The role of inhibitory compounds such as adenosine and GABA in modulating neuronal activity in invertebrate species is not well described. Here I investigate their role in modulating excitability of cluster F neurons in the pedal ganglia of Lymnaea stagnalis. Receptor-specific agonists and antagonists were used to determine that the inhibitory effects of adenosine were mediated through the adenosine A1 receptor, and that action potential frequency varied linearly with intracellular calcium concentrations. These effects had a seasonal dependence, as neurons were resistant to adenosinergic modulation during the summer months. GABAergic modulation of neuronal activity was also seasonal as demonstrated by ionic plasticity in GABAergic transmission. GABA application led to inhibition or excitation of electrical activity in neurons obtained during the fall and winter months, respectively. These effects were mediated through the GABA(A) receptor because of sensitivity to GABA(A) receptor antagonist bicuculline and were likely due to differential cation-chloride cotransporter activity.

The role of inhibitory compounds such as adenosine and GABA in modulating neuronal activity in invertebrate species is not well described. Here I investigate their role in modulating excitability of cluster F neurons in the pedal ganglia of Lymnaea stagnalis. Receptor-specific agonists and antagonists were used to determine that the inhibitory effects of adenosine were mediated through the adenosine A1 receptor, and that action potential frequency varied linearly with intracellular calcium concentrations. These effects had a seasonal dependence, as neurons were resistant to adenosinergic modulation during the summer months. GABAergic modulation of neuronal activity was also seasonal as demonstrated by ionic plasticity in GABAergic transmission. GABA application led to inhibition or excitation of electrical activity in neurons obtained during the fall and winter months, respectively. These effects were mediated through the GABA(A) receptor because of sensitivity to GABA(A) receptor antagonist bicuculline and were likely due to differential cation-chloride cotransporter activity.

Cancer accounts for nearly one-quarter of deaths in the United States, exceeded only by heart diseases. In 2006, there were 559,888 cancer deaths in the US. Finding effective treatments for cancer is a major challenge among researchers. In solid tumor, hypoxia increases the progression of malignancy and metastasis by promoting angiogenesis. The transcription factor HIF-1 is responsible for the regulation of cellular processes, including glycolysis and angiogenesis. Clinical evidence has determined that expression of HIF-1 is strongly associated with poor patient prognosis. Also, activation of HIF-1 contributes to malignant behavior and therapeutic resistance. In view of these observations, there is a need for anti-cancer treatments that addresses hypoxic related tumors. HIF-1 presents a viable target for inhibition of tumor growth with small molecules. Herein, we describe the design and synthesis of small molecules that inhibit the HIF-1 pathway, as well as mechanistic studies involved in the investigation of the mode of action of these compounds.

STK11/LKB1, a serine/threonine protein kinase, is a key upstream kinase of adenine monophosphate-activated protein kinase (AMPK), a necessary kinase in the control of metabolism for maintaining energy homeostasis. Although it has become clear that LKB1 is mutated in a significant number of Peutz¡VJeghers syndrome (PJS) and sporadic cancers, most frequently in adenocarcinoma of the lung, little is known about how the LKB1 signaling regulates the metabolic process and energy production underlying hypoxia and increased radiosensitivity of lung tumor. Here, we employed lung cancer cells as a model system to dissect the functional roles of LKB1 signaling in human lung adenocarcinoma. We found that LKB1 inhibits lung cancer cell migration, transformation and chemo-resistance in vitro after we restored LKB1 expression in LKB1 null A549 and H460 lung cancer cells. We also found that LKB1 prevents UV-induced DNA damage in human lung cancer cell lines by comet assay and activated UV-induced apopotsis by MTT assays. Furthermore, we designed a systems biology approach to provide a comprehensive protein-protein interaction analysis in order to elucidate the LKB1 tumor suppressor network in vivo. We employed Immunoprecipitation-HPLC- Mass Spectrometry (IP-LC-MS) to identify the novel proteins interacting with LKB1 under different cellular stress conditions. We have identified that LKB1 is involved in CFTR synthesis pathway underlying normoxia condition and participates in the glycolysis and gluconeogenesis pathways underlying hypoxia condition. Together, our findings indicated that LKB1 is involved in the regulation of cell migration, energy metabolism and DNA repair in lung cancer cells, and should provides insights to further exploit the concept of deranged cancer bioenergetics and aberrant growth signals to achieve more effective and selective strategies for lung cancer patients.

Hypoxia (dissolved oxygen concentrations less than 1.4 ml/l) is a recurrent seasonal phenomenon on the Louisiana Shelf, caused by the combined effects of nutrient loading by the Mississippi and Atchafalaya River System (MARS), and density stratification. In 2004, three shelf wide cruises (in April, June and August) were conducted on the Louisiana Shelf to understand the mechanisms controlling hypoxia on the shelf, and examine the relationship between dissolved oxygen and nutrient concentrations during the hypoxic periods. The shelf was divided into three geographically separate zones: A (off the mouth of the Mississippi River), B (off the Terrebonne Bay) and C (off the mouth of the Atchafalaya). Each zone was different in terms of the physical and biochemical processes occurring there. In April, no hypoxia was observed on the shelf because of water column mixing by winds, even though high discharge occurred from the MARS. Nutrients were abundant in the surface waters but present only in little amounts at the bottom. In June, the water column was highly stratified. Because of the presence of upwelling favorable winds no vertical mixing occurred and caused extensive hypoxia on the shelf. Dissolved oxygen concentrations were negatively correlated with nutrients at the bottom of the water column. Nutrients were considerably higher at the bottom than at the surface (except for zone A, where high nutrients were seen even at the bottom), indicating remineralization below the pycnocline. Resuspension of organic material and remineralized nitrogen were sustaining hypoxia far from the river sources. In August, hypoxia was patchy on the Louisiana Shelf. Correlations between dissolved oxygen and nutrient concentration varied seasonally with highest correlations occurring during hypoxic conditions in June and August. The spatial distribution of nutrients and other oceanographic parameters, such as light transmission, fluorescence, and dissolved oxygen concentrations, indicate seasonal variability of biochemical processes that are related to physical processes that affect stratification.

Hypoxia, with dissolved oxygen levels < 1.4 ml L-1, is a recurring summer feature of Louisiana shelf bottom waters. Stable isotope characterization (delta^18O and delta D) of surface waters over the hypoxic zone shows a shift of dominant river influence from the Mississippi River during April to the Atchafalaya in July. Carbon isotopes of dissolved inorganic carbon (δ13CDIC) in bottom waters reveal the respiration of terrestrial organic carbon (OC) at inshore localities of 10 m depth and the respiration of marine OC at depths equal to and greater than 20 m. delat^18O and delta^13C profiles of Louisiana shelf Conus shells collected in 1972 show no evidence for summer hypoxia. Comparison with modern Conus records reveal a delta^13CDIC reduction during the last four decades associated with intrusion of ^13C-depleted fossil fuel CO2. Summer delta^13C reductions in Texas shelf Pteria shells may imply dissolved oxygen (DO) was reduced by ≈0.7 ml L-1, although this may be attributed to influence of Brazos River discharge on shell delta^18O and delta^13C. Foraminifera fauna measured in age-calibrated sediments from the Texas shelf reveal a low oxygen conditions on between 1960 and modern sediments. From 1950 to 1960, fauna indicate oxygenated bottom waters. Contemporaneous increases of foraminifera delta^13Cand delta^18O suggest this event is associated with severe drought (the Little Dust Bowl). The synchronicity of these data suggests a link between Brazos River discharge and shelf hypoxia.

Bottom water hypoxia and its influence on the environment have been topics of increasing concern for many coastal regions. This research addresses both spatial and temporal variability in sediment biogeochemistry at the southeastern region of Corpus Christi Bay, TX, where seasonal (summer) hypoxia occurs. Traditional techniques for determination of a variety of dissolved and solid components, benthic oxygen demand, and sulfate reduction rates were augmented by measurements using solid state microelectrodes to simultaneously determine concentrations of dissolved O2, Mn2+, Fe2+, and [sigma]H2S in multiple small - interval (1 mm) depth profiles of sediment microcosms. Oxygen concentrations in the overlying water were manipulated in the sediment microcosms and electrode depth profile measurements were made over ~ 500 hours of experimentation. Laboratory and field microelectrode results were in good agreement for both norm - oxic and anoxic time periods. Results indicated that iron (Fe2+) and sulfide ([sigma]H2S) were the redox reactive species in these sediments. During hypoxic conditions an upward migration of dissolved Fe2+and [sigma]H2S through the sediment column and, at times, into the overlying water was observed as the dissolved oxygen concentrations decreased. A corresponding decline in the vertical extent of these redox species occurred when the overlying water was re-oxidized. When both dissolved iron and sulfide coexisted, FeS minerals were formed in the sediment, preventing sulfide diffusion into the overlying water. However, after a long duration of hypoxia (> 200 hours) this buffering capacity was exceeded and both iron and sulfide penetrated into the overlying waters. Results indicated that iron may have a greater influence on hypoxia than sulfide because its concentration in the overlying waters during induced hypoxia was an order of magnitude greater than those of sulfide. Moreover, in the southeastern region of the Bay, where mixing was minimal and the water column was shallow, the sediments alone may have caused the onset of the hypoxic event in a relatively short time period (< 5.5 days). These results demonstrated that in shallow marine environments where seasonal hypoxia occurs, such as Corpus Christi Bay, the associated major changes that take place in the sediment biogeochemistry must be included in benthic - pelagic models for overlying water hypoxia.

Hypoxia (decreased tissue oxygen levels) has long been considered as a possible mechanism of alcohol-induced developmental deficits, yet research has not conclusively disproved this hypothesis, nor has it provided substantial evidence for a mechanism of developmental alcohol insults involving hypoxia. Previous research has shown that moderate acute doses of alcohol does not induce hypoxemia (decreased arterial oxygen levels), yet these same studies have shown that this same alcohol exposure does transiently decrease cerebral blood flow (CBF). This is significant because although developmental alcohol exposure did not result in hypoxemia, the decreases in CBF seen in these previous studies may induce hypoxia within the brain. Unfortunately, these experiments were only performed after acute doses of alcohol, so it is unknown if a more chronic or repeated alcohol exposure paradigm would have similar effects. The present study examined blood flow in the sheep fetus after repeated alcohol exposure in a bingelike paradigm throughout the third trimester. Additionally, this study examined the fetal neurovascular response to a subsequent infusion of alcohol after the repeated alcohol exposure. This latter experiment was designed to examine the hypothesis that alcohol exposure throughout the third trimester affects the normal responsiveness of the neurovasculature to alcohol (compared to previous research demonstrating acute alcohol-induced decreases in CBF). The results from the present experiments indicate that although few regions were significant, the majority of the regions (especially the brain regions) exhibited a trend for increases in blood flows after alcohol exposure. This phenomenon was especially prominent in the group receiving the lower dose of alcohol. Additionally, the data from this study demonstrated that after repeated alcohol exposures the near-term sheep fetus did not respond to a subsequent dose of alcohol in a similar manner seen in previous experiments when the acute alcohol exposure was administered in alcohol naïve animals. After the final alcohol exposure the subjects in this study had either no effect in terms of blood flow or an increase in CBF. This is opposite to previous observations which demonstrated reduced blood flow in numerous brain regions. The present experiments suggest that alcohol does not induce fetal hypoxia, but does negatively affect the normal neurovascular response to alcohol. This latter phenomenon could have negative consequences on future development of the brain.

Dissertation (Ph.D.)--University of Toledo, 2009. / "Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biomedical Sciences." Title from title page of PDF document. Table of contents (p. iv) gives incorrect starting page numbers for "Bibliography" and "Abstract". "Bibliography" starts on p. 120 (not p. 119); "Abstract" starts on p. 150. Bibliography: p. 64-70, 97-100, 120-149.

Thesis (M.M.A.)--University of Washington, 2009. / Title from Web page (viewed on Feb. 3, 2010). Includes bibliographical references (leaves 41-45).