina, o qual inclui agregados de grãos de quartzo maciço entre as bandas. Os grãos de quartzo mostram contatos poligonais e restritos limites intumescentes. O último sugere recristalização dinâmica por migração de limite de grão e os grãos poligonais (microestrutra em espuma) são melhor explicados por annealing. Os padrões de eixos [c] de quartzo obtido no veio aurífero é idêntico ao observado nos ultramilonitos da ZCI. Este padrão é interpretado como uma textura preservada formada durante o cisalhamento não coaxial. A estrutura bandada é interpretada como o resultado de variações da pressão de fluidos e a formação microfraturas, associadas a eventos de crack-seal. Mecanismos de crack-seal foram ativos antes ou durante a deformação da ZCI. As feições microestruturais suportam evidências para a última possibilidade. / Abstract: The Itapetim shear zone(ISZ) developed both foliation and lineation in the different rock types, from mylonites to ultramylonites. Most of the microstructure types observed in the ISZ preserve evidence of high temperature metamorphic conditions. The quartz [c]-axis, of deformed polycrystalline aggregates, show two distinct symmetries, type I crossed girdles and single girdles. The geometrical analysis of texture, suggest non-coaxial shear for deformation in ISZ. A gold mineralized quartz vein hosted in ultramylonitic rocks, constitutes the hydrothermal precipitation zone. The vein is banded by tourmiline segments, which include massive quartz grains aggregates between the bands. The quartz grains show polygonal contacts and minor intumescent limits. These latter suggest grain boundary migration recrystallization and the polygonal grains seem to be best explained by the annealing after stopping the shear deformation. The quartz [c]-axis obtained in the auriferous vein shows the same single girdle pattern observed in the ultramylonites of the ISZ. This pattern is interpreted as a preserved texture formed during the shear deformation. The banded structure is interpreted as the result of variations of the fluid pressure and the formation of microfractures, associated the crack-seal events. Crack-seal mechanisms can have been active previous or during the deformation of the IZS. The microstructurals features supports evidences for the last possibility. / Doutor

Les écoulements pyroclastiques sont des mélanges à haute température de gaz et de particules volcaniques qui peuvent se propager sur de très grandes distances. Cette forte « mobilité » est souvent attribuée à leur capacité à se fluidiser, c’est-à-dire à générer et conserver une forte pression interstitielle de gaz qui réduit les forces de friction interne. L’objectif principal de cette thèse est de comprendre comment les irrégularités des terrains sur lesquelles se propagent les écoulements pyroclastiques peuvent favoriser leur fluidisation. Une première série d’expériences de laboratoire a consisté à générer des écoulements de particules fines (diamètre de 45-90 μm) sur des substrats de différentes rugosités. Les résultats montrent que la distance de parcours des écoulements augmente avec la rugosité, allant jusqu’à doubler par rapport à la distance de parcours sur fond lisse. Des analyses de vidéos haute vitesse et des mesures de pression interstitielle d’air à la base des écoulements montrent que la tête (partie antérieure) des écoulements qui se propagent sur un substrat rugueux s’auto-fluidisent en conséquence de la sédimentation des particules dans les interstices du substrat, chassant l’air qui remonte et percole dans l’écoulement. Ce mécanisme d’auto-fluidisation est efficace pour toutes les inclinaisons étudiées (0-30°), suggérant qu’il est susceptible de se produire tout au long de la mise en place d’un écoulement pyroclastique. Une seconde étude a consisté à faire chuter des lits de particules dans une colonne statique. Les résultats montrent que même pour une hauteur de relâchement relativement faible (20 cm), le mélange peut entièrement s’auto-fluidiser durant sa chute. Quand les particules sont suffisamment fines (<100 μm) la pression interstitielle dans le dépôt diffuse pendant plusieurs secondes, la durée de cette diffusion augmentant avec l’augmentation de l’épaisseur du lit et la diminution de taille des particules. Les temps de diffusions les plus longs sont observés avec un matériau provenant d’un dépôt d’écoulement pyroclastique (~30 s pour des lits de 28.5 cm d’épaisseur). Ces résultats suggèrent que les écoulements pyroclastiques qui se propagent sur des terrains accidentés peuvent s’auto-fluidiser et conserver une faible friction au cours de leur mise en place. / Pyroclastic flows are hot mixtures of gas and particles that can propagate over large distances. This high “mobility” is often attributed to their ability to be fluidized, that is, to generate and retain high gas pore pressure that reduces internal friction forces. The main objective of this thesis is to understand how irregularities of substrates on which pyroclastic flows propagate can enhance their fluidization. A first set of laboratory experiments consisted of the generation of fine-grained flows (diameter of 45-90 μm) on substrate of various roughness. Results show that the flow runout distance increases with the substrate roughness, and is up to twice the runout on a smooth substrate. High speed video analyses and air pore pressure measurements at the flow base show that the flow head propagating over a rough substrate can auto-fluidize because of particles sedimentation into the substrate interstices, which forces the air to escape upward and percolate through the flow. This auto-fluidization mechanism is efficient at all inclinations investigated (0-30°), suggesting that it could occur during the whole emplacement of a pyroclastic flow. A second study consisted of the vertical release of beds of particles in a static column. Results show that the granular mixture can be fully fluidized, even when collapsing from a relatively low height (20 cm). When particles are fine enough (<100 μm), pore pressure in the deposit diffuses for several seconds, the diffusion duration increasing with increasing bed thickness and decreasing particle size. The longest diffusion durations are observed for pyroclastic flow deposit materials (~30 s for 28.5 cm thick beds). These results suggest that pyroclastic flows propagating on irregular terrains can auto-fluidize and preserve low internal friction during their emplacement.

In vielen industriellen Anwendungen sind Dichtungen im Einsatz. Vergleicht man den Preis mit dem eines Gesamtsystems, in denen Dichtungen verwendet werden, so sind Dichtungen verhältnismäßig günstig. Jedoch führt ein Versagen von Dichtungen meist zu schwerwiegenden Konsequenzen. Dichtungen sind komplexe Subsysteme und ihre Auslegung erfordert umfangreiche Kenntnisse im Bereich Materialmodellierung, Belastung und Versagenskriterien. Die heutige Simulationstechnologie ermöglicht einen parametrischen Workflow für die Berechnung des Verhaltens von Dichtungen mit den auftretenden Effekten wie nichtlinearem Materialverhalten, wechselnden Kontaktbedingungen und Flüssigkeitsunterwanderung bei Druck. Als ein führendes Simulationswerkzeug für diese physikalische Fragestellung wird ANSYS Mechanical für die Auslegung herangezogen. Desweiteren kann das Verständnis für das Produkt erhöht werden, was zu einer Verbesserung der Funktionalität und der Zuverlässigkeit führt. Versuchsdaten können als Spannungs-Dehnungskurven in ANSYS importiert werden, welche das Materialverhalten des hyperelastischen Werkstoffs mit traditionellen Materialmodellen wie Mooney Rivlin, Ogden and Yeoh oder einer neueren Formulierung, der Antwortfunktionsmethode, widerspiegeln. Robuste Kontakttechnologien beschleunigen die Simulation und Entwicklungszeit-Berechnungszeiten und gewährleisten ein genaues Verhalten des Simulationsmodells. Insbesondere bei Dichtungen ist die druckbeaufschlagte Fläche in 2D und 3D Anwendungen von Bedeutung. ANSYS berechnet diese automatisch in Abhängigkeit des aktuellen Kontaktzustandes. Diese benutzerfreundliche Unterstützung führt zu einer höheren Genauigkeit des Simulationsergebnisses, da ein manuelles Schätzen der Druckflächen entfällt. Mit einem parametrischen und durchgängigen Ansatz innerhalb von ANSYS Workbench, beginnend bei der CAD-Geometrie, über die Vernetzung, Material- und Randbedingungsdefinition und Lösung. können eine Reihe von Varianten in kurzer Zeit berechnet werden. Neben einem besseren Verständnis für das Produkt hilft dies dem Ingenieur Änderungen vorzunehmen, was zu exakten und aussagekräftigen Ergebnissen führt. Desweiteren kann der Einfluss von Unsicherheiten berücksichtigt werden, sodass der Berechnungsingenieur fernab von idealen Bedingungen robuste und zuverlässige Dichtungen entwickeln kann.

Mud volcanoes constitute an important component of petroliferous basins and their understanding is essential for successful exploration and development of hydrocarbon fields. They occur in both extensional and compressive tectonic settings, along with passive and active continental margins. Although extensive research exists on the geochemistry, geomorphology and stratigraphic evolution of these localized fluid flow structures, little is known about their geomechanical characteristics. This research investigates the geomechanics of mud volcanoes from the South Caspian Basin and West Nile Delta. This is achieved by establishing a workflow for geomechanical assessment of mud volcanoes using a P-wave velocity dataset from across the mud volcano within the offshore South Caspian Basin. This objective is developed further with the availability of seismic and wellbore data from around the Giza mud volcano, offshore West Nile Delta. Preliminary results of this study from the South Caspian Basin enable confidence in estimating the realistic magnitudes of elastic rock properties, stresses and fluid pressures from empirical and analytical correlations. Moreover, analysis of the variations in fluid pressures allow the fluid flow models around the mud volcano to be constrained and their gradients provide preliminary estimates of the drilling window. Structural and stratigraphic analysis around the Giza mud volcano offers insight into the formation of the mud volcano during the Quaternary and how the fault networks on the hanging wall of the arcuate tectonic fault have acted as conduits for primarily the pre-Pliocene fluids exploiting the areas of weakness along the hanging wall of the fault by entraining the Pliocene sediments. Fluid pressure evaluation reveals small overpressures caused by disequilibrium compaction. Further analysis offers insight into the critical fluid pressures that control fault movement, the stresses responsible for rock deformation around the wellbore and the width of the drilling window constrained by the fracturing of the strata. Analysis presented here provides details on the geomechanical significance of mud volcano environments, with implications for engineering practices. Overall, findings contribute to a systematic understanding of mud volcano settings not only from a field exploration and development point of view, but also at a wider scale for basin analysis and relatively small scale for play analysis.

This dissertation consists of two parts and investigates the crustal deformation associated with great subduction zone earthquake at two different spatial scales. At the small scale, I investigate the stress transfer along the megathrust during great earthquakes and its effects on the forearc wedge. At the large scale, I investigate the viscoelastic crustal deformation of the forearc and the back arc associated with great earthquakes. Part I: In a subduction zone, the frontal region of the forearc can be morphologically divided into the outer wedge and the inner wedge. The outer wedge which features much active plastic deformation has a surface slope angle generally larger than that of the inner wedge which hosts stable geological formations. The megathrust can be represented by a three-segment model, the updip zone (velocity-strengthening), seismogenic zone (velocity-weakening), and downdip zone (velocity-strengthening). Our dynamic Coulomb wedge theory postulates that the outer wedge overlies the updip zone, and the inner wedge overlies the seismogenic zone. During an earthquake, strengthening of the updip zone may result in compressive failure in the outer wedge. The inner wedge undergoes elastic deformation. I have examined the geometry and mechanical processes of outer wedges of twenty-three subduction zones. The surface slope of these wedges is generally too high to be explained by the classical critical taper theory but can be explained by the dynamic Coulomb wedge theory. Part II: A giant earthquake produces coseismic seaward motion of the upper plate and induces shear stresses in the upper mantle. After the earthquake, the fault is re-locked, causing the upper plate to move slowly landward. However, parts of the fault will undergo continuous aseismic afterslip for a short duration, causing areas surrounding the rupture zone to move seaward. At the same time, the viscoelastic relaxation of the earthquake-induced stresses in the upper mantle causes prolonged seaward motion of areas farther landward including the forearc and the back arc. The postseismic and interseismic crustal deformation depends on the interplay of these three primary processes. I have used three-dimensional viscoelastic finite element models to study the contemporary crustal deformation of three margins, Sumatra, Chile, and Cascadia, that are presently at different stages of their great earthquake cycles. Model results indicate that the earthquake cycle deformation of different margins is governed by a common physical process. The afterslip of the fault must be at work immediately after the earthquake. The model of the 2004 Sumatra earthquake constrains the characteristic time of the afterslip to be 1.25 yr. With the incorporation of the transient rheology, the model well explains the near-field and far-field postseismic deformation within a few years after the 2004 Sumatra event. The steady-state viscosity of the continental upper mantle is determined to be 10^19 Pa S, two orders of magnitude smaller than that of the global value obtained through global postglacial rebound models. / Graduate

This dissertation consists of two parts and investigates the crustal deformation associated with great subduction zone earthquake at two different spatial scales. At the small scale, I investigate the stress transfer along the megathrust during great earthquakes and its effects on the forearc wedge. At the large scale, I investigate the viscoelastic crustal deformation of the forearc and the back arc associated with great earthquakes. Part I: In a subduction zone, the frontal region of the forearc can be morphologically divided into the outer wedge and the inner wedge. The outer wedge which features much active plastic deformation has a surface slope angle generally larger than that of the inner wedge which hosts stable geological formations. The megathrust can be represented by a three-segment model, the updip zone (velocity-strengthening), seismogenic zone (velocity-weakening), and downdip zone (velocity-strengthening). Our dynamic Coulomb wedge theory postulates that the outer wedge overlies the updip zone, and the inner wedge overlies the seismogenic zone. During an earthquake, strengthening of the updip zone may result in compressive failure in the outer wedge. The inner wedge undergoes elastic deformation. I have examined the geometry and mechanical processes of outer wedges of twenty-three subduction zones. The surface slope of these wedges is generally too high to be explained by the classical critical taper theory but can be explained by the dynamic Coulomb wedge theory. Part II: A giant earthquake produces coseismic seaward motion of the upper plate and induces shear stresses in the upper mantle. After the earthquake, the fault is re-locked, causing the upper plate to move slowly landward. However, parts of the fault will undergo continuous aseismic afterslip for a short duration, causing areas surrounding the rupture zone to move seaward. At the same time, the viscoelastic relaxation of the earthquake-induced stresses in the upper mantle causes prolonged seaward motion of areas farther landward including the forearc and the back arc. The postseismic and interseismic crustal deformation depends on the interplay of these three primary processes. I have used three-dimensional viscoelastic finite element models to study the contemporary crustal deformation of three margins, Sumatra, Chile, and Cascadia, that are presently at different stages of their great earthquake cycles. Model results indicate that the earthquake cycle deformation of different margins is governed by a common physical process. The afterslip of the fault must be at work immediately after the earthquake. The model of the 2004 Sumatra earthquake constrains the characteristic time of the afterslip to be 1.25 yr. With the incorporation of the transient rheology, the model well explains the near-field and far-field postseismic deformation within a few years after the 2004 Sumatra event. The steady-state viscosity of the continental upper mantle is determined to be 10^19 Pa S, two orders of magnitude smaller than that of the global value obtained through global postglacial rebound models. / Graduate

Made available in DSpace on 2014-06-11T19:32:21Z (GMT). No. of bitstreams: 0 Previous issue date: 2003-08-15Bitstream added on 2014-06-13T20:23:37Z : No. of bitstreams: 1 almeida_hl_dr_rcla.pdf: 806140 bytes, checksum: 7940276ecd62a931d89c15464ccc97db (MD5) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / A zona de cisalhamento Itapetim (ZCI) desenvolveu foliação e lineação nos diferentes tipos de rochas, milonitos a ultramilonitos. Muitos dos tipos de microestruturas observadas na ZCI preservam evidências de condições metamórficas de alto grau e baixo grau de temperatura. O padrão das orientações preferenciais dos eixos [c] de quartzo, obtida a partir de agregados policristalinos deformados, mostra dois diferentes tipos de simetrias, guirlandas do tipo I e simples. A análise da textura sugere partição da deformação com cisalhamento coaxial e não coaxial na ZCI. Um veio de quartzo mineralizado em ouro encaixado em rocha ultramilonítica, constitui a zona de precipitação hidrotermal. O veio é bandado por segmentos de turmalina, o qual inclui agregados de grãos de quartzo maciço entre as bandas. Os grãos de quartzo mostram contatos poligonais e restritos limites intumescentes. O último sugere recristalização dinâmica por migração de limite de grão e os grãos poligonais (microestrutra em espuma) são melhor explicados por annealing. Os padrões de eixos [c] de quartzo obtido no veio aurífero é idêntico ao observado nos ultramilonitos da ZCI. Este padrão é interpretado como uma textura preservada formada durante o cisalhamento não coaxial. A estrutura bandada é interpretada como o resultado de variações da pressão de fluidos e a formação microfraturas, associadas a eventos de crack-seal. Mecanismos de crack-seal foram ativos antes ou durante a deformação da ZCI. As feições microestruturais suportam evidências para a última possibilidade. / The Itapetim shear zone(ISZ) developed both foliation and lineation in the different rock types, from mylonites to ultramylonites. Most of the microstructure types observed in the ISZ preserve evidence of high temperature metamorphic conditions. The quartz [c]-axis, of deformed polycrystalline aggregates, show two distinct symmetries, type I crossed girdles and single girdles. The geometrical analysis of texture, suggest non-coaxial shear for deformation in ISZ. A gold mineralized quartz vein hosted in ultramylonitic rocks, constitutes the hydrothermal precipitation zone. The vein is banded by tourmiline segments, which include massive quartz grains aggregates between the bands. The quartz grains show polygonal contacts and minor intumescent limits. These latter suggest grain boundary migration recrystallization and the polygonal grains seem to be best explained by the annealing after stopping the shear deformation. The quartz [c]-axis obtained in the auriferous vein shows the same single girdle pattern observed in the ultramylonites of the ISZ. This pattern is interpreted as a preserved texture formed during the shear deformation. The banded structure is interpreted as the result of variations of the fluid pressure and the formation of microfractures, associated the crack-seal events. Crack-seal mechanisms can have been active previous or during the deformation of the IZS. The microstructurals features supports evidences for the last possibility.

High interstitial fluid pressure (IFP) in tumours is recognized as a barrier to drug delivery resulting in reduced efficacy. High IFP impedes the normal process of convective fluid flow (CFF) from blood vessels into the interstitium. The aim of this study was to develop an in vitro model that could be used to measure CFF and to study its effects on drug delivery. The model consists of a transwell cell culture insert which supports the growth of multicell layers (MCL) on collagen coated membranes. A graduated tube is inserted into the transwell and a pressure gradient is applied across the membrane by raising the volume of medium in the tube above that of the bottom chamber. CFF is determined by measuring the weight of medium in the bottom chamber as a function of time. CFF was inversely proportional to MCL thickness and 41.1±3.6µm thick MCL has completely stopped CFF. Using a physiologically relevant hydrostatic pressure of 28mmHg, a CFF of 21µL/min was recorded using a DLD-1 MCL that was 12.21±3.2µm thick. Under these conditions, the rates of penetration of doxorubicin, imatinib and gefitinib were respectively 42, 26 and 13 folds greater than when no CFF exists. Reversing the CFF so that it opposed the drug diffusion gradient significantly impairs drug penetration. In conclusion, a novel in vitro model for assessing the impact of CFF on drug delivery has been developed. This model could be used to evaluate strategies designed to increase drug delivery to solid tumours by modifying the CFF.

<p>Molecular mechanisms in the development and progression of thyroid carcinomas are still not fully understood. In the present thesis the highly malignant anaplastic thyroid carcinoma (ATC) was used to study regulation of apoptosis and tumor interstitial fluid pressure (IFP).</p><p>Addition of a natural estrogen metabolite, 2-Methoxyestradiol (2-ME), induced a G2/M cell cycle arrest and apoptosis in five out of six human ATC cell lines. Treatment with 2-ME induced DNA-fragmentation as well as activation of caspase-3. Inhibitors of JNK and p38 MAPKs activity decreased the effect of 2-ME suggesting involvement in the induction of apoptosis.</p><p>Solid tumors have an elevated IFP. High IFP forms or reflects a barrier for exchange of molecules between microvessels and surrounding tissue. The mechanisms for the generation of the high IFP were investigated using a specific TGF-β inhibitor in an ATC model in athymic mice. Tumor IFP was lowered in TGF-β inhibitor-treated compared to control mice. Affymetrix microarray analysis showed a decreased expression of macrophage-associated genes in treated tumors. Furthermore, the number and activity of tumor-associated macrophages was reduced after TGF-β inhibition. A decreased protein leakage together with an increased coverage of α-smooth-muscle actin (SMA)-expressing cells indicated vessel normalization. An adjuvant treatment with the TGF-β inhibitor resulted in an increased treatment efficacy of doxorubicin. Thus, TGF-β inhibitor-treatment suggests improved microvessel function which results in a lowering of tumor IFP and increased tumor drug uptake.</p><p>To create a model for specific inactivation of genes in the thyroid, a transgenic mouse with a thyrocyte-specific expression of Cre recombinase was generated. The thyroglobulin promoter together with an inducible Cre recombinase (<i>creER</i><i>T2</i>) was used. Two transgenic founder lines were identified expressing cre mRNA solely in the thyroid. Functional activity of the CreER^T2 protein was demonstrated by using a ROSA26-LacZ reporter mouse.</p>