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The G protein-coupled estrogen receptor GPER/GPER1, also known as GPR30, was originally cloned as an orphan receptor and later shown to be specifically activated by 17-ß-estradiol. This has led to its classification as an estrogen receptor and expanded the perspective on the mechanisms underlying the rapid estrogenic effects reported over the years. GPER is strongly expressed in the central nervous system and peripheral tissues and appears to be involved in a wide variety of physiological and pathological processes. Estrogens are known to alter the processing of nociceptive sensory information and analgesic responses in the central nervous system. Both analgesic and pro-nociceptive effects of estrogens have been reported. Some pro-algesic estrogenic responses have a short latency, suggesting a non-genomic mechanism of action. Immunohistochemical studies in rodents prove the existence of GPER in pain-relevant areas of the nervous system such as dorsal root ganglia, superficial dorsal horn of the spinal cord, periaqueductal gray (PAG), amygdala, trigeminal sensory nucleus and thalamus. In the periphery, activation of GPER results in pro-nociceptive effects. However, GPER involvement in pain processing at central levels is largely unexplored. Thus, the work presented in this thesis was aimed at investigating whether GPER modulates nociception at spinal and supraspinal sites. The behavioral response to GPER activation in the spinal cord and PAG was evaluated in an acute grooming test (scratching, biting and licking behavior) and in the hot plate test, respectively. Intrathecal challenge of mice with the GPER agonist G-1 (0.1-1 nmol) induced a dose-dependent increase in pain-related behaviors, that was abolished by pre-treatment with the GPER antagonist G15 (1-10 nmol), confirming GPER specificity of the response. Likewise, intra-PAG microinjection of G-1 (10-100 pmol) to rats reduced the nociceptive threshold in the hot plate test, an effect that was G15 sensitive. To obtain further insight on the mechanisms involved in the behavioral effects observed in whole animals, we tested the effect of GPER ligands on neuronal membrane potential, intracellular calcium concentration ([Ca2+]i) and reactive oxygen species (ROS) accumulation. The membrane depolarization and the increases in [Ca2+]i and ROS levels are markers of neuronal activation, underlying pain sensitization in the spinal cord and pain facilitation in the PAG. Electrophysiological recordings from superficial dorsal horn and lateral PAG neurons indicate neuronal depolarization upon G-1 application, an effect that was fully prevented by G15 pre-treatment. Both cultured spinal neurons and cultured PAG neurons responded to G-1 administration by elevating [Ca2+]i and mitochondrial and cytosolic ROS levels. In the presence of G15, G-1 did not elicit the calcium and ROS responses. Collectively, these results demonstrate that GPER modulates both the ascending and descending pain pathways to increase nociception via cytosolic calcium elevation and ROS accumulation in spinal and PAG neurons, respectively. These findings broaden the current knowledge on GPER involvement in physiology and pathophysiology, providing the first evidence of its pro-nociceptive effects at central levels and characterizing some of the mechanisms involved. Moreover, we show for the first time ROS accumulation downstream of GPER activation, extending the current understanding of GPER signaling. / Pharmacology

Purpose: Clinical, epidemiological and basic research evidence supports the inclusion of regular physical activity as a tool for the prevention of chronic disease and the enhancement of overall health. Cardiovascular disease (CVD), the number one cause of death in the United States, is more prevalent in African Americans when compared to other races. Extensive data suggests that increasing physical activity level, particularly with aerobic exercise training (AEXT), can improve modifiable risk factors (hypertension, obesity, dyslipidemia) for CVD. The common pathology for cardiovascular (CV) risk factors is atherosclerosis. Central to the complex pathology of atherosclerosis is the vascular endothelium. In recent years, autocrine and paracrine endothelial biomarkers that directly affect endothelial status (activated vs. inactivated) have been implicated in the pathogenesis of the development and progression of CVD and its precursors. Exercise interventions have been used to modify the concentrations of endothelial biomarkers in populations with varying disease states. The purpose of this study was to identify plasma and urinary biomarkers that are associated with aerobic capacity (VO2max) in a sedentary African American population and further determine the effect of 6-months of AEXT on the concentration and activity of the biomarkers. Methods: Participants were recruited from the Philadelphia, PA area. Twenty two pre-hypertensive African Americans (SBP 122.15±10.33, DBP 77.00±5.88; 52.27±6.25 years of age) were included. Routine fasting blood samples were drawn to assess blood lipids and fasting blood glucose along with urinalysis to rule out kidney dysfunction or disease. Subjects had a physical examination and BP measured under standardized conditions. Exclusion criteria included smoking, a body mass index (BMI) > 40 kg/m2, alcohol intake of more than 3 drinks per day, diabetes (fasting glucose level >126 mg/dl), total cholesterol >240 mg/dl, renal or CV disease. On a separate day, a sub-maximal graded exercise test with gas analysis was conducted to determine aerobic capacity. VO2max was estimated from the baseline submaximal graded exercise test. Regression analysis was used to calculate VO2max. Participants underwent 6 months of AEXT at a prescribed 3 sessions per week for 40 minutes at 65% VO2max. Plasma biomarkers of oxidative stress (8-isoprostane PGF2a), cellular activation (VCAM-1), anti-oxidants (SOD), vascular tone (NO) and anti-thrombosis (2,3 dinor 6-keto Prostaglandin F1a) were measured before and after AEXT by commercially available EIA and ELISA kits. CRP, a biomarker of systemic inflammation and predictor of CV events was assessed. Results: Estimated VO2max values confirmed that the exercise group was untrained (VO2max: 25.31 ± 3.91 ml/kg/min). At baseline the most significant correlations observed were between VO2max and CRP (r= -.50, p= .01) as well as CRP and 8-isoprostane PGF2a (r= .88, p2max and CRP remained statistically significant (r= -.46, p= .02). Nitric oxide and VCAM-1 concentrations significantly differed following the AEXT intervention (NO: pre 24.07 ± 8.80 µmol/L, NO: post 37.17 ± 15.57 µmol/L, p Conclusions: Elevated basal plasma VCAM-1, CRP and 8- isoprostane PGF2α levels are evidence of endothelial activation and systemic inflammation. Pre-intervention findings provide evidence that having a higher VO2max was strongly associated with decreased concentrations of CRP, a marker of systemic inflammation that is highly associated with risk for CVD. Post-intervention analysis suggests 6-months of AEXT is an appropriate intervention for elevating NO and decreasing VCAM-1 concentrations. This suggests there were cardioprotective modifications in the endothelial phenotype. The absence of significant change in SOD activity, 2,3 dinor 6-keto Prostaglandin F1a and CRP concentrations may suggest that AEXT is not a suitable mechanism to elicit improvements in all metabolic pathways that impact the state of the endothelium in previously sedentary African Americans. / Kinesiology

<p> The legacy of disposal practices for radioactive and other heavy metals has resulted in highly contaminated soils at the INL facility in Idaho Falls. Microbial effects on the mobility of a suite of metals (U, As, Cr, Co and Zn) within INL vadose sediments were assessed over a range of solution metal concentrations and biological activity through batch experiments. Sediment associated metals in the bulk sample as well as individual soil compartments increased as a function of total solution metal concentration. System specific trends in partitioning coefficients emerged, reflecting complex interrelations among biological activity, solution metal concentration and the specific metals involved. </p> <p> Results of this study clearly show that cyclic linkages between metal concentration and biological activity play a role in metal sediment biogeochemical behaviour. Differential impacts of biological activity on metal solid retention as a function of solution metal concentration were observed. This result may reflect feedback of metals on the microbial population such that the extent and/or nature of microbial activity is concentration dependent. Typically biological activity has a stronger effect with increased concentration, changing from a beneficial/neutral impact to an increasingly negative effect across the concentration range. The degree of this effect, and whether positive or negative on soil metal retention was however, element specific and dependent on the degree of biological activity. </p> <p> This is one of the first studies to evaluate the relative affinities of a suite of metals for the solid vs. solution phases over varying metal cocktail concentrations and levels of biological activity. My results indicate that differing affinities occur across this suite of metals, and that their relative affinities are non-linearly dependent on both the levels of metal and biological activity present. These results indicate that successful prediction of metal behaviour in complex natural systems, based on mono-metal laboratory experiments is likely limited. </p> / Thesis / Master of Science (MSc)

No / A new technique using ozone loaded on adsorbents for industrial waste-water treatment has been investigated. This is a three-step process: ozone adsorption on a fixed bed column; water treatment on the bed loaded with ozone; and finally drying/ regeneration of the wet bed. Silica gel of mean particle size of 1.5 mm has been tested for ozone loading capacities followed by water treatment, both at ambient temperature. The mechanisms of the mass transfer process during ozone loading and water treatment have been established. The drying of the adsorbent using vacuum and dry air is feasible, but it is a time-consuming operation. A design procedure is described for the whole system.