Heart valve interstitial cells (VICs) undergo activation and proliferation in repair and disease, but the mechanisms are not fully understood. We hypothesize that the establishment of N-cadherin/β-catenin cell-cell contacts may decrease VIC activation, and that Wnt3a/β-catenin signaling may increase VIC proliferation. VIC cultures of different densities are stained for α-SMA, cofilin, TGF-β, pSmad2/3, N-cadherin and β-catenin, and probed for phospho-β-catenin by Western blot. Low density VIC cultures are treated with exogenous Wnt3a and measured for cell number, proliferation, apoptosis, α-SMA, β-catenin, and β-catenin-mediated transcription. β-Catenin siRNA knockdown is used to assess β-catenin specificity. Increased staining of α-SMA, cofilin, TGF-β, pSmad2/3, nuclear β-catenin, and increased phospho-β-catenin are associated with few cell-cell contacts. Wnt3a increased VIC cell number, proliferation, nuclear β-catenin and β-catenin-mediated transcription without affecting activation and apoptosis, and proliferation is abolished by β-catenin siRNA. Thus, N-cadherin/β-catenin cell-cell contacts may inhibit VIC activation and Wnt3a/β-catenin signaling may increase VIC proliferation.

Heart valve interstitial cells (VICs) undergo activation and proliferation in repair and disease, but the mechanisms are not fully understood. We hypothesize that the establishment of N-cadherin/β-catenin cell-cell contacts may decrease VIC activation, and that Wnt3a/β-catenin signaling may increase VIC proliferation. VIC cultures of different densities are stained for α-SMA, cofilin, TGF-β, pSmad2/3, N-cadherin and β-catenin, and probed for phospho-β-catenin by Western blot. Low density VIC cultures are treated with exogenous Wnt3a and measured for cell number, proliferation, apoptosis, α-SMA, β-catenin, and β-catenin-mediated transcription. β-Catenin siRNA knockdown is used to assess β-catenin specificity. Increased staining of α-SMA, cofilin, TGF-β, pSmad2/3, nuclear β-catenin, and increased phospho-β-catenin are associated with few cell-cell contacts. Wnt3a increased VIC cell number, proliferation, nuclear β-catenin and β-catenin-mediated transcription without affecting activation and apoptosis, and proliferation is abolished by β-catenin siRNA. Thus, N-cadherin/β-catenin cell-cell contacts may inhibit VIC activation and Wnt3a/β-catenin signaling may increase VIC proliferation.

Gliomas are the most common and aggressive primary brain tumors. The most common treatment protocols for these brain tumors are combinations of surgery, chemotherapy and radiotherapy. However, even with the most aggressive combination of surgery and radiotherapy and/or chemotherapy schedules, gliomas almost always recur resulting in a median survival time for patients of not more than 12 months. This highly diffusive and invasive nature of brain tumors makes it very important to study the effects of these combined therapeutic strategies in an effort to improve the survival time of patients. It is also important to study the tumor microenvironment, since the complex nature of the cerebral vasculature, including the blood brain barrier and several other tumor-induced conditions such as hypoxia, high interstitial pressure, and cerebral edema affect drug delivery as well as the effectiveness of radiotherapy. Recently, a novel strategy using antiangiogenic therapy has been studied for the treatment of brain tumors. Antiangiogenic therapy interferes with the development of tumor vasculature and indirectly helps in the control of tumor growth. Recent clinical trials suggest that anti-angiogenic therapy is usually more effective when given in combination with other therapeutic strategies. In an effort to study the effects of the aforementioned therapeutic strategies, a spatio-temporal model is considered here that incorporates the tumor cell growth and the effects of radiotherapy and chemotherapy. The effects of different schedules of radiation therapy is then studied using a generalized linear quadratic model and compared against the published clinical data. The model is then extended to include the interactions of tumor vasculature and oxygen concentration, to explain tumor hypoxia and to study various methods of hypoxia characterizations including biomarker estimates and needle electrode measurements. The model predicted hypoxia is also used to analyze the effects of tumor oxygenation status on radiation response as it is known that tumor hypoxia negatively influences the radiotherapy outcome. This thesis also presents a detailed analysis of the effects of heterogenous tumor vasculature on tumor interstitial fluid pressure and interstitial fluid velocity. A mathematical modeling approach is then used to analyze the changes in interstitial fluid pressure with or without antiangiogenic therapy.

Gliomas are the most common and aggressive primary brain tumors. The most common treatment protocols for these brain tumors are combinations of surgery, chemotherapy and radiotherapy. However, even with the most aggressive combination of surgery and radiotherapy and/or chemotherapy schedules, gliomas almost always recur resulting in a median survival time for patients of not more than 12 months. This highly diffusive and invasive nature of brain tumors makes it very important to study the effects of these combined therapeutic strategies in an effort to improve the survival time of patients. It is also important to study the tumor microenvironment, since the complex nature of the cerebral vasculature, including the blood brain barrier and several other tumor-induced conditions such as hypoxia, high interstitial pressure, and cerebral edema affect drug delivery as well as the effectiveness of radiotherapy. Recently, a novel strategy using antiangiogenic therapy has been studied for the treatment of brain tumors. Antiangiogenic therapy interferes with the development of tumor vasculature and indirectly helps in the control of tumor growth. Recent clinical trials suggest that anti-angiogenic therapy is usually more effective when given in combination with other therapeutic strategies. In an effort to study the effects of the aforementioned therapeutic strategies, a spatio-temporal model is considered here that incorporates the tumor cell growth and the effects of radiotherapy and chemotherapy. The effects of different schedules of radiation therapy is then studied using a generalized linear quadratic model and compared against the published clinical data. The model is then extended to include the interactions of tumor vasculature and oxygen concentration, to explain tumor hypoxia and to study various methods of hypoxia characterizations including biomarker estimates and needle electrode measurements. The model predicted hypoxia is also used to analyze the effects of tumor oxygenation status on radiation response as it is known that tumor hypoxia negatively influences the radiotherapy outcome. This thesis also presents a detailed analysis of the effects of heterogenous tumor vasculature on tumor interstitial fluid pressure and interstitial fluid velocity. A mathematical modeling approach is then used to analyze the changes in interstitial fluid pressure with or without antiangiogenic therapy.

<p>Impulse propagation in cardiac muscle is determined not only by the excitable properties of the myocyte membrane, but also by the gross and fine structure of cardiac muscle. Ionic diffusion pathways are defined by the muscle's interconnected myocytes and interweaving interstitial spaces. Resistive variations arising from spatial changes in tissue structure, including geometry, composition and electrical properties have a significant impact on the success or failure of impulse propagation. Although much as been learned about the impact of discrete resistive architecture of the intracellular space, the role of the interstitial space in the spread of electrical activity is less well understood or appreciated at the microscopic scale. </p><p>The interstitial space, or interstitium, occupies from 20-25% of the total heart volume. </p><p>The structural and material composition of the interstitial space is both complex and </p><p>heterogeneous, encompassing non-myocyte cell structures and a conglomeration of </p><p>extracellular matrix proteins. The spatial distribution of the interstitium can vary from confined spaces between abutting myocytes and tightly packed cardiac fibers to large gaps between cardiac bundles and sheets</p><p>This work presents a discrete multidomain formulation that describes the three-dimensional ionic diffusion pathways between connected myocytes within a variable interstitial physiology and morphology. Unlike classically used continuous and discontinuous models of impulse propagation, the intracellular and extracellular spaces are represented as spatially distinct volumes with dynamic and static boundary conditions that electrically couple neighboring spaces to form the electrically cooperative tissue model. The discrete multidomain model provides a flexible platform to simulate impulse propagation at the microscopic scale within a three-dimensional context. The three-dimensional description of the interstitial space that </p><p>encompasses a single cell improves the capability of the model to realistically investigate the impact of the discontinuous and electrotonic inhomogeneities of the myocardium's interstitium.</p><p>Under the discrete multidomain representation, a non-uniformly described interstitium </p><p>capturing the passive properties of the intravascular space or variable distribution and </p><p>composition of the extracellular space that encompasses a cardiac fiber creates an </p><p>electrotonic load perpendicular to the direction of the propagating wavefront. During </p><p>longitudinal propagation along a cardiac fiber, results demonstrate waveshape </p><p>alterations due to variations in loads experienced radially that would have been otherwise masked in traditional model descriptions. Findings present a mechanism for eliminating myocyte membrane participation in impulse propagation, as the result of decreased loading experienced radially from a non-uniformly resistive extracellular space. Ultimately, conduction velocity increases by decreasing the "effective" surface-to-volume ratio, as theoretically hypothesized to occur in the conducting Purkinje tissue.</p> / Dissertation

Aortic valve disease (AVD) affects millions of people of all ages around the world. Current treatment for AVD consists of valvular replacement with a non-living prosthetic valve, which is incapable of growth, self-repair, or remodeling. While tissue engineering has great promise to develop a living heart valve alternative, success in animal models has been limited. This may be attributed to the fact that understanding of valvular cell biology has not kept pace with advances in biomaterial development. Aortic valve leaflets are exposed to a complex and dynamic mechanical environment unlike any in the vasculature, and it is likely that native endothelial and interstitial cells respond to mechanical forces differently from other vascular cells. The objective of this thesis was to compare valvular cell phenotype to vascular cell phenotype, and assess the influence of steady shear stress on valvular cell biology. This thesis demonstrates that valvular endothelial cells respond differently to shear than vascular endothelial cells, by aligning perpendicular to the direction of steady shear stress, and by the differential regulation of hundreds of genes in both static and fluid flow environments. Valvular interstitial cells expressed a combination of contractile and synthetic phenotypes not mimicked by vascular smooth muscle cells. Two three-dimensional leaflet models were developed to assess cellular interactions and the influences of steady laminar shear stress. Valvular co-culture models exhibited a physiological response profile, while interstitial cell-only constructs behaved more pathologically. Steady shear stress enhanced physiological functions of valvular co-cultures, but increased pathological response of interstitial cell-only constructs. These results showed that valvular cells, whether cultured separately or together, behaved distinctly different from vascular cells. It was also determined that shear stress alone cannot induce tissue remodeling to more resemble native valve leaflets. The leaflet models developed in this thesis can be used in future experiments to explore valvular cell biology, assess the progression of certain forms AVD, and develop targeted diagnostic and therapeutic strategies to hopefully eliminate the need for valvular replacement entirely.

An insulation technique has been developed which contains a single or combination of materials to help minimize heat loss in actual industrial applications. For the petroleum industry, insulation for deep sea piping is one of the greatest challenges which would prevent the industry from meeting the high demand for oil through exploration into deeper ocean environments. At current seafloor depths (5,000~10,000ft), pipeline insulation is essential in preventing pipeline blockage resulting from the solidification of paraffin waxes and / or hydrate formation which exist in crude oil. To maintain crude oil temperatures above the paraffin solidification point (68°C or 155°F), new and better insulation techniques are essential to minimize pipeline heat loss and maintain crude oil temperatures. Therefore, the objective of this investigation was to determine whether or not the thermal resistance of a new insulation concept, which involves IIT (Interstitial Insulation Technology) with screen wire, was greater than existing readily available commercial products through analytical modeling and experimentation. The model takes into account both conforming and nonconforming interfaces at the wire screen contacts within the interstitial space between coaxial pipes. In addition, confirmation was needed to determine whether or not laboratory testing of simulated coupons translate to thermal performance for a prototype pipe segment that fabricated with two layers of low conductivity wire-screen (stainless steel) as the interstitial insulation material. Both the inner and outer surface temperatures of the coaxial pipes were measured in order to evaluate the effective thermal conductivity and thermal diffusivity of the insulation concept. The predicted results from the model compared very favorably with the experimental results, confirming both the trends and magnitudes of the experimental data. In other words, whether the reduction in heat transfer observed for small laboratory samples was realistic for application to a pipeline configuration. This effort involved both analytical modeling for all thermal resistances and experimental test runs for validation of the analytical model. Finally, it was a goal of this investigation to develop a simplified model for a multilayer composite structure which will include radiation heat transfer exchange among the layers that constitute the insulation. With the developed model, feasibility and performance characteristics of the insulation concept were predicted. The thermal predictions have demonstrated the thermal competitiveness of the interstitial insulation technology.

No description available.

none

The power of parallel supercomputing resources has progressed to the point where first-principles calculations involving systems up to 10³ atoms are feasible, allowing ab initio exploration of increasingly complex systems such as amorphous networks, nanostructures, and large defect clusters. Expansion of our fundamental understanding of modified Si-based materials is paramount, as these materials will likely flourish in the foreseeable cost-driven future in diverse micro- and nanotechnologies. Here, density-functional theory calculations within the generalized gradient approximation are applied to refine configurations of Si-based materials generated from Metropolis Monte Carlo simulations and study their resultant structural properties. Particular emphasis is given to the contributions of strain and disorder on the mechanical, optical, and electronic properties of modified Si-based materials in which aspects of compositional variation, phase, strain scheme, morphology, native defect incorporation, and quantum confinement are considered. The simulation strategies discussed are easily extendable to other semiconductor systems. / text