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Search Results: 1 - 10 of 88298 matches for " W. Colin Duncan "
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The In Utero Programming Effect of Increased Maternal Androgens and a Direct Fetal Intervention on Liver and Metabolic Function in Adult Sheep
Kirsten Hogg, Charlotte Wood, Alan S. McNeilly, W. Colin Duncan
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0024877
Abstract: Epigenetic changes in response to external stimuli are fast emerging as common underlying causes for the pre-disposition to adult disease. Prenatal androgenization is one such model that results in reproductive and metabolic features that are present in conditions such as polycystic ovary syndrome (PCOS). We examined the effect of prenatal androgens on liver function and metabolism of adult sheep. As non-alcoholic fatty liver disease is increased in PCOS we hypothesized that this, and other important liver pathways including metabolic function, insulin–like growth factor (IGF) and steroid receptivity, would be affected. Pregnant ewes received vehicle control (C; n = 5) or testosterone propionate (TP; n = 9) twice weekly (100 mg; i.m) from d62–102 (gestation 147 days). In a novel treatment paradigm, a second cohort received a direct C (n = 4) or TP (20 mg; n = 7) fetal injection at d62 and d82. In adults, maternal TP exposure resulted in increased insulin secretion to glucose load (P<0.05) and the histological presence of fatty liver (P<0.05) independent of central obesity. Additionally, hepatic androgen receptor (AR; P<0.05), glucocorticoid receptor (GR; P<0.05), UDP- glucose ceramide glucosyltransferase (UGCG; P<0.05) and IGF1 (P<0.01) expression were upregulated. The direct fetal intervention (C and TP) led to early fatty liver changes in all animals without differential changes in insulin secretion. Furthermore, hepatic phosphoenolpyruvate carboxykinase (PEPCK) was up-regulated in the fetal controls (P<0.05) and this was opposed by fetal TP (P<0.05). Hepatic estrogen receptor (ERα; P<0.05) and mitogen activated protein kinase kinase 4 (MAP2K4; P<0.05) were increased following fetal TP exposure. Adult liver metabolism and signaling can be altered by early exposure to sex steroids implicating epigenetic regulation of metabolic disturbances that are common in PCOS.
Glucocorticoid Regulation of SLIT/ROBO Tumour Suppressor Genes in the Ovarian Surface Epithelium and Ovarian Cancer Cells
Rachel E. Dickinson, K. Scott Fegan, Xia Ren, Stephen G. Hillier, W. Colin Duncan
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0027792
Abstract: The three SLIT ligands and their four ROBO receptors have fundamental roles in mammalian development by promoting apoptosis and repulsing aberrant cell migration. SLITs and ROBOs have emerged as candidate tumour suppressor genes whose expression is inhibited in a variety of epithelial tumours. We demonstrated that their expression could be negatively regulated by cortisol in normal ovarian luteal cells. We hypothesised that after ovulation the locally produced cortisol would inhibit SLIT/ROBO expression in the ovarian surface epithelium (OSE) to facilitate its repair and that this regulatory pathway was still present, and could be manipulated, in ovarian epithelial cancer cells. Here we examined the expression and regulation of the SLIT/ROBO pathway in OSE, ovarian cancer epithelial cells and ovarian tumour cell lines. Basal SLIT2, SLIT3, ROBO1, ROBO2 and ROBO4 expression was lower in primary cultures of ovarian cancer epithelial cells when compared to normal OSE (P<0.05) and in poorly differentiated SKOV-3 cells compared to the more differentiated PEO-14 cells (P<0.05). Cortisol reduced the expression of certain SLITs and ROBOs in normal OSE and PEO-14 cells (P<0.05). Furthermore blocking SLIT/ROBO activity reduced apoptosis in both PEO-14 and SKOV-3 tumour cells (P<0.05). Interestingly SLIT/ROBO expression could be increased by reducing the expression of the glucocorticoid receptor using siRNA (P<0.05). Overall our findings indicate that in the post-ovulatory phase one role of cortisol may be to temporarily inhibit SLIT/ROBO expression to facilitate regeneration of the OSE. Therefore this pathway may be a target to develop strategies to manipulate the SLIT/ROBO system in ovarian cancer.
Using a decline in serum hCG between days 0–4 to predict ectopic pregnancy treatment success after single-dose methotrexate: a retrospective cohort study
Monika Skubisz, Philip Dutton, William Colin Duncan, Andrew W Horne, Stephen Tong
BMC Pregnancy and Childbirth , 2013, DOI: 10.1186/1471-2393-13-30
Abstract: We conducted a retrospective study of women (n=206) treated with single-dose methotrexate for ectopic pregnancy (pre-treatment serum hCG levels ≤3000 IU/L) at Scottish hospitals between 2006–2011. Women were divided into two cohorts based on whether their serum hCG levels rose or fell between days 0–4 after methotrexate. Treatment outcomes of women in each cohort were compared, and the test performance characteristics calculated. This methodology was repeated for the current measure (≥15% fall in serum hCG between days 4–7 of treatment) and an alternate early measure (<20% fall in serum hCG between days 0–4 of treatment), and all three measures were compared for their ability to predict medical treatment success.In our cohort, the positive predictive value of the current clinical measure was 89% (95% CI 84-94%) (121/136). A falling serum hCG between days 0–4 predicted treatment success in 85% (95% CI 79-92%) of cases (94/110) and a <20% fall in serum hCG between days 0–4 predicted treatment success in 94% (95% CI 88-100%) of cases (59/63). There was no significant difference in the ability of these tests to predict medical treatment success.We have verified that a decline in serum hCG between days 0–4 after methotrexate treatment for ectopic pregnancies, with pre-treatment serum hCG levels ≤3000 IU/L, provides an early indication of likelihood of treatment success, and performs just as well as the existing measure, which only provides prognostic information on day 7.Ectopic pregnancies occur in 1-2% of pregnancies [1]. Although potentially life threatening, the ability to non-invasively detect ectopic pregnancies before they rupture with ultrasound affords some women the option of medical management. Stovall et al.[2] first demonstrated the safety and efficacy of outpatient methotrexate to treat women with ectopic pregnancies in 1989, and today, approximately 25-30% of women presenting with this condition are eligible for such treatment [3,4].Quantification of serum
Ectopic Pregnancy as a Model to Identify Endometrial Genes and Signaling Pathways Important in Decidualization and Regulated by Local Trophoblast
W. Colin Duncan, Julie L. V. Shaw, Stewart Burgess, Sarah E. McDonald, Hilary O. D. Critchley, Andrew W. Horne
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0023595
Abstract: The endometrium in early pregnancy undergoes decidualization and functional changes induced by local trophoblast, which are not fully understood. We hypothesized that endometrium from tubal ectopic pregnancy (EP) could be interrogated to identify novel genes and pathways involved in these processes. Gestation-matched endometrium was collected from women with EP (n = 11) and intrauterine pregnancies (IUP) (n = 13). RNA was extracted from the tissue. In addition, tissues were prepared for histological analysis for degree of decidualization. We compared a) the samples from EP that were decidualized (n = 6) with non-decidualized samples (n = 5), and b) the decidualized EP (n = 6) with decidualization-matched IUP (n = 6) samples using an Affymetrix gene array platform, with Ingenuity Pathway Analysis, combined with quantitative RT-PCR. Expression of PRL and IGFBP1 was used to confirm the degree of decidualization in each group. There were no differences in PRL or IGFBP1 expression in the decidualization-matched samples but a marked reduction (P<0.001) in the non-decidualized samples. Decidualization was associated with increased expression of 428 genes including SCARA5 (181-fold), DKK1 (71-fold) and PROK1 (32-fold), and decreased expression of 230 genes including MMP-7 (35-fold) and SFRP4 (21-fold). The top canonical pathways associated with these differentially expressed genes were Natural Killer Cell and Wnt/b-Catenin signaling. Local trophoblast was associated with much less alteration of endometrial gene expression with an increase in 56 genes, including CSH1 (8-fold), and a reduction in 29 genes including CRISP3 (8-fold). The top associated canonical pathway was Antigen Presentation. The study of endometrium from tubal EP may promote novel insights into genes involved in decidualization and those influenced by factors from neighboring trophoblast. This has afforded unique information not highlighted by previous studies and adds to our understanding of the endometrium in early pregnancy.
Purification and Structural Characterization of Siderophore (Corynebactin) from Corynebacterium diphtheriae
Sheryl Zajdowicz, Jon C. Haller, Amy E. Krafft, Steve W. Hunsucker, Colin T. Mant, Mark W. Duncan, Robert S. Hodges, David N. M. Jones, Randall K. Holmes
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0034591
Abstract: During infection, Corynebacterium diphtheriae must compete with host iron-sequestering mechanisms for iron. C. diphtheriae can acquire iron by a siderophore-dependent iron-uptake pathway, by uptake and degradation of heme, or both. Previous studies showed that production of siderophore (corynebactin) by C. diphtheriae is repressed under high-iron growth conditions by the iron-activated diphtheria toxin repressor (DtxR) and that partially purified corynebactin fails to react in chemical assays for catecholate or hydroxamate compounds. In this study, we purified corynebactin from supernatants of low-iron cultures of the siderophore-overproducing, DtxR-negative mutant strain C. diphtheriae C7(β) ΔdtxR by sequential anion-exchange chromatography on AG1-X2 and Source 15Q resins, followed by reverse-phase high-performance liquid chromatography (RP-HPLC) on Zorbax C8 resin. The Chrome Azurol S (CAS) chemical assay for siderophores was used to detect and measure corynebactin during purification, and the biological activity of purified corynebactin was shown by its ability to promote growth and iron uptake in siderophore-deficient mutant strains of C. diphtheriae under iron-limiting conditions. Mass spectrometry and NMR analysis demonstrated that corynebactin has a novel structure, consisting of a central lysine residue linked through its α- and ε- amino groups by amide bonds to the terminal carboxyl groups of two different citrate residues. Corynebactin from C. diphtheriae is structurally related to staphyloferrin A from Staphylococcus aureus and rhizoferrin from Rhizopus microsporus in which d-ornithine or 1,4-diaminobutane, respectively, replaces the central lysine residue that is present in corynebactin.
The Association between Smoking and Ectopic Pregnancy: Why Nicotine Is BAD for Your Fallopian Tube
Andrew W. Horne, Jeremy K. Brown, Junko Nio-Kobayashi, Hazirah B. Z. Abidin, Zety E. H. A. Adin, Lyndsey Boswell, Stewart Burgess, Kai-Fai Lee, W. Colin Duncan
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0089400
Abstract: Epidemiological studies have shown that cigarette smoking is a major risk factor for tubal ectopic pregnancy but the reason for this remains unclear. Here, we set out to determine the effect of smoking on Fallopian tube gene expression. An oviductal epithelial cell line (OE-E6/E7) and explants of human Fallopian tubes from non-pregnant women (n = 6) were exposed to physiologically relevant concentrations of cotinine, the principle metabolite of nicotine, and changes in gene expression analyzed using the Illumina Human HT-12 array. Cotinine sensitive genes identified through this process were then localized and quantified in Fallopian tube biopsies from non-pregnant smokers (n = 10) and non-smokers (n = 11) using immunohistochemistry and TaqMan RT-PCR. The principle cotinine induced change in gene expression detected by the array analysis in both explants and the cell line was significant down regulation (P<0.05) of the pro-apoptotic gene BAD. We therefore assessed the effect of smoking on cell turnover in retrospectively collected human samples. Consistent with the array data, smoking was associated with decreased levels of BAD transcript (P<0.01) and increased levels of BCL2 transcript (P<0.05) in Fallopian tube biopsies. BAD and BCL2 specific immunolabelling was localized to Fallopian tube epithelium. Although no other significant differences in levels of apoptosis or cell cycle associated proteins were observed, smoking was associated with significant changes in the morphology of the Fallopian tube epithelium (P<0.05). These results suggest that smoking may alter tubal epithelial cell turnover and is associated with structural, as well as functional, changes that may contribute to the development of ectopic pregnancy.
Neuroinflammation induces glial aromatase expression in the uninjured songbird brain
Kelli A Duncan, Colin J Saldanha
Journal of Neuroinflammation , 2011, DOI: 10.1186/1742-2094-8-81
Abstract: Adult male zebra finches (Taeniopygia guttata) were given a penetrating injury to the entopallium. At several timepoints later, expression of aromatase, IL-1β-like, and IL-6-like were examined using immunohisotchemistry. A second set of zebra birds were exposed to phytohemagglutinin (PHA), an inflammatory agent, directly on the dorsal surface of the telencephalon without creating a penetrating injury. Expression of aromatase, IL-1β-like, and IL-6-like were examined using both quantitative real-time polymerase chain reaction to examine mRNA expression and immunohistochemistry to determine cellular expression. Statistical significance was determined using t-test or one-way analysis of variance followed by the Tukey Kramers post hoc test.Following injury in the zebra finch brain, cytokine expression occurs prior to aromatase expression. This temporal pattern suggests that cytokines may induce aromatase expression in the damaged zebra finch brain. Furthermore, evoking a neuroinflammatory response characterized by an increase in cytokine expression in the uninjured brain is sufficient to induce glial aromatase expression.These studies are among the first to examine a neuroinflammatory response in the songbird brain following mechanical brain injury and to describe a novel neuroimmune signal to initiate aromatase expression in glia.Damage to the homeotherm brain increases aromatase (estrogen synthase) in reactive astroglia [1-3]. Although constitutive aromatase is abundant and neuronal in the undamaged songbird brain, glial aromatase expression is rapidly upregulated following brain damage [1,4-8]. Increased transcription and translation of glial aromatase occurs following damage to the neuropil in songbirds and to a lesser extent in mammals [2,8-10]. In songbirds, this upregulation appears more rapid and robust, since the secondary wave of degeneration characteristic of the mammalian (including human) brain following TBI is only revealed in songbirds following inhibition
Modelling stellar coronae from surface magnetograms: the role of missing magnetic flux
Colin Johnstone,Moira Jardine,Duncan Mackay
Physics , 2010, DOI: 10.1111/j.1365-2966.2010.16298.x
Abstract: Recent advances in spectropolarimetry have allowed the reconstruction of stellar coronal magnetic fields. This uses Zeeman-Doppler magnetograms of the surface magnetic field as a lower boundary condition. The ZDI maps, however, suffer from the absence of information about the magnetic field over regions of the surface due to the presence of dark starspots and portions of the surface out of view due to a tilt in the rotation axis. They also suffer from finite resolution which leads to small scale field structures being neglected. This paper explores the effects of this loss of information on the extrapolated coronal fields. For this we use simulated stellar surface magnetic maps for two hypothetical stars. Using the potential field approximation, the coronal fields and emission measures are calculated. This is repeated for the cases of missing information due to, (i) starspots, (ii) a large area of the stellar surface out of view, (iii) a finite resolution. The largest effect on the magnetic field structure arises when a significant portion of the stellar surface remains out of view. This changes the nature of the field lines that connect to this obscured hemisphere. Nonetheless, the field structure in the visible hemisphere is reliably reproduced. Thus the calculation of the locations and surface filling factors of accretion funnels is reasonably well reproduced for the observed hemisphere. The decrease with height of the magnetic pressure, which is important in calculating disc truncation radii for accreting stars, is also largely unaffected in the equatorial plane. The fraction of surface flux that is open and therefore able to supply angular momentum loss in a wind, however, is often overestimated in the presence of missing flux.
A Dirac sea pilot-wave model for quantum field theory
S. Colin,W. Struyve
Physics , 2007, DOI: 10.1088/1751-8113/40/26/015
Abstract: We present a pilot-wave model for quantum field theory in which the Dirac sea is taken seriously. The model ascribes particle trajectories to all the fermions, including the fermions filling the Dirac sea. The model is deterministic and applies to the regime in which fermion number is superselected. This work is a further elaboration of work by Colin, in which a Dirac sea pilot-wave model is presented for quantum electrodynamics. We extend his work to non-electromagnetic interactions, we discuss a cut-off regularization of the pilot-wave model and study how it reproduces the standard quantum predictions. The Dirac sea pilot-wave model can be seen as a possible continuum generalization of a lattice model by Bell. It can also be seen as a development and generalization of the ideas by Bohm, Hiley and Kaloyerou, who also suggested the use of the Dirac sea for the development of a pilot-wave model for quantum electrodynamics.
Deterministically driven random walks on a finite state space
Colin M. W. Little
Mathematics , 2013,
Abstract: We introduce the concept of a deterministic walk. Confining our attention to the finite state case, we establish hypotheses that ensure that the deterministic walk is transitive, and show that this property is in some sense robust. We also establish conditions that ensure the existence of asymptotic occupation times.
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