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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
1

Inhibition of cholesterol biosynthesis under hypoxia

Tan, Qiulin 12 April 2006 (has links)
Oxygen balance is very important and tightly regulated in mammals. Under hypoxia, hypoxia inducible factor 1(HIF-1) dimerizes with hypoxia inducible factor 1± (HIF-) and activates expression of several genes. Using a mammalian two hybrid assay, we found that HIF-1 interacted with sterol response element binding protein 1a (SREBP1a). SREBP1a regulates transcription of HMG-CoA reductase via binding to the sterol response element (SRE) in the promoter region. HMG-CoA reductase is the rate-limiting enzyme in cholesterol biosynthesis. The interaction between SREBP1a and HIF-1suggests that HIF-1 may play an important role in regulation of cholesterol biosynthesis. We tested the effects of hypoxia on the HMG-CoA reductase. We found that hypoxia caused suppression of SRE-driven luciferase reporter gene expression. HMG-CoA reductase mRNA levels decreased under hypoxia in both hepatoma cells and mouse primary hepatocytes. Electrophoretic mobility shift assay showed that HIF-1 blocked binding of SREBP1a to the SRE sequence in vitro. Ectopic expression of HIF-1 suppressed the SRE- driven luciferase reporter gene expression in BPR cells (HIF-1). Our results suggest that hypoxia inhibits cholesterol biosynthesis by suppressing SREBP1a-regulated gene expression and this suppression is caused by the blockage of SREBP1a binding to SRE sequence by HIF-1.
2

Examination of the relationship of river water to occurrences of bottom water with reduced oxygen concentrations in the northern Gulf of Mexico

Belabbassi, Leila 25 April 2007 (has links)
Six years of comprehensive data sets collected over the northern continental shelf and upper slope of the Gulf of Mexico during the LATEX-A and NEGOM-COH programs showed that low-oxygen waters (<2.4 mL·L-1) are found only in spring and summer and only in water depths between 10 and 60 m. Four regions in the northern Gulf show considerable differences in the occurrence of low-oxygen waters. Lowoxygen waters are observed almost exclusively in regions subject to large riverine influences: the Louisiana and Mississippi-Alabama shelves. Hypoxic waters (oxygen concentrations <1.4 mL·L-1) are found only over the Louisiana shelf. No low-oxygen water is found over the Florida shelf which has minimum riverine influence. Lowoxygen water is found at only one station on the Texas shelf; this is during spring when the volume of low-salinity water is at maximum. The distributions of low-salinity water influenced the different distributions of low-oxygen and hypoxic waters in the four regions. Low-oxygen occurrences are clearly related to vertical stratification. Lowoxygen occurred only in stable water columns with maximum Brunt-Väisälä frequency (Nmax) greater than 40 cycles·h-1. When Nmax exceeded 100 cycles·h-1 in summer over the Louisiana shelf, oxygen concentrations dropped below 1.4 mL·L-1, and the bottom waters became hypoxic. Salinity is more important than temperature in controlling vertical stratification. Locations where temperature influence was larger were found in summer in water depth greater than 20 m over the Louisiana shelf, along the near shore areas of the Mississippi-Alabama shelf west of 87ºW, and in the inner shelf waters of the Texas shelf. The extent of oxygen removal at the bottom of these stable water columns is reflected in the amount of remineralized silicate. Silicate concentrations are highest closest to the Mississippi River Delta and decrease east and west of the Delta. EOF analyses show that more than 65% of the oxygen variance is explained by the first mode. The amplitude functions of the first EOF modes of bottom oxygen, water column Brunt- Väisälä maxima, and bottom silicate are well correlated, indicating that much of the variance in bottom oxygen is explained by water column stratification and bottom remineralization.
3

Monomethylmercury concentrations on the eastern Texas-Louisiana shelf during the formation, peak, and disappearance of hypoxia

Keach, Sara Elizabeth 17 September 2007 (has links)
A study of monomethylmercury (MMHg) concentrations in the water and sediment of the hypoxic zone in the northeastern Gulf of Mexico was conducted on several cruises between April 2004 and May 2005. Surface water MMHg concentrations were low and constant throughout the sampling period. Bottom water concentrations displayed a seasonal trend: maximum MMHg concentrations were in June/July 2004, decreased to a minimum in October 2004, and in May 2005 concentrations had begun to increase. MMHg concentrations and MMHg as a percent of THg in surface sediment (0-2 cm) also followed this trend. Bottom water dissolved oxygen and temperature displayed inverse relationships with bottom water MMHg concentrations. This correlation between dissolved oxygen and MMHg is typical for low-oxygen waters, but the relationship between temperature and MMHg is relatively unique. A possible explanation is that warmer summer temperatures inhibited bacterial methylation. Stratification intensity (quantified as N2) was strongly correlated with bottom water MMHg concentrations, indicating either increased methylation at the pycnocline or that the pycnocline inhibited vertical mixing, thus limiting MMHg to the bottom water. Benthic flux estimations indicate that sediment release of MMHg could be a significant source of MMHg to bottom water. The presence of an oxygenated layer in the surface sediment could have played a role in inhibiting MMHg flux during oxic conditions; a decrease in the thickness of this layer under hypoxic conditions likely allowed MMHg to diffuse into the bottom water. Dissolved oxygen seemed to play an important role in controlling sediment MMHg concentrations with highest methylation rates in sediment under hypoxic water. Overall, sites closest to the Mississippi River mouth displayed the highest MMHg concentrations. Further research will need to be done in this area to fully characterize the relationship between biogeochemical parameters and MMHg concentrations.
4

Role of hypoxia and hypoxia induced factors in the development of breast cancer brain metastasis

Lungu, Gina Florentina 15 May 2009 (has links)
Here we studied the role of hypoxia and hypoxia-induced factors in the development of breast cancer brain metastasis by using ENU1564, a carcinogen-induced mammary adenocarcinoma cell line. We detected hypoxia noninvasively by using a novel spectroscopic photoacoustic tomography technology (SPAT). Sprague-Dawley rats inoculated intracranially with ENU1564, a carcinogen-induced rat mammary adenocarcinoma cell line, were imaged with SPAT three weeks post inoculation. Proteins important for tumor angiogenesis and invasion were detected in hypoxic brain foci identified by SPAT and were elevated compared with control brain. We showed that HIF-1α, MMP-9, VEGF-A, and VEGFR2 (Fkl-1) protein and mRNA expression levels were higher (P < 0.05) in brain tumor tissues compared to normal brain. We also found an increased expression of HIF-1α proteins, MMP-9, VEGF-A and VEGFR2 mRNA and proteins in hypoxic ENU1564 cells in vitro. We also demonstrated the involvement of PI3K-Akt pathway in hypoxic regulation of MMP-9 and VEGF but not VEGFR2 by using specific PI3K inhibitor. Using MEK1/2 inhibitor we showed that hypoxic regulation of MMP-9, VEGF-A and VEGFR2 also involve MEK1/2-ERK pathway. We also investigated the effect of fibroblast growth factor-1 (FGF-1), one of the factors known to be upregulated by hypoxia, on the expression of MMP-9 in ENU1564 cell line. We observed that FGF-1 induces an increase in MMP-9 mRNA, protein, and activity in ENU1564 cells. Next, we investigated the role of components of PI3K-Akt and MEK1/2-ERK signaling pathways in our system. We demonstrated that FGF-1 increases Akt phosphorylation, triggers nuclear translocation of NF-κBp65, and enhances degradation of cytoplasmic IκBα. Pretreatment of cells with LY294002, a PI3K inhibitor, significantly inhibited MMP-9 protein expression in FGF-1-treated cells. Conversely, our data showed that FGF-1 increases ERK phosphorylation in ENU1564 cells, increases c-jun and c-fos mRNA expression in a time-dependent manner, and triggers nuclear translocation of c-jun. Pretreatment of cells with PD98059, a MEK1/2 inhibitor significantly inhibited MMP-9 protein expression in FGF-1 treated cells. Finally, we observed increased DNA binding of NF-κB and AP-1 in FGF-1-treated cells and that mutation of either NF-κB or AP-1 response elements prevented MMP-9 promoter activation by FGF-1.
5

Factors modulating the control of ventilation during exercise in humans

Wood, Helen Elizabeth January 2002 (has links)
No description available.
6

Substrate specificity of factor inhibiting HIF-1 (FIH-1).

Linke, Sarah January 2008 (has links)
To detect and respond to the detrimental situation of hypoxia, metazoan cells employ O₂- sensing prolyl and asparaginyl hydroxylases which directly utilise O₂ to hydroxylate and regulate the Hypoxia Inducible transcription Factor-α (HIF-α). This thesis focuses upon the asparaginyl hydroxylase, ‘Factor Inhibiting HIF-1 (FIH-1), which represses HIF-α in normoxia by asparaginyl hydroxylation of its C-terminal trans-Activation Domain (CAD). During hypoxia FIH-1 is inhibited, allowing non-hydroxylated HIF-α to drive expression of over 70 target genes, leading to tissue and cellular changes that increase O₂ supply and reduce its consumption. This response is central to normal physiology and to the pathophysiology of diseases, including stroke and cancer. The pivotal role of FIH-1 in regulating these processes invites its characterisation, as a key cellular O₂-sensor and therapeutic target. This thesis contributes important information by elucidating a novel FIH-1 substrate and by defining numerous FIH-1 substrate recognition determinants. The first aim was to investigate the cell-fate regulator Notch1 as a potential FIH-1 substrate, due to myriad reports of Notch/hypoxic crosstalk and the discovery by collaborators that FIH- 1 represses Notch1 activity. Mutagenesis, hydroxylation assays, affinity-purification and mass spectrometry techniques enabled definition of two asparaginyl hydroxylations of mouse Notch 1 ankyrin repeat domain (N1945 and N2012), performed by FIH-1 in vitro. These residues were likewise detected to be hydroxylated in mNotch1 expressed in mammalian cells. FIH-1 kinetic assays comparing mNotch1 ankyrin domain with the unstructured hHIF- 1α CAD uncovered major distinctions between substrates; mNotch1 facilitated a 7-fold lower rate of cosubstrate turnover by FIH-1, but affinity was robust (>10-fold higher). Interrogation of the structure/affinity correlate implies FIH-1 binds unstable ankyrins preferentially. Functionally, a non-catalytic mechanism of Notch1 repression by FIH-1 is supported. The second aim derived from literature analyses implicating threonine and RLL motifs in HIF-α as critical hydroxylation determinants. T796 (hHIF-1α) contacts FIH-1 and is a likely phospho-acceptor, thus a mimetic T796D mutant was generated and its hydroxylation kinetics compared with wildtype hHIF-1α CAD. In vitro, the mutant exhibited a 6-fold greater apparent Km, explaining its constitutive activity in cell-based reporter assays, whereas wildtype hHIF-1α CAD is hydroxylated and thus repressed in normoxia by FIH-1. This indicates that phosphorylation reduces hydroxylation by FIH-1 in vitro and in vivo. The RLL motif does not contact FIH-1 in vitro however RLL-AAA mutant HIF-α proteins are constitutively active in normoxia, suggesting resilience to hydroxylation within cells. To reconcile these data I predicted that a cellular Factor X functionalises the RLL motif as an FIH-1 binding site. Reporter assays, in vitro kinetic assays and interaction assays +/- lysate confirmed this hypothesis and additionally showed the motif to increase HIF-α protein turnover 8-fold. Numerous mechanisms for Factor X including nuclear export, posttranslational modifications of FIH-1 or HIF-α, and involvement of small molecules, were experimentally examined, but deemed unlikely. Rather, the data imply Factor X to be a proteinaceous facilitator of a HIF-α/FIH-1 complex, thus proteomic capture screens are underway. This research provides novel insight into FIH-1; its role in Notch/hypoxic crosstalk, its substrate recognition requirements, and its potential functions in cellular O₂-sensing. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1326855 / Thesis (Ph.D.) -- University of Adelaide, School of Molecular and Biomedical Science, 2008
7

Investigating 55 years of nitrogen loading to the Chesapeake Bay using the HSPF model

Lepp, Marinna. January 2009 (has links)
Thesis (M.A.S.)--University of Delaware, 2009. / Principal faculty advisor: Dominic M. Di Toro, Dept. of Civil & Environmental Engineering. Includes bibliographical references.
8

Mechanisms and evolution of hypoxia tolerance in family Cottidae

Mandic, Milica 05 1900 (has links)
A comparative phylogenetically independent contrast (PIC) analysis was employed to investigate the adaptive role of traits involved in hypoxia tolerance in sculpins, a group of closely related fish species that live in the nearshore marine environment. I demonstrated that there was a tight correlation between critical oxygen (O₂) tension (P-crit) and the distribution of species across an environmental gradient. Species of sculpins with the lowest P-crit inhabit the 0₂ variable intertidal zone, while species with higher P-crit inhabit the O₂ stable subtidal zone. Low P-crit values in sculpins were associated with enhanced O₂ extraction capacity, with three principal traits accounting for 83% of the variation in P-crit: low routine O₂ consumption rate (MO2 ), high mass specific gill surface area and high whole cell hemoglobin-oxygen (Hb-0₂) binding affinity. Variation in whole cell Hb-O₂ binding affinity was strongly correlated with the intrinsic affinity of Hb for O₂ and not to differences in the concentration of the allosteric Hb modulators ATP and GTP. When environmental O₂ dropped below a species' P-crit, some species of sculpins behaviorally responded to the severe hypoxia by performing aquatic surface respiration (ASR) and aerial emergence. Although intertidal sculpins consistently performed these behaviors, the clustering of these species into a single phylogenetic Glade did not allow us to draw conclusions regarding the relationship between ASR, aerial emergence and P-crit using PIC analysis. Three species of sculpins, which were chosen because of their low, medium and high P-crit values, exhibited dramatically varied mortality rates when exposed to severe hypoxia equivalent to 40% of their respective P-crit. Although ATP turnover rates were similar between the three species in the initial two hours of hypoxia exposure, the differences in the ability of the three species to survive severe hypoxia appeared to be associated with the concentration of on-board liver glycogen and the degree of liver glycogen depletion. However, when liver glycogen was assessed in twelve species of sculpins at normoxia and compared with P-crit, there was nosignificant PIC correlation between P-crit and liver glycogen. Overall, I have shown that there is a clear relationship between P-crit and the distribution of sculpins along the nearshore environment and that this is primarily related to differences in O₂ extraction capacity. When O₂ tensions are well below their P-crit, there are dramatic differences in behavioral, physiological and biochemical responses among these species of sculpins.
9

Mechanisms and evolution of hypoxia tolerance in family Cottidae

Mandic, Milica 05 1900 (has links)
A comparative phylogenetically independent contrast (PIC) analysis was employed to investigate the adaptive role of traits involved in hypoxia tolerance in sculpins, a group of closely related fish species that live in the nearshore marine environment. I demonstrated that there was a tight correlation between critical oxygen (O₂) tension (P-crit) and the distribution of species across an environmental gradient. Species of sculpins with the lowest P-crit inhabit the 0₂ variable intertidal zone, while species with higher P-crit inhabit the O₂ stable subtidal zone. Low P-crit values in sculpins were associated with enhanced O₂ extraction capacity, with three principal traits accounting for 83% of the variation in P-crit: low routine O₂ consumption rate (MO2 ), high mass specific gill surface area and high whole cell hemoglobin-oxygen (Hb-0₂) binding affinity. Variation in whole cell Hb-O₂ binding affinity was strongly correlated with the intrinsic affinity of Hb for O₂ and not to differences in the concentration of the allosteric Hb modulators ATP and GTP. When environmental O₂ dropped below a species' P-crit, some species of sculpins behaviorally responded to the severe hypoxia by performing aquatic surface respiration (ASR) and aerial emergence. Although intertidal sculpins consistently performed these behaviors, the clustering of these species into a single phylogenetic Glade did not allow us to draw conclusions regarding the relationship between ASR, aerial emergence and P-crit using PIC analysis. Three species of sculpins, which were chosen because of their low, medium and high P-crit values, exhibited dramatically varied mortality rates when exposed to severe hypoxia equivalent to 40% of their respective P-crit. Although ATP turnover rates were similar between the three species in the initial two hours of hypoxia exposure, the differences in the ability of the three species to survive severe hypoxia appeared to be associated with the concentration of on-board liver glycogen and the degree of liver glycogen depletion. However, when liver glycogen was assessed in twelve species of sculpins at normoxia and compared with P-crit, there was nosignificant PIC correlation between P-crit and liver glycogen. Overall, I have shown that there is a clear relationship between P-crit and the distribution of sculpins along the nearshore environment and that this is primarily related to differences in O₂ extraction capacity. When O₂ tensions are well below their P-crit, there are dramatic differences in behavioral, physiological and biochemical responses among these species of sculpins.
10

Hypoxia Suppresses DNA Repair: Implications for Cancer Progression and Treatment

Chan, Norman 14 February 2011 (has links)
Acute and chronic hypoxia exists within the microenvironment of solid tumours and drives therapy resistance, genetic instability and metastasis. Despite its importance in solid tumour progression, very little is known regarding the functional consequences of hypoxia-mediated changes in the expression of DNA repair proteins. I studied the relationship between hypoxia and DNA repair using a prolonged chronic hypoxic gas treatment model in a variety of human tumour cell lines to mimic the dynamic state of proliferation and DNA repair in cells distant from the tumour blood vasculature. I observed decreased expression of homologous recombination (HR) and base excision repair (BER) proteins due to a novel mechanism involving decreased protein synthesis. Error-free HR was suppressed 3-fold under 0.2% O2 as measured by the DR-GFP reporter system and functional BER was impaired as assessed with a functional glycosylase assay. This decrease in protein expression and function resulted in increased sensitivity to the DNA damaging agents MMC, cisplatin, H2O2 and MMS. Additionally, chronically hypoxic cells were relatively radiosensitive (OER = 1.37) when compared to acutely hypoxic or anoxic cells (OER = 1.96 - 2.61). As HR defects are synthetically lethal with poly(ADP-ribose) polymerase 1 (PARP1) inhibition, I evaluated the sensitivity of repair-defective hypoxic cells to PARP inhibition. I observed increased clonogenic killing in HR-deficient hypoxic cells following inhibition or depletion of PARP1. PARP-inhibited hypoxic cells accumulated γH2AX foci consistent with an accumulation of collapsed replication forks. Additionally, tumour xenografts exposed to PARP1 inhibition showed increased γH2AX and cleaved caspase-3 expression in hypoxic subregions with suppressed RAD51 protein expression and decreased ex vivo clonogenic survival. I conclude that persistent down-regulation of DNA repair components by the microenvironment could result in faulty DNA repair with significant implications for therapeutic response and genetic instability in human cancers. Specifically, hypoxic cells may be sensitized to PARP inhibitors and other agents targeting repair pathways down-regulated by hypoxia as a consequence of microenvironment-mediated “contextual synthetic lethality”.

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