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Myocardial infarction (MI) is primarily caused by blockade of the coronary circulation, resulting in ischemic insult. The only available remedy is reperfusion, which induces oxidative stress and activates inflammatory responses at the site of injury. Cysteinyl leukotrienes (cysLTs) are potent pro-inflammatory mediators that exert their effects through two classical receptors: cysLT receptor 1 (CysLT1R) and cysLT receptor 2 (CysLT2R), the latter of which is prevalent in the heart and circulatory system and has been implicated in cardiovascular disease. However, although endothelial CysLT2R overexpression exacerbates MI damage and induces vascular hyperpermeability, understanding of CysLT2R activation-induced mechanisms is poor, as isolating CysLT2R-specific effects has proven difficult due to a lack of appropriate pharmacological agents. We investigate herein the role of CysLT2R activation in myocardial ischemia/reperfusion injury. We have characterized a novel CysLT2R-selective antagonist BayCysLT2 in both in vitro and in vivo systems, and establish that CysLT2R-selective antagonism attenuates exacerbated MI injury, adhesion molecule gene regulation, and myocardial neutrophil presence observed in CysLT2R overexpressing (EC) mice. We also examined effects of CysLT2R antagonism in long-term cardiac remodeling post-myocardial infarction, and found that blockade of CysLT2R post-reperfusion, regardless of whether CysLT2R is overexpressed or not, elicits a mild pathological cardiac hypertrophic response despite mitigating infarction damage to the apical ventricular wall. Finally, we created a novel mouse model (EC/KO) that expresses CysLT2R predominantly in vascular endothelium in order to identify tissue-specific mechanisms of CysLT2R activation. Surprisingly, MI injury was attenuated in EC/KO mice, indicating that both endothelial and non-endothelial CysLT2R expression subsets have roles in mediating infarction injury. Indeed, EC/KO mice demonstrated hyperpermeability in cremaster venules only when leukotrienes are applied, in contrast to EC mice. In addition, endothelial CysLT2R activation facilitates leukocyte transmigration, whereas non-endothelial CysLT2Rs regulate basal rolling leukocyte flux in microvasculature. Although much work remains to be done, the characterization of a CysLT2R-selective antagonist provides a vital tool for CysLT2R research moving forward, and our investigation of CysLT2R activation reveal the existence of a complicated and multi-faceted pathway resulting in activation of pro-inflammatory mechanisms. / Thesis (Ph.D, Physiology) -- Queen's University, 2013-09-26 10:29:03.466

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Angiogenesis and vascular permeability occur in physiological and pathological conditions. Angiogenesis denotes the process of blood vessel formation from preexisting quiescent vessels. Angiogenesis is initiated by proangiogenic factors, inducing endothelial cell sprouting, migration and anastomosis, followed by regression of the new vessels or maturation into a quiescent status. Vascular permeability is the process where blood vessels exchange nutrients, solutes and inflammatory cells with the surrounding tissue. Small molecules freely cross the endothelial wall, however macromolecules and cells leak out from the vasculature only after stimulation by certain factors, including VEGF. Angiogenesis and vascular permeability are tightly regulated physiological processes, but uncontrolled angiogenesis and excessive leakage lead to pathological conditions and the progression of several diseases. VEGF and its receptor VEGFR2 are critical players in angiogenesis and in vascular permeability. The binding of the ligand to the receptor is not the only event involved in the activation and regulation of the signaling cascade. Coreceptors, kinases, phosphatases, and other proteins involved in the trafficking of the complex modulate the signal amplitude and duration. VEGF/VEGFR2 complex combined with the coreceptor NRP1 has a strong pro-angiogenic action and a critical role in angiogenesis. Both VEGFR2 and NRP1 bind VEGF and can present VEGF in cis, when both VEGFR2 and NRP1 are expressed on the same endothelial cell or in trans, when NRP1 is expressed on an adjacent endothelial cell or another type of cell. Y949 and Y1212 are two of the main phosphorylation sites of VEGFR2 induced by VEGFA. The binding of phosphorylated Y949 to the SH2 domain of TSAd regulates vascular permeability leading to Src activation and adherens junction opening in vitro. Phospho-Y1212 is implicated in actin stress fiber remodeling via the adapter Nck, affecting the actin cytoskeleton and endothelial cell migration in vitro. Paladin is a vascular-enriched phosphatase-domain containing protein without reported phosphatase activity and is a negative regulator of insulin receptor and Toll-like receptor 9 signaling. In this thesis work, I have investigated the spatial dynamics of NRP1/VEGFR2 complex formation (in cis and in trans) for coordinating VEGF-mediated angiogenesis in physiological and in pathological conditions (Paper I). I have studied, in vivo, the role of VEGFR2 Y949 in vascular permeability and metastatic spread (Paper II) and the role of VEGFR2 Y1212 in angiogenic remodeling and vessel stability (Paper III). Furthermore, I have examined paladin’s role in regulating VEGF/VEGFR2 signaling and VE-cadherin junction stability, in angiogenic sprouting and vascular permeability (Paper IV). In conclusion, VEGF/VEGFR2 signaling is regulated by a multifactor system and each individual regulatory mechanism leads to a specific outcome in angiogenesis, vascular permeability and vessel stability.

Observations of decreases in plasma volume, shifts in plasma and lymph protein concentrations, and increases in capillary permeability at high altitude have been reported in the literature by several investigators. This investigation was begun in an attempt to elucidate the possible significance of these phenomena in future space exploration, and because of the lack of knowledge concerning the underlying mechanisms. The purpose of this investigation was to determine the effects of exposure to hypobaric pressures on the capillary permeability to the normal plasma and lymph proteins.

Thesis advisor: Alfredo Urzua / Thesis advisor: John Ebel / Nine empirical equations that estimate saturated hydraulic conductivity as a func- tion of grain size in well-graded sands with gravels having large uniformity coecients (U > 50) are evaluated by comparing their accuracy when predicting observed conduc- tivities in constant head permeability tests. According to the ndings of this thesis, in decreasing order of accuracy these equations are: USBR (Vukovic and Soro, 1992; USBR, 1978), Hazen (Hazen, 1892), Slichter (Slichter, 1898), Kozeny-Carman (Carrier, 2003), Fair and Hatch (Fair and Hatch, 1933), Terzaghi (Vukovic and Soro, 1992), Beyer (Beyer, 1966), Kruger (Vukovic and Soro, 1992), and Zunker (Zunker, 1932). These re- sults are based on multiple constant head permeability tests on two samples of granular material corresponding to well-graded sands with gravels. Using the USBR equation sat- urated hydraulic conductivities for a statistical population of 874 samples of well-graded sands with gravels forming 29 loads from a heap leaching mine in northern Chile are calculated. Results indicate that, using the USBR equation, on average the hydraulic conductivity of the leaching heaps has a two standard deviation range between 0.18 and 0.15 cm/s. Permeability tests on the actual material used in the heaps provided by the mine shows that the results presented in this thesis are consistent with actual observa- tions and represent saturated conductivities in heaps up to 3 m high under a pressures of up to 62 Kpa. In future work hydraulic conductivities can be combined with water retention curves, discharge rates, irrigation rates, porosities, and consolidation so as to evaluate the relationship between copper yields and the hydraulic conductivities of the heap. / Thesis (MS) — Boston College, 2016. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Geology and Geophysics.

Concrete repair materials are being widely used to restore and extend the service life of structures. While most cement-based repair materials are compatible with concrete structures, their durability properties do not attract much attention which it deserves from researchers. Since repair materials can deteriorate like conventional concrete, the search for reliable, long-lasting concrete repair materials is becoming more intensive. Amongst other factors, concrete permeability and chloride diffusivity within concrete are believed to play a major role in determining the durability and success of the repair. These two parameters determine the penetration rate of aggressive substances into concrete and how fast degradation could take place. A number of test methods have been proposed to study these two factors, and the commonly used test methods are water penetration, surface/bulk electrical resistivity, rapid chloride permeability (RCP), and half-cell potential. However, the relationship between each durability test method and their correlation with compressive strength measurement have not been fully understood. So, in this study, we aim for using multiple testing techniques, destructive and non-destructive, to evaluate the durability of concrete repair materials as well as correlating different test methods. Three types of commercially available cement-based materials are tested and evaluated, and results have indicated that cementitious concrete mortar (termed as Mix M) amongst others has the best durability performance which means low water permeability, high resistivity, and compressive strength. Whereas, the flexural performance of Mix M still needs some improvement in terms of flexural strength and flexural toughness. For various durability testing methods, surface resistivity is found to have a strong linear relation and a polynomial relation to bulk resistivity and water permeability respectively. No relationship is established between concrete resistivity and compressive strength, though high-strength concrete tends to have a high resistivity in our study. RCP test results do not correlate well with resistivity measurements, which requires further study to overcome its heating and binding effect when measurements are being taken. Half-cell potential method is used for validating test results but it reveals no difference for materials with different permeability and resistivity. A model is proposed to counteract temperature’s effect while calculating the coefficient of diffusion, which indicates the concrete to resist chloride diffusion. It is found that this model can shift the RCP measurement slightly closer to its theoretical prediction but the difference between them is still large. Therefore, further research is required for acquiring more raw data from RCP measurements as the regression analysis input. In addition, a more comprehensive model that involves more correction factors for binding effects, etc., is also needed. / Graduate / 2020-04-30

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