U R Jewell

University of Otago, Taieri, Otago Region, New Zealand

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Publications (9)24.95 Total impact

  • Christine M Morris, Ursula R Jewell
    The New Zealand medical journal 07/2010; 123(1318):6-11.
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    ABSTRACT: Genomic rearrangements are a well-recognized cause of genetic disease and can be formed by a variety of mechanisms. We report a complex rearrangement causing severe hemophilia A, identified and further characterized using a range of PCR-based methods, and confirmed using array-comparative genomic hybridization (array-CGH). This rearrangement consists of a 15.5-kb deletion/16-bp insertion located 0.6 kb from a 28.1-kb deletion/263-kb insertion at Xq28 and is one of the most complex rearrangements described at a DNA sequence level. We propose that the rearrangement was generated by distinct but linked cellular responses to double strand breakage, namely break-induced replication (BIR) and a novel model of break-induced serial replication slippage (SRS). The copy number of several genes is affected by this rearrangement, with deletion of part of the Factor VIII gene (F8, causing hemophilia A) and the FUNDC2 gene, and duplication of the TMEM185A, HSFX1, MAGEA9, and MAGEA11 genes. As the patient exhibits no clinically detectable phenotype other than hemophilia A, it appears that the biological effects of the other genes involved are not dosage-dependent. This investigation has provided novel insights into processes of DNA repair including BIR and the first description of SRS during repair in a pathological context.
    Human Mutation 01/2008; 28(12):1198-206. · 5.21 Impact Factor
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    ABSTRACT: Molecular mechanisms of the inflammatory reaction in hypoxia-induced lung injury are not well defined. Therefore, effects of alveolar hypoxia were studied in rat lungs, exposing rats to 10% oxygen over periods of 1, 2, 4, 6, and 8 h. An increase in the number of macrophages in bronchoalveolar lavage fluid of hypoxic animals was shown between 1 and 8 h. Extravasation of albumin was enhanced after 1 h and remained increased throughout the study period. NF-kappaB-binding activity as well as mRNA for TNF-alpha, macrophage inflammatory protein (MIP)-1beta, and monocyte chemoattractant protein (MCP)-1 were increased within the first 2 h of exposure to hypoxia. Hypoxia-inducible factor (HIF)-1alpha and intercellular adhesion molecule (ICAM)-1 mRNA were upregulated between 1 and 6 h. Elimination of alveolar macrophages by intratracheal application of liposome-encapsulated clodronate led to a decreased expression of NF-kappaB binding activity, HIF-1alpha, TNF-alpha, ICAM-1, and MIP-1beta. In summary, alveolar hypoxia induced macrophage recruitment, an increase in albumin leakage, and enhanced expression of inflammatory mediators, which were mainly macrophage dependent. Alveolar macrophages appear to have a prominent role in the inflammatory response in hypoxia-induced lung injury and the related upregulation of inflammatory mediators.
    AJP Lung Cellular and Molecular Physiology 03/2003; 284(2):L360-7. · 3.52 Impact Factor
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    ABSTRACT: Despite the fact that the use of chicken as immunization host brings many advantages to the production of polyclonal antibodies, the generation of egg yolk immunoglobulins (IgY) is rarely chosen. In this review, we report on the fast and efficient method for generation and affinity purification of IgY, in this case raised against the alpha-subunit of hypoxia-inducible factor-1 (HIF-1). The IgY antibody was successfully applied in a variety of methods and a number of different species for HIF-1alpha detection. In electrophoretic mobility shift assays, the IgY antibody recognized the native HIF-1 complex. The IgY antibody also detected HIF-1alpha protein on Western blots with extracts derived from human, monkey, pig, dog and mouse cell lines grown under hypoxic conditions. Immunofluorescence and immunoprecipitation experiments using the IgY antibody allowed detection and subcellular localization of HIF-1alpha in the nuclei of hypoxic cells. Chicken antibody production brings great benefit concerning the welfare of the immunized animals, due to non-invasive antibody harvesting with the added convenience of simple egg collection. An additional advantage is the fast and simple IgY isolation from egg yolk. IgY technology is a great improvement and should be considered as a good alternative to conventional polyclonal antibody production in mammals.
    Comparative Biochemistry and Physiology - Part A Molecular & Integrative Physiology 04/2002; 131(3):569-74. · 2.17 Impact Factor
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    ABSTRACT: There is increasing evidence that erythropoietin (Epo) has a protective function in cerebral ischemia. When used for treatment, high Epo plasma levels associated with increases in blood viscosity, however, may counteract beneficial effects of Epo in brain ischemia. The authors generated two transgenic mouse lines that overexpress human Epo preferentially, but not exclusively, in neuronal cells. In mouse line tg21, a fourfold increase of Epo protein level was found in brain only, whereas line tg6 showed a dramatic increase of cerebral and systemic transgene expression resulting in hematocrit levels of 80%. Cerebral blood flow (CBF), as determined by bolus tracking magnetic resonance imaging, was not altered in the tg6 line. The time-to-peak interval for the tracer, however, increased approximately threefold in polyglobulic tg6 mice. Immunohistochemical analysis revealed an increase in dilated vessels in tg6 mice, providing an explanation for unaltered CBF in polyglobulic animals. Permanent occlusion of the middle cerebral artery (pMCAO) led to similar perfusion deficits in wild-type, tg6, and tg21 mice. Compared with wild-type controls, infarct volumes were not significantly smaller (22%) in tg21 animals 24 hours after pMCAO, but were 49% enlarged (P < 0.05) in polyglobulic tg6 mice. In the latter animals, elevated numbers of Mac-1 immunoreactive cells in infarcted tissue suggested that leukocyte infiltration contributed to enlarged infarct volume. The current results indicate that moderately increased brain levels of Epo in tg21 transgenic mice were not sufficient to provide significant tissue protection after pMCAO. The results with tg6 mice indicate that systemic chronic treatment with Epo associated with elevated hematocrit might deteriorate outcome after stroke either because of the elevated hematocrit or other chronic effects.
    Journal of Cerebral Blood Flow & Metabolism 08/2001; 21(7):857-64. · 5.40 Impact Factor
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    ABSTRACT: Despite the pivotal role the hypoxia-inducible factor-1 α (HIF-1α ) plays in physiological and pathological processes, little is known regarding the timeframe and mechanisms involved in its regulation. We determined the onset, accumulation, and degradation of HIF-1 α and a number of redox-sensitive nuclear factors over a range of pathophysiological oxygen concentrations. Experiments were carried out on nonadherent human HeLaS3 cells placed in tonometers to achieve rapid equilibration between the cell suspension and the various hypoxic/reoxygenation conditions. Exposure to hypoxia for less than 2 min already revealed nuclear HIF-1 α protein induction on Western blots and HIF-1 DNA binding in EMSAs. One hour after anoxic/hypoxic exposure, nuclear HIF-1α proteins reached maximal levels, which were maintained for 4 h. Reoxygenation reduced HIF-1 DNA binding within 2 min, and nuclear HIF-1α protein levels within 4 to 8 min, down to a level below the detection limit within 32 min. Western blot analysis of the redox sensitive nuclear factors NF- κB, c-Fos, c-Jun, Ref-1, and thioredoxin showed no alteration in their nuclear levels in response to anoxia/hypoxia, but reoxygenation rapidly caused a transient increase in nuclear NF- κB and thioredoxin protein levels. The instant initiation of HIF-1α accumulation shown here limits the hypoxic signaling pathway to below 2 min.
    The FASEB Journal 06/2001; 15(7):1312-4. · 5.70 Impact Factor
  • Ursula R. Jewell, M. a. x. Gassmann
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    ABSTRACT: Hypoxia induces gene expression of specific genes such as erythropoietin (Epo) and vascular endothelial growth factor (VEGF) that allow physiological adaptation to the environmental conditions at the cellular, local, and systemic levels. Reduced oxygenation is also a common precursor of many pathological processes, including coronary artery defects, ischemia, and malignant tumour formation. The hypoxia-inducible transcription factor HIF-1, a heterodimer consisting of the oxygen-regulated alpha-subunit and the constitutively expressed beta or ARNT-subunit, serves as a master regulator of oxygen-dependent gene expression. We observed that upon hypoxic exposure of HeLa cells in tonometer, accumulation of HIF-1alpha occurred within two minutes, while reoxygenation strongly reduced HIF-1alpha levels within four to eight minutes. Thus, hypoxia leads to a rapid cellular adaptation. In another line of investigation, we analysed the impact of hypoxia-independent overexpression of Epo in transgenic mice. Despite a hematocrit of about 80% the transgenic mice did not develop hypertension or thromboembolic complications.
    Zoology 01/2001; 104(3):192-197. · 1.47 Impact Factor
  • Ursula Regina. Jewell
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    ABSTRACT: Diss. phil. II Zürich (Austausch beschränkt). Literaturverz.
  • Ursula R. Jewell, M.a.x. Gassmann
    [Show abstract] [Hide abstract]
    ABSTRACT: Hypoxia induces gene expression of specific genes such as erythropoietin (Epo) and vascular endothelial growth factor (VEGF) that allow physiological adaptation to the environmental conditions at the cellular, local, and systemic levels. Reduced oxygenation is also a common precursor of many pathological processes, including coronary artery defects, ischemia, and malignant tumour formation. The hypoxia-inducible transcription factor HIF-1, a heterodimer consisting of the oxygen-regulated α-subunit and the constitutively expressed β or ARNT-subunit, serves as a master regulator of oxygen-dependent gene expression. We observed that upon hypoxic exposure of HeLa cells in tonometer, accumulation of HIF-1α occurred within two minutes, while reoxygenation strongly reduced HIF-1α levels within four to eight minutes. Thus, hypoxia leads to a rapid cellular adaptation. In another line of investigation, we analysed the impact of hypoxia-independent overexpression of Epo in transgenic mice. Despite a hematocrit of about 80% the transgenic mice did not develop hypertension or thromboembolic complications.
    Zoology 104(s 3–4):192–197. · 1.47 Impact Factor

Publication Stats

483 Citations
24.95 Total Impact Points

Institutions

  • 2008
    • University of Otago
      • Christchurch School of Medicine and Health Sciences
      Taieri, Otago Region, New Zealand
  • 2001
    • Novartis
      Bâle, Basel-City, Switzerland
    • University of Zurich
      • Institute of Physiology
      Zürich, ZH, Switzerland