Ischemic stroke is characterized by a disruption of blood supply to a part of the brain tissue, which leads to a focal ischemic infarct. The expression and activity of MMP-9 is increased in ischemic stroke and is considered to be one of the main factors responsible for damages to the cerebral vasculature, resulting in compromised blood-brain barrier (BBB) integrity. However, the regulatory mechanisms of MMP-9 expression and activity are not well established in ischemic stroke. Since hypoxia/ischemia and reperfusion generates reactive oxygen species (ROS), I hypothesize that ROS is one of factors involved in up-regulation of MMP-9 expression in brain cells and ROS-mediated effect may occur via MAPK signaling pathway. My study has provided the evidence that ROS is responsible for an increase in MMP-9 expression in astrocytes mediated via MAPK-AP1 signaling pathway. Preliminary studies with an in vitro model of the BBB suggest that inhibition of MMP-9 is a critical component of reducing ROS-induced BBB permeability.

The disruption of the blood-brain barrier (BBB) occurs after ischemic and hemorrhagic stroke and contributes to secondary brain damage. Matrix metalloproteinase-9 (MMP9) has been identified to be the main mediator of post-stroke BBB disruption. It is unknown whether deposition of heme/iron in the brain following stroke would affect MMP9 expression. In this study, I have demonstrated that heme/iron up-regulated MMP9 expression in rat astrocytes and that this upregulation was most likely due to reactive oxygen species (ROS) generated by heme/iron deposition on cells. ROS can activate AP-1 and NFκB signaling pathways which were responsible for increased MMP9 expression. Inhibiting AP-1 and NFκB decreased MMP9 expression. Heme/iron deposition also activated Nrf-2 and increased the expression of neuroprotective heme oxygenase-1. My study suggests that heme and iron deposition generates ROS and increases MMP9 expression through AP-1 and NFκB signaling pathways and that targeting these pathways or clearance of heme and iron may modulate MMP9 expression for reduced damage.

No description available.

Studies of nucleation in freezing nanoparticles usually assume that the embryo of the solid phase is completely wet by the liquid and forms in the core of the droplet. However, recent experiments and computer simulations have suggested that some nanoparticles start nucleating at the liquid-vapor interface of the drop in a pseudoheterogeneous process. The goal of the present work is to propose phenomenological models suitable for the study of surface nucleation in nanoparticle systems that can be used to understand the contributions of the various surface phenomena, such as surface and line tensions, to the nucleation barrier.<p/> The nucleation barrier for the freezing of a 276 atom gold cluster is calculated using Monte Carlo simulation techniques while previous simulation studies of a 456 atom gold cluster are extended in order to find the probability that the embryo forms in the surface or core of the nanoparticle. These calculations confirm that the crystal embryo forms at the liquid-vapor interface. Geometric studies measuring the liquid-solid and solid-vapor surface areas of the embryo suggest that it changes shape as it becomes larger and grows in towards the core of the droplet.<p/> Three phenomenological models that are based on the capillarity approximation and can account for surface nucleation are proposed. These models highlight the importance of accounting for the surface curvature contributions related to the Tolman length and the presence of the three phase contact line in calculating the nucleation free energy barrier. In some cases, the models are able to reproduce the qualitative properties of the free energy barriers obtain from simulation but numerical fits of the models generally result in estimates of the solid-liquid surface tension that are lower than the values expected on the basis of partial wetting in the bulk.<p/> Finally, a semi-phenomenological model approach to nucleation is proposed where the usual phenomenological expression for the free energy barrier is retained, but where the geometric prefactors are obtained from molecular simulation of the embryo. This method is applied to nucleation in the gold cluster and to the freezing of a bulk Lennard-Jones liquid.<p/>

Numerous studies have focused on enhancing the flame retardant behavior of cotton and polyurethane foam. Some of the most commonly used treatments (e.g., brominated compounds) have raised concerns with regard to toxicity and environmental persistence. These concerns have led to significant research into the use of alternative approaches, including polymer nanocomposites prepared from more environmentally benign nanoparticles. These particles migrate to the surface from the bulk during fire exposure to form a barrier on the surface that protects the underlying polymer. This theory of fire suppression in bulk nanocomposites inspired the use of layer-by-layer (LbL) assembly to create nanocoatings in an effort to produce more effective and environmentally-benign flame retardant treatments. Negatively charged silica nanoparticles of two different sizes were paired with either positively charged silica or cationic polyethylenimine (PEI) to create thin film assemblies. When applying these films to cotton fabric, all coated fabrics retained their weave structure after being exposed to a vertical flame test, while uncoated cotton was completely destroyed. Micro combustion calorimetry confirmed that coated fabrics exhibited a reduced peak heat release rate, by as much as 20% relative to the uncoated control. Even so, this treatment would not pass the standard UL94 vertical flame test, necessitating a more effective treatment. Positively- charged chitosan (CH) was paired with montmorillonite (MMT) clay to create a renewable flame retardant nanocoating for polyurethane foam. This coating system completely stops the melting of a flexible polyurethane foam when exposed to direct flame from a butane torch, with just 10 bilayers (~ 30 nm thick). The same coated foam exhibited a reduced peak heat release rate, by as much as 52%, relative to the uncoated control. This same nanobrick wall coating is able to impart gas barrier to permeate plastic film. Multilayered thin films were assembled with "green" food contact approved materials (i.e., chitosan, polyacrylic acid (PAA) and montmorillonite clay). Only ten CH-PAA-CH-MMT quadlayers (~90 nm thick) cause polylactic acid (PLA) film to behave like PET in terms of oxygen barrier. A thirty bilayer CH-MMT assembly (~100 nm thick) on PLA exhibits an oxygen transmission rate (OTR) below the detection limit of commercial instrumentation (<= 0.005 cm^3/(m^2*day*atm)). This is the same recipe used to impart flame retardant behavior to foam, but it did not provide effective FR to cotton fabric, so a very different recipe was used. Thin films of fully renewable electrolytes, chitosan and phytic acid (PA), were deposited on cotton fabric in an effort to reduce flammability through an intumescent effect. Altering the pH of aqueous deposition solutions modifies the composition of the final nanocoating. Fabrics coated with highest PA content multilayers completely extinguished the flame and reduced peak heat release (pkHRR) and total heat release of 60% and 76%, respectively. This superior performance is believed to be due to high phosphorus content that enhances the intumescent behavior of these nanocoatings.

During pregnancy, 64-96% of women take at least one prescription drug. The placenta is the primary barrier between substrates in maternal and fetal circulation. The blood-brain barrier (BBB) acts as an additional barrier for the fetal brain, which is particularly susceptible to the effects of xenobiotics. Multidrug resistance phosphoglycoprotein (P-gp; encoded by Abcb1 mRNA) and breast cancer resistance protein (Bcrp1; encoded by Abcg2 mRNA) are efflux transporters localized on placental syncytiotrophoblast and capillary endothelial cells of the BBB. Placental Abcb1/P-gp and Abcg2/Bcrp1 limit maternal-fetal transfer of endogenous and exogenous substrates. Similarly, the neuroprotective roles of Abcb1/P-gp and Abcg2/Bcrp1 in the adult BBB have been demonstrated. However, developmental changes in expression and function and regulation of Abcb1/P-gp and Abcg2/Bcrp1 in these tissues are poorly understood. This thesis investigates gestational changes in expression and function of Abcb1/P-gp and Abcg2/Bcrp1 in the placenta and fetal brain, in addition to regulation by steroids, progesterone and glucocorticoids. The effects of glucocorticoids on Abcb1/P-gp and Abcg2/Bcrp1 in the placenta and fetal brain are of importance given that 10% of pregnant women are treated with synthetic glucocorticoids during the management of threatened preterm labour. These studies demonstrate that the decrease in placental Abcb1/P-gp mediated fetal protection near term is compensated by an increase in Abcb1/P-gp and Abcg2/Bcrp1 mediated neuroprotection in the fetal brain; likely in preparation for life ex-utero. The lack of effects of progesterone and the dose-, age- and sex- dependent regulatory effects of synthetic glucocorticoid have highlighted the complexity associated with regulation of these transporters. Further, these studies are the first to report sexually dimorphic glucocorticoid effects on Abcb1/P-gp and Abcg2/Bcrp1 expression and function, with the female fetus being particularly susceptible to glucocorticoid these effects. In this regard, Abcb1/P-gp and Abcg2/Bcrp1 transport capacity may be altered when synthetic glucocorticoid is administered as a co-therapy, and as such, recipient sex should be considered during pharmacotherapy. Understanding the regulation of Abcb1/P-gp and Abcg2/Bcrp1 expression and function in the placenta and fetal brain during normal development and under pathological conditions is critical for fetal health and development, particularly when therapeutic strategies are utilized in pregnancy.

This study is an optimization approach to the rectilinear interdiction problem by locating a line barrier. Interdiction problems study the eect of a limited disruption action on operations of a system. Network interdiction problems, where nodes and arcs of the network are susceptible to disruption actions, are extensively studied in the operations research literature. In this study, we consider a set of sink points on the plane that are being served by source points and our aim is to study the eect of locating a line barrier on the plane (as a disruption action) such that the total shortest distance between sink and source points is maximized. We compute the shortest distances after disruption using visibility concept and utilizing properties of our problem. The amount of disruption is limited by imposing constraints on the length of the barrier and also the total number of disrupted points. The suggested solution approaches are based on mixed-integer programming and a polynomial-time algorithm.

Studies of nucleation in freezing nanoparticles usually assume that the embryo of the solid phase is completely wet by the liquid and forms in the core of the droplet. However, recent experiments and computer simulations have suggested that some nanoparticles start nucleating at the liquid-vapor interface of the drop in a pseudoheterogeneous process. The goal of the present work is to propose phenomenological models suitable for the study of surface nucleation in nanoparticle systems that can be used to understand the contributions of the various surface phenomena, such as surface and line tensions, to the nucleation barrier.<p/> The nucleation barrier for the freezing of a 276 atom gold cluster is calculated using Monte Carlo simulation techniques while previous simulation studies of a 456 atom gold cluster are extended in order to find the probability that the embryo forms in the surface or core of the nanoparticle. These calculations confirm that the crystal embryo forms at the liquid-vapor interface. Geometric studies measuring the liquid-solid and solid-vapor surface areas of the embryo suggest that it changes shape as it becomes larger and grows in towards the core of the droplet.<p/> Three phenomenological models that are based on the capillarity approximation and can account for surface nucleation are proposed. These models highlight the importance of accounting for the surface curvature contributions related to the Tolman length and the presence of the three phase contact line in calculating the nucleation free energy barrier. In some cases, the models are able to reproduce the qualitative properties of the free energy barriers obtain from simulation but numerical fits of the models generally result in estimates of the solid-liquid surface tension that are lower than the values expected on the basis of partial wetting in the bulk.<p/> Finally, a semi-phenomenological model approach to nucleation is proposed where the usual phenomenological expression for the free energy barrier is retained, but where the geometric prefactors are obtained from molecular simulation of the embryo. This method is applied to nucleation in the gold cluster and to the freezing of a bulk Lennard-Jones liquid.<p/>

During pregnancy, 64-96% of women take at least one prescription drug. The placenta is the primary barrier between substrates in maternal and fetal circulation. The blood-brain barrier (BBB) acts as an additional barrier for the fetal brain, which is particularly susceptible to the effects of xenobiotics. Multidrug resistance phosphoglycoprotein (P-gp; encoded by Abcb1 mRNA) and breast cancer resistance protein (Bcrp1; encoded by Abcg2 mRNA) are efflux transporters localized on placental syncytiotrophoblast and capillary endothelial cells of the BBB. Placental Abcb1/P-gp and Abcg2/Bcrp1 limit maternal-fetal transfer of endogenous and exogenous substrates. Similarly, the neuroprotective roles of Abcb1/P-gp and Abcg2/Bcrp1 in the adult BBB have been demonstrated. However, developmental changes in expression and function and regulation of Abcb1/P-gp and Abcg2/Bcrp1 in these tissues are poorly understood. This thesis investigates gestational changes in expression and function of Abcb1/P-gp and Abcg2/Bcrp1 in the placenta and fetal brain, in addition to regulation by steroids, progesterone and glucocorticoids. The effects of glucocorticoids on Abcb1/P-gp and Abcg2/Bcrp1 in the placenta and fetal brain are of importance given that 10% of pregnant women are treated with synthetic glucocorticoids during the management of threatened preterm labour. These studies demonstrate that the decrease in placental Abcb1/P-gp mediated fetal protection near term is compensated by an increase in Abcb1/P-gp and Abcg2/Bcrp1 mediated neuroprotection in the fetal brain; likely in preparation for life ex-utero. The lack of effects of progesterone and the dose-, age- and sex- dependent regulatory effects of synthetic glucocorticoid have highlighted the complexity associated with regulation of these transporters. Further, these studies are the first to report sexually dimorphic glucocorticoid effects on Abcb1/P-gp and Abcg2/Bcrp1 expression and function, with the female fetus being particularly susceptible to glucocorticoid these effects. In this regard, Abcb1/P-gp and Abcg2/Bcrp1 transport capacity may be altered when synthetic glucocorticoid is administered as a co-therapy, and as such, recipient sex should be considered during pharmacotherapy. Understanding the regulation of Abcb1/P-gp and Abcg2/Bcrp1 expression and function in the placenta and fetal brain during normal development and under pathological conditions is critical for fetal health and development, particularly when therapeutic strategies are utilized in pregnancy.

Ischemic stroke is characterized by a disruption of blood supply to a part of the brain tissue, which leads to a focal ischemic infarct. The expression and activity of MMP-9 is increased in ischemic stroke and is considered to be one of the main factors responsible for damages to the cerebral vasculature, resulting in compromised blood-brain barrier (BBB) integrity. However, the regulatory mechanisms of MMP-9 expression and activity are not well established in ischemic stroke. Since hypoxia/ischemia and reperfusion generates reactive oxygen species (ROS), I hypothesize that ROS is one of factors involved in up-regulation of MMP-9 expression in brain cells and ROS-mediated effect may occur via MAPK signaling pathway. My study has provided the evidence that ROS is responsible for an increase in MMP-9 expression in astrocytes mediated via MAPK-AP1 signaling pathway. Preliminary studies with an in vitro model of the BBB suggest that inhibition of MMP-9 is a critical component of reducing ROS-induced BBB permeability.