The role of adenosine as an endogenous neuromodulator is well established, but the mechanism(s) mediating the extensive modulatory and regulatory actions of adenosine have not yet been fully elucidated. In fact, although adenosine, through activation of adenosine A1 and A2A receptors, has been demonstrated as neuroprotective or neurodegenerative, respectively, little is known about the mechanism by which adenosine mediates these actions. In the hippocampus, essential physiological processes rely on adenosine signaling, including regulation of long-term potentiation (LTP) and long-term depression (LTD). Neuromodulation by adenosine is dominantly inhibitory in the hippocampus, mediated by the abundant and high-affinity adenosine A1 receptor. In ischemia and hypoxia, A1 receptor activation induces rapid synaptic depression which is mediated by multiple signaling pathways including the induction of excitatory AMPA glutamate receptor internalization, which inhibits synaptic transmission in the hippocampus. Considerable effort has been devoted to investigating the role of adenosine in ischemic stroke, due to the fact that in cerebral ischemia or hypoxia, extracellular levels of adenosine increase dramatically. This thesis explores the functional consequences of adenosine signaling in hypoxia and ischemia, which mediate GluA1 AMPA receptor subunit internalization. Three major serine/threonine protein phosphatases (PPs), PP1, PP2A, and PP2B are investigated and shown to mediate A1 receptor-mediated GluA1 internalization in hypoxic conditions in the rat hippocampus. Further experiments demonstrate the role of adenosine A2A receptors in potentiating hippocampal synaptic transmission in reperfusion by increasing GluA1 surface expression through increased phosphorylation of regulatory C-terminal phosphorylation sites of GluA1. The mechanism of extracellular adenosine regulation by equilibrative nucleoside transporters (ENTs) and casein kinase 2 (CK2) are examined and shown to interact in hypoxia/reperfusion experiments on hippocampal slices. Finally, using a pial vessel disruption (PVD) permanent focal cortical ischemia stroke model, experiments demonstrate increased adenosine tone in the hippocampus, which mediates increased adenosine-induced synaptic depression. CK2 inhibition was also neuroprotective after 20min hypoxia. This shows that adenosine tone is increased in the hippocampus after a small cortical stroke, implying a potential global effect of focal ischemia. Together, these studies further reveal the paramount role of adenosine as a neuromodulator in the hippocampus during neuronal insults, furthering our understanding of the mechanism of neuronal death in hypoxic and ischemic conditions.The role of adenosine as an endogenous neuromodulator is well established, but the mechanism(s) mediating the extensive modulatory and regulatory actions of adenosine have not yet been fully elucidated. In fact, although adenosine, through activation of adenosine A1 and A2A receptors, has been demonstrated as neuroprotective or neurodegenerative, respectively, little is known about the mechanism by which adenosine mediates these actions. In the hippocampus, essential physiological processes rely on adenosine signaling, including regulation of long-term potentiation (LTP) and long-term depression (LTD). Neuromodulation by adenosine is dominantly inhibitory in the hippocampus, mediated by the abundant and high-affinity adenosine A1 receptor. In ischemia and hypoxia, A1 receptor activation induces rapid synaptic depression which is mediated by multiple signaling pathways including the induction of excitatory AMPA glutamate receptor internalization, which inhibits synaptic transmission in the hippocampus. Considerable effort has been devoted to investigating the role of adenosine in ischemic stroke, due to the fact that in cerebral ischemia or hypoxia, extracellular levels of adenosine increase dramatically. This thesis explores the functional consequences of adenosine signaling in hypoxia and ischemia, which mediate GluA1 AMPA receptor subunit internalization. Three major serine/threonine protein phosphatases (PPs), PP1, PP2A, and PP2B are investigated and shown to mediate A1 receptor-mediated GluA1 internalization in hypoxic conditions in the rat hippocampus. Further experiments demonstrate the role of adenosine A2A receptors in potentiating hippocampal synaptic transmission in reperfusion by increasing GluA1 surface expression through increased phosphorylation of regulatory C-terminal phosphorylation sites of GluA1. The mechanism of extracellular adenosine regulation by equilibrative nucleoside transporters (ENTs) and casein kinase 2 (CK2) are examined and shown to interact in hypoxia/reperfusion experiments on hippocampal slices. Finally, using a pial vessel disruption (PVD) permanent focal cortical ischemia stroke model, experiments demonstrate increased adenosine tone in the hippocampus, which mediates increased adenosine-induced synaptic depression. CK2 inhibition was also neuroprotective after 20min hypoxia. This shows that adenosine tone is increased in the hippocampus after a small cortical stroke, implying a potential global effect of focal ischemia. Together, these studies further reveal the paramount role of adenosine as a neuromodulator in the hippocampus during neuronal insults, furthering our understanding of the mechanism of neuronal death in hypoxic and ischemic conditions.

Sojourns at high altitude are often accompanied by weight loss and changes in body composition. The aim was to study body composition before and after 40 days high-altitude exposure. The subjects were four women and six men, non-smoking, healthy and active students and a scientist from Mid Sweden University in Östersund with a mean (SD) age of 26 (10) years. All subjects volunteered for a six-week trek to the Mount Everest Base Camp via Rolwaling in Nepal. Before the sojourn subject’s height was 177 (10) cm and weight was 71.9 (10) kg. Body composition was measured with Lunar iDXA at the Swedish Winter Sports Research Centre in Östersund before and after the trek. Total body mass (SD) decreased from 71.8 (10.0) kg before to 69.7 (9.4) kg after the trek (P=0.00). Total fat mass decreased from 14.7 (5.9) kg to 13.8 (4.6) kg (P=0.01). Fat percent decreased from 21.6 (7.9) % to 21.0 (7.2) % (P=0.03). Total lean mass decreased from 54.0 (10.0) kg to 52.9 (9.7) kg (P=0.01). Bone mineral content was unchanged, 3.04 (0.5) kg before and 3.03 (0.5) after (P=0.13). Thus both total body mass and total lean mass had decreased after a six week trekking in Nepal.

Because differences often exist between species in their tolerances to environmental conditions, locations characterized by extreme parameter values (i.e., high temperature, low DO, high turbidity) may provide refuges from predation or competition by altering the outcome of inter-species interactions. This thesis examined the effects and relative importance of water temperature, dissolved oxygen (DO) and turbidity on habitat use by fish species and resulting changes in community composition. The effects of abiotic factors on predator-prey interactions were tested using field surveys, laboratory experiments, field experiments and computer modeling. Field surveys were conducted in Blind Channel, Delta Marsh, Manitoba, and on Lake Winnipeg, Manitoba, to determine if small bodied forage species preferentially used high temperature, low DO or high turbidity habitats and whether predator species avoided these locations. Prey species were more abundant in these extreme locations at both small (Blind Channel) and large (Lake Winnipeg) spatial scales, but predator avoidance was only documented in Blind Channel. The tolerances of fish species to moderate hypoxia (< 3 mg/L DO) was tested in the laboratory to verify that differences did exist among species and that the observed species distributions were not solely the effect of temperature. To quantify the potential for moderately hypoxic locations to provide a refuge from predation for small fish, a field manipulation was conducted in Blind Channel; hypoxic habitats were created without altering water temperature, decoupling the natural covariation between these two factors that occurs in aquatic systems. The abundance of small forage fish was higher in the hypoxic locations compared to controls and while predators still visited the hypoxic habitats, their mean visit duration was reduced from around 300 min to less than 1 min. An individual based computer model was used to test and illustrate current understanding of the relative importance of temperature, DO and turbidity on predator habitat selection decisions and fish community composition. The model showed that DO had a stronger effect on community composition than temperature, and that reduced foraging success from high turbidity was able to overpower the other two factors. Hypoxia affects habitat selection decisions by fish species and can provide refuges from predation and competition, helping maintain higher species diversity. Water temperature appears to have a weaker effect on fish distributions than DO while turbidity primarily affects visual predators, though the strength of turbidity effects depends on the magnitude and duration of individual events.

No description available.

Renal cell carcinoma (RCC) is the commonest urogenital tumor, characterized by increased expression of hypoxia inducible factors (HIFs). During normoxia, HIFα subunits are targeted for proteasomal degradation by the product of the von Hippel Lindau gene (pVHL). In RCC, mutations in the VHL gene allow the HIFα subunits to escape degradation and translocate to the nucleus where they activate transcription of their target genes. Although both HIF1α and HIF2α are upregulated in RCC, it has been suggested that HIF2α plays the dominant role. To further elucidate the function of HIF2α in RCC, we generated a transgenic mouse model that permits temporal stabilization of HIF2α in renal tubular cells. Induction of HIF2α results in the rapid development of renal cysts - a feature observed in RCC. Taken together, these results suggest that HIF2α is a key player in development of RCC and an excellent candidate target for therapy in this disorder.

The Changjiang River provides the main source of sediment and terrestrial derived organic carbon (OC) to the Changjiang large delta-front estuary (LDE) in the East China Sea (ECS). This study analyzed bulk OC, biomarkers including lignin and plant pigment, black carbon (BC) on ECS sediments sampled in winter 2009 and 2010 in order to study the OC cycling under the influence of natural and anthropogenic disturbance. Low-oxygen tolerant foraminiferal microfossils were analyzed in another two sediment cores to study the historical hypoxia events in the Changjiang LDE. Bulk carbon to nitrogen (C/N) ratio and stable isotope δ13C in the surface sediment samples indicated a mixture source of terrestrial, deltaic and marine derived OC. Refractory BC and reworked marine OC seemed to comprise most of the OC pool with older, less reactive signatures as deduced from ∆14C, and BC analyses. Winter wind/wave energy and hydrodynamic sorting had a substantial winnowing effect on surface sediment OC redistribution. As a result, the highest lignin concentration shifted to the south during the 2010 cruise after the summer flood event. In addition, algal inputs from local deltaic lakes due to eutrophication and/or lateral transport likely caused the observed lack of benthic-pelagic coupling of pigment concentrations between the surface sediments and the water column after the summer flood in 2010. For the down-core sediment, the mass accumulation rate distribution followed the dispersal pathway of the ECS sediment. Terrestrial and marine derived OC showed significant spatial and temporal distribution. Lignin rich materials were better preserved in sediments closer to the coast while offshore sediments tended to be composed of lignin-poor, degraded OC, that were likely hydrodynamically sorted to a long distance during transport. Besides eutrophication, plant pigments indicated that marine-derived OC was mostly deposited in the sediment mixed layer with decay in the underlying sediment accumulation layer. The total OC standing stock since 1900 is approximately 1.62±1.15 kgC m^-2, about 1/10 of the total OC stock in all the middle and lower lakes in the Changjiang catchment. There has been an increase in the number of hypoxic bottom water events on the Changjiang LDE over the past 60 yrs indicated from the increases in low-oxygen tolerant foraminiferal microfossils due to excess deposition of OC and summer stratification.

Der Hirninfarkt ist einer der drei häufigsten Todesursachen in Deutschland. Er wird durch eine Unterversorgung des Gewebes mit Sauerstoff und Nährstoffen, häufig infolge von Gefäßverschlüssen, ausgelöst. Die bisher einzige Therapiemöglichkeit ist die Thrombolyse. Deshalb sind neue Therapieansätze nötig. Voraussetzung dafür sind geeignete Modelle. In dieser Arbeit wurden zellbasierte Hypoxiemodelle etabliert und charakterisiert. Es wurde der Einfluss von Sauerstoff- und/oder Glucoseentzug an humanen primären Makrophagen untersucht. Für Screeninguntersuchungen wurden neuronale und periphere (Makrophagen) Zelllinien von Ratte und Mensch verwendet. Im zweiten Teil der Arbeit wurden die Modelle genutzt, um die Wirkung von Adenin, eine rezeptorvermittelte Therapieoption, und des Phytopharmakons STW5 auf mögliche protektive Wirkungen zu untersuchen. Es wurden zellbiologische (MTT-Test, LDH-Test, DAPI-Färbung), immunologische (TNF α- ELISA, immunhistochemische Färbung), elektrophysiologische (Patch Clamp-Technik) und molekularbiologische (RT-PCR, Real-Time-PCR) Methoden angewendet. Es wurde erstmals der Adeninrezeptor an den untersuchten Zelllinien nachgewiesen und der pharmakologische Hinweis für eine bisher unbekannte humane Variante des Rezeptors erbracht. An neuronalen Zellen kam es zu einer Rezeptorinteraktion zwischen Adenin- und Adenosin-A1-Rezeptor. Antagonisten am Adeninrezeptor scheinen zur Behandlung hypoxiebedingter Zellschäden geeignet zu sein. STW5 hemmte unter hypoxischen Bedingungen die TNF α-Freisetzung humaner primärer Makrophagen. Der antiinflammatorischen Wirkung liegt die Blockierung erhöhter Kaliumströme zugrunde. An den untersuchten Zelllinien wirkte STW5 der hypoxieinduzierten Zellschädigung entgegen.

Adaptation to the shortage of oxygen at altitude (hypoxia) promotes physiological changes which could enhance endurance performance. Consequently, altitude training has become a popular practice among competitive endurance athletes. Since its inception, the live-high train-low paradigm (LHTL) has been widely regarded as the most effective approach to altitude training. Over the past decade, brief intermittent simulation of LHTL via the use of hypoxic inhalers and re-breathing devices has gained increased popularity, but the evidence supporting their use is limited and conflicting. The experimental studies in this thesis investigated the response of sea level exercise performance and related physiological measures following adaptation to the usual and a novel protocol of brief intermittent hypoxia. I intended to perform all experimental studies on flat-water kayakers. Therefore, an initial requirement of this thesis was to establish the smallest worthwhile effect in performance for this sport. The final study utilising a meta-analytic approach was conducted to compare the effectiveness of brief intermittent hypoxia to other natural and simulated protocols, and to investigate the topical issue of what physiological responses mediate performance changes following hypoxic exposure. In Study 1, the typical variation in competitive performance of elite flat-water canoeists was investigated using a repeated-measures analysis of race times. For individual flat-water canoeing events, the smallest worthwhile change in performance time was ~0.5%. In two separate experimental studies, adaptation to 60 min per day of brief intermittent hypoxia consisting of alternating 5 min intervals of hypoxia and normoxia for 3 weeks (5 days per week) using a nitrogen filtration device resulted in clear enhancement of endurance performance (~5%) for kayakers (Study 2) and cyclists (Study 3). Clear enhancements in repeat sprint performance were observed for kayaking only. The physiological mechanisms underlying performance changes were unclear. Modification of the hypoxic and normoxic intervals (Study 3) did not result in any clear alterations in performance or physiological mechanisms. The meta-analysis (Study 4) revealed clear enhancements in endurance power output of 1-3% in sub-elites following adaptation to hypoxia with the natural altitude protocols, and with two of the artificial-altitude protocols (LHTL-long and LHTL-brief-intermittent). In elite athletes the enhancements tended to be smaller and were clear only for the natural protocols. These enhancements could be mediated by VO2max, although other mechanisms may be possible.

Thesis (M.S.)--University of Delaware, 2008. / Principal faculty advisor: Timothy E. Targett, College of Marine & Earth Studies. Includes bibliographical references.

Thesis (Ph. D.)--University of Oregon, 2008. / Typescript. Includes vita and abstract. Includes bibliographical references (leaves 45-52). Also available online in ProQuest, free to University of Oregon users.