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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.

Factors modulating the control of ventilation during exercise in humans

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

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

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.

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.

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.

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.

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.

The role of hypoxia for the development of diabetic nephropathy : Temporal relationship and involvement of endothelin receptor signaling

Franzén, Stephanie January 2016 (has links)
Diabetic nephropathy is one of the most common causes of end stage renal disease and develops in approximately one third of all diabetes patients. Disease progression is characterized by deteriorating glomerular filtration rate and escalating urinary albumin/protein excretion; both are used as clinical markers for disease progression. Recently, it has been proposed that intrarenal hypoxia is a unifying mechanism for chronic kidney disease, including diabetic nephropathy. Several mechanistic pathways have been linked to the development of intrarenal hypoxia and diabetic nephropathy including increased angiotensin II signaling, oxidative stress and hyperglycemia per se. Furthermore, pathological endothelin signaling has recently immerged as a possible contributing factor for chronic kidney disease and diabetic nephropathy. The overall aims of this thesis were therefore to determine the temporal relationship between development of intrarenal hypoxia and kidney disease as well as elucidate the potential link between endothelin signaling, intrarenal hypoxia and kidney disease in experimental insulinopenic diabetes. It is well established that different mouse strains have different susceptibility for kidney and cardiovascular disease. The first step was therefore to compare four commonly used mouse strains with regards to development of kidney disease after onset of insulinopenic diabetes. From the results of this study, we concluded that the NMRI mouse strain has a disease progression closest to the human disease and this strain was chosen in the subsequent studies in mice. The next step was to adapt and optimize a suitable method for repetitive measurements of intrarenal oxygen tension during the course of disease development. Electron paramagnetic resonance (EPR) oximetry had previously been used in tumor biology and was now adapted and optimized for measurements of kidney oxygenation in our diabetic mouse model. EPR oximetry in normoglycemic control mice recorded cortical oxygen tension values similar to previous reports using invasive techniques. Surprisingly, intrarenal hypoxia developed already within the first 72h after induction of hyperglycemia and persisted throughout the two-week study period. Importantly, this was well before albuminuria developed. The final part of this thesis was to investigate the role of endothelin signaling for the intrarenal hypoxia in a diabetic rat model. Endothelin 1 signals via two distinctly different receptor-mediated pathways. In normal physiology, endothelin 1 binding to endothelin receptor type A (ETA) induces vasoconstriction, which can be blocked by the specific ETA antagonist BQ123, whereas endothelin 1 binding to endothelin receptor type B (ETB) induces nitric oxide-dependent vasodilation. ETB receptors can be selectively activated by Sarafotoxin 6c. The results from blocking ETA and activating ETB receptors demonstrated that endothelin 1 signaling via ETA receptors contributes to intrarenal hypoxia in the rat diabetic kidney, and that ETB stimulation significantly reduces the diabetes-induced intrarenal hypoxia. The beneficial effects on kidney oxygen availability in diabetes by ETA blockade or ETB stimulation were mainly linked to hemodynamic improvements rather than direct effects on kidney oxygen consumption or oxidative stress status. In conclusion, by applying EPR oximetry in a mouse model of insulinopenic diabetes mimicking the human disease, we demonstrated intrarenal hypoxia already within the first couple of days after the onset of hyperglycemia, which is well before detectable signs of kidney disease development. Furthermore, blockade of ETA or activation of ETB receptors significantly reduced intrarenal hypoxia in the diabetic kidney. These results demonstrate involvement of ETA receptor signaling in diabetes-induced intrarenal hypoxia and ETA blockade or ETB activation might provide new therapeutical targets to reduce kidney hypoxia and disease progression in diabetes.

Vasorelaxant mechanism in pulmonary arteries

Priest, Rachel Michelle January 1996 (has links)
No description available.

Slow adaptations within the chemoreflexes regulating breathing in humans

Ren, Xiaohui January 1999 (has links)
No description available.

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