Stress and permeability variations around a wellbore and in the reservoir are of much interest in petroleum and geothermal reservoir development. Water injection causes significant changes in pore pressure, temperature, and stress in hot reservoirs, changing rock permeability. In this work, two- and three-dimensional finite element methods were developed to simulate coupled reservoirs with damage mechanics and stress-dependent permeability. The model considers the influence of fluid flow, temperature, and solute transport in rock deformation and models nonlinear behavior with continuum damage mechanics and stress-dependent permeability. Numerical modeling was applied to analyze wellbore stability in swelling shale with two- and three-dimensional damage/fracture propagation around a wellbore and injection-induced microseismic events. The finite element method (FEM) was used to solve the displacement, pore pressure, temperature, and solute concentration problems. Solute mass transport between drilling fluid and shale formation was considered to study salinity effects. Results show that shear and tensile failure can occur around a wellbore in certain drilling conditions where the mud pressure lies between the reservoir pore pressure and fracture gradient. The fully coupled thermo-poro-mechanical FEM simulation was used to model damage/fracture propagation and microseismic events caused by fluid injection. These studies considered wellbore geometry in small-scale modeling and point-source injection, assuming singularity fluid flux for large-scale simulation. Damage mechanics was applied to capture the effects of crack initiation, microvoid growth, and fracture propagation. The induced microseismic events were modeled in heterogeneous geological media, assuming the Weibull distribution functions for modulus and permeability. The results of this study indicate that fluid injection causes the effective stress to relax in the damage phase and to concentrate at the interface between the damage phase and the intact rock. Furthermore, induced-stress and far-field stress influence damage propagation. Cold water injection causes the tensile stress and affects the initial fracture and fracture propagation, but fracture initiation pressure and far-field stress are critical to create a damage/fracture plane, which is normal to the minimum far-field stress direction following well stimulation. Microseismic events propagate at both well scale and reservoir-scale simulation; the cloud shape of a microseismic event is affected by permeability anisotropy and far-field stress, and deviatoric horizontal far-field stress especially contributes to the localization of the microseismic cloud.

Hypochlorous acid (HOCl) is a powerful oxidant produced by activated phagocytes at sites of inflammation to kill a wide range of pathogens. Yet, it may also damage and kill the neighbouring host cells. The abundance of dead macrophages in atherosclerotic plaques and their colocalization with HOCl-modified proteins implicate HOCl may play a role in killing macrophages, contributing to disease progression. The first part of this research was to investigate the cytotoxic effect and cell death mechanism(s) of HOCl on macrophages. Macrophages require efficient defense mechanism(s) against HOCl to function properly at inflammatory sites. The second part of the thesis was to examine the antioxidative effects of glutathione (GSH) and 7,8-dihydroneopterin (7,8-NP) on HOCl-induced cellular damage in macrophages. GSH is an efficient scavenger of HOCl and a major intracellular antioxidant against oxidative stress, whereas 7,8-NP is secreted by human macrophages upon interferon-γ (IFN-γ) induction during inflammation and can also scavenge HOCl. HOCl caused concentration-dependent cell viability loss in human monocyte derived macrophage (HMDM) cells above a specific concentration threshold. HOCl reacted with HMDMs to cause viability loss within the first 10 minutes of treatment, and it posed no latent effect on the cells afterwards regardless of the HOCl concentrations. The lack of caspase-3 activation, rapid influx of propidium iodide (PI) dye, rapid loss of intracellular ATP and cell morphological changes (cell swelling, cell membrane integrity loss and rupture) were observed in HMDM cells treated with HOCl. These results indicate that HOCl caused HMDM cells to undergo necrotic cell death. In addition to the loss of intracellular ATP, HOCl also caused rapid loss of GAPDH enzymatic activity and mitochondrial membrane potential, indicating impairment of the metabolic energy production. Loss of the mitochondrial membrane potential was mediated by mitochondrial permeability transition (MPT), as blocking MPT pore formation using cyclosporin A (CSA) prevented mitochondrial membrane potential loss. HOCl caused an increase in cytosolic calcium ion (Ca2+) level, which was due to both intra- and extra-cellular sources. However, extracellular sources only contributed significantly above a certain HOCl concentration. Preventing cytosolic Ca2+ increase significantly inhibited HOCl-induced cell viability loss. This suggests that cytosolic Ca2+ increase was associated with HOCl-induced necrotic cell death in HMDM cells, possibly via the activation of Ca2+-dependent calpain cysteine proteases. Calpain inhibitors prevented HOCl-induced lysosomal destabilisation and cell viability loss in HMDM cells. Calpains induced HOCl-induced necrotic cell death possibly by degrading cytoskeletal and other cellular proteins, or causing the release of cathepsin proteases from ruptured lysosomes that also degraded cellular components. The HOCl-induced cytosolic Ca2+ increase also caused mitochondrial Ca2+ accumulation and MPT activation-mediated mitochondrial membrane potential loss. MPT activation, like calpain activation, was also associated with the HOCl-induced necrotic cell death, as preventing MPT activation completely inhibited HOCl-induced cell viability loss. The involvement of both calpain activation and MPT activation in HOCl-induced necrotic cell death in HMDM cells implies a cause and effect relationship between these two events. HMDM cells depleted of intracellular GSH using diethyl maleate showed increased susceptibility towards HOCl insult compared to HMDM cells with intact intracellular GSH levels, indicating that intracellular GSH played an important role in protecting HMDM cells against HOCl exposure. Intracellular GSH level in each HMDM cell preparation directly correlated with HOCl concentration required to kill 50% of population for each cell preparation, indicating intracellular GSH concentrations determine the efficiency of GSH in preventing HOCl-induced damage to HMDM cells. Intracellular GSH and cell viability loss induced by 400 μM HOCl were significantly prevented by 300 μM extracellular 7,8-NP, indicating that added 7,8-NP is an efficient scavenger of HOCl and out-competed intracellular GSH for HOCl. The amount of 7,8-NP synthesized by HMDM cells upon IFN-γ induction was too low to efficiently prevent HOCl-mediated intracellular GSH and cell viability loss. HOCl clearly causes HMDM cells to undergo necrosis when the concentration exceeds the intracellular GSH concentrations. Above this concentration HOCl causes oxidative damage to the Ca2+ ion channels on cell and ER membranes, resulting in an influx of Ca2+ ions into the cytosol and possibly the mitochondria. The rise in Ca2+ ions triggers calpain activation, resulting in the MPT-mediated loss of mitochondrial membrane potential, lysosomal instability and cellular necrosis.

After water vapour, CO₂ is the most abundant gas associated with magmatic hydrothermal systems. The detection of anomalous soil temperature gradients, and/or a significant flux of magmatic volatiles, is commonly the only surface signature of an underlying high temperature reservoir. For both heat (as water vapour) and gas to ascend to the surface, structural permeability must exist, as the unmodified bulk permeability of reservoir rock is too low to generate the focussed fluid flow typical of magmatic hydrothermal systems. This thesis reports the investigation into the surface heat and mass flow of the Ohaaki hydrothermal field using detailed surface measurements of CO₂ flux and heat flow. Detailed surface measurements form the basis of geostatistical models that quantify and depict the spatial variability of surface heat and mass flow, across the surface of both major thermal areas, as high resolution pixel plots. These maps, in conjunction with earlier heat and mass flow studies, enable: (i) estimates of the pre-production and current CO₂ emissions and heat flow for the Ohaaki Field; (ii) interpretation of the shallow permeability structures governing fluid flow, and; (iii) the spatial relationships between pressure-induced ground subsidence and permeability. Heat flow and CO₂ flux surveys indicate that at Ohaaki the soil zone is the dominant (≥ 70% and up to 99%) pathway of heat and mass release to the atmosphere from the underlying hydrothermal reservoir. Modelling indicates that although the total surface heat and mass flow at Ohaaki is small, it is highly focused (i.e., high volume per unit area) relative to other fields within the Taupo Volcanic Zone (TVZ). Normalised CO₂ emissions are comparable to other volcanic and hydrothermal fields both regionally and globally. Despite 20 years of production, there is little difference between pre-production and current CO₂ emission rates. However, the similarity of CO₂ emission rates masks a 40% increase in CO₂ emissions from new areas of intense steaming ground that have developed in response to production of the field for electrical energy production. This increase in thermal ground emissions is offset by emission losses associated with the drying up of all steam heated pools and alkali-Cl outflows from the Ohaaki West (OHW) thermal area, in response to production-induced pressure decline. The location of surface thermal areas is governed by the occurrence of buried or partially emergent lava domes, whereas the magnitude of CO₂ flux, mass flow, and heat flow occurring within each thermal area is determined by the proximity of each dome (thermal areas) to major upflow zones. Buried or partially emergent silicic lava domes act as cross-stratal pathways for fluid flow, connecting the underlying reservoir to the surface, and bypassing several hundred metres of the poorly permeable Huka Falls Formation (HFF) caprock. For each dome complex the permeable structures governing fluid flow are varied. At Ohaaki West, thermal activity is controlled by a deep-rooted concentric fracture zone, developed during eruption of the Ohaaki Rhyolite dome. Within the steam-heated Ohaaki East (OHE) thermal area, flow is controlled by a high permeability fault damage zone (Broadlands Fault) developed within the apex of the Broadlands Dacite dome. Structures controlling alkali-Cl fluid flow at OHW also iii appear to control the occurrence and shape of major subsidence bowls (e.g., the Main Ohaaki Subsidence Bowl), the propagation of pressure decline to surface, and the development and localization of pore fluid drainage. Across the remainder of the Ohaaki field low amplitude ground subsidence is controlled by the extent of aquifer and aquitard units that underlie the HFF, and proximity to the margins of the hot water reservoir. The correlation between the extent of low amplitude ground subsidence and the margins of the field reflects the coupled relationship between the hot water reservoir and reservoir pressure. Only where thick vapour-phase zones buffer the vertical propagation of deep-seated pressure decline to the surface (i.e., OHE thermal area), is ground subsidence not correlated with subvertical structural permeability developed within the HFF. This thesis makes contributions to regional and global research on geothermal and hydrothermal systems by: (i) quantifying the origin, mass, and upward transport of magmatic carbon from geothermal reservoirs; (ii) assessing the changes to the natural surface heat and mass flow of the Ohaaki Field following 20 years of production; (iii) establishing the utility of surface CO₂ flux and heat flow surveys to identify major upflow zones, estimate minimum mass flow, and determine the enthalpy of reservoirs; (iv) providing insight into the hydrothermal, structural and lithological controls over hydrothermal fluid flow; (v) demonstrating the influence of extinct silicic lava domes as important structural elements in the localisation of hydrothermal fluid flow; (vi) identifying the hydrostructural controls governing the spatial variability in the magnitude of pressure-induced ground subsidence, from which predictive models of subsidence risk may be defined, and; (vii) developing new technologies and characterising methods used for detailed assessment of surface heat and mass flow.

The aim of this study was to investigate the effect the plant matrix and the structure of the flavonoid (i.e. whether aglycone or glycoside) may have on the gastrointestinal uptake and metabolism of luteolin derivatives from Artemisia afra traditional plant medicine. Specifically, how these two factors influenced the intestinal uptake and disposition of luteolin derivatives in pure and in Artemisia afra plant extract forms were to be assessed by investigating the uptake and metabolism of the luteolin derivatives in human intestinal epithelial Caco-2 cells and the perfused rat intestinal loop. To realize this aim, the following were determined: (1) identification and characterization of major luteolin derivatives found in Artemisia afra, (2) the effect of the plant matrix on the uptake of luteolin derivatives in Artemisia afra aqueous-extract forms across the Caco-2 cell monolayer, (3) the effect of the plant matrix on the absorption and metabolism of luteolin derivatives in Artemisia afra aqueous-extract forms in the perfused rat small intestine, (4) the effect of gut contents on the uptake and metabolism of luteolin derivatives in intestinal loop and (5) the metabolic profiles of luteolin derivatives obtained for the pure solutions versus plant aqueous extract solutions in Caco-2 cells and the rat intestine. / Philosophiae Doctor - PhD

Biodegradable edible films are both economically and environmentally important to the food industry as packaging and coating materials, as the industry seeks to find a replacement to traditional petroleum-derived synthetic polymers. The overall goal of this thesis was to design a canola protein isolate (CPI)-based biodegradable and edible film that provides excellent mechanical, optical and water vapor barrier properties. A better understanding of the potential of CPI for use as a film-forming ingredient could lead to enhanced utilization and value of the protein for food and non-food applications. In study one, the mechanical, optical and water vapor barrier properties of CPI-based films were investigated as a function of protein (5.0% and 7.5% w/w) and glycerol (30%, 35%, 40%, 45%, and 50% w/w of CPI) concentrations. Overall, as the glycerol concentration increased for the 5.0% and 7.5% CPI-based films, mechanical strength and flexibility decreased and increased, respectively. Film strength was also found to increase at the higher protein concentration; however corresponding changes to film flexibility differed depending on the testing method used. For instance, puncture deformation testing indicated that film flexibility was reduced as the CPI concentration was raised, whereas tensile elongation testing indicated no change in extensibility between the two CPI concentrations. Film transparency was found to increase with increasing levels of glycerol and decreasing levels of CPI, whereas water vapor permeability was found to increase with increasing levels of both glycerol and protein. In study two, mechanical, optical and vapor barrier properties of CPI-based films were evaluated as a function of plasticizer-type (50% (w/w of CPI), glycerol, sorbitol, polyethylene glycol 400 (PEG-400)) and fixative condition (0% and 1% (w/w of CPI), genipin). CPI films prepared with sorbitol were significantly stronger than films with PEG-400, followed by films with glycerol, whereas the flexibility of CPI-based films with glycerol was higher than films with PEG-400, followed by films with sorbitol. In all cases, films prepared with genipin were stronger and less malleable than un-cross linked films. CPI films with glycerol were more transparent than films with sorbitol, followed by films with PEG-400, and the addition of genipin significantly increased the opacity of CPI films. CPI films prepared with glycerol also showed poorer water vapor barrier property than films with PEG-400, followed by films with sorbitol, however, no differences were observed in the presence and absence of genipin. In summary, as the plasticizer concentration increased or protein concentration decreased, CPI films became weaker, more flexible and clearer; however their water vapor barrier properties became poorer as both plasticizer and protein concentration increased. Moreover, CPI films with sorbitol and genipin were found to be stronger, less malleable and permeable to moisture than CPI films with or without genipin, and in the presence of glycerol or PEG-400. Overall, CPI could be considered as a potential material for the development of biodegradable edible packaging in the future.

This thesis utilizes a combination of landform and soil data and a GIS model to analyze previous subsurface reconnaissance data within the Tipton Till Plain region of Indiana. Survey areas are analyzed according to their location within drainages as well as on their individual surface and subsurface soil characteristics. Additionally, measurements of the valley width at the investigation area and upstream are collected and considered. Soils are also analyzed as a ratio of their individual impermeability in relation to the impermeability of upstream soils. Soil taxonomy and drainage characteristics are analyzed along with the effects stream order and proximity to water have on the potential for an area to contain buried deposits. The conclusion drawn is that comparisons of the permeability of individual drainage basins in relation to the larger drainage basin is not a reliable method of predicting the potential for site burial. The relationship between the valley width at the point of investigation in relation to valley width upstream was analyzed with a weak correlation between valley width stability and the potential for buried deposits. Soil drainage and taxonomic classification analysis appear to show where buried deposits are not likely to be encountered. The analyses of stream order and proximity to water did not reveal any significant differences in the potential for encountering buried deposits. It is recommended that the current guidelines for recommending subsurface investigation should be followed more strictly. / Department of Anthropology

Chitosan membrane has found applications in biomedical, wastewater treatment, and petrochemical fields that involve the use of silver ions (Ag+). However, mobility of Ag+ in chitosan membranes has seldom been studied. In this study, transport properties of Ag+ in chitosan membranes are studied in-depth, to determine diffusivity coefficient, permeability coefficient, and sorption uptake of Ag+ in chitosan. All parameters are evaluated based on the influence of feed concentration, membrane thickness and operating temperature. The diffusivity is determined from the time lag obtained from transient diffusion experiments. The permeability is determined from the steady state of permeation experimentally. The diffusivity and corresponding permeability coefficients of Ag+ in chitosan range from to 2.0 10-7 (cm2/s) and from 6.6 10-8 to 2.0 10-7 {mol m/[m2 s (mol/L)]}, respectively, over the conditions tested. Temperature dependencies of these two parameters are found to follow the Arrhenius relationship. Sorption uptake of the silver salt in chitosan correlates well with the Langmuir isotherm. Also determined from the sorption tests are degree of membrane swelling at different concentrations. This information allows diffusivity coefficients to be determined from the steady state permeation rate. These values of diffusivity are compared with that obtained using the time lag method.

INTRODUCTION: The blood brain barrier (BBB), formed by the brain capillary endothelial cells separating the blood from the brain. Furthermore, the brain endothelial cells also express numerous transporter systems which help regulate and maintain the brain microenvironment. The protective function of the BBB and their transporter systems under pathological disease states, including brain tumor, can be an obstacle for the entry of therapeutic agents to the brain. OBJECTIVES: The current study set out to characterize brain tumor-induced alterations of the BBB of a mouse brain tumor model. Studies were performed to address changes in BBB permeability to P-gp dependent solutes using Rhodamine (R800). Furthermore, the use of lysophosphatidic acid (LPA) to modulate BBB permeability was also examined in healthy mice and tumor-bearing mice. METHODS: Tumors were induced by injecting Lewis Lung carcinoma (3LL) cells into the right hemisphere of female Balb/c mice. Changes in BBB permeability were assessed at various stages of tumor development, using both gadolinium contrast-enhanced agent (Gad) and 3H-mannitol. Functional activity of P-gp in the BBB was examined in adult mice following i.v. injection of R800 in the presence and absence of GF120918 (a P-gp inhibitor). Alterations in BBB permeability were characterized in healthy and tumor-bearing mice using a small (Gad) and large (IRdye800cw PEG) vascular permeability agent as well as R800 (changes in P-gp mediated permeability). RESULTS: Median mouse survival following 3LL injection was 17 days. The BBB was largely intact during tumor development with disruptions observed at the later stages of tumor development as indicated by Gad permeability. By inhibiting the function of P-gp with GF120918, the distribution of R800 in the brain increased by 4-fold. The enhancement effect of LPA on BBB permeability occurs within 3-6 minutes of injection with the barrier being restored back to its normal function within 20 minutes. Furthermore, an increased in brain penetration of IRdye800ce PEG and R800 were observed following LPA injection in both healthy and tumo-bearing mice. CONCLUSION: These studies provide the initial proof of concept for the use of BBB modulators including LPA and GF120918 to enhance drug delivery to the brain and the tumor sites.

<p>The vasculature has a crucial function in normal physiology, enabling the transport of oxygen and nutrients to cells throughout the body. In turn, endothelial cells, which form the inner-most lining of blood vessels, are key regulators of vascular function. In addition to forming a barrier which separates the circulation from underlying tissues, endothelial cells respond to diverse extracellular cues and produce a variety of biologically-active mediators in order to maintain vascular homeostasis. Disruption of normal vascular function is a prominent feature of a variety of pathological conditions. Thus, elucidating the signaling pathways regulating endothelial function is critical for understanding the role of endothelial cells in both normal physiology and pathology, as well as for potential development of therapeutic interventions.</p><p>In this dissertation, we use a combination of pharmacological inhibition and knockdown studies, along with generation of endothelial conditional knockout mice, to demonstrate an important role of the Abelson (Abl) family of non-receptor tyrosine kinases (Abl and Arg) in vascular function. Specifically, loss of endothelial expression of the Abl kinases leads to late-stage embryonic and perinatal lethality in conditional knockout mice, indicating a crucial requirement for Abl/Arg kinases in normal vascular development and function. Endothelial <italic>Abl</italic>/<italic>Arg</italic>-null embryos display focal regions of vascular loss and tissue damage, as well as increased endothelial cell apoptosis. An important pro-survival function for the Abl kinases is further supported by our finding that either microRNA-mediated <italic>Abl</italic>/<italic>Arg</italic> depletion or pharmacological inhibition of the Abl kinases increases endothelial cell susceptibility to stress-induced apoptosis <italic>in vitro</italic>. The Abl kinases are activated in response to treatment with the pro-angiogenic growth factors vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). We show that both VEGF- and bFGF-mediated endothelial cell survival is impaired following Abl kinase inhibition.</p><p>These studies have uncovered a previously unappreciated role for the Abl kinases in the regulation of the angiopoietin/Tie2 signaling pathway, which functions to support endothelial cell survival and vascular stability. Loss of Abl/Arg expression leads to reduced mRNA and protein levels of the Tie2 receptor, resulting in impaired activation of intracellular signaling pathways by the Tie2 ligand angiopoietin-1 (Angpt1), as well as decreased Angpt1-mediated endothelial cell survival following serum-deprivation stress. Notably, we found that the Abl kinases are activated following Angpt1 stimulation, suggesting a unique dual role for Abl and Arg in Angpt/Tie2 signaling, potentially modulating Tie2 downstream signaling responses, as well as regulating Tie2 receptor expression.</p><p>Further, we show an important contribution of the Abl family kinases to the regulation of endothelial permeability responses both <italic>in vitro</italic> and <italic>in vivo</italic>. The Abl kinases are activated in response to a diverse group of permeability-inducing factors, including VEGF and the inflammatory mediators thrombin and histamine. We show that inhibition of Abl kinase activity, using either the ATP-competitive inhibitor imatinib or the allosteric inhibitor GNF-2, protects against disruption of endothelial barrier function by the permeability-inducing factors <italic>in vitro</italic>. VEGF-induced vascular permeability similarly is decreased in conditional knockout mice lacking endothelial Abl expression, as well as following treatment with Abl kinase inhibitors <italic>in vivo</italic>. Mechanistically, we show that loss of Abl kinase activity is accompanied by activation of the barrier-stabilizing GTPases (guanosine triphosphatases) Rac1 and Rap1, as well as inhibition of agonist-induced Ca<super>2+</super> mobilization and generation of acto-myosin contractility.</p><p>Taken together, these results demonstrate involvement of the Abl family kinases in the regulation of endothelial cell responses to a broad range of pro-angiogenic and permeability-inducing factors, as well as a critical requirement for the endothelial Abl kinases in normal vascular development and function <italic>in vivo</italic>. These findings have implications for the clinical use of Abl kinase inhibitors.</p> / Dissertation

Im Rahmen der Dissertation wurde untersucht, wie die Wasserdurchlässigkeit von ToB unter Baustellenbedingungen geprüft werden kann und welcher Zusammenhang zwischen Verformungsmodul und Wasserdurchlässigkeit besteht und ob diese Eigenschaften baustofftech-nisch oder bautechnologisch beeinflussbar sind. Dazu wurden bei einer Vielzahl von Baumaßnahmen beim Ausbau des Autobahnnetzes in den neuen Bundesländern baubegleitende Messungen auf Tragschichten durchgeführt. Außerdem wurden auf verschiedenen ToB-Versuchsfeldern in einem Lysimeter Vergleichsuntersuchungen mit den Prüfgeräten Tropf-, Doppelring- und Standrohr-Infiltrometer durchgeführt. Außerdem fanden Untersuchungen auf zwei Versuchs-Baustraßen in Schotterwerken statt. Untersucht wurde zunächst, wie sich die Variation der Parameter Korngrößenverteilung, Kornform und Sandtyp sowie Verdich-tungswassergehalt und Verdichtungsgrad auf die Eigenschaften der ToB im Neuzustand auswirken. Es wurde außerdem Untersucht, inwieweit sich ein Zusammenhang darstellen lässt zwischen dem Anstieg der Tragfähigkeit (Ev2-Wert) über eine bestimmte Schichtdicke der ToB und ihrer Wasserdurchlässigkeit.