1,785 research outputs found

    Nonrenal regulation of EPO synthesis

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    Erythropoietin (EPO) is a circulating glycoprotein hormone whose principal function is thought to be red blood cell production. It is a classic example of a hypoxia-inducible gene, and studies of the induction of EPO synthesis by low oxygen led to the discovery of a widespread system of hypoxia-inducible transcription factors. Tissue-specific expression of the EPO gene is tightly controlled, and in the adult organism the kidney produces around 90% of systemic EPO. Before birth, the liver is the main site of EPO production; factors contributing to the liver-to-kidney switch are still elusive, but may provide clues to the tissue-specificity of EPO gene expression. EPO has also been detected in non-erythropoietic tissues such as the brain, where it is suggested to exert local protective effects. Apart from classical ways of regulating renal EPO during hypoxia and anemia, novel pathways have been discovered that demonstrate that other organ systems in the adult might not only be important for the production of EPO but also for modulating the hypoxic EPO response. Knowledge of the molecular bases of these non-renal pathways will eventually help to develop pharmacological strategies to induce endogenous EPO production when the main source, the kidney, is significantly impaired. This review will provide an overview of the molecular aspects of EPO gene regulation by hypoxia-inducible transcription factors and of the tissue-specific regulation of EPO production in adult mammals. Insights into the biology of EPO production in genetically modified animals, with an emphasis on recent advances in the understanding of non-renal EPO regulation, will be discussed

    Inhibition of NGF deprivation-induced death by low oxygen involves suppression of BIMEL and activation of HIF-1.

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    Changes in O(2) tension can significantly impact cell survival, yet the mechanisms underlying these effects are not well understood. Here, we report that maintaining sympathetic neurons under low O(2) inhibits apoptosis caused by NGF deprivation. Low O(2) exposure blocked cytochrome c release after NGF withdrawal, in part by suppressing the up-regulation of BIM(EL). Forced BIM(EL) expression removed the block to cytochrome c release but did not prevent protection by low O(2). Exposing neurons to low O(2) also activated hypoxia-inducible factor (HIF) and expression of a stabilized form of HIF-1alpha (HIF-1alpha(PP-->AG)) inhibited cell death in normoxic, NGF-deprived cells. Targeted deletion of HIF-1alpha partially suppressed the protective effect of low O(2), whereas deletion of HIF-1alpha combined with forced BIM(EL) expression completely reversed the ability of low O(2) to inhibit cell death. These data suggest a new model for how O(2) tension can influence apoptotic events that underlie trophic factor deprivation-induced cell death

    Endothelial hypoxic metabolism in carcinogenesis and dissemination: HIF-A isoforms are a NO metastatic phenomenon.

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    Tumor biology is a broad and encompassing field of research, particularly given recent demonstrations of the multicellular nature of solid tumors, which have led to studies of molecular and metabolic intercellular interactions that regulate cancer progression. Hypoxia is a broad stimulus that results in activation of hypoxia inducible factors (HIFs). Downstream HIF targets include angiogenic factors (e.g. vascular endothelial growth factor, VEGF) and highly reactive molecules (e.g. nitric oxide, NO) that act as cell-specific switches with unique spatial and temporal effects on cancer progression. The effect of cell-specific responses to hypoxia on tumour progression and spread, as well as potential therapeutic strategies to target metastatic disease, are currently under active investigation. Vascular endothelial remodelling events at tumour and metastatic sites are responsive to hypoxia, HIF activation, and NO signalling. Here, we describe the interactions between endothelial HIF and NO during tumor growth and spread, and outline the effects of endothelial HIF/NO signalling on cancer progression. In doing so, we attempt to identify areas of metastasis research that require attention, in order to ultimately facilitate the development of novel treatments that reduce or prevent tumour dissemination

    IR Kuiper Belt Constraints

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    We compute the temperature and IR signal of particles of radius aa and albedo α\alpha at heliocentric distance RR, taking into account the emissivity effect, and give an interpolating formula for the result. We compare with analyses of COBE DIRBE data by others (including recent detection of the cosmic IR background) for various values of heliocentric distance, RR, particle radius, aa, and particle albedo, α\alpha. We then apply these results to a recently-developed picture of the Kuiper belt as a two-sector disk with a nearby, low-density sector (40<R<50-90 AU) and a more distant sector with a higher density. We consider the case in which passage through a molecular cloud essentially cleans the Solar System of dust. We apply a simple model of dust production by comet collisions and removal by the Poynting-Robertson effect to find limits on total and dust masses in the near and far sectors as a function of time since such a passage. Finally we compare Kuiper belt IR spectra for various parameter values.Comment: 34 pages, LaTeX, uses aasms4.sty, 11 PostScript figures not embedded. A number of substantive comments by a particularly thoughtful referee have been addresse

    Parameterizing animal sounds and motion with animal-attached tags to study acoustic communication

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    Funding: Dolphin Quest, Inc.; School of Biology, University of St Andrews; Scottish Universities Life Sciences Alliance; Office of Naval Research; Marine Alliance for Science and Technology for Scotland; Horizon H2020.Stemming from the traditional use of field observers to score states and events, the study of animal behaviour often relies on analyses of discrete behavioural categories. Many studies of acoustic communication record sequences of animal sounds, classify vocalizations, and then examine how call categories are used relative to behavioural states and events. However, acoustic parameters can also convey information independent of call type, offering complementary study approaches to call classifications. Animal-attached tags can continuously sample high-resolution behavioural data on sounds and movements, which enables testing how acoustic parameters of signals relate to parameters of animal motion. Here, we present this approach through case studies on wild common bottlenose dolphins (Tursiops truncatus). Using data from sound-and-movement recording tags deployed in Sarasota (FL), we parameterized dolphin vocalizations and motion to investigate how senders and receivers modified movement parameters (including vectorial dynamic body acceleration, “VeDBA”, a proxy for activity intensity) as a function of signal parameters. We show that (1) VeDBA of one female during consortships had a negative relationship with centroid frequency of male calls, matching predictions about agonistic interactions based on motivation-structural rules; (2) VeDBA of four males had a positive relationship with modulation rate of their pulsed vocalizations, confirming predictions that click-repetition rate of these calls increases with agonism intensity. Tags offer opportunities to study animal behaviour through analyses of continuously sampled quantitative parameters, which can complement traditional methods and facilitate research replication. Our case studies illustrate the value of this approach to investigate communicative roles of acoustic parameter changes.Publisher PDFPeer reviewe

    Dietary nitrate increases arginine availability and protects mitochondrial complex I and energetics in the hypoxic rat heart

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    This is the final version. It was first published by Wiley in The Journal of Physiology at http://onlinelibrary.wiley.com/doi/10.1113/jphysiol.2014.275263/abstract.Hypoxic exposure is associated with impaired cardiac energetics in humans and altered mitochondrial function, with suppressed complex I-supported respiration, in rat heart. This response might limit reactive oxygen species (ROS) generation, but at the cost of impaired electron transport chain (ETC) activity. Dietary nitrate supplementation improves mitochondrial efficiency and can promote tissue oxygenation by enhancing blood flow. We therefore hypothesised that ETC dysfunction, impaired energetics and oxidative damage in the hearts of rats exposed to chronic hypoxia could be alleviated by sustained administration of a moderate dose of dietary nitrate. Male Wistar rats (n=40) were given water supplemented with 0.7 mmol/L NaCl (as control) or 0.7 mmol/L NaNO3, elevating plasma nitrate levels by 80%, and were exposed to 13% O2 (hypoxia) or normoxia (n=10 per group) for 14 days. Respiration rates, ETC protein levels, mitochondrial density, ATP content and protein carbonylation were measured in cardiac muscle. Complex I respiration rates and protein levels were 33% lower in hypoxic/NaCl rats compared with normoxic/NaCl controls. Protein carbonylation was 65% higher in hearts of hypoxic rats compared with controls, indicating increased oxidative stress, whilst ATP levels were 62% lower. Respiration rates, complex I protein and activity, protein carbonylation and ATP levels were all fully protected in the hearts of nitrate-supplemented hypoxic rats. Both in normoxia and hypoxia, dietary nitrate suppressed cardiac arginase expression and activity and markedly elevated cardiac L-arginine concentrations, unmasking a novel mechanism of action by which nitrate enhances tissue NO bioavailability. Dietary nitrate therefore alleviates metabolic abnormalities in the hypoxic heart, improving myocardial energetics

    Wavelength Tunability of Ion-bombardment Induced Ripples on Sapphire

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    A study of ripple formation on sapphire surfaces by 300-2000 eV Ar+ ion bombardment is presented. Surface characterization by in-situ synchrotron grazing incidence small angle x-ray scattering and ex-situ atomic force microscopy is performed in order to study the wavelength of ripples formed on sapphire (0001) surfaces. We find that the wavelength can be varied over a remarkably wide range-nearly two orders of magnitude-by changing the ion incidence angle. Within the linear theory regime, the ion induced viscous flow smoothing mechanism explains the general trends of the ripple wavelength at low temperature and incidence angles larger than 30. In this model, relaxation is confined to a few-nm thick damaged surface layer. The behavior at high temperature suggests relaxation by surface diffusion. However, strong smoothing is inferred from the observed ripple wavelength near normal incidence, which is not consistent with either surface diffusion or viscous flow relaxation.Comment: Revtex4, 19 pages, 10 figures with JPEG forma
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