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  1. Antihypoxic effect of miR-24 in SH-SY5Y cells under hypoxia via downregulating expression of neurocan

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    Sun, Xingyuan, E-mail: sunxingyuan@sina.com; Ren, Zhanjun; Pan, Yunzhi; Zhang, Chenxin

    2016-09-02

    Hypoxia-induced apoptosis-related mechanisms involved in the brain damage following cerebral ischemia injury. A subset of the small noncoding microRNA (miRNAs) is regulated by tissue oxygen levels, and miR-24 was found to be activated by hypoxic conditions. However, the roles of miR-24 and its target gene in neuron are not well understood. Here, we validated miRNA-24 is down-regulated in patients with cerebral infarction. Hypoxia suppressed the expression of miR-24, but increased the expression of neurocan in both mRNA and protein levels in SH-SY5Y cells. MiR-24 mimics reduced the expression of neurocan, suppressed cell apoptosis, induced cell cycle progression and cell proliferation in SH-SY5Y cells under hypoxia. By luciferase reporter assay, neurocan is validated a direct target gene of miR-24. Furthermore, knockdown of neurocan suppressed cell apoptosis, induced cell cycle progression and cell proliferation in SH-SY5Y cells under hypoxia. Taken together, miR-24 overexpression or silencing of neurocan shows an antihypoxic effect in SH-SY5Y cells. Therefore, miR-24 and neurocan play critical roles in neuron cell apoptosis and are potential therapeutic targets for ischemic brain disease. - Highlights: • miR-24 and neurocan play critical roles in neuron cell apoptosis. • miR-24 and neurocan are potential therapeutic targets for ischemic brain disease. • Antihypoxic effect of miR-24 and neurocan in SH-SY5Y cells.

  2. Neuroprotection via RNA-binding protein RBM3 expression is regulated by hypothermia but not by hypoxia in human SK-N-SH neurons

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    Rosenthal LM

    2017-05-01

    Full Text Available Lisa-Maria Rosenthal,1 Giang Tong,1 Christoph Walker,1 Sylvia J Wowro,1 Jana Krech,1 Constanze Pfitzer,1,2 Georgia Justus,1 Felix Berger,1,3 Katharina Rose Luise Schmitt1 1Department of Congenital Heart Disease/Pediatric Cardiology, German Heart Institute Berlin, 2Berlin Institute of Health (BIH, 3Department of Pediatric Cardiology, Charité – University Medical Center, Berlin, Germany Objective: Therapeutic hypothermia is an established treatment for perinatal asphyxia. Yet, many term infants continue to die or suffer from neurodevelopmental disability. Several experimental studies have demonstrated a beneficial effect of mild-to-moderate hypothermia after hypoxic injury, but the understanding of hypothermia-induced neuroprotection remains incomplete. In general, global protein synthesis is attenuated by hypothermia, but a small group of RNA-binding proteins including the RNA-binding motif 3 (RBM3 is upregulated in response to cooling. The aim of this study was to establish an in vitro model to investigate the effects of hypoxia and hypothermia on neuronal cell survival, as well as to examine the kinetics of concurrent cold-shock protein RBM3 gene expression. Methods: Experiments were performed by using human SK-N-SH neurons exposed to different oxygen concentrations (21%, 8%, or 0.2% O2 for 24 hours followed by moderate hypothermia (33.5°C or normothermia for 24, 48, or 72 hours. Cell death was determined by quantification of lactate dehydrogenase and neuron-specific enolase releases into the cell cultured medium, and cell morphology was assessed by using immunofluorescence staining. The regulation of RBM3 gene expression was assessed by reverse transcriptase-quantitative polymerase chain reaction and Western blot analysis.Results: Exposure to hypoxia (0.2% O2 for 24 hours resulted in significantly increased cell death in SK-N-SH neurons, whereas exposure to 8% O2 had no significant impact on cell viability. Post-hypoxia treatment with

  3. Peripheral chemoreceptor control of ventilation following sustained hypoxia in young and older adult humans.

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    Vovk, Andrea; Smith, W Donald F; Paterson, Nicole D; Cunningham, David A; Paterson, Donald H

    2004-11-01

    The rate and duration of peripheral chemoreceptor resensitization following sustained hypoxia was characterized in young and older (74-year-old) adults. In addition, cerebral blood velocity (CBV) was measured in young subjects during and following the relief from sustained hypoxia. Following 20 min of sustained eucapnic hypoxia (50 mmHg), subjects were re-exposed to brief (1.5 min) hypoxic pulses (50 mmHg), and the magnitude of the ventilatory response was used to gauge peripheral chemosensitivity. Five minutes after the relief from sustained hypoxia, ventilation (V(E)) increased to 40.3 +/- 4.5% of the initial hypoxic ventilatory response, and by 36 min V(E) increased to 100%, indicating that peripheral chemosensitivity to hypoxia was restored. The V(E) response magnitude plotted versus time demonstrated that V(E), hence peripheral chemosensitivity, was restored at a rate of 1.9% per minute. Cerebral blood flow (CBF, inferred from CBV) remained constant during sustained hypoxia and increased by the same magnitude during the hypoxic pulses, suggesting that CBF has a small, if any, impact on the decline in V(E) during hypoxia and its subsequent recovery. To address the issue of whether hypoxic pulses affect subsequent challenges, series (continuous hypoxic pulses at various recovery intervals) and parallel (only 1 pulse per trial) methods were used. There were no differences in the ventilatory responses between the series and parallel methods. Older adults demonstrated a similar rate of recovery as in the young, suggesting that ageing in active older adults does not affect the peripheral chemoreceptor response.

  4. Acute and Chronic Sustained Hypoxia Do Not Substantially Regulate Amyloid-β Peptide Generation In Vivo.

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    Alberto Serrano-Pozo

    Full Text Available Recent epidemiological evidence has linked hypoxia with the development of Alzheimer disease (AD. A number of in vitro and in vivo studies have reported that hypoxia can induce amyloid-β peptide accumulation through various molecular mechanisms including the up-regulation of the amyloid-β precursor protein, the β-secretase Bace1, or the γγ-secretase complex components, as well as the down-regulation of Aβ-degrading enzymes.To investigate the effects of acute and chronic sustained hypoxia in Aβ generation in vivo.2-3 month-old C57/Bl6J wild-type mice were exposed to either normoxia (21% O2 or hypoxia (9% O2 for either 4 to 72 h (acute or 21-30 days (chronic sustained in a hermetic chamber. Brain mRNA levels of Aβ-related genes were measured by quantitative real-time PCR, whereas levels of Bace1 protein, full length AβPP, and its C-terminal fragments (C99/C88 ratio were measured by Western blot. In addition, 8 and 14-month-old APP/PS1 transgenic mice were subjected to 9% O2 for 21 days and levels of Aβ40, Aβ42, full length AβPP, and soluble AβPPα (sAβPPα were measured by ELISA or WB.Hypoxia (either acute or chronic sustained did not impact the transcription of any of the Aβ-related genes in young wild-type mice. A significant reduction of Bace1 protein level was noted with acute hypoxia for 16 h but did not correlate with an increased level of full length AβPP or a decreased C99/C83 ratio. Chronic sustained hypoxia did not significantly alter the levels of Bace1, full length AβPP or the C99/C83 ratio. Last, chronic sustained hypoxia did not significantly change the levels of Aβ40, Aβ42, full length AβPP, or sAβPPα in either young or aged APP/PS1 mice.Our results argue against a hypoxia-induced shift of AβPP proteolysis from the non-amyloidogenic to the amyloidogenic pathways. We discuss the possible methodological caveats of previous in vivo studies.

  5. Persisting in papyrus: size, oxidative stress, and fitness in freshwater organisms adapted to sustained hypoxia.

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    Joyner-Matos, Joanna; Chapman, Lauren J

    2013-08-01

    Aquatic hypoxia is generally viewed as stressful for aerobic organisms. However, hypoxia may also benefit organisms by decreasing cellular stress, particularly that related to free radicals. Thus, an ideal habitat may have the minimum O2 necessary to both sustain aerobic metabolism and reduce the need to scavenge free radicals and repair free radical damage. The ability of aquatic organisms to sustain aerobic metabolism relates in part to the ability to maximize gas diffusion, which can be facilitated by small body size when O2 uptake occurs across the body surface, by a large gill surface area, or by the ability to use atmospheric air. We use water-breathing organisms in chronically hypoxic papyrus (Cyperus papyrus) swamps of East Africa to test the hypothesis that cellular-level benefits of hypoxia may translate into increased fitness, especially for small organisms. A review of recent studies of fingernail clams (Sphaerium sp.) shows that clams living in sustained hypoxia have minimized oxidative stress and that these cellular-level benefits may lead to increased fitness. We suggest that organisms in the extreme conditions in the papyrus swamps provide a unique opportunity to challenge the conventional classification of hypoxic habitats as 'stressful' and normoxic habitats as 'optimal.' Copyright © 2013 Elsevier Inc. All rights reserved.

  6. Exposure to intermittent hypoxia and sustained hypercapnia reduces therapeutic CPAP in participants with obstructive sleep apnea.

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    El-Chami, Mohamad; Sudan, Sukhesh; Lin, Ho-Sheng; Mateika, Jason H

    2017-07-06

    To determine if exposure to mild intermittent hypoxia leads to a reduction in the therapeutic continuous positive airway pressure required to eliminate breathing events. Ten male participants were treated with twelve 2-minute episodes of hypoxia (PETO2 ≈ 50 mmHg) separated by 2-minute intervals of normoxia in the presence of PETCO2 that was sustained 3 mmHg above baseline. During recovery from the last episode the positive airway pressure was reduced in a step-wise fashion until flow limitation was evident. The participants also completed a sham protocol under normocapnic conditions, which mimicked the timeframe of the intermittent hypoxia protocol. After exposure to intermittent hypoxia the therapeutic pressure was significantly reduced (i.e. 5 cmH2O) without evidence of flow limitation (103.4 ± 6.3 % of baseline, P = 0.5) or increases in upper airway resistance (95.6 ± 15.0 % of baseline, P = 0.6). In contrast, a similar decrease in pressure was accompanied by flow limitation (77.0 ± 1.8 % of baseline, P = 0.001) and an increase in upper airway resistance (167.2 ± 17.5 % of baseline, P = 0.01) after the sham protocol. Consistent with the initiation of long-term facilitation of upper airway muscle activity exposure to intermittent hypoxia reduced the therapeutic pressure required to eliminate apneic events which could improve treatment compliance. This possibility coupled with the potential beneficial effects of intermittent hypoxia on co-morbidities linked to sleep apnea suggests that mild intermittent hypoxia may have a multipronged therapeutic effect on sleep apnea. Copyright © 2017, Journal of Applied Physiology.

  7. Intermittent hypobaric hypoxia exposure does not cause sustained alterations in autonomic control of blood pressure in young athletes.

    NARCIS (Netherlands)

    Fu, Q.; Townsend, N.E.; Shiller, S.M.; Martini, E.R.; Okazaki, K.; Shibata, S.; Truijens, M.J.; Rodriquez, F.A.; Gore, C.J.; Stray-Gundersen, J.; Levine, B.D.

    2007-01-01

    Intermittent hypoxia (IH), which refers to the discontinuous use of hypoxia to reproduce some key features of altitude acclimatization, is commonly used in athletes to improve their performance. However, variations of IH are also used as a model for sleep apnea, causing sustained sympathoexcitation

  8. Injectable supramolecular hydrogel formed from α-cyclodextrin and PEGylated arginine-functionalized poly(l-lysine) dendron for sustained MMP-9 shRNA plasmid delivery.

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    Lin, Qianming; Yang, Yumeng; Hu, Qian; Guo, Zhong; Liu, Tao; Xu, Jiake; Wu, Jianping; Kirk, Thomas Brett; Ma, Dong; Xue, Wei

    2017-02-01

    Hydrogels have attracted much attention in cancer therapy and tissue engineering due to their sustained gene delivery ability. To obtain an injectable and high-efficiency gene delivery hydrogel, methoxypolyethylene glycol (MPEG) was used to conjugate with the arginine-functionalized poly(l-lysine) dendron (PLLD-Arg) by click reaction, and then the synthesized MPEG-PLLD-Arg interacted with α-cyclodextrin (α-CD) to form the supramolecular hydrogel by the host-guest interaction. The gelation dynamics, hydrogel strength and shear viscosity could be modulated by α-CD content in the hydrogel. MPEG-PLLD-Arg was confirmed to bind and deliver gene effectively, and its gene transfection efficiency was significantly higher than PEI-25k under its optimized condition. After gelation, MMP-9 shRNA plasmid (pMMP-9) could be encapsulated into the hydrogel matrix in situ and be released from the hydrogels sustainedly, as the release rate was dependent on α-CD content. The released MPEG-PLLD-Arg/pMMP-9 complex still showed better transfection efficiency than PEI-25k and induced sustained tumor cell apoptosis. Also, in vivo assays indicated that this pMMP-9-loaded supramolecular hydrogel could result in the sustained tumor growth inhibition meanwhile showed good biocompatibility. As an injectable, sustained and high-efficiency gene delivery system, this supramolecular hydrogel is a promising candidate for long-term gene therapy. To realize the sustained gene delivery for gene therapy, a supramolecular hydrogel with high-efficiency gene delivery ability was prepared through the host-guest interaction between α-cyclodextrin and PEGylated arginine-functionalized poly(l-lysine) dendron. The obtained hydrogel was injectable and biocompatible with adjustable physicochemical property. More importantly, the hydrogel showed the high-efficiency and sustained gene transfection to our used cells, better than PEI-25k. The supramolecular hydrogel resulted in the sustained tumor growth

  9. The Role of Anion Exchanger on Pulmonary Vascular Response to Sustained Alveolar Hypoxia in the Isolated Perfused Rabbit Lung

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    Farzaneh Ketabchi

    2015-05-01

    Full Text Available Background: Some respiratory diseases may induce alveolar hypoxia thereby hypoxic pulmonary vasoconstriction (HPV. However, the mechanisms of this physiologic phenomenon are not fully understood. This study was the first to investigate the role of anion exchanger in sustained HPV. Methods: Experiments were performed in the isolated perfused rabbit lung. After preparation, the lungs were divided into six groups: two DIDS (4,4-diisothiocyanostilbene 2,2-disulfonic acid, anion exchanger inhibitor-treated [200 µM (n=5 or 400 µM (n=3] hypoxic groups, two HCO3- free hypoxic groups, one control hypoxic group (n=7 and one control normoxic group (n=4. DIDS were added to the perfusate at 10 minutes before starting the experiments. In the HCO3- free groups, HEPES (4-(2-Hydroxyethylpiperazine-1-ethanesulfonic acid were added to the perfusate instead of bicarbonate. Furthermore, in the HEPES1 (n=4 and HEPES2 (n=4 groups, the lungs were ventilated with hypoxic gas with or without CO2, respectively. Results: Ventilation of the lungs with hypoxic gas resulted in biphasic HPV, the acute (0-20 minutes and sustained (20-60 minutes phases. No alteration in both phases of HPV was detected by DIDS (200 µM. However, DIDS (400 µM, extended the ascending part of acute HPV until min 24. Both phases of HPV were decreased in the HEPES1 group. However, in the HEPES 2 group, HPV tended to increase during the rising part of the acute phase of HPV. Conclusions: Since DIDS (400 µM extended acute phase of HPV, and HCO3- free perfusate buffer enhanced rising phase of it, therefore it can be suggested that anion exchanger may modulate HPV especially during the acute phase. The abstract of this article was presented as a poster in the congress of European Respiratory Society (ERS on Monday, 08 September 2014, Munich, Germany and was published in the ERJ September 1, 2014 vol. 44 no. Suppl 58 P2343.

  10. Angiotensin II type 1a receptors in subfornical organ contribute towards chronic intermittent hypoxia-associated sustained increase in mean arterial pressure.

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    Saxena, Ashwini; Little, Joel T; Nedungadi, T Prashant; Cunningham, J Thomas

    2015-03-01

    Sleep apnea is associated with hypertension. The mechanisms contributing to a sustained increase in mean arterial pressure (MAP) even during normoxic awake-state remain unknown. Rats exposed to chronic intermittent hypoxia for 7 days, a model of the hypoxemia associated with sleep apnea, exhibit sustained increases in MAP even during the normoxic dark phase. Activation of the renin-angiotensin system (RAS) has been implicated in chronic intermittent hypoxia (CIH) hypertension. Since the subfornical organ (SFO) serves as a primary target for the central actions of circulating ANG II, we tested the effects of ANG II type 1a receptor (AT1aR) knockdown in the SFO on the sustained increase in MAP in this CIH model. Adeno-associated virus carrying green fluorescent protein (GFP) and small-hairpin RNA against either AT1aR or a scrambled control sequence (SCM) was stereotaxically injected in the SFO of rats. After recovery, MAP, heart rate, respiratory rate, and activity were continuously recorded using radiotelemetry. In the normoxic groups, the recorded variables did not deviate from the baseline values. Both CIH groups exhibited significant increases in MAP during CIH exposures (P dark phase in the CIH groups, only the SCM-injected group exhibited a sustained increase in MAP (P < 0.05). The AT1aR-CIH group showed significant decreases in FosB/ΔFosB staining in the median preoptic nucleus and the paraventricular nuclei of the hypothalamus compared with the SCM-CIH group. Our data indicate that AT1aRs in the SFO are critical for the sustained elevation in MAP and increased FosB/ΔFosB expression in forebrain autonomic nuclei associated with CIH. Copyright © 2015 the American Physiological Society.

  11. Hypoxia and Fetal Heart Development

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    Patterson, A.J.; Zhang, L

    2010-01-01

    Fetal hearts show a remarkable ability to develop under hypoxic conditions. The metabolic flexibility of fetal hearts allows sustained development under low oxygen conditions. In fact, hypoxia is critical for proper myocardial formation. Particularly, hypoxia inducible factor 1 (HIF-1) and vascular endothelial growth factor play central roles in hypoxia-dependent signaling in fetal heart formation, impacting embryonic outflow track remodeling and coronary vessel growth. Although HIF is not th...

  12. Hypoxia Room

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    Federal Laboratory Consortium — The Hypoxia Room is a 8x8x8 ft. clear vinyl plastic and aluminum frame construction enclosure located within USAREIM laboratory 028. The Hypoxia Room (manufactured...

  13. Hypoxia and Fetal Heart Development

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    Patterson, A.J.; Zhang, L

    2010-01-01

    Fetal hearts show a remarkable ability to develop under hypoxic conditions. The metabolic flexibility of fetal hearts allows sustained development under low oxygen conditions. In fact, hypoxia is critical for proper myocardial formation. Particularly, hypoxia inducible factor 1 (HIF-1) and vascular endothelial growth factor play central roles in hypoxia-dependent signaling in fetal heart formation, impacting embryonic outflow track remodeling and coronary vessel growth. Although HIF is not the only gene involved in adaptation to hypoxia, its role places it as a central figure in orchestrating events needed for adaptation to hypoxic stress. Although “normal” hypoxia (lower oxygen tension in the fetus as compared with the adult) is essential in heart formation, further abnormal hypoxia in utero adversely affects cardiogenesis. Prenatal hypoxia alters myocardial structure and causes a decline in cardiac performance. Not only are the effects of hypoxia apparent during the perinatal period, but prolonged hypoxia in utero also causes fetal programming of abnormality in the heart’s development. The altered expression pattern of cardioprotective genes such as protein kinase c epsilon, heat shock protein 70, and endothelial nitric oxide synthase, likely predispose the developing heart to increased vulnerability to ischemia and reperfusion injury later in life. The events underlying the long-term changes in gene expression are not clear, but likely involve variation in epigenetic regulation. PMID:20712587

  14. Knockdown of CkrL by shRNA deteriorates hypoxia/reoxygenation-induced H9C2 cardiomyocyte apoptosis and survival inhibition Via Bax and downregulation of P-Erk1/2.

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    Zhang, Zhi-Sheng; Yang, Dong-Yan; Fu, Yan-Bo; Zhang, Lei; Zhao, Qian-Ping; Li, Gang

    2015-03-01

    Integrin β1 subunit and its downstream molecule integrin-linked kinase and focal adhesion kinase have been confirmed to be essential to cell survival and inhibition of apoptosis and hypoxia/reoxygenation (H/R)-induced injuries in cardiomyocytes. However, it is still unclear whether CrkL [v-crk avian sarcoma virus CT-10 oncogene homolog (Crk)-like], which acts also as a component of the integrin pathway, could also affect H/R-induced injuries in the cardiomyocytes. The rat-derived H9C2 cardiomyocytes were infected with a CrkL small hairpin RNA interference recombinant lentivirus, which knockdowns the endogenous CrkL expression in the cardiomyocytes. Apoptosis, cell proliferation and survival were examined in the H9C2 cardiomyocytes treated with either H/R or not. Results showed that knockdown of CrkL could significantly increase apoptosis and inhibition of the cell proliferation and survival and deteriorate the previously mentioned injuries induced by H/R. In contrast, overexpression of human CrkL could relieve the exacerbation of the previously mentioned injuries induced by CrkL knockdown in the H9C2 cardiomyocytes via regulation of Bax and extracellular signal-regulated kinase1/2 (p-ERK1/2). In conclusion, these results confirmed that knockdown of CrkL could deteriorate H/R-induced apoptosis and cell survival inhibition in rat-derived H9C2 cardiomyocytes via Bax and downregulation of p-ERK1/2. It implies that CrkL could mitigate H/R-induced injuries in the cardiomyocytes. Copyright © 2015 John Wiley & Sons, Ltd.

  15. Physiological and Genomic Consequences of Intermittent Hypoxia: Invited Review: Oxygen sensing during intermittent hypoxia: cellular and molecular mechanisms

    National Research Council Canada - National Science Library

    Prabhakar, Nanduri R

    2001-01-01

    ... encountered in life than sustained hypoxia. Until recently, much of the information on the long-term effects of intermittent hypoxia has come from studies on human subjects experiencing chronic recurrent apneas...

  16. Intermittent hypoxia induces the proliferation of rat vascular smooth muscle cell with the increases in epidermal growth factor family and erbB2 receptor

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    Kyotani, Yoji, E-mail: cd147@naramed-u.ac.jp [Department of Pharmacology, Nara Medical University School of Medicine, Kashihara 634-8521 (Japan); Department of Pharmacy, Nara Medical University Hospital, Kashihara 634-8522 (Japan); Ota, Hiroyo [Second Department of Internal Medicine, Nara Medical University School of Medicine, Kashihara 634-8522 (Japan); Department of Biochemistry, Nara Medical University School of Medicine, Kashihara 634-8521 (Japan); Itaya-Hironaka, Asako; Yamauchi, Akiyo; Sakuramoto-Tsuchida, Sumiyo [Department of Biochemistry, Nara Medical University School of Medicine, Kashihara 634-8521 (Japan); Zhao, Jing; Ozawa, Kentaro; Nagayama, Kosuke; Ito, Satoyasu [Department of Pharmacology, Nara Medical University School of Medicine, Kashihara 634-8521 (Japan); Takasawa, Shin [Department of Biochemistry, Nara Medical University School of Medicine, Kashihara 634-8521 (Japan); Kimura, Hiroshi [Second Department of Internal Medicine, Nara Medical University School of Medicine, Kashihara 634-8522 (Japan); Uno, Masayuki [Department of Pharmacy, Nara Medical University Hospital, Kashihara 634-8522 (Japan); Yoshizumi, Masanori [Department of Pharmacology, Nara Medical University School of Medicine, Kashihara 634-8521 (Japan)

    2013-11-15

    Obstructive sleep apnea is characterized by intermittent hypoxia (IH), and associated with cardiovascular diseases, such as stroke and heart failure. These cardiovascular diseases have a relation to atherosclerosis marked by the proliferation of vascular smooth muscle cells (VSMCs). In this study, we investigated the influence of IH on cultured rat aortic smooth muscle cell (RASMC). The proliferation of RASMC was significantly increased by IH without changing the level of apoptosis. In order to see what induces RASMC proliferation, we investigated the influence of normoxia (N)-, IH- and sustained hypoxia (SH)-treated cell conditioned media on RASMC proliferation. IH-treated cell conditioned medium significantly increased RASMC proliferation compared with N-treated cell conditioned medium, but SH-treated cell conditioned medium did not. We next investigated the epidermal growth factor (EGF) family as autocrine growth factors. Among the EGF family, we found significant increases in mRNAs for epiregulin (ER), amphiregulin (AR) and neuregulin-1 (NRG1) in IH-treated cells and mature ER in IH-treated cell conditioned medium. We next investigated the changes in erbB family receptors that are receptors for ER, AR and NRG1, and found that erbB2 receptor mRNA and protein expressions were increased by IH, but not by SH. Phosphorylation of erbB2 receptor at Tyr-1248 that mediates intracellular signaling for several physiological effects including cell proliferation was increased by IH, but not by SH. In addition, inhibitor for erbB2 receptor suppressed IH-induced cell proliferation. These results provide the first demonstration that IH induces VSMC proliferation, and suggest that EGF family, such as ER, AR and NRG1, and erbB2 receptor could be involved in the IH-induced VSMC proliferation. - Highlights: ●In vitro system for intermittent hypoxia (IH) and sustained hypoxia (SH). ●IH, but not SH, induces the proliferation of rat vascular smooth muscle cell. ●Epiregulin m

  17. S.H. Baxter

    African Journals Online (AJOL)

    4. 259-264 11974). INTENSIVE HOUSING AND ITS EFFECTS ON FARM ANIMALS. S.H. Baxter. The Scottish Form Buildings Investigation Unit,. Craibstone. Bucksburn, Aberdeen, Scotland lntensive animal production is not a new idea. lt is true that historically the rearing of domestic animals for food has been an extensive ...

  18. Hypoxia sensing through β-adrenergic receptors

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    Cheong, Hoi I.; Asosingh, Kewal; Stephens, Olivia R.; Queisser, Kimberly A.; Xu, Weiling; Willard, Belinda; Hu, Bo; Dermawan, Josephine Kam Tai; Stark, George R.; Naga Prasad, Sathyamangla V.; Erzurum, Serpil C.

    2016-01-01

    Life-sustaining responses to low oxygen, or hypoxia, depend on signal transduction by HIFs, but the underlying mechanisms by which cells sense hypoxia are not completely understood. Based on prior studies suggesting a link between the β-adrenergic receptor (β-AR) and hypoxia responses, we hypothesized that the β-AR mediates hypoxia sensing and is necessary for HIF-1α accumulation. Beta blocker treatment of mice suppressed hypoxia induction of renal HIF-1α accumulation, erythropoietin production, and erythropoiesis in vivo. Likewise, beta blocker treatment of primary human endothelial cells in vitro decreased hypoxia-mediated HIF-1α accumulation and binding to target genes and the downstream hypoxia-inducible gene expression. In mechanistic studies, cAMP-activated PKA and/or GPCR kinases (GRK), which both participate in β-AR signal transduction, were investigated. Direct activation of cAMP/PKA pathways did not induce HIF-1α accumulation, and inhibition of PKA did not blunt HIF-1α induction by hypoxia. In contrast, pharmacological inhibition of GRK, or expression of a GRK phosphorylation–deficient β-AR mutant in cells, blocked hypoxia-mediated HIF-1α accumulation. Mass spectrometry–based quantitative analyses revealed a hypoxia-mediated β-AR phosphorylation barcode that was different from the classical agonist phosphorylation barcode. These findings indicate that the β-AR is fundamental to the molecular and physiological responses to hypoxia. PMID:28018974

  19. Cerebral hypoxia

    Science.gov (United States)

    ... before, during, or soon after birth such as cerebral palsy Stroke Very low blood pressure Brain cells are very sensitive to a lack of ... of the eye to light Exams and Tests Cerebral hypoxia can usually be diagnosed based on the person's medical history and a physical exam. Tests are done to ...

  20. Preexisting hypoxia is associated with a delayed but more sustained rise in T/QRS ratio during prolonged umbilical cord occlusion in near-term fetal sheep

    NARCIS (Netherlands)

    Wibbens, Bert; Bennet, Laura; Westgate, Jenny A.; De Haan, Harmen H.; Wassink, Guido; Gunn, Alistair J.

    There is limited information about whether preexisting fetal hypoxia alters hemodynamic responses and changes in T/ QRS ratio and ST waveform shape during subsequent severe asphyxia. Chronically instrumented near- term sheep fetuses ( 124 +/- 1 days) were identified as either normoxic Pa-O2 > 17

  1. Intermittent Hypoxia Effect on Osteoclastogenesis Stimulated by Neuroblastoma Cells

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    Bhaskara, Vasantha Kumar; Mohanam, Indra; Gujrati, Meena; Mohanam, Sanjeeva

    2014-01-01

    Background Neuroblastoma is the most common extracranial pediatric solid tumor. Intermittent hypoxia, which is characterized by cyclic periods of hypoxia and reoxygenation, has been shown to positively modulate tumor development and thereby induce tumor growth, angiogenic processes, and metastasis. Bone is one of the target organs of metastasis in advanced neuroblastoma Neuroblastoma cells produce osteoclast-activating factors that increase bone resorption by the osteoclasts. The present study focuses on how intermittent hypoxia preconditioned SH-SY5Y neuroblastoma cells modulate osteoclastogenesis in RAW 264.7 cells compared with neuroblastoma cells grown at normoxic conditions. Methods We inhibited HIF-1α and HIF-2α in neuroblastoma SH-SY5Y cells by siRNA/shRNA approaches. Protein expression of HIF-1α, HIF-2α and MAPKs were investigated by western blotting. Expression of osteoclastogenic factors were determined by real-time RT-PCR. The influence of intermittent hypoxia and HIF-1α siRNA on migration of neuroblastoma cells and in vitro differentiation of RAW 264.7 cells were assessed. Intratibial injection was performed with SH-SY5Y stable luciferase-expressing cells and in vivo bioluminescence imaging was used in the analysis of tumor growth in bone. Results Upregulation of mRNAs of osteoclastogenic factors VEGF and RANKL was observed in intermittent hypoxia-exposed neuroblastoma cells. Conditioned medium from the intermittent hypoxia-exposed neuroblastoma cells was found to enhance osteoclastogenesis, up-regulate the mRNAs of osteoclast marker genes including TRAP, CaSR and cathepsin K and induce the activation of ERK, JNK, and p38 in RAW 264.7 cells. Intermittent hypoxia-exposed neuroblastoma cells showed an increased migratory pattern compared with the parental cells. A significant increase of tumor volume was found in animals that received the intermittent hypoxia-exposed cells intratibially compared with parental cells. Conclusions Intermittent hypoxic

  2. Quantitative analysis of ChIP-seq data uncovers dynamic and sustained H3K4me3 and H3K27me3 modulation in cancer cells under hypoxia.

    Science.gov (United States)

    Adriaens, Michiel E; Prickaerts, Peggy; Chan-Seng-Yue, Michelle; van den Beucken, Twan; Dahlmans, Vivian E H; Eijssen, Lars M; Beck, Timothy; Wouters, Bradly G; Voncken, Jan Willem; Evelo, Chris T A

    2016-01-01

    A comprehensive assessment of the epigenetic dynamics in cancer cells is the key to understanding the molecular mechanisms underlying cancer and to improving cancer diagnostics, prognostics and treatment. By combining genome-wide ChIP-seq epigenomics and microarray transcriptomics, we studied the effects of oxygen deprivation and subsequent reoxygenation on histone 3 trimethylation of lysine 4 (H3K4me3) and lysine 27 (H3K27me3) in a breast cancer cell line, serving as a model for abnormal oxygenation in solid tumors. A priori, epigenetic markings and gene expression levels not only are expected to vary greatly between hypoxic and normoxic conditions, but also display a large degree of heterogeneity across the cell population. Where traditionally ChIP-seq data are often treated as dichotomous data, the model and experiment here necessitate a quantitative, data-driven analysis of both datasets. We first identified genomic regions with sustained epigenetic markings, which provided a sample-specific reference enabling quantitative ChIP-seq data analysis. Sustained H3K27me3 marking was located around centromeres and intergenic regions, while sustained H3K4me3 marking is associated with genes involved in RNA binding, translation and protein transport and localization. Dynamic marking with both H3K4me3 and H3K27me3 (hypoxia-induced bivalency) was found in CpG-rich regions at loci encoding factors that control developmental processes, congruent with observations in embryonic stem cells. In silico -identified epigenetically sustained and dynamic genomic regions were confirmed through ChIP-PCR in vitro, and obtained results are corroborated by published data and current insights regarding epigenetic regulation.

  3. CD133 Modulate HIF-1α Expression under Hypoxia in EMT Phenotype Pancreatic Cancer Stem-Like Cells

    Directory of Open Access Journals (Sweden)

    Koki Maeda

    2016-06-01

    Full Text Available Although CD133 is a known representative cancer stem cell marker, its function in tumor aggressiveness under hypoxia is not fully known. The aim of this study is to demonstrate that CD133 regulates hypoxia inducible factor (HIF-1α expression with tumor migration. The CD133+ pancreatic cancer cell line, Capan1M9, was compared with the CD133− cell line, shCD133M9, under hypoxia. HIF-1α expression levels were compared by Western blot, HIF-1α nucleus translocation assay and real-time (RT-PCR. The hypoxia responsive element (HRE was observed by luciferase assay. The migration ability was analyzed by migration and wound healing assays. Epithelial mesenchymal transition (EMT related genes were analyzed by real-time RT-PCR. HIF-1α was highly expressed in Capan1M9 compared to shCD133M9 under hypoxia because of the high activation of HRE. Furthermore, the migration ability of Capan1M9 was higher than that of shCD133M9 under hypoxia, suggesting higher expression of EMT related genes in Capan1M9 compared to shCD133M9. Conclusion: HIF-1α expression under hypoxia in CD133+ pancreatic cancer cells correlated with tumor cell migration through EMT gene expression. Understanding the function of CD133 in cancer aggressiveness provides a novel therapeutic approach to eradicate pancreatic cancer stem cells.

  4. Translating MeSH concepts.

    Science.gov (United States)

    Soualmia, Lina F; Letord, Catherine; Merabti, Tayeb; Griffon, Nicolas; Manel, Jacques; Darmoni, Stéfan J

    2013-01-01

    The concept-oriented structure of the MeSH® thesaurus is not yet in common use. Nevertheless, it has been shown that a concept-based querying of PubMed may be of interest. To take full advantage of the concept-oriented structure of MeSH in the information retrieval tool associated with the CISMeF catalogue, it was necessary to translate such concepts into French.

  5. Migraine induced by hypoxia

    DEFF Research Database (Denmark)

    Arngrim, Nanna; Schytz, Henrik Winther; Britze, Josefine

    2016-01-01

    Migraine with aura is prevalent in high-altitude populations suggesting an association between migraine aura and hypoxia. We investigated whether experimental hypoxia triggers migraine and aura attacks in patients suffering from migraine with aura. We also investigated the metabolic and vascular...... response to hypoxia. In a randomized double-blind crossover study design, 15 migraine with aura patients were exposed to 180 min of normobaric hypoxia (capillary oxygen saturation 70-75%) or sham on two separate days and 14 healthy controls were exposed to hypoxia. Glutamate and lactate concentrations...... in the visual cortex were measured by proton magnetic resonance spectroscopy. The circumference of cranial arteries was measured by 3 T high-resolution magnetic resonance angiography. Hypoxia induced migraine-like attacks in eight patients compared to one patient after sham (P = 0.039), aura in three...

  6. Selective vulnerability in brain hypoxia

    DEFF Research Database (Denmark)

    Cervos-Navarro, J.; Diemer, Nils Henrik

    1991-01-01

    Neuropathology, selective vulnerability, brain hypoxia, vascular factors, excitotoxicity, ion homeostasis......Neuropathology, selective vulnerability, brain hypoxia, vascular factors, excitotoxicity, ion homeostasis...

  7. Hypoxia and brain development

    NARCIS (Netherlands)

    Nyakas, Csaba; Buwalda, Bauke; Luiten, P.

    Hypoxia threatens brain function during the entire life-span starting from early fetal age up to senescence. This review compares the short-term, long-term and life-spanning effects of fetal chronic hypoxia and neonatal anoxia on several behavioural paradigms including novelty-induced spontaneous

  8. FoxO3A promotes metabolic adaptation to hypoxia by antagonizing Myc function

    DEFF Research Database (Denmark)

    Jensen, Kim Steen; Binderup, Tina; Jensen, Klaus Thorleif

    2011-01-01

    Exposure of metazoan organisms to hypoxia engages a metabolic switch orchestrated by the hypoxia-inducible factor 1 (HIF-1). HIF-1 mediates induction of glycolysis and active repression of mitochondrial respiration that reduces oxygen consumption and inhibits the production of potentially harmful...... tumour tissue in vivo and that FoxO3A short-hairpin RNA (shRNA)-expressing xenograft tumours are decreased in size and metabolically changed. Our findings define a novel mechanism by which FoxO3A promotes metabolic adaptation and stress resistance in hypoxia.......Exposure of metazoan organisms to hypoxia engages a metabolic switch orchestrated by the hypoxia-inducible factor 1 (HIF-1). HIF-1 mediates induction of glycolysis and active repression of mitochondrial respiration that reduces oxygen consumption and inhibits the production of potentially harmful...

  9. Hypoxia causes transgenerational impairments in reproduction of fish

    Science.gov (United States)

    Wang, Simon Yuan; Lau, Karen; Lai, Keng-Po; Zhang, Jiang-Wen; Tse, Anna Chung-Kwan; Li, Jing-Woei; Tong, Yin; Chan, Ting-Fung; Wong, Chris Kong-Chu; Chiu, Jill Man-Ying; Au, Doris Wai-Ting; Wong, Alice Sze-Tsai; Kong, Richard Yuen-Chong; Wu, Rudolf Shiu-Sun

    2016-01-01

    Hypoxia is amongst the most widespread and pressing problems in aquatic environments. Here we demonstrate that fish (Oryzias melastigma) exposed to hypoxia show reproductive impairments (retarded gonad development, decrease in sperm count and sperm motility) in F1 and F2 generations despite these progenies (and their germ cells) having never been exposed to hypoxia. We further show that the observed transgenerational reproductive impairments are associated with a differential methylation pattern of specific genes in sperm of both F0 and F2 coupled with relevant transcriptomic and proteomic alterations, which may impair spermatogenesis. The discovered transgenerational and epigenetic effects suggest that hypoxia might pose a dramatic and long-lasting threat to the sustainability of fish populations. Because the genes regulating spermatogenesis and epigenetic modifications are highly conserved among vertebrates, these results may also shed light on the potential transgenerational effects of hypoxia on other vertebrates, including humans. PMID:27373813

  10. Hypoxia and Mucosal Inflammation

    Science.gov (United States)

    Colgan, Sean P.; Campbell, Eric L.; Kominsky, Douglas J.

    2016-01-01

    Sites of inflammation are defined by significant changes in metabolic activity. Recent studies have suggested that O2 metabolism and hypoxia play a prominent role in inflammation so-called “inflammatory hypoxia,” which results from a combination of recruited inflammatory cells (e.g., neutrophils and monocytes), the local proliferation of multiple cell types, and the activation of multiple O2-consuming enzymes during inflammation. These shifts in energy supply and demand result in localized regions of hypoxia and have revealed the important function off the transcription factor HIF (hypoxia-inducible factor) in the regulation of key target genes that promote inflammatory resolution. Analysis of these pathways has provided multiple opportunities for understanding basic mechanisms of inflammation and has defined new targets for intervention. Here, we review recent work addressing tissue hypoxia and metabolic control of inflammation and immunity. PMID:27193451

  11. Hypoxia-Inducible Hydrogels

    Science.gov (United States)

    Park, Kyung Min; Gerecht, Sharon

    2014-01-01

    Oxygen is vital for the existence of all multicellular organisms, acting as a signaling molecule regulating cellular activities. Specifically, hypoxia, which occurs when the partial pressure of oxygen falls below 5%, plays a pivotal role during development, regeneration, and cancer. Here we report a novel hypoxia-inducible (HI) hydrogel composed of gelatin and ferulic acid that can form hydrogel networks via oxygen consumption in a laccase-mediated reaction. Oxygen levels and gradients within the hydrogels can be accurately controlled and precisely predicted. We demonstrate that HI hydrogels guide vascular morphogenesis in vitro via hypoxia-inducible factors activation of matrix metalloproteinases and promote rapid neovascularization from the host tissue during subcutaneous wound healing. The HI hydrogel is a new class of biomaterials that may prove useful in many applications, ranging from fundamental studies of developmental, regenerative and disease processes through the engineering of healthy and diseased tissue models towards the treatment of hypoxia-regulated disorders. PMID:24909742

  12. The effects of sleep hypoxia on coagulant factors and hepatic inflammation in emphysematous rats.

    Directory of Open Access Journals (Sweden)

    Jing Feng

    2010-10-01

    Full Text Available To develop a sleep hypoxia (SH in emphysema (SHE rat model and to explore whether SHE results in more severe hepatic inflammation than emphysema alone and whether the inflammation changes levels of coagulant/anticoagulant factors synthesized in the liver.Seventy-five rats were put into 5 groups: SH control (SHCtrl, treated with sham smoke exposure (16 weeks and SH exposure (12.5% O(2, 3 h/d, latter 8 weeks; emphysema control (ECtrl, smoke exposure and sham SH exposure (21% O(2; short SHE (SHEShort, smoke exposure and short SH exposure (1.5 h/d; mild SHE (SHEMild, smoke exposure and mild SH exposure (15% O(2; standard SHE (SHEStand, smoke exposure and SH exposure. Therefore, ECtrl, SHEShort, SHEMild and SHEStand group were among emphysematous groups. Arterial blood gas (ABG data was obtained during preliminary tests. After exposure, hepatic inflammation (interleukin -6 [IL-6] mRNA and protein, tumor necrosis factor α [TNFα] mRNA and protein and liver coagulant/anticoagulant factors (antithrombin [AT], fibrinogen [FIB] and Factor VIII [F VIII] were evaluated. SPSS 11.5 software was used for statistical analysis.Characteristics of emphysema were obvious in emphysematous groups and ABGs reached SH criteria on hypoxia exposure. Hepatic inflammation parameters and coagulant factors are the lowest in SHCtrl and the highest in SHEStand while AT is the highest in SHCtrl and the lowest in SHEStand. Inflammatory cytokines of liver correlate well with coagulant factors positively and with AT negatively.When SH is combined with emphysema, hepatic inflammation and coagulability enhance each other synergistically and produce a more significant liver-derivative inflammatory and prothrombotic status.

  13. The effects of sleep hypoxia on coagulant factors and hepatic inflammation in emphysematous rats.

    Science.gov (United States)

    Feng, Jing; Wang, Qing-shan; Chiang, Ambrose; Chen, Bao-yuan

    2010-10-06

    To develop a sleep hypoxia (SH) in emphysema (SHE) rat model and to explore whether SHE results in more severe hepatic inflammation than emphysema alone and whether the inflammation changes levels of coagulant/anticoagulant factors synthesized in the liver. Seventy-five rats were put into 5 groups: SH control (SHCtrl), treated with sham smoke exposure (16 weeks) and SH exposure (12.5% O(2), 3 h/d, latter 8 weeks); emphysema control (ECtrl), smoke exposure and sham SH exposure (21% O(2)); short SHE (SHEShort), smoke exposure and short SH exposure (1.5 h/d); mild SHE (SHEMild), smoke exposure and mild SH exposure (15% O(2)); standard SHE (SHEStand), smoke exposure and SH exposure. Therefore, ECtrl, SHEShort, SHEMild and SHEStand group were among emphysematous groups. Arterial blood gas (ABG) data was obtained during preliminary tests. After exposure, hepatic inflammation (interleukin -6 [IL-6] mRNA and protein, tumor necrosis factor α [TNFα] mRNA and protein) and liver coagulant/anticoagulant factors (antithrombin [AT], fibrinogen [FIB] and Factor VIII [F VIII]) were evaluated. SPSS 11.5 software was used for statistical analysis. Characteristics of emphysema were obvious in emphysematous groups and ABGs reached SH criteria on hypoxia exposure. Hepatic inflammation parameters and coagulant factors are the lowest in SHCtrl and the highest in SHEStand while AT is the highest in SHCtrl and the lowest in SHEStand. Inflammatory cytokines of liver correlate well with coagulant factors positively and with AT negatively. When SH is combined with emphysema, hepatic inflammation and coagulability enhance each other synergistically and produce a more significant liver-derivative inflammatory and prothrombotic status.

  14. Application of the biosurfactants produced by Bacillus spp. (SH 20 ...

    African Journals Online (AJOL)

    Application of the biosurfactants produced by Bacillus spp. (SH 20 and SH 26) and P. aeruginosa SH 29 isolated from the rhizosphere soil of an Egyptian salt marsh plant for the cleaning of oil - contaminataed vessels and enhancing the biodegradat.

  15. Dexamethasone mimics aspects of physiological acclimatization to 8 hours of hypoxia but suppresses plasma erythropoietin

    Science.gov (United States)

    Liu, Chun; Croft, Quentin P. P.; Kalidhar, Swati; Brooks, Jerome T.; Herigstad, Mari; Smith, Thomas G.; Dorrington, Keith L.

    2013-01-01

    Dexamethasone ameliorates the severity of acute mountain sickness (AMS) but it is unknown whether it obtunds normal physiological responses to hypoxia. We studied whether dexamethasone enhanced or inhibited the ventilatory, cardiovascular, and pulmonary vascular responses to sustained (8 h) hypoxia. Eight healthy volunteers were studied, each on four separate occasions, permitting four different protocols. These were: dexamethasone (20 mg orally) beginning 2 h before a control period of 8 h of air breathing; dexamethasone with 8 h of isocapnic hypoxia (end-tidal Po2 = 50 Torr); placebo with 8 h of air breathing; and placebo with 8 h of isocapnic hypoxia. Before and after each protocol, the following were determined under both euoxic and hypoxic conditions: ventilation; pulmonary artery pressure (estimated using echocardiography to assess maximum tricuspid pressure difference); heart rate; and cardiac output. Plasma concentrations of erythropoietin (EPO) were also determined. Dexamethasone had no early (2-h) effect on any variable. Both dexamethasone and 8 h of hypoxia increased euoxic values of ventilation, pulmonary artery pressure, and heart rate, together with the ventilatory sensitivity to acute hypoxia. These effects were independent and additive. Eight hours of hypoxia, but not dexamethasone, increased the sensitivity of pulmonary artery pressure to acute hypoxia. Dexamethasone, but not 8 h of hypoxia, increased both cardiac output and systemic arterial pressure. Dexamethasone abolished the rise in EPO induced by 8 h of hypoxia. In summary, dexamethasone enhances ventilatory acclimatization to hypoxia. Thus, dexamethasone in AMS may improve oxygenation and thereby indirectly lower pulmonary artery pressure. PMID:23393065

  16. Nonneurogenic hypoxia sensitivity in rat adrenal slices.

    Science.gov (United States)

    Takeuchi, Y; Mochizuki-Oda, N; Yamada, H; Kurokawa, K; Watanabe, Y

    2001-11-23

    A change in the intracellular Ca(2+) ([Ca(2+)](i)) level induced by hypoxia was detected in rat adrenal slices by use of fura-2/AM. After hypoxic stress, an increase in [Ca(2+)](i) was observed only in the adrenal medulla. This increase was inhibited by nifedipine, but not modified by the cholinergic receptor blockers. The hypoxia-induced increase in [Ca(2+)](i) was observed in all postnatal developmental stages to a similar extent, whereas the nicotine and high K(+) sensitivities increased along with postnatal development. A 10 nM ryanodine enhanced the hypoxia-induced [Ca(2+)](i) increase in adult but not in neonatal rat slices. These results suggest the existence of an oxygen-sensing mechanism in adult rat adrenals even after sympathetic innervation. Hypoxic responses seemed to be similar both in neonate and in adult rat adrenals and were triggered by the influx of Ca(2+) via L-type voltage-sensitive Ca(2+) channels. However, the sustained [Ca(2+)](i) increase caused by hypoxia might depend on postnatal development and be triggered by Ca(2+)-induced Ca(2+) release (CICR). Copyright 2001 Academic Press.

  17. Hypoxia-induced cytotoxic drug resistance in osteosarcoma is independent of HIF-1Alpha.

    Directory of Open Access Journals (Sweden)

    Jennifer Adamski

    Full Text Available Survival rates from childhood cancer have improved dramatically in the last 40 years, such that over 80% of children are now cured. However in certain subgroups, including metastatic osteosarcoma, survival has remained stubbornly poor, despite dose intensive multi-agent chemotherapy regimens, and new therapeutic approaches are needed. Hypoxia is common in adult solid tumours and is associated with treatment resistance and poorer outcome. Hypoxia induces chemotherapy resistance in paediatric tumours including neuroblastoma, rhabdomyosarcoma and Ewing's sarcoma, in vitro, and this drug resistance is dependent on the oxygen-regulated transcription factor hypoxia inducible factor-1 (HIF-1. In this study the effects of hypoxia on the response of the osteosarcoma cell lines 791T, HOS and U2OS to the clinically relevant cytotoxics cisplatin, doxorubicin and etoposide were evaluated. Significant hypoxia-induced resistance to all three agents was seen in all three cell lines and hypoxia significantly reduced drug-induced apoptosis. Hypoxia also attenuated drug-induced activation of p53 in the p53 wild-type U2OS osteosarcoma cells. Drug resistance was not induced by HIF-1α stabilisation in normoxia by cobalt chloride nor reversed by the suppression of HIF-1α in hypoxia by shRNAi, siRNA, dominant negative HIF or inhibition with the small molecule NSC-134754, strongly suggesting that hypoxia-induced drug resistance in osteosarcoma cells is independent of HIF-1α. Inhibition of the phosphoinositide 3-kinase (PI3K pathway using the inhibitor PI-103 did not reverse hypoxia-induced drug resistance, suggesting the hypoxic activation of Akt in osteosarcoma cells does not play a significant role in hypoxia-induced drug resistance. Targeting hypoxia is an exciting prospect to improve current anti-cancer therapy and combat drug resistance. Significant hypoxia-induced drug resistance in osteosarcoma cells highlights the potential importance of hypoxia as a target

  18. DeepMeSH: deep semantic representation for improving large-scale MeSH indexing.

    Science.gov (United States)

    Peng, Shengwen; You, Ronghui; Wang, Hongning; Zhai, Chengxiang; Mamitsuka, Hiroshi; Zhu, Shanfeng

    2016-06-15

    Medical Subject Headings (MeSH) indexing, which is to assign a set of MeSH main headings to citations, is crucial for many important tasks in biomedical text mining and information retrieval. Large-scale MeSH indexing has two challenging aspects: the citation side and MeSH side. For the citation side, all existing methods, including Medical Text Indexer (MTI) by National Library of Medicine and the state-of-the-art method, MeSHLabeler, deal with text by bag-of-words, which cannot capture semantic and context-dependent information well. We propose DeepMeSH that incorporates deep semantic information for large-scale MeSH indexing. It addresses the two challenges in both citation and MeSH sides. The citation side challenge is solved by a new deep semantic representation, D2V-TFIDF, which concatenates both sparse and dense semantic representations. The MeSH side challenge is solved by using the 'learning to rank' framework of MeSHLabeler, which integrates various types of evidence generated from the new semantic representation. DeepMeSH achieved a Micro F-measure of 0.6323, 2% higher than 0.6218 of MeSHLabeler and 12% higher than 0.5637 of MTI, for BioASQ3 challenge data with 6000 citations. The software is available upon request. zhusf@fudan.edu.cn Supplementary data are available at Bioinformatics online. © The Author 2016. Published by Oxford University Press.

  19. Intermittent hypoxia and neurorehabilitation

    Science.gov (United States)

    Gonzalez-Rothi, Elisa J.; Lee, Kun-Ze; Dale, Erica A.; Reier, Paul J.; Mitchell, Gordon S.

    2015-01-01

    In recent years, it has become clear that brief, repeated presentations of hypoxia [i.e., acute intermittent hypoxia (AIH)] can boost the efficacy of more traditional therapeutic strategies in certain cases of neurologic dysfunction. This hypothesis derives from a series of studies in animal models and human subjects performed over the past 35 yr. In 1980, Millhorn et al. (Millhorn DE, Eldridge FL, Waldrop TG. Respir Physiol 41: 87-103, 1980) showed that electrical stimulation of carotid chemoafferent neurons produced a persistent, serotonin-dependent increase in phrenic motor output that outlasts the stimulus for more than 90 min (i.e., a “respiratory memory”). AIH elicits similar phrenic “long-term facilitation” (LTF) by a mechanism that requires cervical spinal serotonin receptor activation and de novo protein synthesis. From 2003 to present, a series of studies demonstrated that AIH can induce neuroplasticity in the injured spinal cord, causing functional recovery of breathing capacity after cervical spinal injury. Subsequently, it was demonstrated that repeated AIH (rAIH) can induce recovery of limb function, and the functional benefits of rAIH are greatest when paired with task-specific training. Since uncontrolled and/or prolonged intermittent hypoxia can elicit pathophysiology, a challenge of intermittent hypoxia research is to ensure that therapeutic protocols are well below the threshold for pathogenesis. This is possible since many low dose rAIH protocols have induced functional benefits without evidence of pathology. We propose that carefully controlled rAIH is a safe and noninvasive modality that can be paired with other neurorehabilitative strategies including traditional activity-based physical therapy or cell-based therapies such as intraspinal transplantation of neural progenitors. PMID:25997947

  20. Secondary hypoxia exacerbates acute disruptions of energy metabolism in rats resulting from fluid percussion injury.

    Science.gov (United States)

    Bauman, Richard A; Widholm, John; Long, Joseph B

    2005-05-07

    The purpose of these experiments was to determine whether secondary hypoxia exacerbates the metabolic consequences of fluid percussion injury (FPI). In Experiment I, rats were trained to press a lever for their entire daily ration of food at any time during a 12-h light/dark cycle and run in an activity wheel. After food intake and body weight stabilized, rats were surgically prepared, assigned to one of four groups [FPI+Hypoxia (IH), FPI+Normoxia (IN), Sham Injury+Hypoxia (SH), Sham Injury+Normoxia (SN)] and, after recovery from surgery, anesthetized with halothane delivered by a 21% O2 source. Immediately after injury or sham injury, the O2 source was switched to 13% for rats in Groups IH and SH for 30 min. Post-traumatic hypoxemia exacerbated the ensuing FPI-induced reductions of food intake and body weight, but did not change FPI-induced reduction in wheel running. In Experiment II, rats were assigned to one of three groups (SH, IN, or IH) and subjected to sham injury and 13% O2 or FPI and either 13 or 21% O2. Immediately after 30 min of hypoxia or normoxia, rats were confined to metabolism cages that were used to quantify rates of oxygen consumption (VO2), carbon dioxide production (VCO2), and heat production (H). Post-traumatic hypoxia exacerbated the FPI-induced increases in VO2, VCO2, and H. The results of Experiments I and II provide convergent confirmation that secondary hypoxemia exacerbates the FPI-induced hypermetabolic state in rats and therefore might significantly exacerbate the brain injury-induced disruptions of energy metabolism in humans.

  1. [Shén Nóng, why not Nóng Shén?].

    Science.gov (United States)

    Uchibayashi, M

    1995-01-01

    In the Chinese language, the word order of 'modifier+modifiee' indicates a Northern origin whereas the order of 'modifiee+modifier' reflects Southern dialects. Shén Nóng, a Chinese mythical diety, is known as an originator of herbal medicines as well as of agriculture, and his name ('modifiee+modifier') clearly suggests a Southern type. This linguistic feature can be related to depiction of Shén Nóng's life which implies a Southern origin. Shén Nóng must have already been so named in the era of Shang dynasty which preceeded the Xia culture of Southern origin. The myth of Shén Nóng may be ethnically of the people of the South.

  2. Temporality in Manyōshū

    Directory of Open Access Journals (Sweden)

    Yamaguchi Toshiko

    2016-12-01

    Full Text Available Using the Manyōshū corpus, the paper argues that conceptual metaphor theory imposes limitations on the diversity of linguistic facts, particularly those concerning the speaker or the poet who is communicating. The paper offers explanations of the nature of time by drawing upon the inference operating within “basic sign structure”, specifically, indexicality and iconicity, both of which are at the heart of human semiotic activity.

  3. Orthopaedic literature and MeSH.

    Science.gov (United States)

    Nelson, Stuart J; Schulman, Jacque-Lynne

    2010-10-01

    Since 1916 there has been a recognized demand for a method of classification of orthopaedic literature inclusive enough to permit the proper collection and retrieval of all literature on the subject. Today, MEDLINE, available through the PubMed interface, has become the de facto standard for organization and retrieval of medical literature. The Medical Subject Headings (MeSH), used to provide indexing and assist in searching, are partly responsible for this standard. Understanding how MeSH is built and maintained may lead the user to a better understanding of how to use MEDLINE, and what to expect from the indexing of an article. The purpose of this review is to provide an understanding of the organization of large quantities of indexed material, the indexing process and the considerations involved in developing an indexing vocabulary. WHERE ARE WE NOW?: Successful terminology development and use, a prerequisite for any sharing of information by electronic means, depends on both user (how the user is expected to use the system) and information (how the information is organized) models. MEDLINE has a simple user model and a simpler information model. The user is expected to determine what is relevant and which MeSH descriptors are appropriate. WHERE DO WE NEED TO GO?: While MEDLINE through PubMed is a success as viewed by the number of hits, further improvements will depend on better, faster indexing with a controlled terminology. Terminology development requires careful consideration of the nature of the subject, how users employ the terminology, the overall purpose of the terminology, and the framework of the systems in which it is used. HOW DO WE GET THERE?: For the future, understanding terminology development might enable the user to comprehend some of the issues involved in sharing of other information by electronic means. Further improvements in the availability and accessibility of medical literature will depend on continued maintenance and development of MeSH

  4. Fundamental modes of new dispersive SH-waves in ...

    Indian Academy of Sciences (India)

    Home; Journals; Pramana – Journal of Physics; Volume 81; Issue 5. Fundamental modes of new dispersive SH-waves in ... Fundamental modes of new dispersive shear-horizontal (SH) acoustic waves propagating in the (6 mm) piezoelectromagnetic plate are studied. These SH-waves can propagate when the following ...

  5. Nocturnal hypoxia and neuropsychological variables.

    Science.gov (United States)

    Berry, D T; Webb, W B; Block, A J; Bauer, R M; Switzer, D A

    1986-06-01

    Hypoxia is a well known cause of brain dysfunction. Neuropsychological impairments have been observed in normal subjects experiencing hypoxia iatrogenically as well as in patients with chronic lung disease. Recent investigations have demonstrated significant nocturnal hypoxia in subjects with sleep-disordered breathing. In the present study, heavy-snoring males, a group known to experience frequent episodes of sleep-disordered breathing received neuropsychological testing and a night of continuous monitoring of respiratory parameters. Partial correlations, controlling for age, weight, and education, indicated reliable relationships between nocturnal hypoxia and measures of general intelligence, verbal and nonverbal memory, and expressive verbal fluency. It is proposed that heavy-snoring males may potentially serve as a population in which to model the neurobehavioral effects of hypoxia. Further research in subjects with sleep-disordered breathing may help clarify the extent of the possible cognitive deficits as well as point out possible ameliorative treatments.

  6. ACLY and ACC1 Regulate Hypoxia-Induced Apoptosis by Modulating ETV4 via α-ketoglutarate.

    Directory of Open Access Journals (Sweden)

    Melissa M Keenan

    2015-10-01

    Full Text Available In order to propagate a solid tumor, cancer cells must adapt to and survive under various tumor microenvironment (TME stresses, such as hypoxia or lactic acidosis. To systematically identify genes that modulate cancer cell survival under stresses, we performed genome-wide shRNA screens under hypoxia or lactic acidosis. We discovered that genetic depletion of acetyl-CoA carboxylase (ACACA or ACC1 or ATP citrate lyase (ACLY protected cancer cells from hypoxia-induced apoptosis. Additionally, the loss of ACLY or ACC1 reduced levels and activities of the oncogenic transcription factor ETV4. Silencing ETV4 also protected cells from hypoxia-induced apoptosis and led to remarkably similar transcriptional responses as with silenced ACLY or ACC1, including an anti-apoptotic program. Metabolomic analysis found that while α-ketoglutarate levels decrease under hypoxia in control cells, α-ketoglutarate is paradoxically increased under hypoxia when ACC1 or ACLY are depleted. Supplementation with α-ketoglutarate rescued the hypoxia-induced apoptosis and recapitulated the decreased expression and activity of ETV4, likely via an epigenetic mechanism. Therefore, ACC1 and ACLY regulate the levels of ETV4 under hypoxia via increased α-ketoglutarate. These results reveal that the ACC1/ACLY-α-ketoglutarate-ETV4 axis is a novel means by which metabolic states regulate transcriptional output for life vs. death decisions under hypoxia. Since many lipogenic inhibitors are under investigation as cancer therapeutics, our findings suggest that the use of these inhibitors will need to be carefully considered with respect to oncogenic drivers, tumor hypoxia, progression and dormancy. More broadly, our screen provides a framework for studying additional tumor cell stress-adaption mechanisms in the future.

  7. Chronic hypoxia increases fetoplacental vascular resistance and vasoconstrictor reactivity in the rat.

    Science.gov (United States)

    Jakoubek, Vít; Bíbová, Jana; Herget, Jan; Hampl, Václav

    2008-04-01

    An increase in fetoplacental vascular resistance caused by hypoxia is considered one of the key factors of placental hypoperfusion and fetal undernutrition leading to intrauterine growth restriction (IUGR), one of the serious problems in current neonatology. However, although acute hypoxia has been shown to cause fetoplacental vasoconstriction, the effects of more sustained hypoxic exposure are unknown. This study was designed to test the hypothesis that chronic hypoxia elicits elevations in fetoplacental resistance, that this effect is not completely reversible by acute reoxygenation, and that it is accompanied by increased acute vasoconstrictor reactivity of the fetoplacental vasculature. We measured fetoplacental vascular resistance as well as acute vasoconstrictor reactivity in isolated perfused placentae from rats exposed to hypoxia (10% O(2)) during the last week of a 3-wk pregnancy. We found that chronic hypoxia shifted the relationship between perfusion pressure and flow rate toward higher pressure values (by approximately 20%). This increased vascular resistance was refractory to a high dose of sodium nitroprusside, implying the involvement of other factors than increased vascular tone. Chronic hypoxia also increased vasoconstrictor responses to angiotensin II (by approximately 75%) and to acute hypoxic challenges (by >150%). We conclude that chronic prenatal hypoxia causes a sustained elevation of fetoplacental vascular resistance and vasoconstrictor reactivity that are likely to produce placental hypoperfusion and fetal undernutrition in vivo.

  8. MeSH Now: automatic MeSH indexing at PubMed scale via learning to rank.

    Science.gov (United States)

    Mao, Yuqing; Lu, Zhiyong

    2017-04-17

    MeSH indexing is the task of assigning relevant MeSH terms based on a manual reading of scholarly publications by human indexers. The task is highly important for improving literature retrieval and many other scientific investigations in biomedical research. Unfortunately, given its manual nature, the process of MeSH indexing is both time-consuming (new articles are not immediately indexed until 2 or 3 months later) and costly (approximately ten dollars per article). In response, automatic indexing by computers has been previously proposed and attempted but remains challenging. In order to advance the state of the art in automatic MeSH indexing, a community-wide shared task called BioASQ was recently organized. We propose MeSH Now, an integrated approach that first uses multiple strategies to generate a combined list of candidate MeSH terms for a target article. Through a novel learning-to-rank framework, MeSH Now then ranks the list of candidate terms based on their relevance to the target article. Finally, MeSH Now selects the highest-ranked MeSH terms via a post-processing module. We assessed MeSH Now on two separate benchmarking datasets using traditional precision, recall and F 1 -score metrics. In both evaluations, MeSH Now consistently achieved over 0.60 in F-score, ranging from 0.610 to 0.612. Furthermore, additional experiments show that MeSH Now can be optimized by parallel computing in order to process MEDLINE documents on a large scale. We conclude that MeSH Now is a robust approach with state-of-the-art performance for automatic MeSH indexing and that MeSH Now is capable of processing PubMed scale documents within a reasonable time frame. http://www.ncbi.nlm.nih.gov/CBBresearch/Lu/Demo/MeSHNow/ .

  9. A unique set of SH3-SH3 interactions controls IB1 homodimerization

    DEFF Research Database (Denmark)

    Kristensen, Ole; Guenat, Sylvie; Dar, Imran

    2006-01-01

    Islet-brain 1 (IB1 or JIP-1) is a scaffold protein that interacts with components of the c-Jun N-terminal kinase (JNK) signal-transduction pathway. IB1 is expressed at high levels in neurons and in pancreatic beta-cells, where it controls expression of several insulin-secretory components...... and secretion. IB1 has been shown to homodimerize, but neither the molecular mechanisms nor the function of dimerization have yet been characterized. Here, we show that IB1 homodimerizes through a novel and unique set of Src homology 3 (SH3)-SH3 interactions. X-ray crystallography studies show that the dimer...... interface covers a region usually engaged in PxxP-mediated ligand recognition, even though the IB1 SH3 domain lacks this motif. The highly stable IB1 homodimer can be significantly destabilized in vitro by three individual point mutations directed against key residues involved in dimerization. Each mutation...

  10. Coastal hypoxia and sediment biogeochemistry

    Directory of Open Access Journals (Sweden)

    J. J. Middelburg

    2009-07-01

    Full Text Available The intensity, duration and frequency of coastal hypoxia (oxygen concentration <63 μM are increasing due to human alteration of coastal ecosystems and changes in oceanographic conditions due to global warming. Here we provide a concise review of the consequences of coastal hypoxia for sediment biogeochemistry. Changes in bottom-water oxygen levels have consequences for early diagenetic pathways (more anaerobic at expense of aerobic pathways, the efficiency of re-oxidation of reduced metabolites and the nature, direction and magnitude of sediment-water exchange fluxes. Hypoxia may also lead to more organic matter accumulation and burial and the organic matter eventually buried is also of higher quality, i.e. less degraded. Bottom-water oxygen levels also affect the organisms involved in organic matter processing with the contribution of metazoans decreasing as oxygen levels drop. Hypoxia has a significant effect on benthic animals with the consequences that ecosystem functions related to macrofauna such as bio-irrigation and bioturbation are significantly affected by hypoxia as well. Since many microbes and microbial-mediated biogeochemical processes depend on animal-induced transport processes (e.g. re-oxidation of particulate reduced sulphur and denitrification, there are indirect hypoxia effects on biogeochemistry via the benthos. Severe long-lasting hypoxia and anoxia may result in the accumulation of reduced compounds in sediments and elimination of macrobenthic communities with the consequences that biogeochemical properties during trajectories of decreasing and increasing oxygen may be different (hysteresis with consequences for coastal ecosystem dynamics.

  11. Meshable: searching PubMed abstracts by utilizing MeSH and MeSH-derived topical terms

    OpenAIRE

    Kim, Sun; Yeganova, Lana; Wilbur, W. John

    2016-01-01

    Summary: Medical Subject Headings (MeSH?) is a controlled vocabulary for indexing and searching biomedical literature. MeSH terms and subheadings are organized in a hierarchical structure and are used to indicate the topics of an article. Biologists can use either MeSH terms as queries or the MeSH interface provided in PubMed? for searching PubMed abstracts. However, these are rarely used, and there is no convenient way to link standardized MeSH terms to user queries. Here, we introduce a web...

  12. Expression of plasmid-based shRNA against the E1 and nsP1 genes effectively silenced Chikungunya virus replication.

    Directory of Open Access Journals (Sweden)

    Shirley Lam

    Full Text Available BACKGROUND: Chikungunya virus (CHIKV is a re-emerging alphavirus that causes chikungunya fever and persistent arthralgia in humans. Currently, there is no effective vaccine or antiviral against CHIKV infection. Therefore, this study evaluates whether RNA interference which targets at viral genomic level may be a novel antiviral strategy to inhibit the medically important CHIKV infection. METHODS: Plasmid-based small hairpin RNA (shRNA was investigated for its efficacy in inhibiting CHIKV replication. Three shRNAs designed against CHIKV Capsid, E1 and nsP1 genes were transfected to establish stable shRNA-expressing cell clones. Following infection of stable shRNA cells clones with CHIKV at M.O.I. 1, viral plaque assay, Western blotting and transmission electron microscopy were performed. The in vivo efficacy of shRNA against CHIKV replication was also evaluated in a suckling murine model of CHIKV infection. RESULTS: Cell clones expressing shRNAs against CHIKV E1 and nsP1 genes displayed significant inhibition of infectious CHIKV production, while shRNA Capsid demonstrated a modest inhibitory effect as compared to scrambled shRNA cell clones and non-transfected cell controls. Western blot analysis of CHIKV E2 protein expression and transmission electron microscopy of shRNA E1 and nsP1 cell clones collectively demonstrated similar inhibitory trends against CHIKV replication. shRNA E1 showed non cell-type specific anti-CHIKV effects and broad-spectrum silencing against different geographical strains of CHIKV. Furthermore, shRNA E1 clones did not exert any inhibition against Dengue virus and Sindbis virus replication, thus indicating the high specificity of shRNA against CHIKV replication. Moreover, no shRNA-resistant CHIKV mutant was generated after 50 passages of CHIKV in the stable cell clones. More importantly, strong and sustained anti-CHIKV protection was conferred in suckling mice pre-treated with shRNA E1. CONCLUSION: Taken together, these

  13. Hyperoxia attenuates muscle sympathetic nerve activity following isocapnic hypoxia in humans.

    Science.gov (United States)

    Querido, Jordan S; Kennedy, Paul M; Sheel, A William

    2010-04-01

    Hypoxia may sensitize the carotid chemoreceptors, resulting in a sustained elevation of muscle sympathetic nerve activity (MSNA) that outlasts the hypoxic stimulus. To test this hypothesis, we determined the effect of carotid body inhibition on the sustained elevation of MSNA following isocapnic hypoxia in humans. Seven healthy subjects (5 male, 2 female) breathed 100% O(2) (hyperoxia) for 1 min before (2 interventions) and after (2-3 interventions) 20 min of isocapnic hypoxia (80% arterial oxyhemoglobin saturation). MSNA was continuously recorded from the common peroneal nerve with microneurography. There was no effect of hyperoxia on MSNA before exposure to isocapnic hypoxia. During the isocapnic hypoxia exposure, there was an increase in minute ventilation and heart rate that subsided once hypoxia was terminated. In contrast, there was an increase in MSNA burst frequency that persisted for approximately 25 min after cessation of the stimulus. Hyperoxia resulted in a transient reduction in MSNA burst frequency of 28% (P 0.05) in the three posthypoxia interventions, respectively. Our results suggest that input from the carotid chemoreceptors is obligatory for the sustained elevation of MSNA initiated by chemoreflex stimulation. We attribute the decrease in MSNA to a transient hyperoxia-induced attenuation of carotid chemoreceptor sensitivity.

  14. Impaired response of mature adipocytes of diabetic mice to hypoxia

    Energy Technology Data Exchange (ETDEWEB)

    Hong, Seok Jong, E-mail: seok-hong@northwestern.edu; Jin, Da P.; Buck, Donald W.; Galiano, Robert D.; Mustoe, Thomas A., E-mail: tmustoe@nmh.org

    2011-10-01

    Adipose tissue contains various cells such as infiltrated monocytes/macrophages, endothelial cells, preadipocytes, and adipocytes. Adipocytes have an endocrine function by secreting adipokines such as interleukin (IL)-6, tumor necrosis factor (TNF)-{alpha}, leptin, and adiponectin. Dysregulation of adipokines in adipose tissues leads to a chronic low-grade inflammation which could result in atherosclerosis, hypertension, and type 2 diabetes. A sustained inflammatory state, which is characterized by prolonged persistence of macrophages and neutrophils, is found in diabetic wounds. In addition, subcutaneous adipocytes are enormously increased in amount clinically in type 2 diabetes. However, the function of subcutaneous adipocytes, which play an important role in injured tissue subjected to hypoxia, has not been well characterized in vitro due to the difficulty of maintaining mature adipocytes in culture using conventional methods because of their buoyancy. In this study, we established a novel in vitro culture method of mature adipocytes by enclosing them in a hyaluronan (HA) based hydrogel to study their role in response to stress such as hypoxia. BrdU labeling and Ki67 immunostaining experiments showed that hydrogel enclosed mature adipocytes proliferate in vitro. Both mRNA and protein expression analyses for hypoxia regulated genes, such as vascular endothelial growth factor (VEGF) and heme oxygenase 1 (HO1), showed that mature adipocytes of wild type mice respond to hypoxia. In contrast, mature adipocytes of diabetic db/db and TallyHo mice did not efficiently respond to hypoxia. Our studies suggest that mature adipocytes are functionally active cells, and their abnormal function to hypoxia can be one of underlining mechanisms in type 2 diabetes.

  15. MeSH ORA framework: R/Bioconductor packages to support MeSH over-representation analysis.

    Science.gov (United States)

    Tsuyuzaki, Koki; Morota, Gota; Ishii, Manabu; Nakazato, Takeru; Miyazaki, Satoru; Nikaido, Itoshi

    2015-02-15

    In genome-wide studies, over-representation analysis (ORA) against a set of genes is an essential step for biological interpretation. Many gene annotation resources and software platforms for ORA have been proposed. Recently, Medical Subject Headings (MeSH) terms, which are annotations of PubMed documents, have been used for ORA. MeSH enables the extraction of broader meaning from the gene lists and is expected to become an exhaustive annotation resource for ORA. However, the existing MeSH ORA software platforms are still not sufficient for several reasons. In this work, we developed an original MeSH ORA framework composed of six types of R packages, including MeSH.db, MeSH.AOR.db, MeSH.PCR.db, the org.MeSH.XXX.db-type packages, MeSHDbi, and meshr. Using our framework, users can easily conduct MeSH ORA. By utilizing the enriched MeSH terms, related PubMed documents can be retrieved and saved on local machines within this framework.

  16. Meshable: searching PubMed abstracts by utilizing MeSH and MeSH-derived topical terms.

    Science.gov (United States)

    Kim, Sun; Yeganova, Lana; Wilbur, W John

    2016-10-01

    Medical Subject Headings (MeSH(®)) is a controlled vocabulary for indexing and searching biomedical literature. MeSH terms and subheadings are organized in a hierarchical structure and are used to indicate the topics of an article. Biologists can use either MeSH terms as queries or the MeSH interface provided in PubMed(®) for searching PubMed abstracts. However, these are rarely used, and there is no convenient way to link standardized MeSH terms to user queries. Here, we introduce a web interface which allows users to enter queries to find MeSH terms closely related to the queries. Our method relies on co-occurrence of text words and MeSH terms to find keywords that are related to each MeSH term. A query is then matched with the keywords for MeSH terms, and candidate MeSH terms are ranked based on their relatedness to the query. The experimental results show that our method achieves the best performance among several term extraction approaches in terms of topic coherence. Moreover, the interface can be effectively used to find full names of abbreviations and to disambiguate user queries. https://www.ncbi.nlm.nih.gov/IRET/MESHABLE/ CONTACT: sun.kim@nih.gov Supplementary data are available at Bioinformatics online. © The Author 2016. Published by Oxford University Press.

  17. Bax/Mcl-1 balance affects neutrophil survival in intermittent hypoxia and obstructive sleep apnea: effects of p38MAPK and ERK1/2 signaling

    Directory of Open Access Journals (Sweden)

    Dyugovskaya Larissa

    2012-10-01

    Full Text Available Abstract Background Prolonged neutrophil survival is evident in various cardiovascular and respiratory morbidities, in hypoxic conditions in-vitro and in patients with obstructive sleep apnea (OSA characterized by nightly intermittent hypoxia (IH. This may lead to persistent inflammation, tissue injury and dysfunction. We therefore investigated by a translational approach the potential contribution of the intrinsic stress-induced mitochondrial pathway in extending neutrophil survival under IH conditions. Thus, neutrophils of healthy individuals treated with IH in-vitro and neutrophils of OSA patients undergoing nightly IH episodes in-vivo were investigated. Specifically, the balance between pro-apoptotic Bax and anti-apoptotic Mcl-1 protein expression, and the potential involvement of p38MAPK and ERK1/2 signaling pathways in the control of Mcl-1 expression were investigated. Methods Purified neutrophils were exposed to IH and compared to normoxia and to sustained hypoxia (SH using a BioSpherix-OxyCycler C42 system. Bax and Mcl-1 levels, and p38MAPK and ERK1/2 phosphorylation were determined by western blotting. Also, Bax/Mcl-1 expression and Bax translocation to the mitochondria were assessed by confocal microscopy in pre-apoptotic neutrophils, before the appearance of apoptotic morphology. Co-localization of Bax and mitochondria was quantified by LSM 510 CarlZeiss MicroImaging using Manders Overlap Coefficient. A paired two-tailed t test, with Bonferroni correction for multiple comparisons, was used for statistical analysis. Results Compared to normoxia, IH and SH up-regulated the anti-apoptotic Mcl-1 by about 2-fold, down-regulated the pro-apoptotic Bax by 41% and 27%, respectively, and inhibited Bax co-localization with mitochondria before visible morphological signs of apoptosis were noted. IH induced ERK1/2 and p38MAPKs phosphorylation, whereas SH induced only p38MAPK phosphorylation. Accordingly, both ERK and p38MAPK inhibitors attenuated

  18. Hypobaric intermittent hypoxia attenuates hypoxia-induced depressor response.

    Directory of Open Access Journals (Sweden)

    Fang Cui

    Full Text Available Hypobaric intermittent hypoxia (HIH produces many favorable effects in the cardiovascular system such as anti-hypertensive effect. In this study, we showed that HIH significantly attenuated a depressor response induced by acute hypoxia.Sprague-Dawley rats received HIH in a hypobaric chamber simulating an altitude of 5000 m. The artery blood pressure (ABP, heart rate (HR and renal sympathetic nerve activity (RSNA were recorded in anesthetized control rats and rats received HIH. The baseline ABP, HR and RSNA were not different between HIH and control rats. Acute hypoxia-induced decrease in ABP was significantly attenuated in HIH rat compared with control rats. However, acute hypoxia-induced increases in HR and RSNA were greater in HIH rat than in control rats. After removal of bilateral ascending depressor nerves, acute hypoxia-induced depressor and sympathoexcitatory responses were comparable in control and HIH rats. Furthermore, acute hypoxia-induced depressor and sympathoexcitatory responses did not differ between control and HIH groups after blocking ATP-dependent K(+ channels by glibenclamide. The baroreflex function evaluated by intravenous injection of phenylephrine and sodium nitroprusside was markedly augmented in HIH rats compared with control rats. The pressor and sympathoexcitatory responses evoked by intravenous injection of cyanide potassium were also significantly greater in HIH rats than in control rats.Our findings suggest that HIH suppresses acute hypoxia-induced depressor response through enhancement of baroreflex and chemoreflex function, which involves activation of ATP-dependent K(+ channels. This study provides new information and underlying mechanism on the beneficiary effect of HIH on maintaining cardiovascular homeostasis.

  19. $\\mathit {SH}(3)$-move and other local moves on knots

    OpenAIRE

    Kanenobu, Taizo

    2014-01-01

    An $\\SH(3)$-move is an unknotting operation on oriented knots introduced by Hoste, Nakanishi and Taniyama. We consider some relationships to other local moves such as a band surgery, $\\Gamma_{0}$-move, and $\\Delta$-move, and give some criteria for estimating the $\\SH(3)$-unknotting number using the Jones, HOMFLYPT, Q polynomials. We also show a table of $\\SH(3)$-unknotting numbers for knots with up to 9 crossings.

  20. SH(3)-MOVE AND OTHER LOCAL MOVES ON KNOTS

    OpenAIRE

    Kanenobu, Taizo

    2014-01-01

    An SH(3)-move is an unknotting operation on oriented knots introduced by Hoste, Nakanishi and Taniyama. We consider some relationships to other local moves such as a band surgery, Γ_0-move, and Δ-move, and give some criteria for estimating the SH(3)-unknotting number using the Jones, HOMFLYPT, Q polynomials. We also show a table of SH(3)-unknotting numbers for knots with up to 9 crossings.

  1. MeSH Now: automatic MeSH indexing at PubMed scale via learning to rank

    OpenAIRE

    Mao, Yuqing; Lu, Zhiyong

    2017-01-01

    Background MeSH indexing is the task of assigning relevant MeSH terms based on a manual reading of scholarly publications by human indexers. The task is highly important for improving literature retrieval and many other scientific investigations in biomedical research. Unfortunately, given its manual nature, the process of MeSH indexing is both time-consuming (new articles are not immediately indexed until 2 or 3?months later) and costly (approximately ten dollars per article). In response, a...

  2. Lung Oxidative Damage by Hypoxia

    Directory of Open Access Journals (Sweden)

    O. F. Araneda

    2012-01-01

    Full Text Available One of the most important functions of lungs is to maintain an adequate oxygenation in the organism. This organ can be affected by hypoxia facing both physiological and pathological situations. Exposure to this condition favors the increase of reactive oxygen species from mitochondria, as from NADPH oxidase, xanthine oxidase/reductase, and nitric oxide synthase enzymes, as well as establishing an inflammatory process. In lungs, hypoxia also modifies the levels of antioxidant substances causing pulmonary oxidative damage. Imbalance of redox state in lungs induced by hypoxia has been suggested as a participant in the changes observed in lung function in the hypoxic context, such as hypoxic vasoconstriction and pulmonary edema, in addition to vascular remodeling and chronic pulmonary hypertension. In this work, experimental evidence that shows the implied mechanisms in pulmonary redox state by hypoxia is reviewed. Herein, studies of cultures of different lung cells and complete isolated lung and tests conducted in vivo in the different forms of hypoxia, conducted in both animal models and humans, are described.

  3. Physiological determinants of human acute hypoxia tolerance.

    Science.gov (United States)

    2013-11-01

    AbstractIntroduction. We investigated possible physiological determinants of variability in hypoxia tolerance in subjects given a 5-minute normobaric exposure to 25,000 ft equivalent. Physiological tolerance to hypoxia was defined as the magnitude of...

  4. THE EFFECT OF HYPOXIA ON THE MAXIMUM MATABOLIC RATE AND SPECIFIC DYNAMIC ACTION IN ATLANTIC COD Gadus morhua

    DEFF Research Database (Denmark)

    Steffensen, John Fleng

    2010-01-01

    of hypoxia compared. Maximum metabolic rate compared to standard metabolic rate is termed the Scope for Activity. The results showed that hypoxia at 6.3 kPa does influence the SDA. The effect on the SDA curve on cod fed 5 % of the wet body mass was that the peak metabolic rate was significantly depressed (44...... and fish kept at high densities. Feeding is followed by an increase in the metabolic rate. termed the specific dynamic action (SDA). SDA integrates all the energetic expenditures involved in feeding. It is generally agreed that the increased metabolic rate is caused by biochemical transformation of food...... the fi sh. The fish were fed single rations of fillets of herring, equivalent to 5 % wet body mass. Hypoxia was controlled by an oxygen regulator injecting compressed nitrogen in the water via a solenoid valve. In addition the maximum metabolic rate of starved fish was measured in normoxia and 4 levels...

  5. Construction of lentiviral shRNA expression vector targeting ...

    African Journals Online (AJOL)

    The optimal interfering target was then selected, while the titer of lentiviral packing PLD2-shRNA was 3.47 × 104 TU/ml and the virus was successfully packaged. PCR and sequencing analyses revealed that lentiviral shRNA vectors of three targeting PLD2 gene were successfully constructed. Key words: RNA interference ...

  6. Exercises in architecture specification using CλaSH

    NARCIS (Netherlands)

    Kuper, Jan; Baaij, C.P.R.; Kooijman, Matthijs; Gerards, Marco Egbertus Theodorus

    2010-01-01

    This paper introduces the hardware specification system ClaSH by elaborating on a few non-trivial examples. ClaSH is a compiling system that translates a subset of Haskell into synthesizable VHDL by a rewriting technique. This subset of Haskell includes higher order functions, polymorphism, lambda

  7. Comparison and combination of several MeSH indexing approaches.

    Science.gov (United States)

    Yepes, Antonio Jose Jimeno; Mork, James G; Demner-Fushman, Dina; Aronson, Alan R

    2013-01-01

    MeSH indexing of MEDLINE is becoming a more difficult task for the group of highly qualified indexing staff at the US National Library of Medicine, due to the large yearly growth of MEDLINE and the increasing size of MeSH. Since 2002, this task has been assisted by the Medical Text Indexer or MTI program. We extend previous machine learning analysis by adding a more diverse set of MeSH headings targeting examples where MTI has been shown to perform poorly. Machine learning algorithms exceed MTI's performance on MeSH headings that are used very frequently and headings for which the indexing frequency is very low. We find that when we combine the MTI suggestions and the prediction of the learning algorithms, the performance improves compared to any single method for most of the evaluated MeSH headings.

  8. Tumorigenesis: cell defense against hypoxia?

    Directory of Open Access Journals (Sweden)

    Nafiseh Pakravan

    2013-04-01

    Full Text Available Microenvironmental elements can directly contribute to the induction and the maintenance of tumor. Oxygen is the main element in the cell microenvironment and hypoxia can affect the process of tumorigenesis. In response to hypoxia, cells change their pattern and characteristics. These changes suggest that it is not just adaptation, but some sort of cell defense against hypoxia. If hypoxia is corrected, then cell defense mechanisms are interrupted. An examination of the process of tumorigenesis helps to design better therapeutic strategies.A systematic review of the English literature was conducted by searching PubMed, Google Scholar, and ISI Web databases for studies on changes that defend and help cells to live in a hypoxic microenvironment. Cells respond to hypoxia by de-differentiation and an increase in heat shock proteins. Angiogenesis and deviation of inflammatory response in favor of hypoxic cell survival also defend and save the oxygen-starved cells from death. Finally, anti-angiogenic therapies and more hypoxia enhance metastasis, as tumors with low oxygen concentration are more malignant than tumors with high oxygen concentration. All these enable cells to migrate away from low oxygen areas and seek a more conducive microenvironment. Therapies that make the microenvironment more hypoxic need to be revised. This has been done for antiangiogenic therapies, previously considered to be anti-tumor approaches. Effective therapies may be correcting therapies which direct the tumor microenvironment towards natural physical/chemical condition. Correcting therapies either bring back tumor cells to a normal form (correct tumor cells or help the immune system to eradicate tumor cells which can not be corrected.

  9. The acquired radioresistance in HeLa cells under conditions mimicking hypoxia was attenuated by a decreased expression of HIF subunit genes induced by RNA interference

    Energy Technology Data Exchange (ETDEWEB)

    Doi, Nobutaka [Department of Radiological Sciences, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194 (Japan); New Products Research & Development, Gene Engineering Division, NIPPON GENE Co., Ltd. (Japan); Ogawa, Ryohei, E-mail: ogawa@med.u-toyama.ac.jp [Department of Radiological Sciences, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194 (Japan); Cui, Zheng-Guo [Department of Public Health, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama (Japan); Morii, Akihiro; Watanabe, Akihiko [Department of Urology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama (Japan); Kanayama, Shinji; Yoneda, Yuko [New Products Research & Development, Gene Engineering Division, NIPPON GENE Co., Ltd. (Japan); Kondo, Takashi [Department of Radiological Sciences, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194 (Japan)

    2015-05-01

    The cancer cells residing in the hypoxic layer are resistant to radiation and these are ones responsible for cancer recurrence after radiation therapy. One of the reasons why hypoxic cancer cells acquire radioresistance may be attributable to changes in the gene expression profile by the activation of hypoxia inducible factors (HIFs). However, the details underlying this process remain unknown. In this study, we investigated the effects of knockdown of HIF subunit genes to elucidate how HIF subunit genes may be involved in the radioresistance acquired by HeLa cells following exposure to a hypoxia mimic. Interestingly, HIF-1α and HIF-2α seemed mutually complementary for each other when either of them was suppressed. We thus suppressed the expression of both genes simultaneously. To do this, we developed a short hairpin RNA (shRNA) targeting a high homology region between HIF-1α and HIF-2α. It was shown that the expression of the shRNA effectively suppressed the acquisition of radioresistance following the hypoxia mimic. Moreover, it was confirmed that suppression of both subunits resulted in the downregulation of stem cell markers and the suppression of spheroid formation during the hypoxia mimicking-conditions. This shRNA-mediated knockdown method targeting a common region shared by a family of genes may offer a new candidate cancer treatment. - Highlights: • Incubation with CoCl{sub 2} confers radioresistance to HeLa cells. • Both HIF-1α and HIF-2α are involved in the acquisition of radioresistance. • An shRNA to a homology region of HIF-1α and HIF-2α suppressed the radioresistance. • The shRNA decreased cells with stem cell markers and a stem cell phenotype.

  10. Coastal hypoxia responses to remediation

    Science.gov (United States)

    Kemp, W. M.; Testa, J. M.; Conley, D. J.; Gilbert, D.; Hagy, J. D.

    2009-07-01

    The incidence and intensity of hypoxic waters in coastal aquatic ecosystems has been expanding in recent decades coincident with eutrophication of the coastal zone. Because of the negative effects hypoxia has on many organisms, extensive efforts have been made to reduce the size and duration of hypoxia in many coastal waters. Although it has been broadly assumed that reductions in nutrient loading rates would reverse eutrophication and consequently, hypoxia, recent analyses of historical data from European and North American coastal systems suggest little evidence for simple linear response trajectories. We review existing data, analyses, and models that relate variations in the extent and intensity of hypoxia to changes in loading rates for inorganic nutrients and labile organic matter. We also assess existing knowledge of physical and ecological factors regulating oxygen in coastal marine waters and examine a broad range of examples where hypoxia responses to reductions in nutrient (or organic matter) inputs have been documented. Of the 22 systems identified where concurrent time series of loading and O2 were available, half displayed relatively clear and direct recoveries following remediation. We explored in detail 5 well-studied systems that have exhibited complex, non-linear responses to loading, including apparent "regime shifts." A summary of these analyses suggests that O2 conditions improved rapidly and linearly in systems where remediation focused on organic inputs from sewage plants, which were the primary drivers of hypoxia. In larger more open systems where diffuse nutrient loads are more important in fueling O2 depletion and where climatic influences are pronounced, responses to remediation tend to follow non-linear trends that may include hysteresis and time-lags. Improved understanding of hypoxia remediation requires that future studies use comparative approaches and consider multiple regulating factors including: (1) the dominant temporal scales

  11. Energy profile and secondary structure impact shRNA efficacy

    Directory of Open Access Journals (Sweden)

    Zeng Xiao

    2009-07-01

    Full Text Available Abstract Background RNA interference (RNAi is a cellular mechanism in which a short/small double stranded RNA induces the degradation of its sequence specific target mRNA, leading to specific gene silencing. Since its discovery, RNAi has become a powerful biological technique for gene function studies and drug discovery. The very first requirement of applying RNAi is to design functional small interfering RNA (siRNA that can uniquely induce the degradation of the targeted mRNA. It has been shown that many functional synthetic siRNAs share some common characteristics, such as GC content limitation and free energy preferences at both terminals, etc. Results Our three-phase algorithm was developed to design siRNA on a whole-genome scale based on those identified characteristics of functional siRNA. When this algorithm was applied to design short hairpin RNA (shRNA, the validated success rate of shRNAs was over 70%, which was almost double the rate reported for TRC library. This indicates that the designs of siRNA and shRNA may share the same concerns. Further analysis of the shRNA dataset of 444 designs reveals that the high free energy states of the two terminals have the largest positive impact on the shRNA efficacy. Enforcing these energy characteristics of both terminals can further improve the shRNA design success rate to 83.1%. We also found that functional shRNAs have less probability for their 3' terminals to be involved in mRNA secondary structure formation. Conclusion Functional shRNAs prefer high free energy states at both terminals. High free energy states of the two terminals were found to be the largest positive impact factor on shRNA efficacy. In addition, the accessibility of the 3' terminal is another key factor to shRNA efficacy.

  12. Locomotory fatigue during moderate and severe hypoxia and hypercapnia in the Atlantic blue crab, Callinectes sapidus.

    Science.gov (United States)

    Stover, Kristin K; Burnett, Karen G; McElroy, Eric J; Burnett, Louis E

    2013-04-01

    The Atlantic blue crab, Callinectes sapidus (Rathbun), is a highly mobile crustacean that must locomote to find food, evade predators, find mates, and avoid adverse conditions such as hypoxia. In this study we tested the effects of two levels of hypoxia (10.4 kPa, 50% air saturation = moderate hypoxia; 4 kPa, 20% air saturation = severe hypoxia) and hypercapnic hypoxia (50% air saturation O(2) with Pco(2) = 2 kPa) on fatigue during sustained continuous exercise. Fatigue was induced by an exercise trial that entailed continuous sideways hexapedal walking on an underwater treadmill. Fatigue was quantified using two methods: (1) a pull force test that measures the holding strength of the legs, and (2) the number of fatigue-resisting behaviors (180° turns and stopping). Fatigue was defined as a pull force of 67% or less of the initial pre-exercise pull force and was reached after 6.12 h of walking for crabs in well-aerated normoxic seawater, 4 h in 50% air saturation, 2.07 h in 20% air saturation, and 4.58 h in 50% air saturation and hypercapnia. The number of fatigue-resisting behaviors increased with walking time in all treatments. Performance decreased in hypoxia, with fatigue being reached more quickly as the level of hypoxia intensified. Hypercapnia in moderate hypoxia did not have a deleterious influence on behavior and lengthened slightly the time it took crabs to fatigue. In addition, severe hypoxia exacerbated changes in gait kinematics as crabs became fatigued, by significantly increasing stride length and decreasing stride frequency.

  13. Hypoxia signaling pathways: modulators of oxygen-related organelles

    Directory of Open Access Journals (Sweden)

    Miriam Johanna Schönenberger

    2015-07-01

    Full Text Available Oxygen (O2 is an essential substrate in cellular metabolism, bioenergetics, and signaling and as such linked to the survival and normal function of all metazoans. Low O2 tension (hypoxia is a fundamental feature of physiological processes as well as pathophysiological conditions such as cancer and ischemic diseases. Central to the molecular mechanisms underlying O2 homeostasis are the hypoxia-inducible factors-1 and -2 alpha (HIF-1a and EPAS1/HIF-2a that function as master regulators of the adaptive response to hypoxia. HIF-induced genes promote characteristic tumor behaviors, including angiogenesis and metabolic reprogramming. The aim of this review is to critically explore current knowledge of how HIF-a signaling regulates the abundance and function of major O2-consuming organelles. Abundant evidence suggests key roles for HIF-1a in the regulation of mitochondrial homeostasis. An essential adaptation to sustained hypoxia is repression of mitochondrial respiration and induction of glycolysis. HIF-1a activates several genes that trigger mitophagy and represses regulators of mitochondrial biogenesis. Several lines of evidence point to a strong relationship between hypoxia, the accumulation of misfolded proteins in the endoplasmic reticulum, and activation of the unfolded protein response. Surprisingly, although peroxisomes depend highly on molecular O2 for their function, there has been no evidence linking HIF signaling to peroxisomes. We discuss our recent findings that establish HIF-2a as a negative regulator of peroxisome abundance and suggest a mechanism by which cells attune peroxisomal function with O2 availability. HIF-2a activation augments peroxisome turnover by pexophagy and thereby changes lipid composition reminiscent of peroxisomal disorders. We discuss potential mechanisms by which HIF-2a might trigger pexophagy and place special emphasis on the potential pathological implications of HIF-2a-mediated pexophagy for human health.

  14. Germinal centre hypoxia and regulation of antibody qualities by a hypoxia response system.

    Science.gov (United States)

    Cho, Sung Hoon; Raybuck, Ariel L; Stengel, Kristy; Wei, Mei; Beck, Thomas C; Volanakis, Emmanuel; Thomas, James W; Hiebert, Scott; Haase, Volker H; Boothby, Mark R

    2016-09-08

    Germinal centres (GCs) promote humoral immunity and vaccine efficacy. In GCs, antigen-activated B cells proliferate, express high-affinity antibodies, promote antibody class switching, and yield B cell memory. Whereas the cytokine milieu has long been known to regulate effector functions that include the choice of immunoglobulin class, both cell-autonomous and extrinsic metabolic programming have emerged as modulators of T-cell-mediated immunity. Here we show in mice that GC light zones are hypoxic, and that low oxygen tension () alters B cell physiology and function. In addition to reduced proliferation and increased B cell death, low impairs antibody class switching to the pro-inflammatory IgG2c antibody isotype by limiting the expression of activation-induced cytosine deaminase (AID). Hypoxia induces HIF transcription factors by restricting the activity of prolyl hydroxyl dioxygenase enzymes, which hydroxylate HIF-1α and HIF-2α to destabilize HIF by binding the von Hippel-Landau tumour suppressor protein (pVHL). B-cell-specific depletion of pVHL leads to constitutive HIF stabilization, decreases antigen-specific GC B cells and undermines the generation of high-affinity IgG, switching to IgG2c, early memory B cells, and recall antibody responses. HIF induction can reprogram metabolic and growth factor gene expression. Sustained hypoxia or HIF induction by pVHL deficiency inhibits mTOR complex 1 (mTORC1) activity in B lymphoblasts, and mTORC1-haploinsufficient B cells have reduced clonal expansion, AID expression, and capacities to yield IgG2c and high-affinity antibodies. Thus, the normal physiology of GCs involves regional variegation of hypoxia, and HIF-dependent oxygen sensing regulates vital functions of B cells. We propose that the restriction of oxygen in lymphoid organs, which can be altered in pathophysiological states, modulates humoral immunity.

  15. Minocycline blocks glial cell activation and ventilatory acclimatization to hypoxia.

    Science.gov (United States)

    Stokes, Jennifer A; Arbogast, Tara E; Moya, Esteban A; Fu, Zhenxing; Powell, Frank L

    2017-04-01

    centers during chronic hypoxia and ventilatory acclimatization. However, minocycline cannot reverse ventilatory acclimatization after it is established. Hence, glial cells may provide signals that initiate but do not sustain ventilatory acclimatization. Copyright © 2017 the American Physiological Society.

  16. Preeclampsia, Hypoxia, Thrombosis, and Inflammation

    Directory of Open Access Journals (Sweden)

    Amir A. Shamshirsaz

    2012-01-01

    Full Text Available Reductions in uteroplacental flow initiate a cascade of molecular effects leading to hypoxia, thrombosis, inflammation, and endothelial cell dysfunction resulting in untoward pregnancy outcomes. In this review, we detail these effects and their relationship to preeclampsia (PE and intrauterine growth restriction (IUGR.

  17. Plasma volume in acute hypoxia

    DEFF Research Database (Denmark)

    Poulsen, T D; Klausen, T; Richalet, J P

    1998-01-01

    Exposure to acute hypoxia is associated with changes in body fluid homeostasis and plasma volume (PV). This study compared a dye dilution technique using Evans' blue (PV[Evans']) with a carbon monoxide (CO) rebreathing method (PV[CO]) for measurements of PV in ten normal subjects at sea level...

  18. Immunologic Consequences of Hypoxia during Critical Illness

    Science.gov (United States)

    Kiers, Harmke D.; Scheffer, Gert-Jan; van der Hoeven, Johannes G.; Eltzschig, Holger K.; Pickkers, Peter; Kox, Matthijs

    2016-01-01

    Hypoxia and immunity are highly intertwined at the clinical, cellular, and molecular level. The prevention of tissue hypoxia and modulation of systemic inflammation are cornerstones of daily practice in the Intensive Care Unit. Potentially, immunologic effects of hypoxia may contribute to outcome and represent possible therapeutic targets. Hypoxia and activation of downstream signaling pathways result in enhanced innate immune responses, aimed to augment pathogen clearance. On the other hand, hypoxia also exerts anti-inflammatory and tissue-protective effects in lymphocytes and other tissues. Although human data on the net immunologic effects of hypoxia and pharmacological modulation of downstream pathways are limited, preclinical data support the concept of tailoring the immune response through modulation of the oxygen status or pharmacological modulation of hypoxia-signaling pathways in critically ill patients. PMID:27183167

  19. Regulation of red blood cell deformability is independent of red blood cell-nitric oxide synthase under hypoxia.

    Science.gov (United States)

    Grau, Marijke; Lauten, Alexander; Hoeppener, Steffen; Goebel, Bjoern; Brenig, Julian; Jung, Christian; Bloch, Wilhelm; Suhr, Frank

    2016-09-12

    The aim was to study impacts of mild to severe hypoxia on human red blood cell (RBC)-nitric oxide synthase (NOS)-dependent NO production, protein S-nitrosylation and deformability.Ambient air oxygen concentration of 12 healthy subjects was step-wisely reduced from 20.95% to 16.21%, 12.35%, 10% and back to 20.95%. Additional in vitro experiments involved purging of blood (±sodium nitrite) with gas mixtures corresponding to in vivo intervention.Vital and hypoxia-associated parameters showed physiological adaptation to changing demands. Activation of RBC-NOS decreased with increasing hypoxia. RBC deformability, which is influenced by RBC-NOS activation, decreased under mild hypoxia, but surprisingly increased at severe hypoxia in vivo and in vitro. This was causatively induced by nitrite reduction to NO which increased S-nitrosylation of RBC α- and β-spectrins -a critical step to improve RBC deformability. The addition of sodium nitrite prevented decreases of RBC deformability under hypoxia by sustaining S-nitrosylation of spectrins suggesting compensatory mechanisms of non-RBC-NOS-produced NO.The results first time indicate a direct link between maintenance of RBC deformability under severe hypoxia by non-enzymatic NO production because RBC-NOS activation is reduced. These data improve our understanding of physiological mechanisms supporting adequate blood and, thus, oxygen supply to different tissues under severe hypoxia.

  20. Nitric oxide signaling in hypoxia.

    Science.gov (United States)

    Ho, J J David; Man, H S Jeffrey; Marsden, Philip A

    2012-03-01

    Endothelial-derived nitric oxide (NO) is classically viewed as a regulator of vasomotor tone. NO plays an important role in regulating O(2) delivery through paracrine control of vasomotor tone locally and cardiovascular and respiratory responses centrally. Very soon after the cloning and functional characterization of the endothelial nitric oxide synthase (eNOS), studies on the interaction between O(2) and NO made the paradoxical finding that hypoxia led to decreases in eNOS expression and function. Why would decreases in O(2) content in tissues elicit a loss of a potent endothelial-derived vasodilator? We now know that restricting our view of NO as a regulator of vasomotor tone or blood pressure limited deeper levels of mechanistic insight. Exciting new studies indicate that functional interactions between NO and O(2) exhibit profound complexity and are relevant to diseases states, especially those associated with hypoxia in tissues. NOS isoforms catalytically require O(2). Hypoxia regulates steady-state expression of the mRNA and protein abundance of the NOS enzymes. Animals genetically deficient in NOS isoforms have perturbations in their ability to adapt to changes in O(2) supply or demand. Most interestingly, the intracellular pathways for O(2) sensing that evolved to ensure an appropriate balance of O(2) delivery and utilization intersect with NO signaling networks. Recent studies demonstrate that hypoxia-inducible factor (HIF) stabilization and transcriptional activity is achieved through two parallel pathways: (1) a decrease in O(2)-dependent prolyl hydroxylation of HIF and (2) S-nitrosylation of HIF pathway components. Recent findings support a role for S-nitrosothiols as hypoxia-mimetics in certain biological and/or disease settings, such as living at high altitude, exposure to small molecules that can bind NO, or anemia.

  1. Hypoxia, Hypoxia-inducible Transcription Factors, and Renal Cancer.

    Science.gov (United States)

    Schödel, Johannes; Grampp, Steffen; Maher, Eamonn R; Moch, Holger; Ratcliffe, Peter J; Russo, Paul; Mole, David R

    2016-04-01

    Renal cancer is a common urologic malignancy, and therapeutic options for metastatic disease are limited. Most clear cell renal cell carcinomas (ccRCC) are associated with loss of von Hippel-Lindau tumor suppressor (pVHL) function and deregulation of hypoxia pathways. This review summarizes recent evidence from genetic and biological studies showing that hypoxia and hypoxia-related pathways play critical roles in the development and progress of renal cancer. We used a systematic search for articles using the keywords hypoxia, HIF, renal cancer, and VHL. Identification of the tumor suppressor pVHL has allowed the characterization of important ccRCC-associated pathways. pVHL targets α-subunits of hypoxia-inducible transcription factors (HIF) for proteasomal degradation. The two main HIF-α isoforms have opposing effects on RCC biology, possibly through distinct interactions with additional oncogenes. Furthermore, HIF-1α activity is commonly diminished by chromosomal deletion in ccRCCs, and increased HIF-1 activity reduces tumor burden in xenograft tumor models. Conversely, polymorphisms at the HIF-2α gene locus predispose to the development of ccRCCs, and HIF-2α promotes tumor growth. Genetic studies have revealed a prominent role for chromatin-modifying enzyme genes in ccRCC, and these may further modulate specific aspects of the HIF response. This suggests that, rather than global activation of HIF, specific components of the response are important in promoting kidney cancer. Some of these processes are already targets for current therapeutic strategies, and further dissection of this pathway might yield novel methods of treating RCC. In contrast to many tumor types, HIF-1α and HIF-2α have opposing effects in ccRCC biology, with HIF-1α acting as a tumor suppressor and HIF-2α acting as an oncogene. The overall effect of VHL inactivation will depend on fine-tuning of the HIF response. High levels of hypoxia-inducible transcription factors (HIF) are

  2. Interproximal grooving in the Atapuerca-SH hominid dentitions.

    Science.gov (United States)

    Bermúdez de Castro, J M; Arsuaga, J L; Pérez, P J

    1997-03-01

    The dental sample recovered from the Sima de los Huesos (SH) Middle Pleistocene cave site of the Sierra de Atapuerca (Spain) includes 296 specimens. Interproximal wear grooves have been observed in 20 maxillary and mandibular posterior teeth belonging to at least five of the 32 individuals identified so far in the SH hypodigm. Interproximal grooving affected only the adults, and at an age between 25 and 40 years. The appearance, morphology, and location pattern of the SH wear grooves are similar to those reported in other fossil hominids and in more recent human populations. Two alternative proposals, the toothpicking and the fiber or sinew processing hypotheses, compete for explaining the formation of this anomalous wear. The characteristics observed in the wear grooves of the SH teeth are compatible only with the habitual probing of interdental spaces by means of hard and inflexible objects. Dietary grit may also have contributed to the abrasion of the root walls during the motion of the dental probes.

  3. Organizational structures and communications on the SH 130 project.

    Science.gov (United States)

    2006-03-01

    This product summarizes the findings from research analyzing SH 130 organizational structures and communication flows. A set of guidelines pertaining to team organization and communication improvement and the design-build environment is also included...

  4. Fundamental modes of new dispersive SH-waves in ...

    Indian Academy of Sciences (India)

    and α2 = 0.99εμ) are studied because they satisfy the limitation condition of α2 < εμ. Keywords. ... can have combined large and robust electric and magnetic polarizations at room tempera- ture, except for the .... SH-waves because as soon as α becomes zero, the other new SH-waves given in [53] can exist, except the case ...

  5. A theoretical study of the dissociative recombination of SH+ with electrons through the 2Π states of SH.

    Science.gov (United States)

    Kashinski, D O; Talbi, D; Hickman, A P; Di Nallo, O E; Colboc, F; Chakrabarti, K; Schneider, I F; Mezei, J Zs

    2017-05-28

    A quantitative theoretical study of the dissociative recombination of SH+ with electrons has been carried out. Multireference, configuration interaction calculations were used to determine accurate potential energy curves for SH+ and SH. The block diagonalization method was used to disentangle strongly interacting SH valence and Rydberg states and to construct a diabatic Hamiltonian whose diagonal matrix elements provide the diabatic potential energy curves. The off-diagonal elements are related to the electronic valence-Rydberg couplings. Cross sections and rate coefficients for the dissociative recombination reaction were calculated with a stepwise version of the multichannel quantum defect theory, using the molecular data provided by the block diagonalization method. The calculated rates are compared with the most recent measurements performed on the ion Test Storage Ring (TSR) in Heidelberg, Germany.

  6. Biochemical Measurement of Neonatal Hypoxia

    OpenAIRE

    Plank, Megan S; Calderon, Teleka C.; Asmerom, Yayesh; Boskovic, Danilo S.; Angeles, Danilyn M.

    2011-01-01

    Neonatal hypoxia ischemia is characterized by inadequate blood perfusion of a tissue or a systemic lack of oxygen. This condition is thought to cause/exacerbate well documented neonatal disorders including neurological impairment 1-3. Decreased adenosine triphosphate production occurs due to a lack of oxidative phosphorylation. To compensate for this energy deprived state molecules containing high energy phosphate bonds are degraded 2. This leads to increased levels of adenosine which is s...

  7. Hypoxia-Sensitive Materials for Biomedical Applications.

    Science.gov (United States)

    Yu, Jicheng; Zhang, Yuqi; Hu, Xiuli; Wright, Grace; Gu, Zhen

    2016-06-01

    Hypoxia is a typical hallmark of various diseases, including cancer, ischemic diseases, and stroke. It is also associated with the disease progression. Therefore, it is critical to develop an effective strategy to target the hypoxic region for diagnosis and treatment. In this review, we summarize recent progress in the development of hypoxia-responsive systems for imaging, sensing and therapy. Two types of hypoxia-sensitive systems, the hypoxia inducible factor-1 based systems and bioreductive molecule based systems, were reviewed with comments on their advantages and limitations. Future opportunities and challenges are also discussed in the end.

  8. Hypoxia: The Force that Drives Chronic Kidney Disease.

    Science.gov (United States)

    Fu, Qiangwei; Colgan, Sean P; Shelley, Carl Simon

    2016-03-01

    In the United States the prevalence of end-stage renal disease (ESRD) reached epidemic proportions in 2012 with over 600,000 patients being treated. The rates of ESRD among the elderly are disproportionally high. Consequently, as life expectancy increases and the baby-boom generation reaches retirement age, the already heavy burden imposed by ESRD on the US health care system is set to increase dramatically. ESRD represents the terminal stage of chronic kidney disease (CKD). A large body of evidence indicating that CKD is driven by renal tissue hypoxia has led to the development of therapeutic strategies that increase kidney oxygenation and the contention that chronic hypoxia is the final common pathway to end-stage renal failure. Numerous studies have demonstrated that one of the most potent means by which hypoxic conditions within the kidney produce CKD is by inducing a sustained inflammatory attack by infiltrating leukocytes. Indispensable to this attack is the acquisition by leukocytes of an adhesive phenotype. It was thought that this process resulted exclusively from leukocytes responding to cytokines released from ischemic renal endothelium. However, recently it has been demonstrated that leukocytes also become activated independent of the hypoxic response of endothelial cells. It was found that this endothelium-independent mechanism involves leukocytes directly sensing hypoxia and responding by transcriptional induction of the genes that encode the β2-integrin family of adhesion molecules. This induction likely maintains the long-term inflammation by which hypoxia drives the pathogenesis of CKD. Consequently, targeting these transcriptional mechanisms would appear to represent a promising new therapeutic strategy. © 2016 Marshfield Clinic.

  9. Hypoxia: The Force that Drives Chronic Kidney Disease

    Science.gov (United States)

    Fu, Qiangwei; Colgan, Sean P; Shelley, Carl Simon

    2016-01-01

    In the United States the prevalence of end-stage renal disease (ESRD) reached epidemic proportions in 2012 with over 600,000 patients being treated. The rates of ESRD among the elderly are disproportionally high. Consequently, as life expectancy increases and the baby-boom generation reaches retirement age, the already heavy burden imposed by ESRD on the US health care system is set to increase dramatically. ESRD represents the terminal stage of chronic kidney disease (CKD). A large body of evidence indicating that CKD is driven by renal tissue hypoxia has led to the development of therapeutic strategies that increase kidney oxygenation and the contention that chronic hypoxia is the final common pathway to end-stage renal failure. Numerous studies have demonstrated that one of the most potent means by which hypoxic conditions within the kidney produce CKD is by inducing a sustained inflammatory attack by infiltrating leukocytes. Indispensable to this attack is the acquisition by leukocytes of an adhesive phenotype. It was thought that this process resulted exclusively from leukocytes responding to cytokines released from ischemic renal endothelium. However, recently it has been demonstrated that leukocytes also become activated independent of the hypoxic response of endothelial cells. It was found that this endothelium-independent mechanism involves leukocytes directly sensing hypoxia and responding by transcriptional induction of the genes that encode the β2-integrin family of adhesion molecules. This induction likely maintains the long-term inflammation by which hypoxia drives the pathogenesis of CKD. Consequently, targeting these transcriptional mechanisms would appear to represent a promising new therapeutic strategy. PMID:26847481

  10. Assembling cyavanaprāsh, Ayurveda's best-selling medicine.

    Science.gov (United States)

    Bode, Maarten

    2015-04-01

    The paper discusses the many forms and representations of cyavanaprāsh, Ayurveda's best-selling medicine, already mentioned in Caraka's Compendium (c. 200 CE). The medicine's compositions, applications, and meanings, change over time and from locality to locality. Cyavanaprāsh is, for example, a patriotic formula, a booster of the immune system, a modern geriatric drug, and one of the elements in canonical Ayurvedic treatments. In the beginning of the 19th century cyavanaprāsh was a patriotic formula for fortifying Indian bodies and the nascent Indian nation. Nowadays the medicine is a Fast Moving Consumer Good (FMCG) and a money maker for Dabur India Ltd., the world largest Ayurvedic manufacturer. Instead of vitalising the nation its consumption now promises to make urban middle class consumers effectively modern. Branding and modern science must make Dabur Chyawanprash attractive in the eyes of these consumers. Ayurveda and cyavanaprāsh are also part of a global counter culture marked by neo-Orientalism and Ayurvedic medicines as facilitators of spirituality. The marketing of cyavanaprāsh by India's largest Ayurvedic manufacturer is used as a case study for discussing the proliferation of Ayurvedic brands and its critics. The imaging of Ayurvedic brands such as Dabur Chyawanprash threatens to obscure the fact that Ayurveda represents a unique way of looking upon health, disease and the human body. The proliferation of brands also makes Ayurvedic medicines more expensive and puts pressure on the natural environment as the main supplier of Ayurvedic ingredients.

  11. Hypoxia: From Placental Development to Fetal Programming.

    Science.gov (United States)

    Fajersztajn, Lais; Veras, Mariana Matera

    2017-10-16

    Hypoxia may influence normal and different pathological processes. Low oxygenation activates a variety of responses, many of them regulated by hypoxia-inducible factor 1 complex, which is mostly involved in cellular control of O 2 consumption and delivery, inhibition of growth and development, and promotion of anaerobic metabolism. Hypoxia plays a significant physiological role in fetal development; it is involved in different embryonic processes, for example, placentation, angiogenesis, and hematopoiesis. More recently, fetal hypoxia has been associated directly or indirectly with fetal programming of heart, brain, and kidney function and metabolism in adulthood. In this review, the role of hypoxia in fetal development, placentation, and fetal programming is summarized. Hypoxia is a basic mechanism involved in different pregnancy disorders and fetal health developmental complications. Although there are scientific data showing that hypoxia mediates changes in the growth trajectory of the fetus, modulates gene expression by epigenetic mechanisms, and determines the health status later in adulthood, more mechanistic studies are needed. Furthermore, if we consider that intrauterine hypoxia is not a rare event, and can be a consequence of unavoidable exposures to air pollution, nutritional deficiencies, obesity, and other very common conditions (drug addiction and stress), the health of future generations may be damaged and the incidence of some diseases will markedly increase as a consequence of disturbed fetal programming. Birth Defects Research 109:1377-1385, 2017.© 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  12. Megakaryocytic leukemia 1 (MKL1 regulates hypoxia induced pulmonary hypertension in rats.

    Directory of Open Access Journals (Sweden)

    Zhibin Yuan

    Full Text Available Hypoxia induced pulmonary hypertension (HPH represents a complex pathology that involves active vascular remodeling, loss of vascular tone, enhanced pulmonary inflammation, and increased deposition of extracellular matrix proteins. Megakaryocytic leukemia 1 (MKL1 is a transcriptional regulator known to influence cellular response to stress signals in the vasculature. We report here that in response to chronic hypobaric hypoxia, MKL1 expression was up-regulated in the lungs in rats. Short hairpin RNA (shRNA mediated depletion of MKL1 significantly ameliorated the elevation of pulmonary arterial pressure in vivo with a marked alleviation of vascular remodeling. MKL1 silencing also restored the expression of NO, a key vasoactive molecule necessary for the maintenance of vascular tone. In addition, hypoxia induced pulmonary inflammation was dampened in the absence of MKL1 as evidenced by normalized levels of pro-inflammatory cytokines and chemokines as well as reduced infiltration of pro-inflammatory immune cells in the lungs. Of note, MKL1 knockdown attenuated fibrogenesis in the lungs as indicated by picrosirius red staining. Finally, we demonstrate that MKL1 mediated transcriptional activation of type I collagen genes in smooth muscle cells under hypoxic conditions. In conclusion, we data highlight a previously unidentified role for MKL1 in the pathogenesis of HPH and as such lay down groundwork for future investigation and drug development.

  13. VEGF secretion during hypoxia depends on free radicals-induced Fyn kinase activity in mast cells

    Energy Technology Data Exchange (ETDEWEB)

    Garcia-Roman, Jonathan; Ibarra-Sanchez, Alfredo; Lamas, Monica [Departamento de Farmacobiologia, Centro de Investigacion y de Estudios Avanzados del IPN (Cinvestav, IPN) (Mexico); Gonzalez Espinosa, Claudia, E-mail: cgonzal@cinvestav.mx [Departamento de Farmacobiologia, Centro de Investigacion y de Estudios Avanzados del IPN (Cinvestav, IPN) (Mexico)

    2010-10-15

    Research highlights: {yields} Bone marrow-derived mast cells (BMMCs) secrete functional VEGF but do not degranulate after Cobalt chloride-induced hypoxia. {yields} CoCl{sub 2}-induced VEGF secretion in mast cells occurs by a Ca{sup 2+}-insensitive but brefeldin A and Tetanus toxin-sensitive mechanism. {yields} Trolox and N-acetylcysteine inhibit hypoxia-induced VEGF secretion but only Trolox inhibits Fc{epsilon}RI-dependent anaphylactic degranulation in mast cells. {yields} Src family kinase Fyn activation after free radical production is necessary for hypoxia-induced VEGF secretion in mast cells. -- Abstract: Mast cells (MC) have an important role in pathologic conditions such as asthma and chronic obstructive pulmonary disease (COPD), where hypoxia conduce to deleterious inflammatory response. MC contribute to hypoxia-induced angiogenesis producing factors such as vascular endothelial growth factor (VEGF), but the mechanisms behind the control of hypoxia-induced VEGF secretion in this cell type is poorly understood. We used the hypoxia-mimicking agent cobalt chloride (CoCl{sub 2}) to analyze VEGF secretion in murine bone marrow-derived mast cells (BMMCs). We found that CoCl{sub 2} promotes a sustained production of functional VEGF, able to induce proliferation of endothelial cells in vitro. CoCl{sub 2}-induced VEGF secretion was independent of calcium rise but dependent on tetanus toxin-sensitive vesicle-associated membrane proteins (VAMPs). VEGF exocytosis required free radicals formation and the activation of Src family kinases. Interestingly, an important deficiency on CoCl{sub 2}-induced VEGF secretion was observed in Fyn kinase-deficient BMMCs. Moreover, Fyn kinase was activated by CoCl{sub 2} in WT cells and this activation was prevented by treatment with antioxidants such as Trolox and N-acetylcysteine. Our results show that BMMCs are able to release VEGF under hypoxic conditions through a tetanus toxin-sensitive mechanism, promoted by free radicals

  14. Natural and human-induced hypoxia and consequences for coastal areas: synthesis and future development

    Directory of Open Access Journals (Sweden)

    J. Zhang

    2010-05-01

    Full Text Available Hypoxia has become a world-wide phenomenon in the global coastal ocean and causes a deterioration of the structure and function of ecosystems. Based on the collective contributions of members of SCOR Working Group #128, the present study provides an overview of the major aspects of coastal hypoxia in different biogeochemical provinces, including estuaries, coastal waters, upwelling areas, fjords and semi-enclosed basins, with various external forcings, ecosystem responses, feedbacks and potential impact on the sustainability of the fishery and economics. The obvious external forcings include freshwater runoff and other factors contributing to stratification, organic matter and nutrient loadings, as well as exchange between coastal and open ocean water masses. Their different interactions set up mechanisms that drive the system towards hypoxia. Coastal systems also vary in their relative susceptibility to hypoxia depending on their physical and geographic settings. It is understood that coastal hypoxia has a profound impact on the sustainability of ecosystems, which can be seen, for example, by the change in the food-web structure and system function; other influences include compression and loss of habitat, as well as changes in organism life cycles and reproduction. In most cases, the ecosystem responds to the low dissolved oxygen in non-linear ways with pronounced feedbacks to other compartments of the Earth System, including those that affect human society. Our knowledge and previous experiences illustrate that there is a need to develop new observational tools and models to support integrated research of biogeochemical dynamics and ecosystem behavior that will improve confidence in remediation management strategies for coastal hypoxia.

  15. Adaptive Evolution of Energy Metabolism-Related Genes in Hypoxia-Tolerant Mammals.

    Science.gov (United States)

    Tian, Ran; Yin, Daiqing; Liu, Yanzhi; Seim, Inge; Xu, Shixia; Yang, Guang

    2017-01-01

    Animals that are able to sustain life under hypoxic conditions have long captured the imagination of biologists and medical practitioners alike. Although the associated morphological modifications have been extensively described, the mechanisms underlying the evolution of hypoxia tolerance are not well understood. To provide such insights, we investigated genes in four major energy metabolism pathways, and provide evidence of distinct evolutionary paths to mammalian hypoxia-tolerance. Positive selection of genes in the oxidative phosphorylation pathway mainly occurred in terrestrial hypoxia-tolerant species; possible adaptations to chronically hypoxic environments. The strongest candidate for positive selection along cetacean lineages was the citrate cycle signaling pathway, suggestive of enhanced aerobic metabolism during and after a dive. Six genes with cetacean-specific amino acid changes are rate-limiting enzymes involved in the gluconeogenesis pathway, which would be expected to enhance the lactate removal after diving. Intriguingly, 38 parallel amino acid substitutions in 29 genes were observed between hypoxia-tolerant mammals. Of these, 76.3% were radical amino acid changes, suggesting that convergent molecular evolution drives the adaptation to hypoxic stress and similar phenotypic changes. This study provides further insights into life under low oxygen conditions and the evolutionary trajectories of hypoxia-tolerant species.

  16. Adaptive Evolution of Energy Metabolism-Related Genes in Hypoxia-Tolerant Mammals

    Directory of Open Access Journals (Sweden)

    Ran Tian

    2017-12-01

    Full Text Available Animals that are able to sustain life under hypoxic conditions have long captured the imagination of biologists and medical practitioners alike. Although the associated morphological modifications have been extensively described, the mechanisms underlying the evolution of hypoxia tolerance are not well understood. To provide such insights, we investigated genes in four major energy metabolism pathways, and provide evidence of distinct evolutionary paths to mammalian hypoxia-tolerance. Positive selection of genes in the oxidative phosphorylation pathway mainly occurred in terrestrial hypoxia-tolerant species; possible adaptations to chronically hypoxic environments. The strongest candidate for positive selection along cetacean lineages was the citrate cycle signaling pathway, suggestive of enhanced aerobic metabolism during and after a dive. Six genes with cetacean-specific amino acid changes are rate-limiting enzymes involved in the gluconeogenesis pathway, which would be expected to enhance the lactate removal after diving. Intriguingly, 38 parallel amino acid substitutions in 29 genes were observed between hypoxia-tolerant mammals. Of these, 76.3% were radical amino acid changes, suggesting that convergent molecular evolution drives the adaptation to hypoxic stress and similar phenotypic changes. This study provides further insights into life under low oxygen conditions and the evolutionary trajectories of hypoxia-tolerant species.

  17. AEG-1 is associated with hypoxia-induced hepatocellular carcinoma chemoresistance via regulating PI3K/AKT/HIF-1alpha/MDR-1 pathway.

    Science.gov (United States)

    Xie, Yong; Zhong, De-Wu

    2016-01-01

    Hypoxia is a common characteristic of hepatocellular carcinoma (HCC) associated with reduced response to chemotherapy, thus increasing the probability of tumor recurrence. Astrocyte elevated gene-1 (AEG-1) has been involved in a wide array of cancer progression including proliferation, chemoresistance, angiogenesis and metastasis, but its effect on HCC chemoresistance induced by hypoxia is unclear. In this study, expression of AEG-1 and multiple drug resistance (MDR-1) were examined in HCC using immunohistochemical staining and RT-PCR. Furthermore, their expression levels were detected in HCC HepG2 cells in normoxia or hypoxia via RT-PCR and Western blot assays. Specific shRNAs were used to silence AEG-1 expression in HepG2 cells. Results showed AEG-1 and MDR-1 expression were higher in HCC tissues than in adjacent normal tissues. Incubation of HepG2 cells in hypoxia increased expression of AEG-1 and MDR-1, compared to incubation in normoxia. Exposure to hypoxia blunted sensitivity of HepG2 cells to Adriamycin, 5-fluorouracil and cis-platinum, as evidenced by modest alterations in cell viability and apoptosis rate, however the sensitivity was elevated with AEG-1 knockdown. PI3K/AKT/HIF-1/MDR-1 pathway was attenuated following AEG-1 knockdown in hypoxia. Based on these data, it was suggested that AEG-1 is associated with hypoxia-induced hepatocellular carcinoma chemoresistance via regulating PI3K/AKT/HIF-1/MDR-1 pathway. This study uncovered a novel potential target for development of an effective therapy against hypoxia-induced HCC chemoresistance.

  18. p21WAF1 and hypoxia/reoxygenation-induced premature senescence of H9c2 cardiomyocytes

    Directory of Open Access Journals (Sweden)

    Dan Wang

    2011-10-01

    Full Text Available We have previously reported on hypoxia/reoxygenation-induced premature senescence in neonatalrat cardiomyocytes. In this research, we investigated the effects of p21WAF1 (p21 in hypoxia/reoxygenation-inducedsenescence, using H9c2 cells. A plasmid overexpressing wild type p21WAF1 and a plasmid expressing smallhairpin RNA (shRNA targeting p21WAF1 were constructed, and transfected into H9c2 cells to control the p21expression. Hypoxia/reoxygenation conditions were 1% O2 and 5% CO2, balancing the incubator chamber withN2 for 6 h (hypoxia 6 h, then 21% oxygen for 8 h (reoxygenation 8 h. Cell cycle was examined using flowcytometry. Senescence was assessed using b-galactosidase staining. The expression of p53, p21, p16INK4a, andcyclin D1 was assayed using Western blotting. At hypoxia 6 h, cells overexpressing p21 had a larger G1 distribution,stronger b-galactosidase activity, and lower cyclin D1 expression compared to control cells, while the oppositeresults and higher p53 expression were obtained in p21-knockdown cells. At reoxygenation 8 h, p21-silencedcells had a smaller percentage of G1 cells, weaker b-galactosidase activity and lower 16INK4a expression, andhigher cyclin D1 expression, but the overexpression group showed no difference. Taken together, this data impliesthat p21WAF1 is important for the hypoxia phase, but not the reoxygenation phase, in the H9c2 senescenceprocess. (Folia Histochemica et Cytobiologica 2011, Vol. 49, No. 3, 445–451

  19. p21WAF1 and hypoxia/reoxygenation-induced premature senescence of H9c2 cardiomyocytes

    Directory of Open Access Journals (Sweden)

    Ming-Yong Cao

    2011-10-01

    Full Text Available We have previously reported on hypoxia/reoxygenation-induced premature senescence in neonatal rat cardiomyocytes. In this research, we investigated the effects of p21WAF1 (p21 in hypoxia/reoxygenation-induced senescence, using H9c2 cells. A plasmid overexpressing wild type p21WAF1 and a plasmid expressing small hairpin RNA (shRNA targeting p21WAF1 were constructed, and transfected into H9c2 cells to control the p21 expression. Hypoxia/reoxygenation conditions were 1% O2 and 5% CO2, balancing the incubator chamber with N2 for 6 h (hypoxia 6 h, then 21% oxygen for 8 h (reoxygenation 8 h. Cell cycle was examined using flow cytometry. Senescence was assessed using β-galactosidase staining. The expression of p53, p21, p16INK4a, and cyclin D1 was assayed using Western blotting. At hypoxia 6 h, cells overexpressing p21 had a larger G1 distribution, stronger β-galactosidase activity, and lower cyclin D1 expression compared to control cells, while the opposite results and higher p53 expression were obtained in p21-knockdown cells. At reoxygenation 8 h, p21-silenced cells had a smaller percentage of G1 cells, weaker β-galactosidase activity and lower 16INK4a expression, and higher cyclin D1 expression, but the overexpression group showed no difference. Taken together, this data implies that p21WAF1 is important for the hypoxia phase, but not the reoxygenation phase, in the H9c2 senescence process. (Folia Histochemica et Cytobiologica 2011, Vol. 49, No. 3, 445–451

  20. Ecosystem impacts of hypoxia: thresholds of hypoxia and pathways to recovery

    Energy Technology Data Exchange (ETDEWEB)

    Steckbauer, A; Duarte, C M; Vaquer-Sunyer, R [Department of Global Change Research, IMEDEA (CSIC-UIB), Institut Mediterrani d' Estudis Avancats, C/Miquel Marques 21, 07190 Esporles (Mallorca), Islas Baleares (Spain); Carstensen, J [Department of Marine Ecology, National Environmental Research Institute, Aarhus University, PO Box 358, DK-4000 Roskilde (Denmark); Conley, D J, E-mail: asteckbauer@imedea.uib-csic.es [Department of Earth and Ecosystem Sciences, Lund University, SE-223 62 Lund (Sweden)

    2011-04-15

    Coastal hypoxia is increasing in the global coastal zone, where it is recognized as a major threat to biota. Managerial efforts to prevent hypoxia and achieve recovery of ecosystems already affected by hypoxia are largely based on nutrient reduction plans. However, these managerial efforts need to be informed by predictions on the thresholds of hypoxia (i.e. the oxygen levels required to conserve biodiversity) as well as the timescales for the recovery of ecosystems already affected by hypoxia. The thresholds for hypoxia in coastal ecosystems are higher than previously thought and are not static, but regulated by local and global processes, being particularly sensitive to warming. The examination of recovery processes in a number of coastal areas managed for reducing nutrient inputs and, thus, hypoxia (Northern Adriatic; Black Sea; Baltic Sea; Delaware Bay; and Danish Coastal Areas) reveals that recovery timescales following the return to normal oxygen conditions are much longer than those of loss following the onset of hypoxia, and typically involve decadal timescales. The extended lag time for ecosystem recovery from hypoxia results in non-linear pathways of recovery due to hysteresis and the shift in baselines, affecting the oxygen thresholds for hypoxia through time.

  1. Improving the utility of MeSH® terms using the TopicalMeSH representation.

    Science.gov (United States)

    Yu, Zhiguo; Bernstam, Elmer; Cohen, Trevor; Wallace, Byron C; Johnson, Todd R

    2016-06-01

    To evaluate whether vector representations encoding latent topic proportions that capture similarities to MeSH terms can improve performance on biomedical document retrieval and classification tasks, compared to using MeSH terms. We developed the TopicalMeSH representation, which exploits the 'correspondence' between topics generated using latent Dirichlet allocation (LDA) and MeSH terms to create new document representations that combine MeSH terms and latent topic vectors. We used 15 systematic drug review corpora to evaluate performance on information retrieval and classification tasks using this TopicalMeSH representation, compared to using standard encodings that rely on either (1) the original MeSH terms, (2) the text, or (3) their combination. For the document retrieval task, we compared the precision and recall achieved by ranking citations using MeSH and TopicalMeSH representations, respectively. For the classification task, we considered three supervised machine learning approaches, Support Vector Machines (SVMs), logistic regression, and decision trees. We used these to classify documents as relevant or irrelevant using (independently) MeSH, TopicalMeSH, Words (i.e., n-grams extracted from citation titles and abstracts, encoded via bag-of-words representation), a combination of MeSH and Words, and a combination of TopicalMeSH and Words. We also used SVM to compare the classification performance of tf-idf weighted MeSH terms, LDA Topics, a combination of Topics and MeSH, and TopicalMeSH to supervised LDA's classification performance. For the document retrieval task, using the TopicalMeSH representation resulted in higher precision than MeSH in 11 of 15 corpora while achieving the same recall. For the classification task, use of TopicalMeSH features realized a higher F1 score in 14 of 15 corpora when used by SVMs, 12 of 15 corpora using logistic regression, and 12 of 15 corpora using decision trees. TopicalMeSH also had better document classification

  2. HypoxamiRs : Regulators of cardiac hypoxia and energy metabolism

    NARCIS (Netherlands)

    Azzouzi, Hamid el; Leptidis, Stefanos; Doevendans, Pieter A.; De Windt, Leon J.

    2015-01-01

    Hypoxia and its intricate regulation are at the epicenter of cardiovascular research. Mediated by hypoxia-inducible factors as well as by several microRNAs, recently termed 'hypoxamiRs', hypoxia affects several cardiac pathophysiological processes. Hypoxia is the driving force behind the regulation

  3. Notch3 is activated by chronic hypoxia and contributes to the progression of human prostate cancer.

    Science.gov (United States)

    Danza, Giovanna; Di Serio, Claudia; Ambrosio, Maria Raffaella; Sturli, Niccolò; Lonetto, Giuseppe; Rosati, Fabiana; Rocca, Bruno Jim; Ventimiglia, Giuseppina; del Vecchio, Maria Teresa; Prudovsky, Igor; Marchionni, Niccolò; Tarantini, Francesca

    2013-12-01

    Prostate cancer (PC) is still the second cause of cancer-related death among men. Although patients with metastatic presentation have an ominous outcome, the vast majority of PCs are diagnosed at an early stage. Nonetheless, even among patients with clinically localized disease the outcome may vary considerably. Other than androgen sensitivity, little is known about which other signaling pathways are deranged in aggressive, localized cancers. The elucidation of such pathways may help to develop innovative therapies aimed at specific molecular targets. We report that in a hormone-sensitive PC cell line, LNCaP, Notch3 was activated by hypoxia and sustained cell proliferation and colony formation in soft agar. Hypoxia also modulated cellular cholesterol content and the number and size of lipid rafts, causing a coalescence of small rafts into bigger clusters; under this experimental condition, Notch3 migrated from the non-raft into the raft compartment where it colocalized with the γ-secretase complex. We also looked at human PC biopsies and found that expression of Notch3 positively correlated with Gleason score and with expression of carbonic anhydrase IX, a marker of hypoxia. In conclusion, hypoxia triggers the activation of Notch3, which, in turn, sustains proliferation of PC cells. Notch3 pathway represents a promising target for adjuvant therapy in patients with PC. Copyright © 2013 UICC.

  4. Safety of Lactobacillus plantarum ST8Sh and Its Bacteriocin.

    Science.gov (United States)

    Todorov, Svetoslav Dimitrov; Perin, Luana M; Carneiro, Bruno M; Rahal, Paula; Holzapfel, Wilhelm; Nero, Luís Augusto

    2017-09-01

    Total DNA extracted from Lb. plantarum ST8Sh was screened for the presence of more than 50 genes related to production of biogenic amines (histidine decarboxylase, tyrosine decarboxylase, and ornithine decarboxylase), virulence factors (sex pheromones, gelatinase, cytolysin, hyaluronidase, aggregation substance, enterococcal surface protein, endocarditis antigen, adhesion of collagen, integration factors), and antibiotic resistance (vancomycin, tetracycline, erythromycin, gentamicin, chloramphenicol, bacitracin). Lb. plantarum ST8Sh showed a low presence of virulence genes. Only 13 genes were detected (related to sex pheromones, aggregation substance, adhesion of collagen, tetracycline, gentamicin, chloramphenicol, erythromycin, but not to vancomycin, and bacitracin) and may be considered as indication of safety for application in fermented food products. In addition, interaction between Lb. plantarum ST8Sh and drugs from different groups were determined in order to establish possible application of the strain in combination with commercial drugs. Cytotoxicity of the semi-purified bacteriocins produced by Lb. plantarum ST8Sh was depended on applied concentration-highly cytotoxic when applied at 25 μg/mL and no cytotoxicity at 5 μg/mL.

  5. Hiding State in CλaSH Hardware Descriptions

    NARCIS (Netherlands)

    Gerards, Marco Egbertus Theodorus; Baaij, C.P.R.; Kuper, Jan; Kooijman, Matthijs

    Synchronous hardware can be modelled as a mapping from input and state to output and a new state, such mappings are referred to as transition functions. It is natural to use a functional language to implement transition functions. The CaSH compiler is capable of translating transition functions to

  6. Mammalian target of rapamycin complex 1 activation sensitizes human glioma cells to hypoxia-induced cell death.

    Science.gov (United States)

    Thiepold, Anna-Luisa; Lorenz, Nadja I; Foltyn, Martha; Engel, Anna L; Divé, Iris; Urban, Hans; Heller, Sonja; Bruns, Ines; Hofmann, Ute; Dröse, Stefan; Harter, Patrick N; Mittelbronn, Michel; Steinbach, Joachim P; Ronellenfitsch, Michael W

    2017-10-01

    Glioblastomas are characterized by fast uncontrolled growth leading to hypoxic areas and necrosis. Signalling from EGFR via mammalian target of rapamycin complex 1 (mTORC1) is a major driver of cell growth and proliferation and one of the most commonly altered signalling pathways in glioblastomas. Therefore, epidermal growth factor receptor and mTORC1 signalling are plausible therapeutic targets and clinical trials with inhibitors are in progress. However, we have previously shown that epidermal growth factor receptor and mTORC1 inhibition triggers metabolic changes leading to adverse effects under the conditions of the tumour microenvironment by protecting from hypoxia-induced cell death. We hypothesized that conversely mTORC1 activation sensitizes glioma cells to hypoxia-induced cell death. As a model for mTORC1 activation we used gene suppression of its physiological inhibitor TSC2 (TSC2sh). TSC2sh glioma cells showed increased sensitivity to hypoxia-induced cell death that was accompanied by an earlier ATP depletion and an increase in reactive oxygen species. There was no difference in extracellular glucose consumption but an altered intracellular metabolic profile with an increase of intermediates of the pentose phosphate pathway. Mechanistically, mTORC1 upregulated the first and rate limiting enzyme of the pentose phosphate pathway, G6PD. Furthermore, an increase in oxygen consumption in TSC2sh cells was detected. This appeared to be due to higher transcription rates of genes involved in mitochondrial respiratory function including PPARGC1A and PPARGC1B (also known as PGC-1α and -β). The finding that mTORC1 activation causes an increase in oxygen consumption and renders malignant glioma cells susceptible to hypoxia and nutrient deprivation could help identify glioblastoma patient cohorts more likely to benefit from hypoxia-inducing therapies such as the VEGFA-targeting antibody bevacizumab in future clinical evaluations. © The Author (2017). Published by

  7. Palaeodemography of the Atapuerca-SH Middle Pleistocene hominid sample.

    Science.gov (United States)

    Bermúdez de Castro, J M; Nicolás, M E

    1997-01-01

    We report here on the palaeodemographic analysis of the hominid sample recovered to date from the Sima de los Huesos (SH) Middle Pleistocene cave site in the Sierra de Atapuerca (Burgos, Spain). The analysis of the mandibular, maxillary, and dental remains has made it possible to estimate that a minimum of 32 individuals, who probably belonged to the same biological population, are represented in the current SH human hypodigm. The remains of nine-individuals are assigned to males, and nine to females, suggesting that a 1:1 sex ratio characterizes this hominid sample. The survivorship curve shows a low representation of infants and children, a high mortality among the adolescents and prime-age adults, and a low older adult mortality. Longevity was probably no greater than 40 years. This mortality pattern (adolescents and adults); which in some aspects resembles that observed in Neandertals, is quite different from those reported for recent foraging human groups. The adult age-at-death distribution of the SH hominid sample appears to be neither the consequence of underaging the older adults, nor of differential preservation or of the recognition of skeletal remains. Thus if we accept that they had a life history pattern similar to that of modern humans there would appear to be a clear contradiction between the demographic distribution and the demographic viability of the population represented by the SH hominid fossils. The possible representational bias of the SH hominid sample, as well as some aspects of the reproductive biology of the Pleistocene populations are also discussed.

  8. Modeling dissolved oxygen dynamics and hypoxia

    Directory of Open Access Journals (Sweden)

    M. A. Peña

    2010-03-01

    Full Text Available Hypoxia conditions are increasing throughout the world, influencing biogeochemical cycles of elements and marine life. Hypoxia results from complex interactions between physical and biogeochemical processes, which can not be understood by observations alone. Models are invaluable tools at studying system dynamics, generalizing discrete observations and predicting future states. They are also useful as management tools for evaluating site-specific responses to management scenarios. Here we review oxygen dynamics models that have significantly contributed to a better understanding of the effects of natural processes and human perturbations on the development of hypoxia, factors controlling the extent and temporal variability of coastal hypoxia, and the effects of oxygen depletion on biogeochemical cycles. Because hypoxia occurs in a variety of environments and can be persistent, periodic or episodic, models differ significantly in their complexity and temporal and spatial resolution. We discuss the progress in developing hypoxia models for benthic and pelagic systems that range from simple box models to three dimensional circulation models. Applications of these models in five major hypoxia regions are presented. In the last decades, substantial progress has been made towards the parameterization of biogeochemical processes in both hypoxic water columns and sediments. In coastal regions, semi-empirical models have been used more frequently than mechanistic models to study nutrient enrichment and hypoxia relationships. Recent advances in three-dimensional coupled physical-ecological-biogeochemical models have allowed a better representation of physical-biological interactions in these systems. We discuss the remaining gaps in process descriptions and suggest directions for improvement. Better process representations in models will help us answer several important questions, such as those about the causes of the observed worldwide increase in

  9. Pol II-expressed shRNA knocks down Sod2 gene expression and causes phenotypes of the gene knockout in mice.

    Directory of Open Access Journals (Sweden)

    Xu-Gang Xia

    2006-01-01

    Full Text Available RNA interference (RNAi has been used increasingly for reverse genetics in invertebrates and mammalian cells, and has the potential to become an alternative to gene knockout technology in mammals. Thus far, only RNA polymerase III (Pol III-expressed short hairpin RNA (shRNA has been used to make shRNA-expressing transgenic mice. However, widespread knockdown and induction of phenotypes of gene knockout in postnatal mice have not been demonstrated. Previous studies have shown that Pol II synthesizes micro RNAs (miRNAs-the endogenous shRNAs that carry out gene silencing function. To achieve efficient gene knockdown in mammals and to generate phenotypes of gene knockout, we designed a construct in which a Pol II (ubiquitin C promoter drove the expression of an shRNA with a structure that mimics human miRNA miR-30a. Two transgenic lines showed widespread and sustained shRNA expression, and efficient knockdown of the target gene Sod2. These mice were viable but with phenotypes of SOD2 deficiency. Bigenic heterozygous mice generated by crossing these two lines showed nearly undetectable target gene expression and phenotypes consistent with the target gene knockout, including slow growth, fatty liver, dilated cardiomyopathy, and premature death. This approach opens the door of RNAi to a wide array of well-established Pol II transgenic strategies and offers a technically simpler, cheaper, and quicker alternative to gene knockout by homologous recombination for reverse genetics in mice and other mammalian species.

  10. Kinetic modeling in PET imaging of hypoxia

    DEFF Research Database (Denmark)

    Joergensen, Jesper T; Hansen, Anders E; Kjaer, Andreas

    2014-01-01

    be used for non-invasive mapping of tissue oxygenation in vivo and several hypoxia specific PET tracers have been developed. Evaluation of PET data in the clinic is commonly based on visual assessment together with semiquantitative measurements e.g. standard uptake value (SUV). However, dynamic PET......Tumor hypoxia is associated with increased therapeutic resistance leading to poor treatment outcome. Therefore the ability to detect and quantify intratumoral oxygenation could play an important role in future individual personalized treatment strategies. Positron Emission Tomography (PET) can...... analysis for PET imaging of hypoxia....

  11. Hypoxia tolerance, nitric oxide, and nitrite

    DEFF Research Database (Denmark)

    Fago, Angela; Jensen, Frank Bo

    2015-01-01

    survival resides in concerted physiological responses, including strong metabolic depression, protection against oxidative damage and – in air breathing animals - redistribution of blood flow. Each of these responses is known to be tightly regulated by nitric oxide (NO) and during hypoxia by its metabolite...... of NO and nitrite signaling in the adaptive response to hypoxia in vertebrate animals.......Among vertebrates able to tolerate periods of oxygen deprivation, the painted and red-eared slider turtles (Chrysemys picta and Trachemys scripta) and the crucian carp (Carassius carassius) are the most extreme and can survive even months of total lack of oxygen during winter. The key to hypoxia...

  12. Kinetic modeling in PET imaging of hypoxia

    DEFF Research Database (Denmark)

    Li, Fan; Jørgensen, Jesper Tranekjær; Hansen, Anders E

    2014-01-01

    Tumor hypoxia is associated with increased therapeutic resistance leading to poor treatment outcome. Therefore the ability to detect and quantify intratumoral oxygenation could play an important role in future individual personalized treatment strategies. Positron Emission Tomography (PET) can...... be used for non-invasive mapping of tissue oxygenation in vivo and several hypoxia specific PET tracers have been developed. Evaluation of PET data in the clinic is commonly based on visual assessment together with semiquantitative measurements e.g. standard uptake value (SUV). However, dynamic PET...... analysis for PET imaging of hypoxia....

  13. Reciprocal Regulation of Hypoxia-Inducible Factor 2α and GLI1 Expression Associated With the Radioresistance of Renal Cell Carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Zhou, Jiancheng [Department of Urology, First Affiliated Hospital of Medical School, Xi' an Jiaotong University, Xi' an (China); Department of Urology, Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas (United States); Wu, Kaijie [Department of Urology, First Affiliated Hospital of Medical School, Xi' an Jiaotong University, Xi' an (China); Gao, Dexuan [Department of Urology, Shandong Provincial Hospital affiliated with Shandong University, Ji' nan (China); Zhu, Guodong; Wu, Dapeng; Wang, Xinyang; Chen, Yule; Du, Yuefeng; Song, Wenbin; Ma, Zhenkun [Department of Urology, First Affiliated Hospital of Medical School, Xi' an Jiaotong University, Xi' an (China); Authement, Craig; Saha, Debabrata [Department of Urology, Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas (United States); Hsieh, Jer-Tsong, E-mail: jt.hsieh@utsouthwestern.edu [Department of Urology, Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas (United States); He, Dalin, E-mail: dalinhe@yahoo.com [Department of Urology, First Affiliated Hospital of Medical School, Xi' an Jiaotong University, Xi' an (China)

    2014-11-15

    Purpose: Renal cell carcinoma (RCC) is often considered a radioresistant tumor, but the molecular mechanism underlying its radioresistance is poorly understood. This study explored the roles of hypoxia-inducible factor 2α (HIF2α) and sonic hedgehog (SHH)-GLI1 signaling in mediating the radioresistance of RCC cells and to unveil the interaction between these 2 signaling pathways. Methods and Materials: The activities of SHH-GLI1 signaling pathway under normoxia and hypoxia in RCC cells were examined by real-time polymerase chain reaction, Western blot, and luciferase reporter assay. The expression of HIF2α and GLI1 in RCC patients was examined by immunohistochemistry, and their correlation was analyzed. Furthermore, RCC cells were treated with HIF2α-specific shRNA (sh-HIF2α), GLI1 inhibitor GANT61, or a combination to determine the effect of ionizing radiation (IR) on RCC cells based on clonogenic assay and double-strand break repair assay. Results: RCC cells exhibited elevated SHH-GLI1 activities under hypoxia, which was mediated by HIF2α. Hypoxia induced GLI1 activation through SMO-independent pathways that could be ablated by PI3K inhibitor or MEK inhibitor. Remarkably, the SHH-GLI1 pathway also upregulated HIF2α expression in normoxia. Apparently, there was a positive correlation between HIF2α and GLI1 expression in RCC patients. The combination of sh-HIF2α and GLI1 inhibitor significantly sensitized RCC cells to IR. Conclusions: Cross-talk between the HIF2α and SHH-GLI1 pathways was demonstrated in RCC. Cotargeting these 2 pathways, significantly sensitizing RCC cells to IR, provides a novel strategy for RCC treatment.

  14. HYPOXIA IN THE GULF OF MEXICO: ASSESSING AND MANAGING RISKS FROM NONPOINT SOURCE POLLUTANTS IN THE MISSISSIPPI RIVER BASIN

    Science.gov (United States)

    . Hypoxia is the condition in which dissolved oxygen levels are below that necessary to sustain most animal life. The largest zone of oxygen depletion in U.S. coastal waters is found in the northern Gulf of Mexico (NGOM) on the Louisiana/Texas continental shelf. In response to...

  15. Cerebral hypoxia and ischemia in preterm infants

    Directory of Open Access Journals (Sweden)

    Alberto Ravarino

    2014-06-01

    Full Text Available Premature birth is a major public health issue internationally affecting 13 million babies worldwide. Hypoxia and ischemia is probably the commonest type of acquired brain damage in preterm infants. The clinical manifestations of hypoxic-ischemic injury in survivors of premature birth include a spectrum of cerebral palsy and intellectual disabilities. Until recently, the extensive brain abnormalities in preterm neonates appeared to be related mostly to destructive processes that lead to substantial deletion of neurons, axons, and glia from necrotic lesions in the developing brain. Advances in neonatal care coincide with a growing body of evidence that the preterm gray and white matter frequently sustain less severe insults, where tissue destruction is the minor component. Periventricular leukomalacia (PVL is the major form of white matter injury and consists classically of focal necrotic lesions, with subsequent cyst formation, and a less severe but more diffuse injury to cerebral white mater, with prominent astrogliosis and microgliosis but without overt necrosis. With PVL a concomitant injury occurs to subplate neurons, located in the subcortical white matter. Severe hypoxic-ischemic insults that trigger significant white matter necrosis are accompanied by neuronal degeneration in cerebral gray and white matter. This review aims to illustrate signs of cerebral embryology of the second half of fetal life and correlate hypoxic-ischemic brain injury in the premature infant. This should help us better understand the symptoms early and late and facilitate new therapeutic strategies. Proceedings of the International Course on Perinatal Pathology (part of the 10th International Workshop on Neonatology · October 22nd-25th, 2014 · Cagliari (Italy · October 25th, 2014 · The role of the clinical pathological dialogue in problem solving Guest Editors: Gavino Faa, Vassilios Fanos, Peter Van Eyken

  16. Human erythropoietin response to hypocapnic hypoxia, normocapnic hypoxia, and hypocapnic normoxia

    DEFF Research Database (Denmark)

    Klausen, T; Christensen, H; Hansen, J M

    1996-01-01

    exposed to 2 h each of hypocapnic hypoxia, normocapnic hypoxia, hypocapnic normoxia, and normal breathing of room air (control experiment). During the control experiment, serum-EPO showed significant variations (ANOVA P = 0.047) with a 15% increase in mean values. The serum-EPO measured in the other...... (10% Co2 with 10% O2) to the hypoxic gas mixture. This elicited an increased ventilation, unaltered arterial pH and haemoglobin oxygen affinity, a lower degree of hypoxia than during hypocapnic hypoxia, and no significant changes in serum-EPO (ANOVA P > 0.05). Hypocapnic normoxia, produced...

  17. Sedimentary organic and inorganic records of eutrophication and hypoxia in and off the Changjiang Estuary over the last century.

    Science.gov (United States)

    Zhao, Jun; Feng, Xuwen; Shi, Xiaolai; Bai, Youcheng; Yu, Xiaoguo; Shi, Xuefa; Zhang, Weiyan; Zhang, Rongping

    2015-10-15

    Organic and inorganic sedimentary parameters in and off the Changjiang Estuary have been analyzed to reconstruct historical trends in eutrophication and hypoxia over the last century. The lipid biomarker concentrations in the Changjiang Estuary mud area (CEMA) indicated eutrophication accelerated after the 1970s. Meanwhile, Mo/Al indicated hypoxia has increased since 1960s. Eutrophication and hypoxia in the CEMA are primarily a result of the dramatically increased load of terrestrial nutrients from the Changjiang to the East China Sea. The lipid biomarker concentrations in the southwest Cheju Island mud area (SCIMA) showed primary production is controlled mainly by changes in regional climate and marine current. No significant hypoxia occurred in the SCIMA over the past century as indicated by Mo/Al. Therefore, geochemical indicators of eutrophication and hypoxia revealed different patterns between the CEMA and SCIMA, suggesting the role of river-derived nutrients in sustaining eutrophication and hypoxia in the CEMA since the 1960s. Copyright © 2015 Elsevier Ltd. All rights reserved.

  18. 2001 Hypoxia Watch Bottom CTD Station Locations

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The NOAA Hypoxia Watch project provides near-real-time, web-based maps of dissolved oxygen near the sea floor over the Texas-Louisiana continental shelf during a...

  19. 2005 Hypoxia Watch Bottom CTD Station Locations

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The NOAA Hypoxia Watch project provides near-real-time, web-based maps of dissolved oxygen near the sea floor over the Texas-Louisiana continental shelf during a...

  20. 2004 Hypoxia Watch Bottom CTD Station Locations

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The NOAA Hypoxia Watch project provides near-real-time, web-based maps of dissolved oxygen near the sea floor over the Texas-Louisiana continental shelf during a...

  1. 2003 Hypoxia Watch Bottom CTD Station Locations

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The NOAA Hypoxia Watch project provides near-real-time, web-based maps of dissolved oxygen near the sea floor over the Texas-Louisiana continental shelf during a...

  2. 2007 Hypoxia Watch Bottom CTD Station Locations

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The NOAA Hypoxia Watch project provides near-real-time, web-based maps of dissolved oxygen near the sea floor over the Texas-Louisiana continental shelf during a...

  3. 2002 Hypoxia Watch Bottom CTD Station Locations

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The NOAA Hypoxia Watch project provides near-real-time, web-based maps of dissolved oxygen near the sea floor over the Texas-Louisiana continental shelf during a...

  4. Quantification of compensatory processes of postnatal hypoxia in newborn piglets applying short-term nonlinear dynamics analysis

    Directory of Open Access Journals (Sweden)

    Walter Bernd

    2011-10-01

    Full Text Available Abstract Background Newborn mammals suffering from moderate hypoxia during or after birth are able to compensate a transitory lack of oxygen by adapting their vital functions. Exposure to hypoxia leads to an increase in the sympathetic tone causing cardio-respiratory response, peripheral vasoconstriction and vasodilatation in privileged organs like the heart and brain. However, there is only limited information available about the time and intensity changes of the underlying complex processes controlled by the autonomic nervous system. Methods In this study an animal model involving seven piglets was used to examine an induced state of circulatory redistribution caused by moderate oxygen deficit. In addition to the main focus on the complex dynamics occurring during sustained normocapnic hypoxia, the development of autonomic regulation after induced reoxygenation had been analysed. For this purpose, we first introduced a new algorithm to prove stationary conditions in short-term time series. Then we investigated a multitude of indices from heart rate and blood pressure variability and from bivariate interactions, also analysing respiration signals, to quantify the complexity of vegetative oscillations influenced by hypoxia. Results The results demonstrated that normocapnic hypoxia causes an initial increase in cardiovascular complexity and variability, which decreases during moderate hypoxia lasting one hour (p Conclusions In conclusion, indices from linear and nonlinear dynamics reflect considerable temporal changes of complexity in autonomous cardio-respiratory regulation due to normocapnic hypoxia shortly after birth. These findings might be suitable for non-invasive clinical monitoring of hypoxia-induced changes of autonomic regulation in newborn humans.

  5. Intracellular targeted co-delivery of shMDR1 and gefitinib with chitosan nanoparticles for overcoming multidrug resistance

    Science.gov (United States)

    Yu, Xiwei; Yang, Guang; Shi, Yijie; Su, Chang; Liu, Ming; Feng, Bo; Zhao, Liang

    2015-01-01

    Nowadays, multidrug resistance and side effects of drugs limit the effectiveness of chemotherapies in clinics. P-glycoprotein (P-gp) (MDR1), as a member of the ATP-binding cassette family, acts on transporting drugs into cell plasma across the membrane of cancer cells and leads to the occurrence of multidrug resistance, thus resulting in the failure of chemotherapy in cancer. The main aims of this research were to design a nanodelivery system for accomplishing the effective co-delivery of gene and antitumor drug and overcoming multidrug resistance effect. In this study, shMDR1 and gefitinib-encapsulating chitosan nanoparticles with sustained release, small particle size, and high encapsulation efficiency were prepared. The serum stability, protection from nuclease, and transfection efficiency of gene in vitro were investigated. The effects of co-delivery of shMDR1 and gefitinib in nanoparticles on reversing multidrug resistance were also evaluated by investigating the cytotoxicity, cellular uptake mechanism, and cell apoptosis on established gefitinib-resistant cells. The results demonstrated that chitosan nanoparticles entrapping gefitinib and shMDR1 had the potential to overcome the multidrug resistance and improve cancer treatment efficacy, especially toward resistant cells. PMID:26648717

  6. Protein-phosphotyrosine proteome profiling by superbinder-SH2 domain affinity purification mass spectrometry, sSH2-AP-MS.

    Science.gov (United States)

    Tong, Jiefei; Cao, Biyin; Martyn, Gregory D; Krieger, Jonathan R; Taylor, Paul; Yates, Bradley; Sidhu, Sachdev S; Li, Shawn S C; Mao, Xinliang; Moran, Michael F

    2017-03-01

    Recently, "superbinder" SH2 domain variants with three amino acid substitutions (sSH2) were reported to have 100-fold or greater affinity for protein-phosphotyrosine (pY) than natural SH2 domains. Here we report a protocol in which His-tagged Src sSH2 efficiently captures pY-peptides from protease-digested HeLa cell total protein extracts. Affinity purification of pY-peptides by this method shows little bias for pY-proximal amino acid sequences, comparable to that achieved by using antibodies to pY, but with equal or higher yield. Superbinder-SH2 affinity purification mass spectrometry (sSH2-AP-MS) therefore provides an efficient and economical approach for unbiased pY-directed phospho-proteome profiling without the use of antibodies. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  7. SH ultrasonic guided waves for the evaluation of interfacial adhesion.

    Science.gov (United States)

    Castaings, Michel

    2014-09-01

    Shear-Horizontally (SH) polarized, ultrasonic, guided wave modes are considered in order to infer changes in the adhesive properties at several interfaces located within an adhesive bond joining two metallic plates. Specific aluminium lap-joint samples were produced, with different adhesive properties at up to four interfaces when a glass-epoxy film is inserted into the adhesive bond. EMAT transducers were used to generate and detect the fundamental SH0 mode. This is launched from one plate and detected at the other plate, past the lap joint. Signals are picked up for different propagation paths along each sample, in order to check measurement reproducibility as well as the uniformity of the adhesively bonded zones. Signals measured for four samples are then compared, showing very good sensitivity of the SH0 mode to changes in the interfacial adhesive properties. In addition, a Finite Element-based model is used to simulate the experimental measurements. The model includes adhesive viscoelasticity, as well as spatial distributions of shear springs (with shear stiffness KT) at both metal-adhesive interfaces, and also at the adhesive-film interfaces when these are present. This model is solved in the frequency domain, but temporal excitation and inverse FFT procedure are implemented in order to simulate the measured time traces. Values of the interfacial adhesive parameters, KT, are determined by an optimization process so that best fit is obtained between both sets of measured and numerically predicted waveforms. Such agreement was also possible by adjusting the shear modulus of the adhesive component. This work suggests a promising use of SH-like guided modes for quantifying shear properties at adhesive interfaces, and shows that such waves can be used for inferring adhesive and cohesive properties of bonds separately. Finally, the paper considers improvements that could be made to the process, and its potential for testing the interfacial adhesion of adhesively

  8. Feature engineering for MEDLINE citation categorization with MeSH.

    Science.gov (United States)

    Jimeno Yepes, Antonio Jose; Plaza, Laura; Carrillo-de-Albornoz, Jorge; Mork, James G; Aronson, Alan R

    2015-04-08

    Research in biomedical text categorization has mostly used the bag-of-words representation. Other more sophisticated representations of text based on syntactic, semantic and argumentative properties have been less studied. In this paper, we evaluate the impact of different text representations of biomedical texts as features for reproducing the MeSH annotations of some of the most frequent MeSH headings. In addition to unigrams and bigrams, these features include noun phrases, citation meta-data, citation structure, and semantic annotation of the citations. Traditional features like unigrams and bigrams exhibit strong performance compared to other feature sets. Little or no improvement is obtained when using meta-data or citation structure. Noun phrases are too sparse and thus have lower performance compared to more traditional features. Conceptual annotation of the texts by MetaMap shows similar performance compared to unigrams, but adding concepts from the UMLS taxonomy does not improve the performance of using only mapped concepts. The combination of all the features performs largely better than any individual feature set considered. In addition, this combination improves the performance of a state-of-the-art MeSH indexer. Concerning the machine learning algorithms, we find that those that are more resilient to class imbalance largely obtain better performance. We conclude that even though traditional features such as unigrams and bigrams have strong performance compared to other features, it is possible to combine them to effectively improve the performance of the bag-of-words representation. We have also found that the combination of the learning algorithm and feature sets has an influence in the overall performance of the system. Moreover, using learning algorithms resilient to class imbalance largely improves performance. However, when using a large set of features, consideration needs to be taken with algorithms due to the risk of over-fitting. Specific

  9. MeSH indexing based on automatically generated summaries.

    Science.gov (United States)

    Jimeno-Yepes, Antonio J; Plaza, Laura; Mork, James G; Aronson, Alan R; Díaz, Alberto

    2013-06-26

    MEDLINE citations are manually indexed at the U.S. National Library of Medicine (NLM) using as reference the Medical Subject Headings (MeSH) controlled vocabulary. For this task, the human indexers read the full text of the article. Due to the growth of MEDLINE, the NLM Indexing Initiative explores indexing methodologies that can support the task of the indexers. Medical Text Indexer (MTI) is a tool developed by the NLM Indexing Initiative to provide MeSH indexing recommendations to indexers. Currently, the input to MTI is MEDLINE citations, title and abstract only. Previous work has shown that using full text as input to MTI increases recall, but decreases precision sharply. We propose using summaries generated automatically from the full text for the input to MTI to use in the task of suggesting MeSH headings to indexers. Summaries distill the most salient information from the full text, which might increase the coverage of automatic indexing approaches based on MEDLINE. We hypothesize that if the results were good enough, manual indexers could possibly use automatic summaries instead of the full texts, along with the recommendations of MTI, to speed up the process while maintaining high quality of indexing results. We have generated summaries of different lengths using two different summarizers, and evaluated the MTI indexing on the summaries using different algorithms: MTI, individual MTI components, and machine learning. The results are compared to those of full text articles and MEDLINE citations. Our results show that automatically generated summaries achieve similar recall but higher precision compared to full text articles. Compared to MEDLINE citations, summaries achieve higher recall but lower precision. Our results show that automatic summaries produce better indexing than full text articles. Summaries produce similar recall to full text but much better precision, which seems to indicate that automatic summaries can efficiently capture the most

  10. Representations of Parenting and Gender Roles in the Shōshika Era: Comparisons of Japanese and English-Language Parenting Magazines

    OpenAIRE

    Shimoda, Tomoko

    2008-01-01

    This article examines how Japanese parenting magazines portray parenting and gender roles in the shōshika era, an era of sustained decline in the Japanese birth-rate. Recent surveys indicate that Japanese society remains ambivalent about the need for fathers to be involved in child rearing. This article examines why these attitudes and ideas persist and how the Japanese media, specifically Japanese parenting magazines, may contribute to perpetuating traditional attitudes towards parenting rol...

  11. Neuromuscular Fatigue during Prolonged Exercise in Hypoxia.

    Science.gov (United States)

    Jubeau, Marc; Rupp, Thomas; Temesi, John; Perrey, Stéphane; Wuyam, Bernard; Millet, Guillaume Y; Verges, Samuel

    2017-03-01

    Prolonged cycling exercise performance in normoxia is limited because of both peripheral and central neuromuscular impairments. It has been reported that cerebral perturbations are greater during short-duration exercise in hypoxia compared with normoxia. The purpose of this study was to test the hypothesis that central deficits are accentuated in hypoxia compared with normoxia during prolonged (three bouts of 80 min separated by 25 min) whole-body exercise at the same relative intensity. Ten subjects performed two sessions consisting of three 80-min cycling bouts at 45% of their relative maximal aerobic power in normoxia and hypoxia (FiO2 = 0.12). Before exercise and after each bout, maximal voluntary force, voluntary activation assessed with nerve stimulation and transcranial magnetic stimulation, corticospinal excitability (motor evoked potential), intracortical inhibition (cortical silent period), and electrical (M-wave) and contractile (twitch and doublet peak forces) properties of the knee extensors were measured. Prefrontal and motor cortical oxygenation was also recorded during each cycling bout in both conditions. A significant but similar force reduction (≈-22%) was observed at the end of exercise in normoxia and hypoxia. The modifications of voluntary activation assessed with transcranial magnetic stimulation and nerve stimulation, motor evoked potential, cortical silent period, and M-wave were also similar in both conditions. However, cerebral oxygenation was reduced in hypoxia compared with normoxia. These findings show that when performed at the same relative low intensity, prolonged exercise does not induce greater supraspinal fatigue in hypoxia compared with normoxia. Despite lower absolute exercise intensities in hypoxia, reduced brain O2 availability might contribute to similar amounts of central fatigue compared with normoxia.

  12. Hypoxia-on-a-chip

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    Busek Mathias

    2016-09-01

    Full Text Available In this work a microfluidic cell cultivation device for perfused hypoxia assays as well as a suitable controlling unit are presented. The device features active components like pumps for fluid actuation and valves for fluid direction as well as an oxygenator element to ensure a sufficient oxygen transfer. It consists of several individually structured layers which can be tailored specifically to the intended purpose. Because of its clearness, its mechanical strength and chemical resistance as well as its well-known biocompatibility polycarbonate was chosen to form the fluidic layers by thermal diffusion bonding. Several oxygen sensing spots are integrated into the device and monitored with fluorescence lifetime detection. Furthermore an oxygen regulator module is implemented into the controlling unit which is able to mix different process gases to achieve a controlled oxygenation. First experiments show that oxygenation/deoxygenation of the system is completed within several minutes when pure nitrogen or air is applied to the oxygenator. Lastly the oxygen input by the pneumatically driven micro pump was quantified by measuring the oxygen content before and after the oxygenator.

  13. Effects of hypercapnia and NO synthase inhibition in sustained hypoxic pulmonary vasoconstriction.

    Science.gov (United States)

    Ketabchi, Farzaneh; Ghofrani, Hossein A; Schermuly, Ralph T; Seeger, Werner; Grimminger, Friedrich; Egemnazarov, Bakytbek; Shid-Moosavi, S Mostafa; Dehghani, Gholam A; Weissmann, Norbert; Sommer, Natascha

    2012-01-31

    Acute respiratory disorders may lead to sustained alveolar hypoxia with hypercapnia resulting in impaired pulmonary gas exchange. Hypoxic pulmonary vasoconstriction (HPV) optimizes gas exchange during local acute (0-30 min), as well as sustained (> 30 min) hypoxia by matching blood perfusion to alveolar ventilation. Hypercapnia with acidosis improves pulmonary gas exchange in repetitive conditions of acute hypoxia by potentiating HPV and preventing pulmonary endothelial dysfunction. This study investigated, if the beneficial effects of hypercapnia with acidosis are preserved during sustained hypoxia as it occurs, e.g in permissive hypercapnic ventilation in intensive care units. Furthermore, the effects of NO synthase inhibitors under such conditions were examined. We employed isolated perfused and ventilated rabbit lungs to determine the influence of hypercapnia with or without acidosis (pH corrected with sodium bicarbonate), and inhibitors of endothelial as well as inducible NO synthase on acute or sustained HPV (180 min) and endothelial permeability. In hypercapnic acidosis, HPV was intensified in sustained hypoxia, in contrast to hypercapnia without acidosis when HPV was amplified during both phases. L-NG-Nitroarginine (L-NNA), a non-selective NO synthase inhibitor, enhanced acute as well as sustained HPV under all conditions, however, the amplification of sustained HPV induced by hypercapnia with or without acidosis compared to normocapnia disappeared. In contrast 1400 W, a selective inhibitor of inducible NO synthase (iNOS), decreased HPV in normocapnia and hypercapnia without acidosis at late time points of sustained HPV and selectively reversed the amplification of sustained HPV during hypercapnia without acidosis. Hypoxic hypercapnia without acidosis increased capillary filtration coefficient (Kfc). This increase disappeared after administration of 1400 W. Hypercapnia with and without acidosis increased HPV during conditions of sustained hypoxia. The

  14. Effects of hypercapnia and NO synthase inhibition in sustained hypoxic pulmonary vasoconstriction

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    Ketabchi Farzaneh

    2012-01-01

    Full Text Available Abstract Background Acute respiratory disorders may lead to sustained alveolar hypoxia with hypercapnia resulting in impaired pulmonary gas exchange. Hypoxic pulmonary vasoconstriction (HPV optimizes gas exchange during local acute (0-30 min, as well as sustained (> 30 min hypoxia by matching blood perfusion to alveolar ventilation. Hypercapnia with acidosis improves pulmonary gas exchange in repetitive conditions of acute hypoxia by potentiating HPV and preventing pulmonary endothelial dysfunction. This study investigated, if the beneficial effects of hypercapnia with acidosis are preserved during sustained hypoxia as it occurs, e.g in permissive hypercapnic ventilation in intensive care units. Furthermore, the effects of NO synthase inhibitors under such conditions were examined. Method We employed isolated perfused and ventilated rabbit lungs to determine the influence of hypercapnia with or without acidosis (pH corrected with sodium bicarbonate, and inhibitors of endothelial as well as inducible NO synthase on acute or sustained HPV (180 min and endothelial permeability. Results In hypercapnic acidosis, HPV was intensified in sustained hypoxia, in contrast to hypercapnia without acidosis when HPV was amplified during both phases. L-NG-Nitroarginine (L-NNA, a non-selective NO synthase inhibitor, enhanced acute as well as sustained HPV under all conditions, however, the amplification of sustained HPV induced by hypercapnia with or without acidosis compared to normocapnia disappeared. In contrast 1400 W, a selective inhibitor of inducible NO synthase (iNOS, decreased HPV in normocapnia and hypercapnia without acidosis at late time points of sustained HPV and selectively reversed the amplification of sustained HPV during hypercapnia without acidosis. Hypoxic hypercapnia without acidosis increased capillary filtration coefficient (Kfc. This increase disappeared after administration of 1400 W. Conclusion Hypercapnia with and without acidosis

  15. MeSH-Informed Enrichment Analysis and MeSH-Guided Semantic Similarity Among Functional Terms and Gene Products in Chicken

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    Gota Morota

    2016-08-01

    Full Text Available Biomedical vocabularies and ontologies aid in recapitulating biological knowledge. The annotation of gene products is mainly accelerated by Gene Ontology (GO, and more recently by Medical Subject Headings (MeSH. Here, we report a suite of MeSH packages for chicken in Bioconductor, and illustrate some features of different MeSH-based analyses, including MeSH-informed enrichment analysis and MeSH-guided semantic similarity among terms and gene products, using two lists of chicken genes available in public repositories. The two published datasets that were employed represent (i differentially expressed genes, and (ii candidate genes under selective sweep or epistatic selection. The comparison of MeSH with GO overrepresentation analyses suggested not only that MeSH supports the findings obtained from GO analysis, but also that MeSH is able to further enrich the representation of biological knowledge and often provide more interpretable results. Based on the hierarchical structures of MeSH and GO, we computed semantic similarities among vocabularies, as well as semantic similarities among selected genes. These yielded the similarity levels between significant functional terms, and the annotation of each gene yielded the measures of gene similarity. Our findings show the benefits of using MeSH as an alternative choice of annotation in order to draw biological inferences from a list of genes of interest. We argue that the use of MeSH in conjunction with GO will be instrumental in facilitating the understanding of the genetic basis of complex traits.

  16. Ghrelin Increases Lymphocytes in Chronic Normobaric Hypoxia

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    Fariba Mirzaie Bavil

    2014-12-01

    Full Text Available Purpose: Hypoxia is a condition of decreased availability of oxygen. To adapt hypoxia, some changes in blood cells occur in the body. The aim of this study was to evaluate the effect of ghrelin on different types of blood cell in normobaric hypoxia situation. Methods: Thirty-two animals were divided in 4 groups (n=8: control (C, ghrelin (G, hypoxia (H, and hypoxic animals that received ghrelin (H+G. Hypoxia (11% was induced by an Environmental Chamber System GO2 Altitude. Animals in ghrelin groups received a subcutaneous injection of ghrelin (150 μg/kg/day for 14 days. Results: Our results show that ghrelin significantly (p<0.05 increased RBC and Hct levels, whereas it significantly (p<0.05 decreased lymphocytes in the blood. RBC, Hct, Hb concentration, platelet and MCV increased significantly (p<0.05 in hypoxic conditions but lymphocytes, monocytes and Polymorphonuclears did not show any significant changes. Platelets had a significant (p<0.05 decrease in hypoxic conditions and ghrelin administration in hypoxic conditions could increase lymphocyte levels significantly (p<0.05. Conclusion: Effect of ghrelin on blood cells could be related to blood oxygen level. Ghrelin in normal oxygen conditions increases RBC and Hct levels but decreases lymphocytes, whereas in hypoxic conditions, ghrelin increases blood lymphocytes.

  17. [Effects of acute hypoxia on plasma metabolome in mice].

    Science.gov (United States)

    Wang, Yu-ping; Guo, Chang-jiang; Yang, Ji-jun; Wei, Jing-yu; Zhang, Qi; Yan, Xian-zhong

    2009-05-01

    To explore the metabolic effects of acute hypoxia on mice plasma. Fourteen mice were randomly divided into two groups: control and hypoxia group. The mice of hypoxia group were exposed to a simulated altitude of 6000 meters for 8 hours. Nuclear magnetic resonance spectrometer was used to identify the metabolic changes after acute hypoxia. Compared with control, the most notable significantly after acute hypoxia exposure. remarkably and lactate increased metabolic changes in plasma were as follows: camrnitine decreased levels of lipids and pyruvate, alanine, taurine, Decreases in levels of beta-HB, ethanol glycerol, glutamate, glycine and serine, and increased choline, glucose, and glutamine were also observed in hypoxia group. Significant changes in the plasma carbohydrate, lipid and amino acid profiles were observed following acute hypoxia, suggesting a hypoxia-induced alteration in energy and related substances metabolism.

  18. Hypoxia Inhibits Hypertrophic Differentiation and Endochondral Ossification in Explanted Tibiae

    NARCIS (Netherlands)

    Leijten, Jeroen Christianus Hermanus; Moreira Teixeira, Liliana; Landman, Ellie; van Blitterswijk, Clemens; Karperien, Hermanus Bernardus Johannes

    2012-01-01

    Purpose: Hypertrophic differentiation of growth plate chondrocytes induces angiogenesis which alleviates hypoxia normally present in cartilage. In the current study, we aim to determine whether alleviation of hypoxia is merely a downstream effect of hypertrophic differentiation as previously

  19. Hypoxia in a neonate caused by intermittent positive pressure ventilation.

    OpenAIRE

    Beddis, I R; Silverman, M

    1980-01-01

    A newborn baby receiving mechanical ventilation was noted to have an extremely variable degree of hypoxia, despite the administration of 100% oxygen. The hypoxia was relieved rapidly when mechanical ventilation was withdrawn.

  20. SH2-catalytic domain linker heterogeneity influences allosteric coupling across the SFK family.

    Science.gov (United States)

    Register, A C; Leonard, Stephen E; Maly, Dustin J

    2014-11-11

    Src-family kinases (SFKs) make up a family of nine homologous multidomain tyrosine kinases whose misregulation is responsible for human disease (cancer, diabetes, inflammation, etc.). Despite overall sequence homology and identical domain architecture, differences in SH3 and SH2 regulatory domain accessibility and ability to allosterically autoinhibit the ATP-binding site have been observed for the prototypical SFKs Src and Hck. Biochemical and structural studies indicate that the SH2-catalytic domain (SH2-CD) linker, the intramolecular binding epitope for SFK SH3 domains, is responsible for allosterically coupling SH3 domain engagement to autoinhibition of the ATP-binding site through the conformation of the αC helix. As a relatively unconserved region between SFK family members, SH2-CD linker sequence variability across the SFK family is likely a source of nonredundant cellular functions between individual SFKs via its effect on the availability of SH3 and SH2 domains for intermolecular interactions and post-translational modification. Using a combination of SFKs engineered with enhanced or weakened regulatory domain intramolecular interactions and conformation-selective inhibitors that report αC helix conformation, this study explores how SH2-CD sequence heterogeneity affects allosteric coupling across the SFK family by examining Lyn, Fyn1, and Fyn2. Analyses of Fyn1 and Fyn2, isoforms that are identical but for a 50-residue sequence spanning the SH2-CD linker, demonstrate that SH2-CD linker sequence differences can have profound effects on allosteric coupling between otherwise identical kinases. Most notably, a dampened allosteric connection between the SH3 domain and αC helix leads to greater autoinhibitory phosphorylation by Csk, illustrating the complex effects of SH2-CD linker sequence on cellular function.

  1. Effect of chemokine receptor CXCR4 on hypoxia-induced pulmonary hypertension and vascular remodeling in rats

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    Hales Charles A

    2011-02-01

    Full Text Available Abstract Background CXCR4 is the receptor for chemokine CXCL12 and reportedly plays an important role in systemic vascular repair and remodeling, but the role of CXCR4 in development of pulmonary hypertension and vascular remodeling has not been fully understood. Methods In this study we investigated the role of CXCR4 in the development of pulmonary hypertension and vascular remodeling by using a CXCR4 inhibitor AMD3100 and by electroporation of CXCR4 shRNA into bone marrow cells and then transplantation of the bone marrow cells into rats. Results We found that the CXCR4 inhibitor significantly decreased chronic hypoxia-induced pulmonary hypertension and vascular remodeling in rats and, most importantly, we found that the rats that were transplanted with the bone marrow cells electroporated with CXCR4 shRNA had significantly lower mean pulmonary pressure (mPAP, ratio of right ventricular weight to left ventricular plus septal weight (RV/(LV+S and wall thickness of pulmonary artery induced by chronic hypoxia as compared with control rats. Conclusions The hypothesis that CXCR4 is critical in hypoxic pulmonary hypertension in rats has been demonstrated. The present study not only has shown an inhibitory effect caused by systemic inhibition of CXCR4 activity on pulmonary hypertension, but more importantly also has revealed that specific inhibition of the CXCR4 in bone marrow cells can reduce pulmonary hypertension and vascular remodeling via decreasing bone marrow derived cell recruitment to the lung in hypoxia. This study suggests a novel therapeutic approach for pulmonary hypertension by inhibiting bone marrow derived cell recruitment.

  2. Ionized gas, molecules and dust in Sh2-132

    Science.gov (United States)

    Vasquez, J.; Cappa, C. E.; Pineault, S.; Duronea, N. U.

    2010-07-01

    We analyse the various interstellar components of the HII region Sh2-132. The main stellar source is the double binary system that includes the Wolf-Rayet star WR153ab. We use radio continuum images at 408 and 1420 MHz, and HI 21-cm line data taken from the Canadian Galactic Plane Survey, molecular observations of the 12CO(1-0) line at 115GHz from the Five College Radio Astronomy Observatory, and available mid- and far-infrared observations obtained with the MSX and IRAS satellites, respectively. Sh2-132 is composed of two shells showing radio continuum counterparts at both frequencies. The emission is thermal in nature. The estimated rms electron density and ionized mass of the nebula are ne ~= 20cm-3 and . The distribution of the CO emission shows molecular gas bordering the ionized nebula and interacting with it. The velocities of the molecular gas is in the range -38 to -53kms-1, similar to the velocity of the ionized gas. The emission at 8.3μm reveals a ring-like feature of about 15arcmin that encircles the bright optical regions. This emission is due to the polycyclic aromatic hydrocarbons and marks the location of photodissociation regions. The gas distribution in the environs of Sh2-132 can be explained in a scenario where the massive stars in the region photodissociated, ionized and swept up the dense molecular material from the parental cloud through their strong stellar winds and intense ultraviolet (UV) photon flux.

  3. Nitric oxide and hypoxia signaling.

    Science.gov (United States)

    Jeffrey Man, H S; Tsui, Albert K Y; Marsden, Philip A

    2014-01-01

    Nitric oxide (NO) production is catalyzed by three distinct enzymes, namely, neuronal nitric oxide synthase (nNOS), inducible NOS (iNOS), and endothelial NOS (eNOS). The production of NO by vascular endothelium relies mainly on eNOS. Curiously, iNOS and nNOS also are relevant for vascular NO production in certain settings. By relaxing vascular smooth muscle, the classical view is that NO participates in O2 homeostasis by increasing local blood flow and O2 delivery. It is now appreciated that NO has an even more fundamental role in cellular oxygen sensing at the cellular and physiological level. A key component of cellular oxygen sensing is the hypoxia-inducible factor (HIF) that activates a transcriptional program to promote cellular survival under conditions of inadequate oxygen supply. Important new insights demonstrate that HIF protein is stabilized by two parallel pathways: (1) a decrease in the O2-dependent prolyl hydroxylation of HIF and (2) NO-dependent S-nitrosylation of HIF pathway components including HIF-α. The need for these two complementary pathways to HIF activation arises because decreased oxygen delivery can occur not only by decreased ambient oxygen but also by decreased blood oxygen-carrying capacity, as with anemia. In turn, NO production is tightly linked to O2 homeostasis. O2 is a key substrate for the generation of NO and impacts the enzymatic activity and expression of the enzymes that catalyze the production of NO, the nitric oxide synthases. These relationships manifest in a variety of clinical settings ranging from the unique situation of humans living in hypoxic environments at high altitudes to the common scenario of anemia and the use of therapeutics that can bind or release NO. © 2014 Elsevier Inc. All rights reserved.

  4. DSM complete synthetic seismograms: SH, spherically symmetric, case

    Science.gov (United States)

    Cummins, Phil R.; Geller, Robert J.; Hatori, Tomohiko; Takeuchi, Nozomu

    1994-04-01

    We present a new technique, based om the Direct Solution Method (DSM) (Geller et al., 1990; Hara et al., 1991; Geller and Ohminato, 1994), for calculating SH (toroidal) synthetic seismograms for spherically symmetric, isotropic, media. No asymptotic approximations are used and the synthetics, which fully include both body and surface waves, can be computed for a broad range of frequencies. Our algorithm accurately handles sources that require discontinuities in the vertically dependent part of the displacement. We use matrix operators that minimize the numerical error of the solutions. An example synthetic profile is presented for a 600km deep source in the IASP91 model for the period range 4-5000s.

  5. Star formation around the HII region Sh2-235

    OpenAIRE

    Kirsanova, M. S.; Sobolev, A. M.; Thomasson, M.; Wiebe, D. S.; Johansson, L. E. B.; Seleznev, A. F.

    2008-01-01

    We present a picture of star formation around the HII region Sh2-235 (S235) based upon data on the spatial distribution of young stellar clusters and the distribution and kinematics of molecular gas around S235. We observed 13CO(1-0) and CS(2-1) emission toward S235 with the Onsala Space Observatory 20-m telescope and analysed the star density distribution with archival data from the 2MASS survey. Dense molecular gas forms a shell-like structure at the south-eastern part of S235. The young cl...

  6. Overexpression of Hypoxia-Inducible Factor-1α Exacerbates Endothelial Barrier Dysfunction Induced by Hypoxia

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    Pei Wang

    2013-09-01

    Full Text Available Background/Aims: The mechanisms involved in endothelial barrier dysfunction induced by hypoxia are incompletely understood. There is debate about the role of hypoxia-inducible factor-1α (HIF-1α in endothelial barrier disruption. The aim of this study was to investigate the effect of genetic overexpression of HIF-1α on barrier function and the underlying mechanisms in hypoxic endothelial cells. Methods: The plasmid pcDNA3.1/V5-His-HIF-1α was stably transfected into human endothelial cells. The cells were exposed to normoxia or hypoxia. The mRNA and protein expressions of HIF-1α were detected by RT-PCR and Western blot respectively. The barrier function was assessed by measuring the transendothelial electrical resistance (TER. The Western blot analysis was used to determine the protein expression of glucose transporter-1 (GLUT-1, zonular occludens-1 (ZO-1, occludin, and myosin light chain kinase (MLCK in endothelial cells. The mRNA expression of proinflammatory cytokines was detected by qRT-PCR. Results: Genetic overexpression of HIF-1α significantly increased the mRNA and protein expression of HIF-1α in endothelial cells. The overexpression of HIF-1α enhanced the hypoxia-induced increase of HIF-1α and GLUT-1 protein expression. HIF-1α overexpression not only exacerbated hypoxia-induced endothelial barrier dysfunction but also augmented hypoxia-induced up-regulation of MLCK protein expression. HIF-1α overexpression also enhanced IL-1β, IL-6 and TNF-α mRNA expression. Conclusion: We provide evidence that genetic overexpression of HIF-1α aggravates the hypoxia-induced endothelial barrier dysfunction via enhancing the up-regulation of MLCK protein expression caused by hypoxia, suggesting a potential role for HIF-1α in the pathogenesis of endothelial barrier dysfunction in hypoxia.

  7. Hypoxia reduces arylsulfatase B activity and silencing arylsulfatase B replicates and mediates the effects of hypoxia.

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    Sumit Bhattacharyya

    Full Text Available This report presents evidence of 1 a role for arylsulfatase B (ARSB; N-acetylgalactosamine-4-sulfatase in mediating intracellular oxygen signaling; 2 replication between the effects of ARSB silencing and hypoxia on sulfated glycosaminoglycan content, cellular redox status, and expression of hypoxia-associated genes; and 3 a mechanism whereby changes in chondroitin-4-sulfation that follow either hypoxia or ARSB silencing can induce transcriptional changes through galectin-3. ARSB removes 4-sulfate groups from the non-reducing end of chondroitin-4-sulfate and dermatan sulfate and is required for their degradation. For activity, ARSB requires modification of a critical cysteine residue by the formylglycine generating enzyme and by molecular oxygen. When primary human bronchial and human colonic epithelial cells were exposed to 10% O(2 × 1 h, ARSB activity declined by ~41% and ~30% from baseline, as nuclear hypoxia inducible factor (HIF-1α increased by ~53% and ~37%. When ARSB was silenced, nuclear HIF-1α increased by ~81% and ~61% from baseline, and mRNA expression increased to 3.73 (± 0.34 times baseline. Inversely, ARSB overexpression reduced nuclear HIF-1α by ~37% and ~54% from baseline in the epithelial cells. Hypoxia, like ARSB silencing, significantly increased the total cellular sulfated glycosaminoglycans and chondroitin-4-sulfate (C4S content. Both hypoxia and ARSB silencing had similar effects on the cellular redox status and on mRNA expression of hypoxia-associated genes. Transcriptional effects of both ARSB silencing and hypoxia may be mediated by reduction in galectin-3 binding to more highly sulfated C4S, since the galectin-3 that co-immunoprecipitated with C4S declined and the nuclear galectin-3 increased following ARSB knockdown and hypoxia.

  8. Protective effect of salidroside on cardiac apoptosis in mice with chronic intermittent hypoxia.

    Science.gov (United States)

    Lai, Mei-Chih; Lin, Jaung-Geng; Pai, Pei-Ying; Lai, Mei-Hsin; Lin, Yueh-Min; Yeh, Yu-Lan; Cheng, Shiu-Min; Liu, Yi-fan; Huang, Chih-Yang; Lee, Shin-Da

    2014-07-01

    The goal of this study is to determine if salidroside has protective effects on hypoxia-induced cardiac widely dispersed apoptosis in mice with severe sleep apnea model. Sixty-four C57BL/6J mice 5-6 months of age were divided into four groups, i.e. Control group (21% O2, 24h per day, 8 weeks, n=16); Hypoxia group (Hypoxia: 7% O2 60s, 20% O2 alternating 60s, 8h per day, 8 weeks, n=16); and Hypoxia+S10 and Hypoxia+S 30 groups (Hypoxia for 1st 4 weeks, hypoxia pretreated 10mg/kg and 30 mg/kg salidroside by oral gavage per day for 2nd 4 weeks, n=16 and 16). The excised hearts from four groups were measured by the heart weight index, H&E staining, TUNEL-positive assays and Western blotting. TUNEL-positive apoptotic cells in mice heart were less in Hypoxia+S10 and Hypoxia+S30 than those in the Hypoxia group. Compared with Hypoxia, the protein levels of Fas ligand, Fas death receptors, Fas-Associated Death Domain (FADD), activated caspase 8, and activated caspase 3 (Fas pathways) were decreased in Hypoxia+S10 and Hypoxia+S30. In the mitochondria pathway, the protein levels of BcLx, Bcl2, and Bid (anti-apoptotic Bcl2 family) in Hypoxia+S10 and Hypoxia+S30 were more than those in Hypoxia. The protein levels of Bax, t-Bid, activated caspase 9, and activated caspase 3 were less in Hypoxia+S10 and Hypoxia+S30 than those in hypoxia. Our findings suggest that salidroside has protective effects on chronic intermittent hypoxia-induced Fas-dependent and mitochondria-dependent apoptotic pathways in mice hearts. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  9. Hypoxia as a therapy for mitochondrial disease.

    Science.gov (United States)

    Jain, Isha H; Zazzeron, Luca; Goli, Rahul; Alexa, Kristen; Schatzman-Bone, Stephanie; Dhillon, Harveen; Goldberger, Olga; Peng, Jun; Shalem, Ophir; Sanjana, Neville E; Zhang, Feng; Goessling, Wolfram; Zapol, Warren M; Mootha, Vamsi K

    2016-04-01

    Defects in the mitochondrial respiratory chain (RC) underlie a spectrum of human conditions, ranging from devastating inborn errors of metabolism to aging. We performed a genome-wide Cas9-mediated screen to identify factors that are protective during RC inhibition. Our results highlight the hypoxia response, an endogenous program evolved to adapt to limited oxygen availability. Genetic or small-molecule activation of the hypoxia response is protective against mitochondrial toxicity in cultured cells and zebrafish models. Chronic hypoxia leads to a marked improvement in survival, body weight, body temperature, behavior, neuropathology, and disease biomarkers in a genetic mouse model of Leigh syndrome, the most common pediatric manifestation of mitochondrial disease. Further preclinical studies are required to assess whether hypoxic exposure can be developed into a safe and effective treatment for human diseases associated with mitochondrial dysfunction. Copyright © 2016, American Association for the Advancement of Science.

  10. Oxygen-Loaded Nanodroplets Effectively Abrogate Hypoxia Dysregulating Effects on Secretion of MMP-9 and TIMP-1 by Human Monocytes

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    Giulia Rossana Gulino

    2015-01-01

    Full Text Available Monocytes play a key role in the inflammatory stage of the healing process. To allow monocyte migration to injured tissues, the balances between secreted matrix metalloproteinases (MMPs and their inhibitors (TIMPs must be finely modulated. However, a reduction of blood supply and local oxygen tension can modify the phenotype of immune cells. Intriguingly, hypoxia might be targeted by new effective oxygenating devices such as 2H,3H-decafluoropentane- (DFP- based oxygen-loaded nanodroplets (OLNs. Here, hypoxia effects on gelatinase/TIMP release from human peripheral monocytes were investigated, and the therapeutic potential of dextran-shelled OLNs was evaluated. Normoxic monocytes constitutively released ~500 ng/mL MMP-9, ~1.3 ng/mL TIMP-1, and ~0.6 ng/mL TIMP-2 proteins. MMP-2 was not detected. After 24 hours, hypoxia significantly altered MMP-9/TIMP-1 balance by reducing MMP-9 and increasing TIMP-1, without affecting TIMP-2 secretion. Interestingly OLNs, not displaying toxicity to human monocytes after cell internalization, effectively counteracted hypoxia, restoring a normoxia-like MMP-9/TIMP-1 ratio. The action of OLNs was specifically dependent on time-sustained oxygen diffusion up to 24 h from their DFP-based core. Therefore, OLNs appear as innovative, nonconventional, cost-effective, and nontoxic therapeutic tools, to be potentially employed to restore the physiological invasive phenotype of immune cells in hypoxia-associated inflammation.

  11. Nitric oxide-driven hypoxia initiates synovial angiogenesis, hyperplasia and inflammatory lesions in mice.

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    Fei Bao

    Full Text Available Rheumatoid arthritis (RA is an inflammatory articular disease with cartilage and bone damage due to hyperplasic synoviocyte invasion and subsequent matrix protease digestion. Although monoclonal antibodies against tumor necrosis factor alpha (TNFα have been approved for clinical use in patients with RA, desired therapeutic regimens suitable for non-responders are still unavailable because etiological initiators leading to RA remain enigmatic and unidentified.Bacteria-induced arthritis (BIA that simulates collagen-induced arthritis (CIA is developed in mice upon daily live bacterial feeding. The morphological lesions of paw erythema and edema together with the histological alterations of synovial hyperplasia and lymphocytic infiltration emerge as the early-phase manifestations of BIA and CIA. Bacteria- or collagen-mediated global upregulation of pro-inflammatory cytokines is accompanied by the burst of nitric oxide (NO. Elevation of the serum NO level is correlated with decline of the blood oxygen saturation percentage (SpO2, reflecting a hypoxic consequence during development towards arthritis. NO-driven hypoxia is further evident from a positive relationship between NO and lactic acid (LA, an end product from glycolysis. Upregulation of hypoxia inducible factor 1 alpha (HIF-1α and vascular endothelial growth factor (VEGF validates hypoxia-induced angiogenesis in the inflamed synovium of modeling mice. Administration of the NO donor compound sodium nitroprusside (SNP causes articular inflammation by inducing synovial hypoxia. Anti-bacteria by the antibiotic cefotaxime and/or the immunosuppressant rapamycin or artesunate that also inhibits nitric oxide synthase (NOS can abrogate NO production, mitigate hypoxia, and considerably ameliorate or even completely abort synovitis, hence highlighting that NO may serve as an initiator of inflammatory arthritis.Like collagen, bacteria also enable synovial lesions via upregulating pro

  12. Ezrin regulating the cytoskeleton remodelling is required for hypoxia-induced Myofibroblast proliferation and migration

    Directory of Open Access Journals (Sweden)

    Bin eYi

    2015-03-01

    Full Text Available Background: Hypoxia pulmonary arterial hypertension (HPAH is a disease of the small vessels characterized by sustained vasoconstriction, thickening of arterial walls, vascular remodelling, and progressive increase in pulmonary vascular resistance, thus leading to right heart failure and finally death. Recent evidence demonstrated that massive Pulmonary Artery Smooth Muscle-like Cells (PASMLCs accumulating in the intima might also be developed from the differentiation of Pulmonary Myofibroblast (PMF of tunica media. And PMF appeared the phenomenon of the cytoskeleton remodeling. So, it would be important in the clarification of the pivotal factors controlling this cytoskeleton structure change. Methods: PMFs were cultured from the normal rats and then divided into three groups and incubated by nomal or hypoxic conditions respectively. mRNA level was evaluated by real time reverse transcription polymerase chain reaction, and protein expression was detected by western blot. Cell proliferation was determined by the MTT and thymidine incorporation assay. Results: Here, we report that the hypoxia increased the expression levels of Ezrin mRNA and protein in PMFs, which might explain the expression of cytoskeletal proteins (Destrin, a1-actin, and a1-tubulin in PMFs was significantly induced by hypoxia. After inhibiting Ezrin in PMFs by siRNA transfection, we found the over-expression of cytoskeletal proteins induced by hypoixa were significantly suppressed at all time points. Additionally, we found that hypoxia or over-expression of Ezrin through Ad-Ezrin transfection significantly increases the proliferation and migration of PMFs, and which could be inverted by the transfection of siRNA. Conclusion: These findings suggest that Ezrin regulating of aberrant dysregulation of cytoskeletal proteins may be the major cause of PMFs' proliferation and migration under the condition of hypoxia and may, therefore, play a fundamental role in the accumulation of

  13. Homeostatic response to hypoxia is regulated by the N-end rule pathway in plants

    Science.gov (United States)

    Gibbs, Daniel J.; Lee, Seung Cho; Isa, Nurulhikma Md; Gramuglia, Silvia; Fukao, Takeshi; Bassel, George W.; Correia, Cristina Sousa; Corbineau, Françoise; Theodoulou, Frederica L.; Bailey-Serres, Julia; Holdsworth, Michael J.

    2011-01-01

    Plants and animals are obligate aerobes, requiring oxygen for mitochondrial respiration and energy production. In plants, an unanticipated decline in oxygen availability (hypoxia), as caused by root waterlogging or foliage submergence, triggers changes in gene transcription and mRNA translation that promote anaerobic metabolism and thus sustain substrate-level ATP production1. In contrast to animals2, oxygen sensing has not been ascribed to a mechanism of gene regulation in response to oxygen deprivation in plants. Here we show that the N-end rule pathway of targeted proteolysis acts as a homeostatic sensor of severe low oxygen in Arabidopsis, through its regulation of key hypoxia response transcription factors. We found that plants lacking components of the N-end rule pathway constitutively express core hypoxia response genes and are more tolerant of hypoxic stress. We identify the hypoxia-associated Ethylene Response Factor (ERF) Group VII transcription factors of Arabidopsis as substrates of this pathway. Regulation of these proteins by the N-end rule pathway occurs through a characteristic conserved motif at the N-terminus initiating with MetCys- (MC-). Enhanced stability of one of these proteins, HRE2, under low oxygen conditions improves hypoxia survival and reveals a molecular mechanism for oxygen sensing in plants via the evolutionarily conserved N-end rule pathway. SUB1A-1, a major determinant of submergence tolerance in rice3, was shown not to be a substrate for the N-end rule pathway despite containing the N-terminal motif, suggesting that it is uncoupled from N-end rule pathway regulation, and that enhanced stability may relate to the superior tolerance of Sub1 rice varieties to multiple abiotic stresses4. PMID:22020279

  14. 14-3-3 binding and phosphorylation of neuroglobin during hypoxia modulate six-to-five heme pocket coordination and rate of nitrite reduction to nitric oxide.

    Science.gov (United States)

    Jayaraman, Thottala; Tejero, Jesús; Chen, Bill B; Blood, Arlin B; Frizzell, Sheila; Shapiro, Calli; Tiso, Mauro; Hood, Brian L; Wang, Xunde; Zhao, Xuejun; Conrads, Thomas P; Mallampalli, Rama K; Gladwin, Mark T

    2011-12-09

    Neuroglobin protects neurons from hypoxia in vitro and in vivo; however, the underlying mechanisms for this effect remain poorly understood. Most of the neuroglobin is present in a hexacoordinate state with proximal and distal histidines in the heme pocket directly bound to the heme iron. At equilibrium, the concentration of the five-coordinate neuroglobin remains very low (0.1-5%). Recent studies have shown that post-translational redox regulation of neuroglobin surface thiol disulfide formation increases the open probability of the heme pocket and allows nitrite binding and reaction to form NO. We hypothesized that the equilibrium between the six- and five-coordinate states and secondary reactions with nitrite to form NO could be regulated by other hypoxia-dependent post-translational modification(s). Protein sequence models identified candidate sites for both 14-3-3 binding and phosphorylation. In both in vitro experiments and human SH-SY5Y neuronal cells exposed to hypoxia and glucose deprivation, we observed that 1) neuroglobin phosphorylation and protein-protein interactions with 14-3-3 increase during hypoxic and metabolic stress; 2) neuroglobin binding to 14-3-3 stabilizes and increases the half-life of phosphorylation; and 3) phosphorylation increases the open probability of the heme pocket, which increases ligand binding (CO and nitrite) and accelerates the rate of anaerobic nitrite reduction to form NO. These data reveal a series of hypoxia-dependent post-translational modifications to neuroglobin that regulate the six-to-five heme pocket equilibrium and heme access to ligands. Hypoxia-regulated reactions of nitrite and neuroglobin may contribute to the cellular adaptation to hypoxia.

  15. Sustainable Food & Sustainable Economics

    OpenAIRE

    Alvarez, Mavis Dora

    2012-01-01

    Cuba today is immersed in a very intense process of perfecting its agricultural production structures with the goal of making them more efficient and sustainable in their economic administration and in their social and environmental management. Agricultural cooperatives in Cuba have the responsibility of producing on 73% of the country's farmland. Their contributions are decisive to developing agricultural production and to ensuring more and better food for the population, in addition to redu...

  16. Current advances in the novel functions of hypoxia-inducible factor and prolyl hydroxylase in invertebrates.

    Science.gov (United States)

    Wang, L; Cui, S; Ma, L; Kong, L; Geng, X

    2015-12-01

    Oxygen is essential for aerobic life, and hypoxia has very severe consequences. Organisms need to overcome low oxygen levels to maintain biological functions during normal development and in disease states. The mechanism underlying the hypoxic response has been widely investigated in model animals such as Drosophila melanogaster and Caenorhabditis elegans. Hypoxia-inducible factor (HIF), a key gene product in the response to oxygen deprivation, is primarily regulated by prolyl hydroxylase domain enzymes (PHDs). However, recent findings have uncovered novel HIF-independent functions of PHDs. This review provides an overview of how invertebrates are able to sustain hypoxic damages, and highlights some recent discoveries in the regulation of cellular signalling by PHDs. Given that some core genes and major pathways are evolutionarily conserved, these research findings could provide insight into oxygen-sensitive signalling in mammals, and have biomedical implications for human diseases. © 2015 The Royal Entomological Society.

  17. Hypoxia-induced invadopodia formation involves activation of NHE-1 by the p90 ribosomal S6 kinase (p90RSK.

    Directory of Open Access Journals (Sweden)

    Fabrice Lucien

    Full Text Available The hypoxic and acidic microenvironments in tumors are strongly associated with malignant progression and metastasis, and have thus become a central issue in tumor physiology and cancer treatment. Despite this, the molecular links between acidic pH- and hypoxia-mediated cell invasion/metastasis remain mostly unresolved. One of the mechanisms that tumor cells use for tissue invasion is the generation of invadopodia, which are actin-rich invasive plasma membrane protrusions that degrade the extracellular matrix. Here, we show that hypoxia stimulates the formation of invadopodia as well as the invasive ability of cancer cells. Inhibition or shRNA-based depletion of the Na(+/H(+ exchanger NHE-1, along with intracellular pH monitoring by live-cell imaging, revealed that invadopodia formation is associated with alterations in cellular pH homeostasis, an event that involves activation of the Na(+/H(+ exchange rate by NHE-1. Further characterization indicates that hypoxia triggered the activation of the p90 ribosomal S6 kinase (p90 RSK, which resulted in invadopodia formation and site-specific phosphorylation and activation of NHE-1. This study reveals an unsuspected role of p90RSK in tumor cell invasion and establishes p90RS kinase as a link between hypoxia and the acidic microenvironment of tumors.

  18. Role of hypoxia and hypoxia inducible factor in physiological and pathological conditions

    Directory of Open Access Journals (Sweden)

    Mozhgan Jahani

    2017-11-01

    Full Text Available Introduction: Organisms are exposed to oxygen deprivation (Hypoxia in various physiological and pathological conditions. There are different conserve evolutionary responses to counterview with this stress that primary transcriptional response to stress related to hypoxia is interceded by hypoxia-inducible factor (HIF-1 in mammals. This factor can regulate different genes that have essential roles in adaptation to this condition. In this review, the role of this factor in physiological and pathological conditions under hypoxic condition has been evaluated after examining structural features and regulation characteristics of HIF-1. Methods: First, articles related to the keywords of hypoxia and HIF-1 (from 1991-2016 were searched from valid databases such as Springer Link, Google Scholar, PubMed and Science direct. Then, the articles correlated with hypoxia, HIF-1 and their roles in physiological and pathological conditions (120 articles were searched and just 64 articles were selected for this study. Result: According to studies, there are different genes in cells and organs that can be regulated by HIF-1. Activation of genes expression by this protein occurs through its linkage to cis-acting of 50 base pair hypoxia response element (HRE region located in their promotor and enhancer. Depending on circumstances, activation of these genes can be beneficial or harmful. Conclusion: Activation of different genes in hypoxia by HIF-1 has different effects on physiological and pathological conditions. Therefore, HIF-1, as a hypoxia-inducible factor in hypoxic conditions, plays an essential role in the adaptation of cells and organs to changes related to the presence of oxygen.

  19. Modulation of Muscle Fiber Compositions in Response to Hypoxia via Pyruvate Dehydrogenase Kinase-1

    Directory of Open Access Journals (Sweden)

    Daniel Nguyen

    2016-12-01

    Full Text Available Muscle fiber-type changes in hypoxic conditions in accordance with pyruvate dehydrogenase kinase (Pdk-1 and hypoxia inducible factor (Hif-1α were investigated in rats. Hif-1α and its down-stream molecule Pdk-1 are well known for readily response to hypoxia. We questioned their roles in relation to changes in myosin heavy chain (MyHC composition in skeletal muscles. We hypothesize that the level of Pdk-1 with respect to the level of Hif-1α determines MyHC composition of the muscle in rats in hypoxia. Young male rats were housed in a chamber maintained at 11.5% (for sustained hypoxia or fluctuating between 11.5% and 20.8% (for intermittent hypoxia or IH oxygen levels. Then, muscle tissues from the geniohyoid (GH, soleus, and anterior tibialis (TA were obtained at the end of hypoxic conditionings. After both hypoxic conditionings, protein levels of Pdk-1 and Hif-1 increased in GH muscles. GH muscles in acute sustained hypoxia favor an anaerobic glycolytic pathway, resulting in an increase in glycolytic MyHC IIb protein-rich fibers while maintain original fatigue-resistant MyHC IIa protein in the fibers; thus, the numbers of IIa- and IIb MyHC co-expressing fibers increased. Exogenous Pdk-1 over-expression using plasmid vectors elevated not only the glycolytic MyHC IIb, but also IIx as well as IIa expressions in C2C12 myotubes in ambient air significantly. The increase of dual expression of IIa- and IIb MyHC proteins in fibers harvested from the geniohyoid muscle has a potential to improve endurance as shown in our fatigability tests. By increasing the Pdk-1/Hif-1 ratio, a mixed-type muscle could alter endurance within the innate characteristics of the muscle toward more fatigue resistant. We conclude that an increased Pdk-1 level in skeletal muscle helps maintain MyHC compositions to be a fatigue resistant mixed-type muscle.

  20. A systematic study of labelling an α-helix in a protein with a lanthanide using IDA-SH or NTA-SH tags.

    Science.gov (United States)

    Yagi, Hiromasa; Maleckis, Ansis; Otting, Gottfried

    2013-02-01

    The previously published IDA-SH and NTA-SH tags are small synthetic lanthanide-binding tags derived from cysteine, which afford site-specific lanthanide labelling by disulfide-bond formation with a cysteine residue of the target protein. Following attachment to a single cysteine in an α-helix, sizeable pseudocontact shifts (PCS) can be observed, if the lanthanide is immobilized by additional coordination to a negatively charged amino-acid side chain that is located in a neighboring turn of the helix. To identify the best labelling strategy for PCS measurements, we performed a systematic study, where IDA-SH or NTA-SH tags were ligated to a cysteine residue in position i of an α-helix, and aspartate or glutamate residues were placed in the positions i - 4 or i + 4. The largest anisotropy components of the magnetic susceptibility tensor were observed for an NTA-SH tag in position i with a glutamate residue in position i - 4. While the NTA-SH tag produced sizeable PCSs regardless of the presence of nearby carboxyl groups of the protein, the IDA-SH tag generated a good lanthanide binding site only if an aspartate was placed in position i + 4. The findings provide a firm basis for the design of site-directed mutants that are suitable for the reliable generation of PCSs in proteins with paramagnetic lanthanides.

  1. Caudwell Xtreme Everest: A prospective study of the effects of environmental hypoxia on cognitive functioning.

    Directory of Open Access Journals (Sweden)

    Konstadina Griva

    Full Text Available The neuropsychological consequences of exposure to environmental hypobaric hypoxia (EHH remain unclear. We thus investigated them in a large group of healthy volunteers who trekked to Mount Everest base camp (5,300 m.A neuropsychological (NP test battery assessing memory, language, attention, and executive function was administered to 198 participants (age 44.5±13.7 years; 60% male. These were studied at baseline (sea level, 3,500 m (Namche Bazaar, 5,300 m (Everest Base Camp and on return to 1,300 m (Kathmandu (attrition rate 23.7%. A comparable control group (n = 25; age 44.5±14.1 years; 60% male for comparison with trekkers was tested at/or near sea level over an equivalent timeframe so as to account for learning effects associated with repeat testing. The Reliable Change Index (RCI was used to calculate changes in cognition and neuropsychological function during and after exposure to EHH relative to controls.Overall, attention, verbal ability and executive function declined in those exposed to EHH when the performance of the control group was taken into account (RCI .05 to -.95 with decline persisting at descent. Memory and psychomotor function showed decline at highest ascent only (RCI -.08 to -.56. However, there was inter-individual variability in response: whilst NP performance declined in most, this improved in some trekkers. Cognitive decline was greater amongst older people (r = .42; p < .0001, but was otherwise not consistently associated with socio-demographic, mood, or physiological variables.After correcting for learning effects, attention, verbal abilities and executive functioning declined with exposure to EHH. There was considerable individual variability in the response of brain function to sustained hypoxia with some participants not showing any effects of hypoxia. This might have implications for those facing sustained hypoxia as a result of any disease.

  2. Tumor hypoxia: Impact on gene amplification in glioblastoma.

    Science.gov (United States)

    Fischer, Ulrike; Radermacher, Jens; Mayer, Jens; Mehraein, Yasmin; Meese, Eckart

    2008-09-01

    Gene amplification is frequently found in human glioblastoma but the mechanisms driving amplifications remain to be elucidated. Hypoxia as hallmark of glioblastoma is known to be involved in the induction of fragile sites that are central to gene amplification. We analyzed the potential of hypoxia (pO2 0%) and mini hypoxia (pO2 5%) to induce fragile sites within a homogeneously staining region (HSR) at 12q14-15 in a glioblastoma cell line (TX3868). Treatment of cells by hypoxia or by mini hypoxia induced double minutes (DMs) and caused breakage of the HSR structure at 12q14-15, suggesting a novel hypoxia inducible fragile site on 12q. Treatment with aphidicolin, a known fragile site inducer, indicates that the hypoxia inducible fragile site is a common fragile site. Reintegration of amplified sequences and occurrence of anaphase-bridge-like structures shows that mini hypoxia and hypoxia are able to initiate amplification processes in human glioblastoma cells. Hypoxia as known tumor microenvironment factor is crucial for the development of amplifications in glioblastoma. The identification and characterization of novel common fragile sites induced by hypoxia will improve the understanding of mechanisms underlying amplifications in glioblastoma.

  3. Frequently asked questions in hypoxia research

    Directory of Open Access Journals (Sweden)

    Wenger RH

    2015-09-01

    Full Text Available Roland H Wenger,1,2 Vartan Kurtcuoglu,1,2 Carsten C Scholz,1,2 Hugo H Marti,3 David Hoogewijs1,2,4 1Institute of Physiology and Zurich Center for Human Physiology (ZIHP, University of Zurich, 2National Center of Competence in Research “Kidney.CH”, Zurich, Switzerland; 3Institute of Physiology and Pathophysiology, University of Heidelberg, Heidelberg, 4Institute of Physiology, University of Duisburg-Essen, Essen, Germany Abstract: “What is the O2 concentration in a normoxic cell culture incubator?” This and other frequently asked questions in hypoxia research will be answered in this review. Our intention is to give a simple introduction to the physics of gases that would be helpful for newcomers to the field of hypoxia research. We will provide background knowledge about questions often asked, but without straightforward answers. What is O2 concentration, and what is O2 partial pressure? What is normoxia, and what is hypoxia? How much O2 is experienced by a cell residing in a culture dish in vitro vs in a tissue in vivo? By the way, the O2 concentration in a normoxic incubator is 18.6%, rather than 20.9% or 20%, as commonly stated in research publications. And this is strictly only valid for incubators at sea level. Keywords: gas laws, hypoxia-inducible factor, Krogh tissue cylinder, oxygen diffusion, partial pressure, tissue oxygen levels

  4. Hypoxia and Angiogenesis in Endometrioid Endometrial Carcinogenesis

    Directory of Open Access Journals (Sweden)

    Nicole Horrée

    2007-01-01

    Full Text Available Background: Hypoxia-inducible factor 1α (HIF-1α plays an essential role in the adaptive response of cells to hypoxia, triggering biologic events associated with aggressive tumor behavior. Methods: Expression of HIF-1α and proteins in the HIF-1α pathway (Glut-1, CAIX, VEGF in paraffin-embedded specimens of normal (n = 17, premalignant (n = 17 and endometrioid endometrial carcinoma (n = 39 was explored by immunohistochemistry, in relation to microvessel density (MVD. Results: HIF-1α overexpression was absent in inactive endometrium but present in hyperplasia (61% and carcinoma (87%, with increasing expression in a perinecrotic fashion pointing to underlying hypoxia. No membranous expression of Glut-1 and CAIX was noticed in inactive endometrium, in contrast with expression in hyperplasia (Glut-1 0%, CAIX 61%, only focal and diffuse and carcinoma (Glut-1 94.6%, CAIX 92%, both mostly perinecrotically. Diffuse HIF-1α was accompanied by activation of downstream targets. VEGF was significantly higher expressed in hyperplasias and carcinomas compared to inactive endometrium. MVD was higher in hyperplasias and carcinomas than in normal endometrium (p < 0.001. Conclusion: HIF-1α and its downstream genes are increasingly expressed from normal through premalignant to endometrioid adenocarcinoma of the endometrium, paralleled by activation of its downstream genes and increased angiogenesis. This underlines the potential importance of hypoxia and its key regulator HIF-1α in endometrial carcinogenesis.

  5. Human erythropoietin response to hypocapnic hypoxia, normocapnic hypoxia, and hypocapnic normoxia

    DEFF Research Database (Denmark)

    Klausen, T; Christensen, H; Hansen, J M

    1996-01-01

    by hyperventilation of room air, elicited a normoxic increase in the haemoglobin oxygen affinity without changing serum-EPO. Among the measured blood gas and acid-base parameters, only the partial pressures of oxygen in arterial blood during hypocapnic hypoxia were related to the peak values of serum-EPO (r = -0...... exposed to 2 h each of hypocapnic hypoxia, normocapnic hypoxia, hypocapnic normoxia, and normal breathing of room air (control experiment). During the control experiment, serum-EPO showed significant variations (ANOVA P = 0.047) with a 15% increase in mean values. The serum-EPO measured in the other...... experiments were corrected for these spontaneous variations in each individual. At 2 h after ending hypocapnic hypoxia (10% O2 in nitrogen), mean serum-EPO increased by 28% [baseline 8.00 (SEM 0.84) U.l-1, post-hypoxia 10.24 (SEM 0.95) U.l-1, P = 0.005]. Normocapnic hypoxia was produced by the addition of CO2...

  6. Adipose Tissue Hypoxia in Obesity and Its Impact on Preadipocytes and Macrophages: Hypoxia Hypothesis.

    Science.gov (United States)

    Engin, Atilla

    2017-01-01

    Obese subjects exhibit lower adipose tissue oxygen consumption in accordance with the lower adipose tissue blood flow. Thus, compared with lean subjects, obese subjects have 44% lower capillary density and 58% lower vascular endothelial growth factor (VEGF). The VEGF expression together with hypoxia-inducible transcription factor-1 (HIF-1) activity also requires phosphatidylinositol 3-kinase (PI3K)- and target of rapamycin (TOR)-mediated signaling. HIF-1alpha is an important signaling molecule for hypoxia to induce the inflammatory responses. Hypoxia affects a number of biological functions, such as angiogenesis, cell proliferation, apoptosis, inflammation and insulin resistance. Additionally, reactive oxygen radical (ROS) generation at mitochondria is responsible for propagation of the hypoxic signal. Actually mitochondrial ROS (mtROS) production, but not oxygen consumption is required for hypoxic HIF-1alpha protein stabilization. Adipocyte mitochondrial oxidative capacity is reduced in obese compared with non-obese adults. In this respect, mitochondrial dysfunction of adipocyte is associated with the overall adiposity. Furthermore, hypoxia also inhibits macrophage migration from the hypoxic adipose tissue. Alterations in oxygen availability of adipose tissue directly affect the macrophage polarization and are responsible from dysregulated adipocytokines production in obesity. Hypoxia also inhibits adipocyte differentiation from preadipocytes. In addition to stressed adipocytes, hypoxia contributes to immune cell immigration and activation which further aggravates adipose tissue fibrosis. Fibrosis is initiated in response to adipocyte hypertrophy in obesity.

  7. French MeSH Browser: a cross-language tool to access MEDLINE/PubMed.

    Science.gov (United States)

    Thirion, Benoit; Pereira, Susanne; Névéol, Aurélie; Dahamna, Badisse; Darmoni, Stéfan

    2007-10-11

    When searching the medical literature, health professionals and lay people strongly prefer to use their native language. Therefore, Medical Subject Headings (MeSH) translations would be helpful to those who are not fluent in English to access scientific papers indexed in the MEDLINE bibliographic database. Furthermore, medical terminologies such as MeSH are challenging in any language. In this context, a French MeSH Browser was developed.

  8. Erythropoietin enhances mitochondrial biogenesis in cardiomyocytes exposed to chronic hypoxia through Akt/eNOS signalling pathway.

    Science.gov (United States)

    Qin, Chuan; Zhou, Shengkai; Xiao, Yingbin; Chen, Lin

    2014-03-01

    Adaptation of cardiomyocytes to chronic hypoxia in cyanotic patients remains unclear. Mitochondrial biogenesis is enhanced in myocardium from cyanotic patients, which is possibly an adaptive response. Erythropoietin (EPO) in blood and its receptor (EPOR) on cardiomyocytes are upregulated by chronic hypoxia, suggesting that EPO-EPOR interaction is increased, which is inferred to positively regulate mitochondrial biogenesis through protein kinase B (Akt)/endothelial nitric oxide synthase (eNOS) signalling pathway. H9c2 cardiomyocytes were exposed to hypoxia (1% O(2)) for 1 week and treated with different doses of recombinant human erythropoietin (rhEPO). Mitochondrial number, mitochondrial DNA (mtDNA) copy number and peroxisome proliferator activated receptor gamma coactivator alpha (PGC-1α) mRNA expression increased in a dose-dependent manner induced by rhEPO. Akt and eNOS were significantly phosphorylated by rhEPO. Both blocking Akt with Wortmannin and silencing eNOS expression with shRNA plasmid decreased the mtDNA copy number and PGC-1α mRNA expression induced by rhEPO. Blocking Akt was associated with the decreased phosphorylation of Akt and eNOS. RNA interference led to a reduction in the total and phosphorylated proteins of eNOS. Thus EPO enhances mitochondrial biogenesis in cardiomyocytes exposed to chronic hypoxia, at least partly through Akt/eNOS signalling, which might be an adaptive mechanism of cardiomyocytes associated with the increased EPO-EPOR interaction in patients with cyanotic congenital heart disease (CCHD). © 2013 International Federation for Cell Biology.

  9. Differential Sensitivity of Src-Family Kinases to Activation by SH3 Domain Displacement

    Science.gov (United States)

    Moroco, Jamie A.; Craigo, Jodi K.; Iacob, Roxana E.; Wales, Thomas E.; Engen, John R.; Smithgall, Thomas E.

    2014-01-01

    Src-family kinases (SFKs) are non-receptor protein-tyrosine kinases involved in a variety of signaling pathways in virtually every cell type. The SFKs share a common negative regulatory mechanism that involves intramolecular interactions of the SH3 domain with the PPII helix formed by the SH2-kinase linker as well as the SH2 domain with a conserved phosphotyrosine residue in the C-terminal tail. Growing evidence suggests that individual SFKs may exhibit distinct activation mechanisms dictated by the relative strengths of these intramolecular interactions. To elucidate the role of the SH3:linker interaction in the regulation of individual SFKs, we used a synthetic SH3 domain-binding peptide (VSL12) to probe the sensitivity of downregulated c-Src, Hck, Lyn and Fyn to SH3-based activation in a kinetic kinase assay. All four SFKs responded to VSL12 binding with enhanced kinase activity, demonstrating a conserved role for SH3:linker interaction in the control of catalytic function. However, the sensitivity and extent of SH3-based activation varied over a wide range. In addition, autophosphorylation of the activation loops of c-Src and Hck did not override regulatory control by SH3:linker displacement, demonstrating that these modes of activation are independent. Our results show that despite the similarity of their downregulated conformations, individual Src-family members show diverse responses to activation by domain displacement which may reflect their adaptation to specific signaling environments in vivo. PMID:25144189

  10. Differential sensitivity of Src-family kinases to activation by SH3 domain displacement.

    Directory of Open Access Journals (Sweden)

    Jamie A Moroco

    Full Text Available Src-family kinases (SFKs are non-receptor protein-tyrosine kinases involved in a variety of signaling pathways in virtually every cell type. The SFKs share a common negative regulatory mechanism that involves intramolecular interactions of the SH3 domain with the PPII helix formed by the SH2-kinase linker as well as the SH2 domain with a conserved phosphotyrosine residue in the C-terminal tail. Growing evidence suggests that individual SFKs may exhibit distinct activation mechanisms dictated by the relative strengths of these intramolecular interactions. To elucidate the role of the SH3:linker interaction in the regulation of individual SFKs, we used a synthetic SH3 domain-binding peptide (VSL12 to probe the sensitivity of downregulated c-Src, Hck, Lyn and Fyn to SH3-based activation in a kinetic kinase assay. All four SFKs responded to VSL12 binding with enhanced kinase activity, demonstrating a conserved role for SH3:linker interaction in the control of catalytic function. However, the sensitivity and extent of SH3-based activation varied over a wide range. In addition, autophosphorylation of the activation loops of c-Src and Hck did not override regulatory control by SH3:linker displacement, demonstrating that these modes of activation are independent. Our results show that despite the similarity of their downregulated conformations, individual Src-family members show diverse responses to activation by domain displacement which may reflect their adaptation to specific signaling environments in vivo.

  11. Multiple shRNA combinations for near-complete coverage of all HIV-1 strains

    Directory of Open Access Journals (Sweden)

    Tran Anna

    2011-01-01

    Full Text Available Abstract Background Combinatorial RNA interference (co-RNAi approaches are needed to account for viral variability in treating HIV-1 with RNAi, as single short hairpin RNAs (shRNA are rapidly rendered ineffective by resistant strains. Current work suggests that 4 simultaneously expressed shRNAs may prevent the emergence of resistant strains. Results In this study we assembled combinations of highly-conserved shRNAs to target as many HIV-1 strains as possible. We analyzed intersecting conservations of 10 shRNAs to find combinations with 4+ matching the maximum number of strains using 1220+ HIV-1 sequences from the Los Alamos National Laboratory (LANL. We built 26 combinations of 2 to 7 shRNAs with up to 87% coverage for all known strains and 100% coverage of clade B subtypes, and characterized their intrinsic suppressive activities in transient expression assays. We found that all combinations had high combined suppressive activities, though there were also large changes in the individual activities of the component shRNAs in our multiple expression cassette configurations. Conclusion By considering the intersecting conservations of shRNA combinations we have shown that it is possible to assemble combinations of 6 and 7 highly active, highly conserved shRNAs such that there is always at least 4 shRNAs within each combination covering all currently known variants of entire HIV-1 subtypes. By extension, it may be possible to combine several combinations for complete global coverage of HIV-1 variants.

  12. Structural characterization of CAS SH3 domain selectivity and regulation reveals new CAS interaction partners.

    Science.gov (United States)

    Gemperle, Jakub; Hexnerová, Rozálie; Lepšík, Martin; Tesina, Petr; Dibus, Michal; Novotný, Marian; Brábek, Jan; Veverka, Václav; Rosel, Daniel

    2017-08-14

    CAS is a docking protein downstream of the proto-oncogene Src with a role in invasion and metastasis of cancer cells. The CAS SH3 domain is indispensable for CAS-mediated signaling, but structural aspects of CAS SH3 ligand binding and regulation are not well understood. Here, we identified the consensus CAS SH3 binding motif and structurally characterized the CAS SH3 domain in complex with ligand. We revealed the requirement for an uncommon centrally localized lysine residue at position +2 of CAS SH3 ligands and two rather dissimilar optional anchoring residues, leucine and arginine, at position +5. We further expanded the knowledge of CAS SH3 ligand binding regulation by manipulating tyrosine 12 phosphorylation and confirmed the negative role of this phosphorylation on CAS SH3 ligand binding. Finally, by exploiting the newly identified binding requirements of the CAS SH3 domain, we predicted and experimentally verified two novel CAS SH3 binding partners, DOK7 and GLIS2.

  13. Interaction between human BAP31 and respiratory syncytial virus small hydrophobic (SH) protein

    Energy Technology Data Exchange (ETDEWEB)

    Li, Yan; Jain, Neeraj; Limpanawat, Suweeraya; To, Janet [School of Biological Sciences, Nanyang Technological University, 637551 (Singapore); Quistgaard, Esben M. [Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm (Sweden); Nordlund, Par [School of Biological Sciences, Nanyang Technological University, 637551 (Singapore); Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm (Sweden); Thanabalu, Thirumaran [School of Biological Sciences, Nanyang Technological University, 637551 (Singapore); Torres, Jaume, E-mail: jtorres@ntu.edu.sg [School of Biological Sciences, Nanyang Technological University, 637551 (Singapore)

    2015-08-15

    The small hydrophobic (SH) protein is a short channel-forming polypeptide encoded by the human respiratory syncytial virus (hRSV). Deletion of SH protein leads to the viral attenuation in mice and primates, and delayed apoptosis in infected cells. We have used a membrane-based yeast two-hybrid system (MbY2H) and a library from human lung cDNA to detect proteins that bind SH protein. This led to the identification of a membrane protein, B-cell associated protein 31 (BAP31). Transfected SH protein co-localizes with transfected BAP31 in cells, and pulls down endogenous BAP31. Titration of purified C-terminal endodomain of BAP31 against isotopically labeled SH protein in detergent micelles suggests direct interaction between the two proteins. Given the key role of BAP31 in protein trafficking and its critical involvement in pro- and anti-apoptotic pathways, this novel interaction may constitute a potential drug target. - Highlights: • A yeast two-hybrid system (MbY2H) detected BAP31 as a binder of RSV SH protein. • Transfected SH and BAP31 co-localize in lung epithelial cells. • Endogenous BAP31 is pulled down by RSV SH protein. • BAP31 endodomain interacts with the N-terminal α-helix of SH protein in micelles. • This interaction is proposed to be a potential drug target.

  14. S.H. and others v. Austria and circumvention tourism.

    Science.gov (United States)

    Glenn Cohen, I

    2012-12-01

    This commentary discusses the decision in S.H. and Others v. Austria from a political theoretical and bioethical perspective. I focus on the opinion's discussion of what I call 'circumvention tourism', travelling abroad for the purpose of circumventing domestic prohibitions, especially as to medical services. The majority opinion in the case touts Austria's allowance of circumvention tourism for reproductive technology services that are illegal on Austrian soil as a reason to find as lawful Austria's prohibition on using those services on Austrian soil. To the contrary, I show that, in many ways, permitting circumvention tourism for these services while prohibiting them domestically is deeply problematic. Copyright © 2012 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

  15. Analysis of the genetic variability of the mumps SH gene in viruses circulating in the UK between 1996 and 2005.

    Science.gov (United States)

    Cui, Aili; Myers, Richard; Xu, Wenbo; Jin, Li

    2009-01-01

    Genetic analysis (genotyping) of mumps viruses has been applied to the molecular epidemiology of mumps for over 10 years in the UK. To explore further the variation of mumps strains over time, in total, 965 sequences of the entire SH gene were analysed and compared, including 954 mumps virus strains collected in the UK between 1996 and 2005 were characterised as genotypes G2 (426), G5 (369), J (157) and F (2), which were compared with 11 F sequences found in China. Phylogenetic trees drawn for G2, G5 and J sequences showed that the diversities were greater between the sequences in earlier years (before 2001/2002) than those in later years and could be divided into two clusters within each of the three genotypes over the 10-year period. One transmission of G2, G5 and a J strain was sustained from earlier years with mutations and eventually became predominant strains. Divergences amongst the same genotype or sub-genotype was up to 4.6% for G2, 5.3% for G5 and 4.9% for J. Mutation rates per site per year based on the 316nt of SH gene were 0.94, 1.3, 0.96 and 1.86 x 10(-2) for G2, G5, J and F respectively. The ratio of d(N)/d(S) was 0.556, 0.909, 0.357 and 0.811 calculated based on the sequences of G2, G5, J and F respectively. The results revealed that the possible mumps evolution process based on the SH gene was not driven by positive selection during the 10 years between 1996 and 2005.

  16. Hepatocyte Hypoxia Inducible Factor-1 Mediates the Development of Liver Fibrosis in a Mouse Model of Nonalcoholic Fatty Liver Disease.

    Directory of Open Access Journals (Sweden)

    Omar A Mesarwi

    Full Text Available Obstructive sleep apnea (OSA is associated with the progression of non-alcoholic fatty liver disease (NAFLD to steatohepatitis and fibrosis. This progression correlates with the severity of OSA-associated hypoxia. In mice with diet induced obesity, hepatic steatosis leads to liver tissue hypoxia, which worsens with exposure to intermittent hypoxia. Emerging data has implicated hepatocyte cell signaling as an important factor in hepatic fibrogenesis. We hypothesized that hepatocyte specific knockout of the oxygen sensing α subunit of hypoxia inducible factor-1 (HIF-1, a master regulator of the global response to hypoxia, may be protective against the development of liver fibrosis.Wild-type mice and mice with hepatocyte-specific HIF-1α knockout (Hif1a-/-hep were fed a high trans-fat diet for six months, as a model of NAFLD. Hepatic fibrosis was evaluated by Sirius red stain and hydroxyproline assay. Liver enzymes, fasting insulin, and hepatic triglyceride content were also assessed. Hepatocytes were isolated from Hif1a-/-hep mice and wild-type controls and were exposed to sustained hypoxia (1% O2 or normoxia (16% O2 for 24 hours. The culture media was used to reconstitute type I collagen and the resulting matrices were examined for collagen cross-linking.Wild-type mice on a high trans-fat diet had 80% more hepatic collagen than Hif1a-/-hep mice (2.21 μg collagen/mg liver tissue, versus 1.23 μg collagen/mg liver tissue, p = 0.03, which was confirmed by Sirius red staining. Body weight, liver weight, mean hepatic triglyceride content, and fasting insulin were similar between groups. Culture media from wild-type mouse hepatocytes exposed to hypoxia allowed for avid collagen cross-linking, but very little cross-linking was seen when hepatocytes were exposed to normoxia, or when hepatocytes from Hif1a-/-hep mice were used in hypoxia or normoxia.Hepatocyte HIF-1 mediates an increase in liver fibrosis in a mouse model of NAFLD, perhaps due to liver

  17. Criteria for effective design, construction, and gene knockdown by shRNA vectors

    Directory of Open Access Journals (Sweden)

    Lich John D

    2006-01-01

    Full Text Available Abstract Background RNA interference (RNAi technology is a powerful methodology recently developed for the specific knockdown of targeted genes. RNAi is most commonly achieved either transiently by transfection of small interfering (si RNA oligonucleotides, or stably using short hairpin (sh RNA expressed from a DNA vector or virus. Much controversy has surrounded the development of rules for the design of effective siRNA oligonucleotides; and whether these rules apply to shRNA is not well characterized. Results To determine whether published algorithms for siRNA oligonucleotide design apply to shRNA, we constructed 27 shRNAs from 11 human genes expressed stably using retroviral vectors. We demonstrate an efficient method for preparing wild-type and mutant control shRNA vectors simultaneously using oligonucleotide hybrids. We show that sequencing through shRNA vectors can be problematic due to the intrinsic secondary structure of the hairpin, and we determine a strategy for effective sequencing by using a combination of modified BigDye chemistries and DNA relaxing agents. The efficacy of knockdown for the 27 shRNA vectors was evaluated against six published algorithms for siRNA oligonucleotide design. Our results show that none of the scoring algorithms can explain a significant percentage of variance in shRNA knockdown efficacy as assessed by linear regression analysis or ROC curve analysis. Application of a modification based on the stability of the 6 central bases of each shRNA provides fair-to-good predictions of knockdown efficacy for three of the algorithms. Analysis of an independent set of data from 38 shRNAs pooled from previous publications confirms these findings. Conclusion The use of mixed oligonucleotide pairs provides a time and cost efficient method of producing wild type and mutant control shRNA vectors. The addition to sequencing reactions of a combination of mixed dITP/dGTP chemistries and DNA relaxing agents enables read

  18. Selective Targeting of SH2 Domain–Phosphotyrosine Interactions of Src Family Tyrosine Kinases with Monobodies

    Energy Technology Data Exchange (ETDEWEB)

    Kükenshöner, Tim; Schmit, Nadine Eliane; Bouda, Emilie; Sha, Fern; Pojer, Florence; Koide, Akiko; Seeliger, Markus; Koide, Shohei; Hantschel, Oliver

    2017-05-01

    The binding of Src-homology 2 (SH2) domains to phosphotyrosine (pY) sites is critical for the autoinhibition and substrate recognition of the eight Src family kinases (SFKs). The high sequence conservation of the 120 human SH2 domains poses a significant challenge to selectively perturb the interactions of even the SFK SH2 family against the rest of the SH2 domains. We have developed synthetic binding proteins, termed monobodies, for six of the SFK SH2 domains with nanomolar affinity. Most of these monobodies competed with pY ligand binding and showed strong selectivity for either the SrcA (Yes, Src, Fyn, Fgr) or SrcB subgroup (Lck, Lyn, Blk, Hck). Interactome analysis of intracellularly expressed monobodies revealed that they bind SFKs but no other SH2-containing proteins. Three crystal structures of monobody–SH2 complexes unveiled different and only partly overlapping binding modes, which rationalized the observed selectivity and enabled structure-based mutagenesis to modulate inhibition mode and selectivity. In line with the critical roles of SFK SH2 domains in kinase autoinhibition and T-cell receptor signaling, monobodies binding the Src and Hck SH2 domains selectively activated respective recombinant kinases, whereas an Lck SH2-binding monobody inhibited proximal signaling events downstream of the T-cell receptor complex. Our results show that SFK SH2 domains can be targeted with unprecedented potency and selectivity using monobodies. They are excellent tools for dissecting SFK functions in normal development and signaling and to interfere with aberrant SFK signaling networks in cancer cells.

  19. Hypoxia-inducible factor-1α plays roles in Epstein-Barr virus's natural life cycle and tumorigenesis by inducing lytic infection through direct binding to the immediate-early BZLF1 gene promoter.

    Directory of Open Access Journals (Sweden)

    Richard J Kraus

    2017-06-01

    Full Text Available When confronted with poor oxygenation, cells adapt by activating survival signaling pathways, including the oxygen-sensitive transcriptional regulators called hypoxia-inducible factor alphas (HIF-αs. We report here that HIF-1α also regulates the life cycle of Epstein-Barr virus (EBV. Incubation of EBV-positive gastric carcinoma AGS-Akata and SNU-719 and Burkitt lymphoma Sal and KemIII cell lines with a prolyl hydroxylase inhibitor, L-mimosine or deferoxamine, or the NEDDylation inhibitor MLN4924 promoted rapid and sustained accumulation of both HIF-1α and lytic EBV antigens. ShRNA knockdown of HIF-1α significantly reduced deferoxamine-mediated lytic reactivation. HIF-1α directly bound the promoter of the EBV primary latent-lytic switch BZLF1 gene, Zp, activating transcription via a consensus hypoxia-response element (HRE located at nt -83 through -76 relative to the transcription initiation site. HIF-1α did not activate transcription from the other EBV immediate-early gene, BRLF1. Importantly, expression of HIF-1α induced EBV lytic-gene expression in cells harboring wild-type EBV, but not in cells infected with variants containing base-pair substitution mutations within this HRE. Human oral keratinocyte (NOK and gingival epithelial (hGET cells induced to differentiate by incubation with either methyl cellulose or growth in organotypic culture accumulated both HIF-1α and Blimp-1α, another cellular factor implicated in lytic reactivation. HIF-1α activity also accumulated along with Blimp-1α during B-cell differentiation into plasma cells. Furthermore, most BZLF1-expressing cells observed in lymphomas induced by EBV in NSG mice with a humanized immune system were located distal to blood vessels in hypoxic regions of the tumors. Thus, we conclude that HIF-1α plays central roles in both EBV's natural life cycle and EBV-associated tumorigenesis. We propose that drugs that induce HIF-1α protein accumulation are good candidates for

  20. Hypoxia-inducible factor-1α plays roles in Epstein-Barr virus’s natural life cycle and tumorigenesis by inducing lytic infection through direct binding to the immediate-early BZLF1 gene promoter

    Science.gov (United States)

    Kraus, Richard J.; Cordes, Blue-leaf A.; Nawandar, Dhananjay M.; Ma, Shidong; McChesney, Kyle G.; Lin, Zhen; Makielski, Kathleen R.; Lee, Denis L.; Lambert, Paul F.; Johannsen, Eric C.; Kenney, Shannon C.

    2017-01-01

    When confronted with poor oxygenation, cells adapt by activating survival signaling pathways, including the oxygen-sensitive transcriptional regulators called hypoxia-inducible factor alphas (HIF-αs). We report here that HIF-1α also regulates the life cycle of Epstein-Barr virus (EBV). Incubation of EBV-positive gastric carcinoma AGS-Akata and SNU-719 and Burkitt lymphoma Sal and KemIII cell lines with a prolyl hydroxylase inhibitor, L-mimosine or deferoxamine, or the NEDDylation inhibitor MLN4924 promoted rapid and sustained accumulation of both HIF-1α and lytic EBV antigens. ShRNA knockdown of HIF-1α significantly reduced deferoxamine-mediated lytic reactivation. HIF-1α directly bound the promoter of the EBV primary latent-lytic switch BZLF1 gene, Zp, activating transcription via a consensus hypoxia-response element (HRE) located at nt -83 through -76 relative to the transcription initiation site. HIF-1α did not activate transcription from the other EBV immediate-early gene, BRLF1. Importantly, expression of HIF-1α induced EBV lytic-gene expression in cells harboring wild-type EBV, but not in cells infected with variants containing base-pair substitution mutations within this HRE. Human oral keratinocyte (NOK) and gingival epithelial (hGET) cells induced to differentiate by incubation with either methyl cellulose or growth in organotypic culture accumulated both HIF-1α and Blimp-1α, another cellular factor implicated in lytic reactivation. HIF-1α activity also accumulated along with Blimp-1α during B-cell differentiation into plasma cells. Furthermore, most BZLF1-expressing cells observed in lymphomas induced by EBV in NSG mice with a humanized immune system were located distal to blood vessels in hypoxic regions of the tumors. Thus, we conclude that HIF-1α plays central roles in both EBV’s natural life cycle and EBV-associated tumorigenesis. We propose that drugs that induce HIF-1α protein accumulation are good candidates for development of a

  1. Hypoxia induces adipogenic differentitation of myoblastic cell lines

    Energy Technology Data Exchange (ETDEWEB)

    Itoigawa, Yoshiaki [Tohoku University School of Medicine, Sendai (Japan); Juntendo University School of Medicine, Tokyo (Japan); Kishimoto, Koshi N., E-mail: kishimoto@med.tohoku.ac.jp [Tohoku University School of Medicine, Sendai (Japan); Okuno, Hiroshi; Sano, Hirotaka [Tohoku University School of Medicine, Sendai (Japan); Kaneko, Kazuo [Juntendo University School of Medicine, Tokyo (Japan); Itoi, Eiji [Tohoku University School of Medicine, Sendai (Japan)

    2010-09-03

    Research highlights: {yields} C2C12 and G8 myogenic cell lines treated by hypoxia differentiate into adipocytes. {yields} The expression of C/EBP{beta}, {alpha} and PPAR{gamma} were increased under hypoxia. {yields} Myogenic differentiation of C2C12 was inhibited under hypoxia. -- Abstract: Muscle atrophy usually accompanies fat accumulation in the muscle. In such atrophic conditions as back muscles of kyphotic spine and the rotator cuff muscles with torn tendons, blood flow might be diminished. It is known that hypoxia causes trans-differentiation of mesenchymal stem cells derived from bone marrow into adipocytes. However, it has not been elucidated yet if hypoxia turned myoblasts into adipocytes. We investigated adipogenesis in C2C12 and G8 murine myogenic cell line treated by hypoxia. Cells were also treated with the cocktail of insulin, dexamethasone and IBMX (MDI), which has been known to inhibit Wnt signaling and promote adipogenesis. Adipogenic differentiation was seen in both hypoxia and MDI. Adipogenic marker gene expression was assessed in C2C12. CCAAT/enhancer-binding protein (C/EBP) {beta}, {alpha} and peroxisome proliferator activating receptor (PPAR) {gamma} were increased by both hypoxia and MDI. The expression profile of Wnt10b was different between hypoxia and MDI. The mechanism for adipogenesis of myoblasts in hypoxia might be regulated by different mechanism than the modification of Wnt signaling.

  2. Interspecific differences in hypoxia-induced gill remodeling in carp.

    Science.gov (United States)

    Dhillon, Rashpal S; Yao, Lili; Matey, Victoria; Chen, Bo-Jian; Zhang, An-Jie; Cao, Zhen-Dong; Fu, Shi-Jian; Brauner, Colin J; Wang, Yuxiang S; Richards, Jeffrey G

    2013-01-01

    The gills of many fish, but in particular those of crucian carp (Carassius carassius) and goldfish (Carassius auratus), are capable of extensive remodeling in response to changes in oxygen (O2), temperature, and exercise. In this study, we investigated the interspecific variation in hypoxia-induced gill modeling and hypoxia tolerance in 10 closely related groups of cyprinids (nine species, with two strains of Cyprinus carpio). There was significant variation in hypoxia tolerance, measured as the O2 tension (P(O2)) at which fish lost equilibrium (LOEcrit), among the 10 groups of carp. In normoxia, there was a significant, phylogenetically independent relationship between mass-specific gill surface area and LOEcrit, with the more hypoxia-tolerant carp having smaller gills than their less hypoxia-tolerant relatives. All groups of carp, except the Chinese bream (Megalobrama pellegrini), increased mass-specific gill surface area in response to 48 h of exposure to hypoxia (0.7 kPa) through reductions in the interlamellar cell mass (ILCM) volume. The magnitude of the hypoxia-induced reduction in the ILCM was negatively correlated with LOEcrit (and thus positively correlated with hypoxia tolerance), independent of phylogeny. The hypoxia-induced changes in gill morphology resulted in reduced variation in mass-specific gill surface area among species and eliminated the relationship between LOEcrit and mass-specific gill surface area. While behavioral responses to hypoxia differed among the carp groups, there were no significant relationships between hypoxia tolerance and the Po2 at which aquatic surface respiration (ASR) was initiated or the total number of ASR events observed during progressive hypoxia. Our results are the first to show that the extent of gill remodeling in cyprinids is associated with hypoxia tolerance in a phylogenetically independent fashion.

  3. Chitosan-shelled oxygen-loaded nanodroplets abrogate hypoxia dysregulation of human keratinocyte gelatinases and inhibitors: New insights for chronic wound healing

    Energy Technology Data Exchange (ETDEWEB)

    Khadjavi, Amina [Dipartimento di Neuroscienze, Università di Torino, Torino (Italy); Magnetto, Chiara [Istituto Nazionale di Ricerca Metrologica (INRIM), Torino (Italy); Panariti, Alice [Dipartimento di Scienze della Salute, Università di Milano Bicocca, Monza (Italy); Argenziano, Monica [Dipartimento di Scienza e Tecnologia del Farmaco, Università di Torino, Torino (Italy); Gulino, Giulia Rossana [Dipartimento di Oncologia, Università di Torino, Torino (Italy); Rivolta, Ilaria [Dipartimento di Scienze della Salute, Università di Milano Bicocca, Monza (Italy); Cavalli, Roberta [Dipartimento di Scienza e Tecnologia del Farmaco, Università di Torino, Torino (Italy); Giribaldi, Giuliana [Dipartimento di Oncologia, Università di Torino, Torino (Italy); Guiot, Caterina [Dipartimento di Neuroscienze, Università di Torino, Torino (Italy); Prato, Mauro, E-mail: mauro.prato@unito.it [Dipartimento di Neuroscienze, Università di Torino, Torino (Italy); Dipartimento di Scienze della Sanità Pubblica e Pediatriche, Università di Torino, Torino (Italy)

    2015-08-01

    Background: : In chronic wounds, efficient epithelial tissue repair is hampered by hypoxia, and balances between the molecules involved in matrix turn-over such as matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are seriously impaired. Intriguingly, new oxygenating nanocarriers such as 2H,3H-decafluoropentane-based oxygen-loaded nanodroplets (OLNs) might effectively target chronic wounds. Objective: : To investigate hypoxia and chitosan-shelled OLN effects on MMP/TIMP production by human keratinocytes. Methods: : HaCaT cells were treated for 24 h with 10% v/v OLNs both in normoxia or hypoxia. Cytotoxicity and cell viability were measured through biochemical assays; cellular uptake by confocal microscopy; and MMP and TIMP production by enzyme-linked immunosorbent assay or gelatin zymography. Results: : Normoxic HaCaT cells constitutively released MMP-2, MMP-9, TIMP-1 and TIMP-2. Hypoxia strongly impaired MMP/TIMP balances by reducing MMP-2, MMP-9, and TIMP-2, without affecting TIMP-1 release. After cellular uptake by keratinocytes, nontoxic OLNs abrogated all hypoxia effects on MMP/TIMP secretion, restoring physiological balances. OLN abilities were specifically dependent on time-sustained oxygen diffusion from OLN core. Conclusion: : Chitosan-shelled OLNs effectively counteract hypoxia-dependent dysregulation of MMP/TIMP balances in human keratinocytes. Therefore, topical administration of exogenous oxygen, properly encapsulated in nanodroplet formulations, might be a promising adjuvant approach to promote healing processes in hypoxic wounds. - Highlights: • Hypoxia impairs MMP9/TIMP1 and MMP2/TIMP2 balances in HaCaT human keratinocytes. • Chitosan-shelled oxygen-loaded nanodroplets (OLNs) are internalised by HaCaT cells. • OLNs are not toxic to HaCaT cells. • OLNs effectively counteract hypoxia effects on MMP/TIMP balances in HaCaT cells. • OLNs appear as promising and cost-effective therapeutic tools for hypoxic

  4. Sustainable agriculture

    National Research Council Canada - National Science Library

    Lichtfouse, Eric

    2009-01-01

    ... : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : 9 Part I CLIMATE CHANGE Soils and Sustainable Agriculture: A Review : : : : : : : : : : : : : : : : : : : : : : : : : : Rattan Lal 15 Soils and Food Sufficiency...

  5. The adaptor protein SH2B3 (Lnk negatively regulates neurite outgrowth of PC12 cells and cortical neurons.

    Directory of Open Access Journals (Sweden)

    Tien-Cheng Wang

    Full Text Available SH2B adaptor protein family members (SH2B1-3 regulate various physiological responses through affecting signaling, gene expression, and cell adhesion. SH2B1 and SH2B2 were reported to enhance nerve growth factor (NGF-induced neuronal differentiation in PC12 cells, a well-established neuronal model system. In contrast, SH2B3 was reported to inhibit cell proliferation during the development of immune system. No study so far addresses the role of SH2B3 in the nervous system. In this study, we provide evidence suggesting that SH2B3 is expressed in the cortex of embryonic rat brain. Overexpression of SH2B3 not only inhibits NGF-induced differentiation of PC12 cells but also reduces neurite outgrowth of primary cortical neurons. SH2B3 does so by repressing NGF-induced activation of PLCγ, MEK-ERK1/2 and PI3K-AKT pathways and the expression of Egr-1. SH2B3 is capable of binding to phosphorylated NGF receptor, TrkA, as well as SH2B1β. Our data further demonstrate that overexpression of SH2B3 reduces the interaction between SH2B1β and TrkA. Consistent with this finding, overexpressing the SH2 domain of SH2B3 is sufficient to inhibit NGF-induced neurite outgrowth. Together, our data demonstrate that SH2B3, unlike the other two family members, inhibits neuronal differentiation of PC12 cells and primary cortical neurons. Its inhibitory mechanism is likely through the competition of TrkA binding with the positive-acting SH2B1 and SH2B2.

  6. Sustainable Marketing

    NARCIS (Netherlands)

    Dam, van Y.K.

    2017-01-01

    In this article, three different conceptions of sustainable marketing are discussed and compared. These different conceptions are referred to as social, green, and critical sustainable marketing. Social sustainable marketing follows the logic of demand-driven marketing management and places the

  7. Ultraviolet absorption spectra and kinetics of CH3S and CH2SH radicals

    DEFF Research Database (Denmark)

    Anastasi, C.; Broomfield, M.; Nielsen, O.J.

    1991-01-01

    The ultraviolet absorption spectra of CH3S and CH2SH radicals have been measured between 215 and 380 nm using the pulse-radiolysis/kinetic-absorption method. One absorption band between 250 and 300 nm and one around 215 nm have been tentatively assigned to the CH2SH and CH3S radicals, respectively...

  8. SH3 Domains Differentially Stimulate Distinct Dynamin I Assembly Modes and G Domain Activity.

    Directory of Open Access Journals (Sweden)

    Sai Krishnan

    Full Text Available Dynamin I is a highly regulated GTPase enzyme enriched in nerve terminals which mediates vesicle fission during synaptic vesicle endocytosis. One regulatory mechanism involves its interactions with proteins containing Src homology 3 (SH3 domains. At least 30 SH3 domain-containing proteins bind dynamin at its proline-rich domain (PRD. Those that stimulate dynamin activity act by promoting its oligomerisation. We undertook a systematic parallel screening of 13 glutathione-S-transferase (GST-tagged endocytosis-related SH3 domains on dynamin binding, GTPase activity and oligomerisation. No correlation was found between dynamin binding and their potency to stimulate GTPase activity. There was limited correlation between the extent of their ability to stimulate dynamin activity and the level of oligomerisation, indicating an as yet uncharacterised allosteric coupling of the PRD and G domain. We examined the two variants, dynamin Iab and Ibb, which differ in the alternately splice middle domain α2 helix. They responded differently to the panel of SH3s, with the extent of stimulation between the splice variants varying greatly between the SH3s. This study reveals that SH3 binding can act as a heterotropic allosteric regulator of the G domain via the middle domain α2 helix, suggesting an involvement of this helix in communicating the PRD-mediated allostery. This indicates that SH3 binding both stabilises multiple conformations of the tetrameric building block of dynamin, and promotes assembly of dynamin-SH3 complexes with distinct rates of GTP hydrolysis.

  9. Lentiviral vector design for multiple shRNA expression and durable HIV-1 inhibition

    NARCIS (Netherlands)

    ter Brake, Olivier; 't Hooft, Karen; Liu, Ying Poi; Centlivre, Mireille; von Eije, Karin Jasmijn; Berkhout, Ben

    2008-01-01

    Human immunodeficiency virus type 1 (HIV-1) replication in T cells can be inhibited by RNA interference (RNAi) through short hairpin RNA (shRNA) expression from a lentiviral vector. However, for the development of a durable RNAi-based gene therapy against HIV-1, multiple shRNAs need to be expressed

  10. Hypoxia and hypoxia mimetics decrease aquaporin 5 (AQP5) expression through both hypoxia inducible factor-1α and proteasome-mediated pathways.

    Science.gov (United States)

    Kawedia, Jitesh D; Yang, Fan; Sartor, Maureen A; Gozal, David; Czyzyk-Krzeska, Maria; Menon, Anil G

    2013-01-01

    The alveolar epithelium plays a central role in gas exchange and fluid transport, and is therefore critical for normal lung function. Since the bulk of water flux across this epithelium depends on the membrane water channel Aquaporin 5 (AQP5), we asked whether hypoxia had any effect on AQP5 expression. We show that hypoxia causes a significant (70%) decrease in AQP5 expression in the lungs of mice exposed to hypoxia. Hypoxia and the hypoxia mimetic, cobalt, also caused similar decreases in AQP5 mRNA and protein expression in the mouse lung epithelial cell line MLE-12. The action of hypoxia and cobalt on AQP5 transcription was demonstrated by directly quantifying heternonuclear RNA by real-time PCR. Dominant negative mutants of Hypoxia Inducible Factor (HIF-1α) and HIF-1α siRNA blocked the action of cobalt, showing that HIF-1α is a key component in this mechanism. The proteasome inhibitors, lactacystin or proteasome inhibitor-III completely abolished the effect of hypoxia and cobalt both at the protein and mRNA level indicating that the proteasome pathway is probably involved not only for the stability of HIF-1α protein, but for the stability of unidentified transcription factors that regulate AQP5 transcription. These studies reveal a potentially important physiological mechanism linking hypoxic stress and membrane water channels.

  11. Hypoxia in patients with acute hemiplegia.

    Science.gov (United States)

    Walshaw, M J; Pearson, M G

    1984-01-01

    Sixteen patients with an early dense hemiplegia due to cerebrovascular accidents were shown to have a greater degree of hypoxia than 16 matched control patients. The patients with hemiplegia had a reflex compensatory fall in arterial carbon dioxide tensions (PaCO2) with possible reduction in cerebral blood flow. Oxygen treatment led to an increase in PaCO2 in the patients with hemiplegia, but the increase in oxygen tensions in these patients was significantly less than that in the control group, suggesting increased pulmonary shunting as the cause for the hypoxia. Oxygen treatment may improve cerebral blood flow and oxygenation and have a useful role in the early management of patients with a dense hemiplegia. PMID:6418296

  12. Psychomotor skills learning under chronic hypoxia.

    Science.gov (United States)

    Bouquet, C A; Gardette, B; Gortan, C; Abraini, J H

    1999-09-29

    Psychomotor deficits are a prominent feature in subjects exposed to hypoxia. Eight subjects exposed to chronic hypoxia during a simulated climb to 8848 m (Everest-Comex 97) were investigated using both a simple psychomotor task (Purdue pegboard) and two complex psychomotor tasks including a recognition task of either a color stimulus (high semantic level) or an abstract sign (low semantic level). Exposure to hypoxic stress mainly produced psychomotor skills learning deficits compared to control study, with greater deficits in the complex psychomotor task. The pattern of results suggests disruptions of motor strategic process. Our data further suggest that the relative strength of implicit or automatic memory processes associated with semantic information processing may increase when disturbances occur in brain functions.

  13. Fetal hypoxia and programming of matrix metalloproteinases.

    Science.gov (United States)

    Tong, Wenni; Zhang, Lubo

    2012-02-01

    Fetal hypoxia adversely affects the brain and heart development, yet the mechanisms responsible remain elusive. Recent studies indicate an important role of the extracellular matrix in fetal development and tissue remodeling. The matrix metalloproteinases (MMPs) and their endogenous inhibitors, tissue inhibitors of metalloproteinases (TIMPs) have been implicated in a variety of physiological and pathological processes in the cardiovascular and central nervous systems. This review summarizes current knowledge of the mechanisms by which fetal hypoxia induces the imbalance of MMPs, TIMPs and collagen expression patterns, resulting in growth restriction and aberrant tissue remodeling in the developing heart and brain. Collectively, this information could lead to the development of preventive diagnoses and therapeutic strategies in the fetal programming of cardiovascular and neurological disorders. Copyright © 2011 Elsevier Ltd. All rights reserved.

  14. Receptor channel TRPC6 orchestrate the activation of human hepatic stellate cell under hypoxia condition

    Energy Technology Data Exchange (ETDEWEB)

    Iyer, Soumya C, E-mail: chidambaram.soumya@gmail.com [Unit of Biochemistry, Department of Zoology, School of Life Sciences, University of Madras, Guindy Campus, Chennai 600025, Tamilnadu (India); Kannan, Anbarasu [Department of Biochemistry, University of Madras, Guindy Campus, Chennai 600025, Tamilnadu (India); Gopal, Ashidha [Unit of Biochemistry, Department of Zoology, School of Life Sciences, University of Madras, Guindy Campus, Chennai 600025, Tamilnadu (India); Devaraj, Niranjali [Department of Biochemistry, University of Madras, Guindy Campus, Chennai 600025, Tamilnadu (India); Halagowder, Devaraj [Unit of Biochemistry, Department of Zoology, School of Life Sciences, University of Madras, Guindy Campus, Chennai 600025, Tamilnadu (India)

    2015-08-01

    Hepatic stellate cells (HSCs), a specialized stromal cytotype have a great impact on the biological behaviors of liver diseases. Despite this fact, the underlying mechanism that regulates HSC still remains poorly understood. The aim of the present study was to understand the role of TRPC6 signaling in regulating the molecular mechanism of HSCs in response to hypoxia. In the present study we showed that under hypoxia condition, the upregulated Hypoxia Inducible Factor 1α (HIF1α) increases NICD activation, which in turn induces the expression of transient receptor potential channel 6 (TRPC6) in HSC line lx-2. TRPC6 causes a sustained elevation of intracellular calcium which is coupled with the activation of the calcineurin-nuclear factor of activated T-cell (NFAT) pathway which activates the synthesis of extracellular matrix proteins. TRPC6 also activates SMAD2/3 dependent TGF-β signaling in facilitating upregulated expression of αSMA and collagen. As activated HSCs may be a suitable target for HCC therapy and targeting these cells rather than the HCC cells may result in a greater response. Collectively, our studies indicate for the first time the detailed mechanism of activation of HSC through TRPC6 signaling and thus being a promising therapeutic target. - Highlights: • HIF1α increases NICD, induces TRPC6 in lx2 cells. • TRPC6 a novel regulator in the activation of HSC. • HSCs as target for HCC therapy.

  15. Cognition Effects of Low-Grade Hypoxia

    Science.gov (United States)

    2016-07-01

    Journal Article 3. DATES COVERED (From – To) Jan 2003 – Sep 2005 4. TITLE AND SUBTITLE Cognition Effects of Low-Grade Hypoxia 5a. CONTRACT NUMBER... cognitive function are reported in this paper. The study compared cognitive function during short exposures at four different altitudes. Ninety-one...pressure chamber in a balanced design. Oxygen saturation, heart rate, and cognitive performance on seven different cognitive tasks were measured. In

  16. Hypoxia: Exposure Time Until Significant Performance Effects

    Science.gov (United States)

    2016-03-07

    as a failing of sensory function, working memory , and motor skills leading up to the time at which corrective action is no longer able to be taken...questionnaire which confirmed compliance with pre-established alcohol, caffeine , supplement, and medication usage standards given during consent and...1994). Acute hypoxia fails to influence two aspects of short-term memory : implications for the source of cognitive deficits. Aviation, Space

  17. SH wave propagation in joined half-spaces composed of elastic metamaterials

    Science.gov (United States)

    Shi, Xiaona; Shu, Haisheng; Zhou, Haiyong; Zhao, Lei; Liu, Ru; An, Shuowei; Zhu, Jie

    2017-12-01

    Based on the effective-medium theory, the propagation of a shear horizontal (SH) wave in joined half-spaces composed of elastic metamaterials (EMMs) is investigated. From the dispersion relations, the effects of negative effective-medium parameters on the properties of a SH wave traveling near the interface are analyzed in detail. It is found that a SH wave can always appear and travel along the interface under specific effective-parameter combinations no matter whether the effective transverse wave velocity is imaginary or real. This is significantly different from the classical case (joined half-spaces composed of natural media), and the existence of these SH interfacial wave modes may have important impacts on EMM-based SH wave manipulation, especially wave isolation and object protection.

  18. Hypoxia selects bortezomib-resistant stem cells of chronic myeloid leukemia.

    Directory of Open Access Journals (Sweden)

    Michele Tanturli

    Full Text Available We previously demonstrated that severe hypoxia inhibits growth of Chronic Myeloid Leukemia (CML cells and selects stem cells where BCR/Abl(protein is suppressed, although mRNA is not, so that hypoxia-selected stem cells, while remaining leukemic, are independent of BCR/Abl signaling and thereby refractory to Imatinib-mesylate. The main target of this study was to address the effects of the proteasome inhibitor Bortezomib (BZ on the maintenance of stem or progenitor cells in hypoxic primary cultures (LC1, by determining the capacity of LC1 cells to repopulate normoxic secondary cultures (LC2 and the kinetics of this repopulation. Unselected K562 cells from day-2 hypoxic LC1 repopulated LC2 with rapid, progenitor-type kinetics; this repopulation was suppressed by BZ addition to LC1 at time 0, but completely resistant to day-1 BZ, indicating that progenitors require some time to adapt to stand hypoxia. K562 cells selected in hypoxic day-7 LC1 repopulated LC2 with stem-type kinetics, which was largely resistant to BZ added at either time 0 or day 1, indicating that hypoxia-selectable stem cells are BZ-resistant per se, i.e. before their selection. Furthermore, these cells were completely resistant to day-6 BZ, i.e. after selection. On the other hand, hypoxia-selected stem cells from CD34-positive cells of blast-crisis CML patients appeared completely resistant to either time-0 or day-1 BZ. To exploit in vitro the capacity of CML cells to adapt to hypoxia enabled to detect a subset of BZ-resistant leukemia stem cells, a finding of particular relevance in light of the fact that our experimental system mimics the physiologically hypoxic environment of bone marrow niches where leukemia stem cells most likely home and sustain minimal residual disease in vivo. This suggests the use of BZ as an enhanced strategy to control CML. in particular to prevent relapse of disease, to be considered with caution and to need further deepening.

  19. Structural integration in hypoxia-inducible factors

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Dalei; Potluri, Nalini; Lu, Jingping; Kim, Youngchang; Rastinejad, Fraydoon

    2015-08-20

    The hypoxia-inducible factors (HIFs) coordinate cellular adaptations to low oxygen stress by regulating transcriptional programs in erythropoiesis, angiogenesis and metabolism. These programs promote the growth and progression of many tumours, making HIFs attractive anticancer targets. Transcriptionally active HIFs consist of HIF-alpha and ARNT (also called HIF-1 beta) subunits. Here we describe crystal structures for each of mouse HIF-2 alpha-ARNT and HIF-1 alpha-ARNT heterodimers in states that include bound small molecules and their hypoxia response element. A highly integrated quaternary architecture is shared by HIF-2 alpha-ARNT and HIF-1 alpha-ARNT, wherein ARNT spirals around the outside of each HIF-alpha subunit. Five distinct pockets are observed that permit small-molecule binding, including PAS domain encapsulated sites and an interfacial cavity formed through subunit heterodimerization. The DNA-reading head rotates, extends and cooperates with a distal PAS domain to bind hypoxia response elements. HIF-alpha mutations linked to human cancers map to sensitive sites that establish DNA binding and the stability of PAS domains and pockets.

  20. The Role of Hypoxia in Glioblastoma Invasion

    Directory of Open Access Journals (Sweden)

    Ana Rita Monteiro

    2017-11-01

    Full Text Available Glioblastoma multiforme (GBM, a grade IV astrocytoma, is the most common and deadly type of primary malignant brain tumor, with a patient’s median survival rate ranging from 15 to 17 months. The current treatment for GBM involves tumor resection surgery based on MRI image analysis, followed by radiotherapy and treatment with temozolomide. However, the gradual development of tumor resistance to temozolomide is frequent in GBM patients leading to subsequent tumor regrowth/relapse. For this reason, the development of more effective therapeutic approaches for GBM is of critical importance. Low tumor oxygenation, also known as hypoxia, constitutes a major concern for GBM patients, since it promotes cancer cell spreading (invasion into the healthy brain tissue in order to evade this adverse microenvironment. Tumor invasion not only constitutes a major obstacle to surgery, radiotherapy, and chemotherapy, but it is also the main cause of death in GBM patients. Understanding how hypoxia triggers the GBM cells to become invasive is paramount to developing novel and more effective therapies against this devastating disease. In this review, we will present a comprehensive examination of the available literature focused on investigating how GBM hypoxia triggers an invasive cancer cell phenotype and the role of these invasive proteins in GBM progression.

  1. Modeling and validating HL7 FHIR profiles using semantic web Shape Expressions (ShEx).

    Science.gov (United States)

    Solbrig, Harold R; Prud'hommeaux, Eric; Grieve, Grahame; McKenzie, Lloyd; Mandel, Joshua C; Sharma, Deepak K; Jiang, Guoqian

    2017-03-01

    HL7 Fast Healthcare Interoperability Resources (FHIR) is an emerging open standard for the exchange of electronic healthcare information. FHIR resources are defined in a specialized modeling language. FHIR instances can currently be represented in either XML or JSON. The FHIR and Semantic Web communities are developing a third FHIR instance representation format in Resource Description Framework (RDF). Shape Expressions (ShEx), a formal RDF data constraint language, is a candidate for describing and validating the FHIR RDF representation. Create a FHIR to ShEx model transformation and assess its ability to describe and validate FHIR RDF data. We created the methods and tools that generate the ShEx schemas modeling the FHIR to RDF specification being developed by HL7 ITS/W3C RDF Task Force, and evaluated the applicability of ShEx in the description and validation of FHIR to RDF transformations. The ShEx models contributed significantly to workgroup consensus. Algorithmic transformations from the FHIR model to ShEx schemas and FHIR example data to RDF transformations were incorporated into the FHIR build process. ShEx schemas representing 109 FHIR resources were used to validate 511 FHIR RDF data examples from the Standards for Trial Use (STU 3) Ballot version. We were able to uncover unresolved issues in the FHIR to RDF specification and detect 10 types of errors and root causes in the actual implementation. The FHIR ShEx representations have been included in the official FHIR web pages for the STU 3 Ballot version since September 2016. ShEx can be used to define and validate the syntax of a FHIR resource, which is complementary to the use of RDF Schema (RDFS) and Web Ontology Language (OWL) for semantic validation. ShEx proved useful for describing a standard model of FHIR RDF data. The combination of a formal model and a succinct format enabled comprehensive review and automated validation. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. The impact of Zika virus infection on human neuroblastoma (SH-SY5Y) cell line.

    Science.gov (United States)

    Luplertlop, Natthanej; Suwanmanee, San; Muangkaew, Watcharamat; Ampawong, Sumate; Kitisin, Thitinan; Poovorawan, Yong

    2017-01-01

    An increase in Zika virus (ZIKV) epidemic during the last decade has become a major global concern as the virus affects both newborns and adult humans. Earlier studies have shown the impact of ZIKV infection in developing human foetus. However, effective in vitro model of target cells for studying the ZIKV infection in adult human neurons is not available. This study aimed to establish the use of human neuroblastoma cell line (SH-SY5Y) for studying an infection of ZIKV in vitro. ZIKV growth kinetics, viral toxicity, and SH-SY5Y cell vialibity were determined after ZIKV infection in SH-SY5Y cells in vitro. ZIKV-infected SH-SY5Y cells were morphologically analysed and compared with nonhuman primate Vero cells. Furthermore, the susceptibility of SH-SY5Y cells to ZIKV infection was also determined. The results showed that ZIKV efficiently infects SH-SY5Y cell lines in vitro. Gradual changes of several cellular homeostasis parameters including cell viability, cytotoxicity, and cell morphology were observed in ZIKVinfected SH-SY5Y cells when compared to mock-treated or non-human primate cells. Interestingly, ZIKV particles were detected in the nucleoplasmic compartment of the infected SH-SY5Y cells. The results suggest that ZIKV particle can be detected in the nucleoplasmic compartment of the infected SH-SY5Y cells beside the known viral replicating cytoplasmic area. Hence, SH-SY5Y cells can be used as an in vitro adult human neuronal cell-based model, for further elucidating the ZIKV biology, and highlight other possible significance of Zika virus distribution through nuclear localization, which may correlate to the neuropathological defects in ZIKV-infected adult humans.

  3. Vitamin C Supplementation Does not Improve Hypoxia-Induced Erythropoiesis

    OpenAIRE

    Martinez-Bello, Vladimir E.; Sanchis-Gomar, Fabian; Martinez-Bello, Daniel; Olaso-Gonzalez, Gloria; Gomez-Cabrera, Mari Carmen; Viña, Jose

    2012-01-01

    Martinez-Bello,Vladimir E., Fabian Sanchis-Gomar, Daniel Martinez-Bello, Gloria Olaso-Gonzalez, Mari Carmen Gomez-Cabrera, and Jose Viña. Vitamin C Supplementation Does Not Improve Hypoxia-Induced Erythropoiesis. High Alt Med Biol 13:269–274, 2012.—Hypoxia induces reactive oxygen species production. Supplements with antioxidant mixtures can compensate for the decline in red cell membrane stability following intermittent hypobaric hypoxia by decreasing protein and lipid oxidation. We aimed to ...

  4. NITRIC OXIDE INTERFERES WITH HYPOXIA SIGNALING DURING COLONIC INFLAMMATION

    OpenAIRE

    CARIA,Cintia Rabelo e Paiva; MOSCATO,Camila Henrique; TOMÉ,Renata Bortolin Guerra; PEDRAZZOLI Jr,José; RIBEIRO,Marcelo Lima; GAMBERO,Alessandra

    2014-01-01

    Context Intestinal inflammation can induce a local reduction in oxygen levels that triggers an adaptive response centered on the expression of hypoxia-inducible factors (HIFs). Nitric oxide, a well-described inflammatory mediator, may interfere with hypoxia signaling. Objectives We aimed to evaluate the role of nitric oxide in hypoxia signaling during colonic inflammation. Methods Colitis was induced by single (acute) or repeated (reactivated colitis) trinitrobenzenosulfonic acid administ...

  5. Molecular Probes for Imaging of Hypoxia in the Retina

    OpenAIRE

    Evans, Stephanie M.; Kim, Kwangho; Moore, Chauca E.; Uddin, Md Imam; Capozzi, Megan E.; Craft, Jason R.; Gary A Sulikowski; Jayagopal, Ashwath

    2014-01-01

    Hypoxia has been associated with retinal diseases which lead the causes of irreversible vision loss, including diabetic retinopathy, retinopathy of prematurity, and age-related macular degeneration. Therefore, technologies for imaging hypoxia in the retina are needed for early disease detection, monitoring of disease progression, and assessment of therapeutic responses in the patient. Toward this goal, we developed two hypoxia-sensitive imaging agents based on nitroimidazoles which are capabl...

  6. Prolonged lobar hypoxia in vivo enhances the responsivity of isolated pulmonary veins to hypoxia

    Science.gov (United States)

    Sheehan, D. W.; Farhi, L. E.; Russell, J. A.

    1992-01-01

    The hypoxic response of pulmonary vessels isolated from eight sheep whose right apical lobes (RAL) had inspired 100% N2 for 20 h was studied. The RAL of these conscious sheep inspired hypoxic gas and the remainder of the lung inspired air. During hypoxia, RAL perfusion was 33 +/- 3% of its air value, carotid arterial PO2 averaged 86 +/- 3 mm Hg and pulmonary perfusion pressure was not significantly different from the initial control period when the RAL inspired air. At the end of the hypoxic exposure, the sheep were killed, and pulmonary artery and vein rings (0.5 to 2 mm inner diameter) were isolated from both the RAL and the right cardiac lobe, which served as the control lobe (CL). Arteries from the RAL and CL did not contract in response to 6% O2/6% CO2/88% N2 (hypoxia). In contrast, RAL veins did contract vigorously in response to hypoxia, whereas CL veins did not contract or contracted only minimally. Rubbing of the endothelium or prior incubation of RAL veins with catalase (1,200 units/ml), indomethacin (10(-5) M), or the thromboxane A2/prostaglandin H2 (TxA2/PGH2) receptor antagonist, SQ 29,548 (3 X 10(-6) M) each significantly reduced the response to hypoxia. RAL veins were also found to be more reactive than CL veins to the prostaglandin endoperoxide analogue U46619. We conclude that prolonged lobar hypoxia in vivo increases the responsivity of isolated pulmonary veins to hypoxia. These contractions may result from an increase in reactive O2 species, which in turn modify production of, metabolism of, and/or tissue responsivity to TxA2/PGH2.

  7. Cognitive responses to hypobaric hypoxia: implications for aviation training

    Directory of Open Access Journals (Sweden)

    Neuhaus C

    2014-11-01

    Full Text Available Christopher Neuhaus,1,2 Jochen Hinkelbein2,31Department of Anesthesiology, Heidelberg University Hospital, Ruprecht Karls University of Heidelberg, Heidelberg, 2Emergency Medicine and Air Rescue Working Group, German Society of Aviation and Space Medicine (DGLRM, Munich, 3Department of Anesthesiology and Intensive Care Medicine, University Hospital of Cologne, Cologne, GermanyAbstract: The aim of this narrative review is to provide an overview on cognitive responses to hypobaric hypoxia and to show relevant implications for aviation training. A principal element of hypoxia-awareness training is the intentional evocation of hypoxia symptoms during specific training sessions within a safe and controlled environment. Repetitive training should enable pilots to learn and recognize their personal hypoxia symptoms. A time span of 3–6 years is generally considered suitable to refresh knowledge of the more subtle and early symptoms especially. Currently, there are two different technical approaches available to induce hypoxia during training: hypobaric chamber training and reduced-oxygen breathing devices. Hypoxia training for aircrew is extremely important and effective, and the hypoxia symptoms should be emphasized clearly to aircrews. The use of tight-fitting masks, leak checks, and equipment checks should be taught to all aircrew and reinforced regularly. It is noteworthy that there are major differences in the required quality and quantity of hypoxia training for both military and civilian pilots.Keywords: cognitive response, aviation training, pilot, hypoxia, oxygen, loss of consciousness

  8. Imaging tumor hypoxia by near-infrared fluorescence tomography.

    Science.gov (United States)

    Biswal, Nrusingh C; Pavlik, Christopher; Smith, Michael B; Aguirre, Andres; Xu, Yan; Zanganeh, Saeid; Kuhn, Liisa T; Claffey, Kevin P; Zhu, Quing

    2011-06-01

    We have developed a novel nitroimidazole indocyanine dye conjugate for tumor-targeted hypoxia fluorescence tomography. The hypoxia probe has been evaluated in vitro using tumor cell lines and in vivo with tumor targeting in mice. The in vitro cell studies were performed to assess fluorescence labeling differences between hypoxia and normoxia conditions. When treated with the hypoxia probe, a fluorescence emission ratio of 2.5-fold was found between the cells incubated under hypoxia compared to the cells in normoxia condition. Hypoxia specificity was also confirmed by comparing the cells treated with indocyanine dye alone. In vivo tumor targeting in mice showed that the fluorescence signals measured at the tumor site were twice those at the normal site after 150 min post-injection of the hypoxia probe. On the other hand, the fluorescence signals measured after injection of indocyanine dye were the same at tumor and normal sites. In vivo fluorescence tomography images of mice injected with the hypoxia probe showed that the probe remained for more than 5 to 7 h in the tumors, however, the images of mice injected with indocyanine only dye confirmed that the unbound dye washed out in less than 3 h. These findings are supported with fluorescence images of histological sections of tumor samples using a Li-COR scanner and immunohistochemistry technique for tumor hypoxia.

  9. The dominant folding route minimizes backbone distortion in SH3.

    Directory of Open Access Journals (Sweden)

    Heiko Lammert

    Full Text Available Energetic frustration in protein folding is minimized by evolution to create a smooth and robust energy landscape. As a result the geometry of the native structure provides key constraints that shape protein folding mechanisms. Chain connectivity in particular has been identified as an essential component for realistic behavior of protein folding models. We study the quantitative balance of energetic and geometrical influences on the folding of SH3 in a structure-based model with minimal energetic frustration. A decomposition of the two-dimensional free energy landscape for the folding reaction into relevant energy and entropy contributions reveals that the entropy of the chain is not responsible for the folding mechanism. Instead the preferred folding route through the transition state arises from a cooperative energetic effect. Off-pathway structures are penalized by excess distortion in local backbone configurations and contact pair distances. This energy cost is a new ingredient in the malleable balance of interactions that controls the choice of routes during protein folding.

  10. SH Wave Scattering Problems for Multiple Orthotropic Elliptical Inclusions

    Directory of Open Access Journals (Sweden)

    Jung-Ki Lee

    2013-01-01

    Full Text Available A volume integral equation method (VIEM is applied for the effective analysis of elastic wave scattering problems in unbounded solids containing general anisotropic inclusions. It should be noted that this numerical method does not require use of Green's function for anisotropic inclusions to solve this class of problems since only Green's function for the unbounded isotropic matrix is necessary for the analysis. This new method can also be applied to general two-dimensional elastodynamic problems involving arbitrary shapes and numbers of anisotropic inclusions. A detailed analysis of SH wave scattering problems is developed for an unbounded isotropic matrix containing multiple orthotropic elliptical inclusions. Numerical results are presented for the displacement fields at the interfaces of the inclusions in a broad frequency range of practical interest. Through the analysis of plane elastodynamic problems in an unbounded isotropic matrix with multiple orthotropic elliptical inclusions, it is established that this new method is very accurate and effective for solving plane elastic problems in unbounded solids containing general anisotropic inclusions of arbitrary shapes.

  11. Acclimation to hypoxia increases carbohydrate use during exercise in high-altitude deer mice.

    Science.gov (United States)

    Lau, Daphne S; Connaty, Alex D; Mahalingam, Sajeni; Wall, Nastashya; Cheviron, Zachary A; Storz, Jay F; Scott, Graham R; McClelland, Grant B

    2017-03-01

    The low O2 experienced at high altitude is a significant challenge to effective aerobic locomotion, as it requires sustained tissue O2 delivery in addition to the appropriate allocation of metabolic substrates. Here, we tested whether high- and low-altitude deer mice (Peromyscus maniculatus) have evolved different acclimation responses to hypoxia with respect to muscle metabolism and fuel use during submaximal exercise. Using F1 generation high- and low-altitude deer mice that were born and raised in common conditions, we assessed 1) fuel use during exercise, 2) metabolic enzyme activities, and 3) gene expression for key transporters and enzymes in the gastrocnemius. After hypoxia acclimation, highland mice showed a significant increase in carbohydrate oxidation and higher relative reliance on this fuel during exercise at 75% maximal O2 consumption. Compared with lowland mice, highland mice had consistently higher activities of oxidative and fatty acid oxidation enzymes in the gastrocnemius. In contrast, only after hypoxia acclimation did activities of hexokinase increase significantly in the muscle of highland mice to levels greater than lowland mice. Highland mice also responded to acclimation with increases in muscle gene expression for hexokinase 1 and 2 genes, whereas both populations increased mRNA expression for glucose transporters. Changes in skeletal muscle with acclimation suggest that highland mice had an increased capacity for the uptake and oxidation of circulatory glucose. Our results demonstrate that highland mice have evolved a distinct mode of hypoxia acclimation that involves an increase in carbohydrate use during exercise. Copyright © 2017 the American Physiological Society.

  12. Developmental Hypoxia Has Negligible Effects on Long-Term Hypoxia Tolerance and Aerobic Metabolism of Atlantic Salmon (Salmo salar).

    Science.gov (United States)

    Wood, Andrew T; Clark, Timothy D; Andrewartha, Sarah J; Elliott, Nicholas G; Frappell, Peter B

    Exposure to developmental hypoxia can have long-term impacts on the physiological performance of fish because of irreversible plasticity. Wild and captive-reared Atlantic salmon (Salmo salar) can be exposed to hypoxic conditions during development and continue to experience fluctuating oxygen levels as juveniles and adults. Here, we examine whether developmental hypoxia impacts subsequent hypoxia tolerance and aerobic performance of Atlantic salmon. Individuals at 8°C were exposed to 50% (hypoxia) or 100% (normoxia) dissolved oxygen (DO) saturation (as percent of air saturation) from fertilization for ∼100 d (800 degree days) and then raised in normoxic conditions for a further 15 mo. At 18 mo after fertilization, aerobic scope was calculated in normoxia (100% DO) and acute (18 h) hypoxia (50% DO) from the difference between the minimum and maximum oxygen consumption rates ([Formula: see text] and [Formula: see text], respectively) at 10°C. Hypoxia tolerance was determined as the DO at which loss of equilibrium (LOE) occurred in a constantly decreasing DO environment. There was no difference in [Formula: see text], [Formula: see text], or aerobic scope between fish raised in hypoxia or normoxia. There was some evidence that hypoxia tolerance was lower (higher DO at LOE) in hypoxia-raised fish compared with those raised in normoxia, but the magnitude of the effect was small (12.52% DO vs. 11.73% DO at LOE). Acute hypoxia significantly reduced aerobic scope by reducing [Formula: see text], while [Formula: see text] remained unchanged. Interestingly, acute hypoxia uncovered individual-level relationships between DO at LOE and [Formula: see text], [Formula: see text], and aerobic scope. We discuss our findings in the context of developmental trajectories and the role of aerobic performance in hypoxia tolerance.

  13. Effect of vitamin E on cerebral cortical oxidative stress and brain-derived neurotrophic factor gene expression induced by hypoxia and exercise in rats.

    Science.gov (United States)

    Sakr, H F; Abbas, A M; El Samanoudy, A Z

    2015-04-01

    Brain-derived neurotrophic factor (BDNF) is involved in the proliferation of neurons, and its expression increases significantly with exercise. We aimed to investigate the effects of chronic exercise (swimming) and sustained hypoxia on cortical BDNF expression in both the presence and absence of vitamin E. Sixty four male Sprague-Dawley rats were divided into two equal groups; a normoxic group and a hypoxic group. Both groups were equally subdivided into four subgroups: sedentary, sedentary with vitamin E, chronic exercise either with or without vitamin E supplementation. Arterial PO(2), and the levels of cortical malondialdehyde (MDA), antioxidants (reduced glutathione GSH, superoxide dismutase (SOD), catalase (CAT) and vitamin E) and BDNF gene expression were investigated. Hypoxia significantly increased MDA production and BDNF gene expression and decreased the antioxidants compared to control rats. Chronic exercise in hypoxic and normoxic rats increased MDA level and BDNF gene expression and decreased the antioxidants. Providing vitamin E supplementation to the hypoxic and normoxic rats significantly reduced MDA and BDNF gene expression and increased antioxidants. We conclude that sustained hypoxia and chronic exercise increased BDNF gene expression and induced oxidative stress. Moreover, vitamin E attenuated the oxidative stress and decreased BDNF gene expression in sustained hypoxia and chronic exercise which confirms the oxidative stress-induced stimulation of BDNF gene expression.

  14. Acrylamide affects proliferation and differentiation of the neural progenitor cell line C17.2 and the neuroblastoma cell line SH-SY5Y.

    Science.gov (United States)

    Attoff, K; Kertika, D; Lundqvist, J; Oredsson, S; Forsby, A

    2016-09-01

    Acrylamide is a well-known neurotoxic compound and people get exposed to the compound by food consumption and environmental pollutants. Since acrylamide crosses the placenta barrier, the fetus is also being exposed resulting in a risk for developmental neurotoxicity. In this study, the neural progenitor cell line C17.2 and the neuroblastoma cell line SH-SY5Y were used to study proliferation and differentiation as alerting indicators for developmental neurotoxicity. For both cell lines, acrylamide reduced the number of viable cells by reducing proliferation and inducing cell death in undifferentiated cells. Acrylamide concentrations starting at 10fM attenuated the differentiation process in SH-SY5Y cells by sustaining cell proliferation and neurite outgrowth was reduced at concentrations from 10pM. Acrylamide significantly reduced the number of neurons starting at 1μM and altered the ratio between the different phenotypes in differentiating C17.2 cell cultures. Ten micromolar of acrylamide also reduced the expression of the neuronal and astrocyte biomarkers. Although the neurotoxic concentrations in the femtomolar range seem to be specific for the SH-SY5Y cell line, the fact that micromolar concentrations of acrylamide seem to attenuate the differentiation process in both cell lines raises the interest to further investigations on the possible developmental neurotoxicity of acrylamide. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

  15. Sustainable Disruptions

    DEFF Research Database (Denmark)

    Friis, Silje Alberthe Kamille; Kjær, Lykke Bloch

    2016-01-01

    Since 2012 the Sustainable Disruptions (SD) project at the Laboratory for Sustainability at Design School Kolding (DK) has developed and tested a set of design thinking tools, specifically targeting the barriers to economically, socially, and environmentally sustainable business development....... The tools have been applied in practice in collaboration with 11 small and medium sized companies (SMEs). The study investigates these approaches to further understand how design thinking can contribute to sustainable transition in a business context. The study and the findings are relevant to organizations...... invested in the issue of sustainable business development, in particular the leaders and employees of SMEs, but also to design education seeking new ways to consciously handle and teach the complexity inherent in sustainable transformation. Findings indicate that the SD design thinking approach contributes...

  16. Synthetic Pre-miRNA-Based shRNA as Potent RNAi Triggers

    Directory of Open Access Journals (Sweden)

    Kazuya Terasawa

    2011-01-01

    Full Text Available RNA interference (RNAi is a powerful tool for studying gene function owing to the ease with which it can selectively silence genes of interest, and it has also attracted attention because of its potential for therapeutic applications. Chemically synthesized small interfering RNAs (siRNAs and DNA vector-based short hairpin RNAs (shRNAs are now widely used as RNAi triggers. In contrast to expressed shRNAs, the use of synthetic shRNAs is limited. Here we designed shRNAs modeled on a precursor microRNA (pre-miRNA and evaluated their biological activity. We demonstrated that chemically synthetic pre-miRNA-based shRNAs have more potent RNAi activity than their corresponding siRNAs and found that their antisense strands are more efficiently incorporated into the RNA-induced silencing complex. Although greater off-target effects and interferon responses were induced by shRNAs than by their corresponding siRNAs, these effects could be overcome by simply using a lower concentration or by optimizing and chemically modifying shRNAs similar to synthetic siRNAs. These are challenges for the future.

  17. SH3BP2 is rarely mutated in exon 9 in giant cell lesions outside cherubism.

    Science.gov (United States)

    Lietman, Steven A; Prescott, Nichole L; Hicks, David G; Westra, William H; Levine, Michael A

    2007-06-01

    Giant cell tumor of bone and giant cell reparative granuloma are benign lesions with prominent giant (multinucleated) cells, and an understanding of the molecular biology and genetics of these lesions will likely aid in more effective treatment. Cherubism is a benign lesion of the maxilla and mandible histologically similar to giant cell tumor of bone and giant cell reparative granuloma. Germline mutations in exon 9 of the gene encoding Src homology 3 binding protein 2 (SH3BP2) occur in most patients with cherubism. We therefore hypothesized SH3BP2 and its putative downstream effector nuclear factor of activated T cells c1 isoform (NFATc1) are highly expressed in sporadic nonsyndromic giant cell lesions and associated with somatic SH3BP2 mutations. We analyzed giant cell lesions for SH3BP2 and NFATc1 expression by RNA blot and/or immunohistochemistry and for exon 9 SH3BP2 mutations. We found the SH3BP2 transcripts and protein were abundantly expressed in giant cell tumors of bone, as well as NFATc1 protein. Sequencing of exon 9 of SH3BP2 was normal in all sporadic nonsyndromic giant cell lesions. Although many multinucleated giant cell lesions of bone share histologic features, the primary genetic defect in cherubism and these other giant cell lesions appears different.

  18. [Gene mutation and expression of SH-3BP-2 in cherubism].

    Science.gov (United States)

    Li, You-wei; Meng, Xue-mei; Yu, Shi-feng; Gao, Ping

    2009-04-01

    To detect the mutation and expression of SH-3BP-2 in Chinese patients of cherubism and to investigate the possible relationship of gene mutation and multinucleated giant cells in lesions. Genomic DNA was extracted from paraffin-imbedded tissues and peripheral blood samples of 10 cases of cherubism (6 familial cherubism and 4 sporadic cherubism). SH-3BP-2 mutations were detected by PCR-direct sequencing. The nature of multinucleated giant cells in lesions was detected by enzyme histochemical staining and immunohistochemical staining using paraffin-imbedded tissues sections. The SH-3BP-2 protein was detected by immunohistochemical staining. Three missense mutations (G1520A, G1505A, G1505C) in exon 9 of SH-3BP-2 were identified which led to 3 transitions (Gly420Glu, Arg415Gln, Arg415Pro). There were no abnormalities in exon 3 of SH-3BP-2 except 1 case which had not PCR products. The protein SH-3BP-2, the calcitonin receptor and the tartrate-resistant acid phosphatase were detected in the cytoplasm of all multinucleated giant cells and parts of monokaryon matrix cells in 8 paraffin-imbedded samples. The SH-3BP-2 mutation may participate in the differentiation and maturation of osteoclast-like cells in the lesion of cherubism.

  19. MeSH term explosion and author rank improve expert recommendations.

    Science.gov (United States)

    Lee, Danielle H; Schleyer, Titus

    2010-11-13

    Information overload is an often-cited phenomenon that reduces the productivity, efficiency and efficacy of scientists. One challenge for scientists is to find appropriate collaborators in their research. The literature describes various solutions to the problem of expertise location, but most current approaches do not appear to be very suitable for expert recommendations in biomedical research. In this study, we present the development and initial evaluation of a vector space model-based algorithm to calculate researcher similarity using four inputs: 1) MeSH terms of publications; 2) MeSH terms and author rank; 3) exploded MeSH terms; and 4) exploded MeSH terms and author rank. We developed and evaluated the algorithm using a data set of 17,525 authors and their 22,542 papers. On average, our algorithms correctly predicted 2.5 of the top 5/10 coauthors of individual scientists. Exploded MeSH and author rank outperformed all other algorithms in accuracy, followed closely by MeSH and author rank. Our results show that the accuracy of MeSH term-based matching can be enhanced with other metadata such as author rank.

  20. Mapping of medical acronyms and initialisms to Medical Subject Headings (MeSH) across selected systems.

    Science.gov (United States)

    Shultz, Mary

    2006-10-01

    Given the common use of acronyms and initialisms in the health sciences, searchers may be entering these abbreviated terms rather than full phrases when searching online systems. The purpose of this study is to evaluate how various MEDLINE Medical Subject Headings (MeSH) interfaces map acronyms and initialisms to the MeSH vocabulary. The interfaces used in this study were: the PubMed MeSH database, the PubMed Automatic Term Mapping feature, the NLM Gateway Term Finder, and Ovid MEDLINE. Acronyms and initialisms were randomly selected from 2 print sources. The test data set included 415 randomly selected acronyms and initialisms whose related meanings were found to be MeSH terms. Each acronym and initialism was entered into each MEDLINE MeSH interface to determine if it mapped to the corresponding MeSH term. Separately, 46 commonly used acronyms and initialisms were tested. While performance differed widely, the success rates were low across all interfaces for the randomly selected terms. The common acronyms and initialisms tested at higher success rates across the interfaces, but the differences between the interfaces remained. Online interfaces do not always map medical acronyms and initialisms to their corresponding MeSH phrases. This may lead to inaccurate results and missed information if acronyms and initialisms are used in search strategies.

  1. Computational sustainability

    CERN Document Server

    Kersting, Kristian; Morik, Katharina

    2016-01-01

    The book at hand gives an overview of the state of the art research in Computational Sustainability as well as case studies of different application scenarios. This covers topics such as renewable energy supply, energy storage and e-mobility, efficiency in data centers and networks, sustainable food and water supply, sustainable health, industrial production and quality, etc. The book describes computational methods and possible application scenarios.

  2. Hypoxia symptoms during altitude training in professional Iranian fighter pilots.

    Science.gov (United States)

    Alagha, Babak; AhmadBeygi, Shervin; Ahmadbeigy, Shervin; Moosavi, Seyed Ali Javad; Jalali, Seyed Mahmood

    2012-01-01

    Susceptibility to hypoxia is influenced by a multitude of factors, including fatigue, physical activity, illnesses, ambient temperature, rate of ascent, destination altitude, medications, and alcohol. Anecdotally, several reports have been made regarding changes in the form of hypoxia presentation in Iranian fighter pilots in the absence of these factors. This study focused specifically on the effect of pilot age on susceptibility to hypoxia and its initial presentation. We assumed that a pilot's age may increase his susceptibility to hypoxia and consequently reduce the amount of time it takes for hypoxia to present. Because our literature review did not reveal any previous study addressing the possible relationship between age and susceptibility to hypoxia, the purpose of this study is to address and clarify this relationship. In this retrospective study, we collected information from Iranian fighter pilots (n = 30) through an anonymous questionnaire in 2000. The form of hypoxia presentation of each subject was evaluated during five altitude chamber training (ACT) sessions that were conducted routinely from 1972 to 1984. To enhance the accuracy of the study's results, confounding factors such as prior hypoxia experience in an ACT session have been taken into consideration. The results revealed a statistically significant relationship between age and a change in the form of hypoxia presentation in our subjects. Increased age reduced the amount of time before the first individual hypoxia symptom appeared (P pilots to recognize their symptoms earlier, its effect was not statistically significant (P pilot age and change in the nature of symptoms. Susceptibility ot hypoxia increases with pilot age. Copyright © 2012 Air Medical Journal Associates. Published by Elsevier Inc. All rights reserved.

  3. Developing vascular and hypoxia based theranostics in solid tumors

    Science.gov (United States)

    Koonce, Nathan A.

    Tissue hypoxia was recognized for its biological attenuating effects on ionizing radiation over a century ago and is a characteristic feature of many solid tumors. Clinical and experimental evidence indicates tumor hypoxia plays diverse and key roles in tumor progression, angiogenesis, and resistance to chemotherapy/radiotherapy. Hypoxia has known effects on progression and resistance to several standard treatment approaches and the significant history of study might suggest diagnostic imaging and therapeutic interventions would be routine in oncological practice. Curiously, this is not the case and the research results involved in this report will attempt to better understand and contribute to why this gap in knowledge exists and a rationale for harnessing the potential of detecting and targeting hypoxia. Despite the addition of oxygen and reversal of hypoxia being known as the best radiosensitizer, hypoxia remains unexploited in clinical cancer therapy. The studies reported herein detail development of a novel imaging technique to detect a subtype of tumor hypoxia, vascular hypoxia or hypoxemia, with a 17-fold increase (pradiotherapy resulted in a 5.25-fold growth delay that was found to be synergistic (p<0.05) and suggests clinical evaluation is warranted. An additional study to evaluate an approach to use thermal ablation of intratumoral hypoxia by an image-guided technique developed in our group is described along with a sequence dependence of radiation preceding ablation. A final study on the use of galectin-1 antagonist to significantly decrease (p<0.05) hypoxia in the tumor microenvironment by altering tumor vessel characteristics is illustrated in Chapter 5. Overall, this thesis details imaging approaches of tumor hypoxia and its detection, quantification and targeting in therapeutic approaches.

  4. Sustainable transformation

    DEFF Research Database (Denmark)

    Andersen, Nicolai Bo

    This paper is about sustainable transformation with a particular focus on listed buildings. It is based on the notion that sustainability is not just a question of energy conditions, but also about the building being robust. Robust architecture means that the building can be maintained and rebuilt...... theoretical lenses. It is proposed that three parameters concerning the ꞌtransformabilityꞌ of the building can contribute to a more nuanced understanding of sustainable transformation: technical aspects, programmatic requirements and narrative value. It is proposed that the concept of ꞌsustainable...

  5. Modulation of cardiac mitochondrial permeability transition and apoptotic signaling by endurance training and intermittent hypobaric hypoxia.

    Science.gov (United States)

    Magalhães, J; Gonçalves, I O; Lumini-Oliveira, J; Marques-Aleixo, I; Passos, E; Rocha-Rodrigues, S; Machado, N G; Moreira, A C; Rizo, D; Viscor, G; Oliveira, P J; Torrella, J R; Ascensão, A

    2014-04-15

    Modulation of the mitochondrial permeability transition pore (MPTP) and inhibition of the apoptotic signaling are critically associated with the cardioprotective phenotypes afforded by both intermittent hypobaric-hypoxia (IHH) and endurance-training (ET). We recently proposed that IHH and ET improve cardiac function and basic mitochondrial capacity, although without showing addictive effects. Here we investigate whether a combination of IHH and ET alters cardiac mitochondrial vulnerability to MPTP and related apoptotic signaling. Male Wistar rats were divided into normoxic-sedentary (NS), normoxic-exercised (NE, 1h/day/5 week treadmill-running), hypoxic-sedentary (HS, 6000 m, 5h/day/5 weeks) and hypoxic-exercised (HE) to study susceptibility to calcium-induced cardiac MPTP opening. Mitochondrial cyclophilin D (CypD), adenine nucleotide translocator (ANT), Bax and Bcl-2 protein contents were semi-quantified by Western blotting. Cardiac caspase 3-, 8- and 9-like activities were measured. Mitochondrial aconitase and superoxide dismutase (MnSOD) activity and malondialdehyde (MDA) and sulphydryl group (-SH) content were determined. Susceptibility to MPTP decreased in NE and HS vs. NS and even further in HE. The ANT content increased in HE vs. NS. Bcl-2/Bax ratio increased in NE and HS compared to NS. Decreased activities in tissue caspase 3-like (HE vs. NS) and caspase 9-like (HS and HE vs. NS) were observed. Mitochondrial aconitase increased in NE and HS vs. NS. No alterations between groups were observed for caspase 8-like activity, MnSOD, CypD, MDA and -SH. Data confirm that IHH and ET modulate cardiac mitochondria to a protective phenotype characterized by decreased MPTP induction and apoptotic signaling, although without visible addictive effects as initially hypothesized. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  6. The Spectrum of Jupiters Great Red Spot: the Case for Ammonium Hydrosulfide (NH4SH)

    Science.gov (United States)

    Loeffler, Mark J.; Hudson, Reggie L.; Chanover, Nancy J.; Simon, Amy A.

    2016-01-01

    Here we present new ultraviolet-visible spectra of irradiated ammonium hydrosul?de (NH4SH), a reported Jovian atmospheric cloud component, for a range of temperatures and radiation doses and make assignments to the spectral features. We show that the combination of radiolysis and thermal annealing of NH4SH causes the originally featureless ultraviolet-visible re?ectance spectrum to evolve into one that absorbs in the ultraviolet-visible region. Furthermore, we ?nd that our laboratory spectra resemble HST (Hubble Space Telescope) spectra below 500 nanometers, suggesting that the more stable reaction products of NH4SH radiolysis are likely an important component of the Great Red Spot.

  7. Kit (W-sh) Mutation Prevents Cancellous Bone Loss during Calcium Deprivation.

    Science.gov (United States)

    Lotinun, Sutada; Suwanwela, Jaijam; Poolthong, Suchit; Baron, Roland

    2017-10-14

    Calcium is essential for normal bone growth and development. Inadequate calcium intake increases the risk of osteoporosis and fractures. Kit ligand/c-Kit signaling plays an important role in regulating bone homeostasis. Mice with c-Kit mutations are osteopenic. The present study aimed to investigate whether impairment of or reduction in c-Kit signaling affects bone turnover during calcium deprivation. Three-week-old male WBB6F1/J-Kit (W) /Kit (W-v) /J (W/W (v) ) mice with c-Kit point mutation, Kit (W-sh) /HNihrJaeBsmJ (W (sh) /W (sh) ) mice with an inversion mutation in the regulatory elements upstream of the c-Kit promoter region, and their wild-type controls (WT) were fed either a normal (0.6% calcium) or a low calcium diet (0.02% calcium) for 3 weeks. μCT analysis indicated that both mutants fed normal calcium diet had significantly decreased cortical thickness and cancellous bone volume compared to WT. The low calcium diet resulted in a comparable reduction in cortical bone volume and cortical thickness in the W/W (v) and W (sh) /W (sh) mice, and their corresponding controls. As expected, the low calcium diet induced cancellous bone loss in the W/W (v) mice. In contrast, W (sh) /W (sh) cancellous bone did not respond to this diet. This c-Kit mutation prevented cancellous bone loss by antagonizing the low calcium diet-induced increase in osteoblast and osteoclast numbers in the W (sh) /W (sh) mice. Gene expression profiling showed that calcium deficiency increased Osx, Ocn, Alp, type I collagen, c-Fms, M-CSF, and RANKL/OPG mRNA expression in controls; however, the W (sh) mutation suppressed these effects. Our findings indicate that although calcium restriction increased bone turnover, leading to osteopenia, the decreased c-Kit expression levels in the W (sh) /W (sh) mice prevented the low calcium diet-induced increase in cancellous bone turnover and bone loss but not the cortical bone loss.

  8. The Spectrum of Jupiter's Great Red Spot: The Case for Ammonium Hydrosulfide (NH4SH)

    Science.gov (United States)

    Loeffler, Mark J.; Hudson, Reggie L.; Chanover, Nancy J.; Simon, Amy A.

    2016-01-01

    Here we present new ultraviolet-visible spectra of irradiated ammonium hydrosul?de (NH4SH), a reported Jovian atmospheric cloud component, for a range of temperatures and radiation doses and make assignments to the spectral features. We show that the combination of radiolysis and thermal annealing of NH4SH causes the originally featureless ultraviolet-visible re?ectance spectrum to evolve into one that absorbs in the ultraviolet-visible region. Furthermore, we ?nd that our laboratory spectra resemble HST (Hubble Space Telescope) spectra below 500 nanometers, suggesting that the more stable reaction products of NH4SH radiolysis are likely an important component of the Great Red Spot.

  9. Hypoxia positron emission tomography imaging: combining information on perfusion and tracer retention to improve hypoxia specificity

    DEFF Research Database (Denmark)

    Busk, Morten; Munk, Ole L; Jakobsen, Steen S

    2017-01-01

    protocols suitable for routine clinical use are warranted. A modeling study proposed that hypoxia specificity can be improved by a clinically feasible blood-flow normalization procedure that only requires a 10- to 15-min dynamic scan (perfusion), followed by a short late static scan, but experimental...

  10. Intermittent hypoxia training in prediabetes patients: Beneficial effects on glucose homeostasis, hypoxia tolerance and gene expression.

    Science.gov (United States)

    Serebrovska, Tetiana V; Portnychenko, Alla G; Drevytska, Tetiana I; Portnichenko, Vladimir I; Xi, Lei; Egorov, Egor; Gavalko, Anna V; Naskalova, Svitlana; Chizhova, Valentina; Shatylo, Valeriy B

    2017-09-01

    The present study aimed at examining beneficial effects of intermittent hypoxia training (IHT) under prediabetic conditions. We investigate the effects of three-week IHT on blood glucose level, tolerance to acute hypoxia, and leukocyte mRNA expression of hypoxia inducible factor 1α (HIF-1α) and its target genes, i.e. insulin receptor, facilitated glucose transporter-solute carrier family-2, and potassium voltage-gated channel subfamily J. Seven healthy and 11 prediabetic men and women (44-70 years of age) were examined before, next day and one month after three-week IHT (3 sessions per week, each session consisting 4 cycles of 5-min 12% O 2 and 5-min room air breathing). We found that IHT afforded beneficial effects on glucose homeostasis in patients with prediabetes reducing fasting glucose and during standard oral glucose tolerance test. The most pronounced positive effects were observed at one month after IHT termination. IHT also significantly increased the tolerance to acute hypoxia (i.e. SaO 2 level at 20th min of breathing with 12% O 2 ) and improved functional parameters of respiratory and cardiovascular systems. IHT stimulated HIF-1α mRNA expression in blood leukocytes in healthy and prediabetic subjects, but in prediabetes patients the maximum increase was lagged. The greatest changes in mRNA expression of HIF-1α target genes occurred a month after IHT and coincided with the largest decrease in blood glucose levels. The higher expression of HIF-1α was positively associated with higher tolerance to hypoxia and better glucose homeostasis. In conclusion, our results suggest that IHT may be useful for preventing the development of type 2 diabetes. Impact statement The present study investigated the beneficial effects of intermittent hypoxia training (IHT) in humans under prediabetic conditions. We found that three-week moderate IHT induced higher HIF-1α mRNA expressions as well as its target genes, which were positively correlated with higher tolerance

  11. Hypoxia-regulated MicroRNAs in gastroesophageal cancer

    DEFF Research Database (Denmark)

    Winther, M.; Alsner, J.; Sørensen, B.S.

    2016-01-01

    Background/aim: The present study aimed to identify hypoxia-regulated microRNAs (HRMs) in vitro and investigate the clinical role of candidate HRMs in patients with gastroesophageal cancer (GEC). Materials and Methods: microRNA expression changes induced by hypoxia in human GEC cell lines were...

  12. Brain adaptation to hypoxia and hyperoxia in mice

    Directory of Open Access Journals (Sweden)

    Laura Terraneo

    2017-04-01

    Conclusion: Prolonged mild hyperoxia leads to persistent cerebral damage, comparable to that inferred by prolonged mild hypoxia. The underlying mechanism appears related to a model whereby the imbalance between ROS generation and anti-ROS defense is similar, but occurs at higher levels in hypoxia than in hyperoxia.

  13. Effect of Chronic hypoxia on Carotid vascular responses to ...

    African Journals Online (AJOL)

    Aim: The aim of the present study was to examine whether chronic hypoxia would alter the noradrenaline (NA)-evoked vascular responses in carotid circulation in rats. Furthermore, whether the carotid autoregulatory response to NA-evoked rise in arterial blood pressure (ABP) is compromised by chronic hypoxia or not. Also ...

  14. Evaluation of Notch and Hypoxia Signaling Pathways in Chemically ...

    African Journals Online (AJOL)

    Hepatocellular carcinoma (HCC) is a common worldwide malignancy. Notch signaling pathway contributes to the genesis of diverse cancers, however, its role in HCC is unclear. Hypoxia is a common feature of HCC. Signal integration between Notch and hypoxia may be involved in HCC. The aim of this study was to ...

  15. The infectious hypoxia: occurrence and causes during Shigella infection.

    Science.gov (United States)

    Arena, Ellen T; Tinevez, Jean-Yves; Nigro, Giulia; Sansonetti, Philippe J; Marteyn, Benoit S

    2017-03-01

    Hypoxia is defined as a tissue oxygenation status below physiological needs. During Shigella infection, an infectious hypoxia is induced within foci of infection. In this review, we discuss how Shigella physiology and virulence are modulated and how the main recruited immune cells, the neutrophils, adapt to this environment. Copyright © 2016 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.

  16. Hypoxia-inducible factor 1-α in chronic gastrointestinal ischemia

    NARCIS (Netherlands)

    Harki, Jihan; Sana, Aria; van Noord, Désirée; van Diest, Paul J; van der Groep, Petra; Kuipers, Ernst J; Moons, Leon M G; Biermann, Katharina; Tjwa, Eric T T L

    Chronic gastrointestinal ischemia (CGI) is the result of decreased mucosal perfusion. Typical histological characteristics are lacking which hamper its early diagnosis. Hypoxia-inducible factor-1α (HIF-1α) is expressed under acute hypoxia. We investigated HIF-1α expression in chronic ischemic and

  17. Hypoxia-inducible factor 1-α in chronic gastrointestinal ischemia

    NARCIS (Netherlands)

    J. Harki (Jihan); A. Sana (Aria); D. van Noord (Désirée); P.J. van Diest (Paul); P. van der Groep (Petra); E.J. Kuipers (Ernst); L.M.G. Moons (Leon); K. Biermann (Katharina); E.T.T.L. Tjwa (Eric)

    2014-01-01

    textabstractChronic gastrointestinal ischemia (CGI) is the result of decreased mucosal perfusion. Typical histological characteristics are lacking which hamper its early diagnosis. Hypoxia-inducible factor-1α (HIF-1α) is expressed under acute hypoxia. We investigated HIF-1α expression in chronic

  18. Hypoxia-inducible factor 1-alpha in chronic gastrointestinal ischemia

    NARCIS (Netherlands)

    Harki, J.; Sana, A.; Noord, D. van; Diest, P.J. van; Groep, P. van der; Kuipers, E.J.; Moons, L.M.; Biermann, K.; Tjwa, E.T.

    2015-01-01

    Chronic gastrointestinal ischemia (CGI) is the result of decreased mucosal perfusion. Typical histological characteristics are lacking which hamper its early diagnosis. Hypoxia-inducible factor-1alpha (HIF-1alpha) is expressed under acute hypoxia. We investigated HIF-1alpha expression in chronic

  19. The effect of altitude hypoxia on glucose homeostasis in men

    DEFF Research Database (Denmark)

    Larsen, J J; Hansen, J M; Olsen, Niels Vidiendal

    1997-01-01

    1. Exposure to altitude hypoxia elicits changes in glucose homeostasis with increases in glucose and insulin concentrations within the first few days at altitude. Both increased and unchanged hepatic glucose production (HGP) have previously been reported in response to acute altitude hypoxia...

  20. Sustainable Transportation

    DEFF Research Database (Denmark)

    Hall, Ralph P.; Gudmundsson, Henrik; Marsden, Greg

    2014-01-01

    that relate to the construction and maintenance of transportation infrastructure and the operation or use of the different transportation modes. The concept of sustainable transportation emerged in response to these concerns as part of the broader notion of sustainable development. Given the transportation...

  1. Sustaining dairy

    NARCIS (Netherlands)

    Villarreal Herrera, Georgina

    2017-01-01

    Dairy in Europe has undergone many changes in the last few years—the abolition of milk production quotas being a fundamental one. This study explores these changes in relation to the sustained social and environmental viability of the sector and how dairy processors' sustainability

  2. Sustainable Universities

    DEFF Research Database (Denmark)

    Grindsted, Thomas Skou

    2011-01-01

    . Declarations tend to have impact on three trends. Firstly, there is emerging international consensus on the university’s role and function in relation to sustainable development; secondly, the emergence of national legislation, and thirdly, an emerging international competition to be leader in sustainable...... campus performance....

  3. Sustainable Transition

    DEFF Research Database (Denmark)

    Hansen, Ole Erik; Søndergård, Bent

    2014-01-01

    of agendas/vision, technologies, actors and institutions in the emergent design of an urban mobility system based on an electric car sharing system. Why. Designing for sustainability is a fundamental challenge for future design practices; designers have to obtain an ability to contribute to sustainable...

  4. Sustainable Learning

    Science.gov (United States)

    Cadwell, Louise; Dillon, Robert

    2011-01-01

    Green schools have moved into a new era that focuses on building a culture of sustainability in every aspect of learning in schools. In the early stages of sustainability education, the focus was on recycling and turning off the lights. Now, students and adults together are moving into the areas of advocacy and action that are based on a deep…

  5. Intermittent hypoxia training: Powerful, non-invasive cerebroprotection against ethanol withdrawal excitotoxicity.

    Science.gov (United States)

    Jung, Marianna E; Mallet, Robert T

    2017-08-12

    Ethanol intoxication and withdrawal exact a devastating toll on the central nervous system. Abrupt ethanol withdrawal provokes massive release of the excitatory neurotransmitter glutamate, which over-activates its postsynaptic receptors, causing intense Ca 2+ loading, p38 mitogen activated protein kinase activation and oxidative stress, culminating in ATP depletion, mitochondrial injury, amyloid β deposition and neuronal death. Collectively, these mechanisms produce neurocognitive and sensorimotor dysfunction that discourages continued abstinence. Although the brain is heavily dependent on blood-borne O 2 to sustain its aerobic ATP production, brief, cyclic episodes of moderate hypoxia and reoxygenation, when judiciously applied over the course of days or weeks, evoke adaptations that protect the brain from ethanol withdrawal-induced glutamate excitotoxicity, mitochondrial damage, oxidative stress and amyloid β accumulation. This review summarizes evidence from ongoing preclinical research that demonstrates intermittent hypoxia training to be a potentially powerful yet non-invasive intervention capable of affording robust, sustained neuroprotection during ethanol withdrawal. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. Normobaric hypoxia overnight impairs cognitive reaction time.

    Science.gov (United States)

    Pramsohler, Stephan; Wimmer, Stefan; Kopp, Martin; Gatterer, Hannes; Faulhaber, Martin; Burtscher, Martin; Netzer, Nikolaus Cristoph

    2017-05-15

    Impaired reaction time in patients suffering from hypoxia during sleep, caused by sleep breathing disorders, is a well-described phenomenon. High altitude sleep is known to induce periodic breathing with central apneas and oxygen desaturations, even in perfectly healthy subjects. However, deficits in reaction time in mountaineers or workers after just some nights of hypoxia exposure are not sufficiently explored. Therefore, we aimed to investigate the impact of sleep in a normobaric hypoxic environment on reaction time divided by its cognitive and motoric components. Eleven healthy non acclimatized students (5f, 6m, 21 ± 2.1 years) slept one night at a simulated altitude of 3500 m in a normobaric hypoxic room, followed by a night with polysomnography at simulated 5500 m. Preexisting sleep disorders were excluded via BERLIN questionnaire. All subjects performed a choice reaction test (SCHUHFRIED RT, S3) at 450 m and directly after the nights at simulated 3500 and 5500 m. We found a significant increase of cognitive reaction time with higher altitude (p = 0.026). No changes were detected in movement time (p = n.s.). Reaction time, the combined parameter of cognitive- and motoric reaction time, didn't change either (p = n.s.). Lower SpO2 surprisingly correlated significantly with shorter cognitive reaction time (r = 0.78, p = 0.004). Sleep stage distribution and arousals at 5500 m didn't correlate with reaction time, cognitive reaction time or movement time. Sleep in hypoxia does not seem to affect reaction time to simple tasks. The component of cognitive reaction time is increasingly delayed whereas motoric reaction time seems not to be affected. Low SpO2 and arousals are not related to increased cognitive reaction time therefore the causality remains unclear. The fact of increased cognitive reaction time after sleep in hypoxia, considering high altitude workers and mountaineering operations with overnight stays, should be further investigated.

  7. Association between receptor protein-tyrosine phosphatase RPTPalpha and the Grb2 adaptor. Dual Src homology (SH) 2/SH3 domain requirement and functional consequences

    DEFF Research Database (Denmark)

    Su, J; Yang, L T; Sap, J

    1996-01-01

    Receptor protein-tyrosine phosphatase RPTPalpha is found associated in vivo with the adaptor protein Grb2. Formation of this complex, which contains no detectable levels of Sos, is known to depend on a C-terminal phosphorylated tyrosine residue (Tyr798) in RPTPalpha and on the Src homology (SH) 2...... in vivo. These observations constitute a novel mode of Grb2 association and suggest a model in which association with a tyrosine-phosphorylated protein restricts the repertoire of SH3 binding proteins with which Grb2 can simultaneously interact. The function of the Tyr798 tyrosine phosphorylation/Grb2...

  8. Mechanism of hypoxia-induced NFκB

    Science.gov (United States)

    Melvin, Andrew; Mudie, Sharon

    2011-01-01

    The cellular response to hypoxia relies on the activation of a specific transcriptional program. Although, most of the attention is focused on the transcription factor HIF, other transcription factors are also activated in hypoxia. We have recently described the mechanism for hypoxia induced NFκB. We have demonstrated the crucial dependency on the IKK complex as well as in the upstream IKK kinase TAK1. TAK1 and IKK activation is dependent upon the calcium calmodulin kinase, CaMK2 and requires Ubc13 as the E2 ubiquitin conjugation enzyme. We report a role for XIAP as the possible E3-ubiquitin ligase for this system. Interestingly, hypoxia induced IKK mediated phosphorylation of IκBα, does not lead to degradation. Hypoxia prevents IκBα de-sumoylation of Sumo-2/3 chains on critical lysine residues, normally required for K-48 linked polyubiquitination. Our results define a novel pathway regulating NFκB activation. PMID:21325892

  9. Acquiring Plausible Predications from MEDLINE by Clustering MeSH Annotations.

    Science.gov (United States)

    Miñarro-Giménez, Jose Antonio; Kreuzthaler, Markus; Bernhardt-Melischnig, Johannes; Martínez-Costa, Catalina; Schulz, Stefan

    2015-01-01

    The massive accumulation of biomedical knowledge is reflected by the growth of the literature database MEDLINE with over 23 million bibliographic records. All records are manually indexed by MeSH descriptors, many of them refined by MeSH subheadings. We use subheading information to cluster types of MeSH descriptor co-occurrences in MEDLINE by processing co-occurrence information provided by the UMLS. The goal is to infer plausible predicates to each resulting cluster. In an initial experiment this was done by grouping disease-pharmacologic substance co-occurrences into six clusters. Then, a domain expert manually performed the assignment of meaningful predicates to the clusters. The mean accuracy of the best ten generated biomedical facts of each cluster was 85%. This result supports the evidence of the potential of MeSH subheadings for extracting plausible medical predications from MEDLINE.

  10. Infrared Spectra and Band Strengths of CH3SH, an Interstellar Molecule

    Science.gov (United States)

    Hudson, R. L.

    2016-01-01

    Three solid phases of CH3SH (methanethiol or methyl mercaptan) have been prepared and their mid-infrared spectra recorded at 10-110 degrees Kelvin, with an emphasis on the 17-100 degrees Kelvin region. Refractive indices have been measured at two temperatures and used to estimate ice densities and infrared band strengths. Vapor pressures for the two crystalline phases of CH3SH at 110 degrees Kelvin are estimated. The behavior of amorphous CH3SH on warming is presented and discussed in terms of Ostwald's step rule. Comparisons to CH3OH under similar conditions are made, and some inconsistencies and ambiguities in the CH3SH literature are examined and corrected.

  11. Hypoxia, hypoxia-inducible transcription factor, and macrophages in human atherosclerotic plaques are correlated with intraplaque angiogenesis

    NARCIS (Netherlands)

    Sluimer, Judith C.; Gasc, Jean-Marie; van Wanroij, Job L.; Kisters, Natasja; Groeneweg, Mathijs; Sollewijn Gelpke, Maarten D.; Cleutjens, Jack P.; van den Akker, Luc H.; Corvol, Pierre; Wouters, Bradly G.; Daemen, Mat J.; Bijnens, Ann-Pascale J.

    2008-01-01

    We sought to examine the presence of hypoxia in human carotid atherosclerosis and its association with hypoxia-inducible transcription factor (HIF) and intraplaque angiogenesis. Atherosclerotic plaques develop intraplaque angiogenesis, which is a typical feature of hypoxic tissue and expression of

  12. Semi-supervised prediction of SH2-peptide interactions from imbalanced high-throughput data.

    Directory of Open Access Journals (Sweden)

    Kousik Kundu

    Full Text Available Src homology 2 (SH2 domains are the largest family of the peptide-recognition modules (PRMs that bind to phosphotyrosine containing peptides. Knowledge about binding partners of SH2-domains is key for a deeper understanding of different cellular processes. Given the high binding specificity of SH2, in-silico ligand peptide prediction is of great interest. Currently however, only a few approaches have been published for the prediction of SH2-peptide interactions. Their main shortcomings range from limited coverage, to restrictive modeling assumptions (they are mainly based on position specific scoring matrices and do not take into consideration complex amino acids inter-dependencies and high computational complexity. We propose a simple yet effective machine learning approach for a large set of known human SH2 domains. We used comprehensive data from micro-array and peptide-array experiments on 51 human SH2 domains. In order to deal with the high data imbalance problem and the high signal-to-noise ration, we casted the problem in a semi-supervised setting. We report competitive predictive performance w.r.t. state-of-the-art. Specifically we obtain 0.83 AUC ROC and 0.93 AUC PR in comparison to 0.71 AUC ROC and 0.87 AUC PR previously achieved by the position specific scoring matrices (PSSMs based SMALI approach. Our work provides three main contributions. First, we showed that better models can be obtained when the information on the non-interacting peptides (negative examples is also used. Second, we improve performance when considering high order correlations between the ligand positions employing regularization techniques to effectively avoid overfitting issues. Third, we developed an approach to tackle the data imbalance problem using a semi-supervised strategy. Finally, we performed a genome-wide prediction of human SH2-peptide binding, uncovering several findings of biological relevance. We make our models and genome-wide predictions, for all

  13. An EMAT-based shear horizontal (SH) wave technique for adhesive bond inspection

    Science.gov (United States)

    Arun, K.; Dhayalan, R.; Balasubramaniam, Krishnan; Maxfield, Bruce; Peres, Patrick; Barnoncel, David

    2012-05-01

    The evaluation of adhesively bonded structures has been a challenge over the several decades that these structures have been used. Applications within the aerospace industry often call for particularly high performance adhesive bonds. Several techniques have been proposed for the detection of disbonds and cohesive weakness but a reliable NDE method for detecting interfacial weakness (also sometimes called a kissing bond) has been elusive. Different techniques, including ultrasonic, thermal imaging and shearographic methods, have been proposed; all have had some degree of success. In particular, ultrasonic methods, including those based upon shear and guided waves, have been explored for the assessment of interfacial bond quality. Since 3-D guided shear horizontal (SH) waves in plates have predominantly shear displacement at the plate surfaces, we conjectured that SH guided waves should be influenced by interfacial conditions when they propagate between adhesively bonded plates of comparable thickness. This paper describes a new technique based on SH guided waves that propagate within and through a lap joint. Through mechanisms we have yet to fully understand, the propagation of an SH wave through a lap joint gives rise to a reverberation signal that is due to one or more reflections of an SH guided wave mode within that lap joint. Based upon a combination of numerical simulations and measurements, this method shows promise for detecting and classifying interfacial bonds. It is also apparent from our measurements that the SH wave modes can discriminate between adhesive and cohesive bond weakness in both Aluminum-Epoxy-Aluminum and Composite-Epoxy-Composite lap joints. All measurements reported here used periodic permanent magnet (PPM) Electro-Magnetic Acoustic Transducers (EMATs) to generate either or both of the two lowest order SH modes in the plates that comprise the lap joint. This exact configuration has been simulated using finite element (FE) models to

  14. THE EMISSION NEBULA Sh 2-174: A RADIO INVESTIGATION OF THE SURROUNDING REGION

    Energy Technology Data Exchange (ETDEWEB)

    Ransom, R. R. [Department of Physics and Astronomy, Okanagan College, 583 Duncan Avenue West, Penticton, BC V2A 8E1 (Canada); Kothes, R.; Geisbuesch, J.; Landecker, T. L. [National Research Council Herzberg, Dominion Radio Astrophysical Observatory, P.O. Box 248, Penticton, BC V2A 6J9 (Canada); Reich, W., E-mail: RRansom@okanagan.bc.ca [Max-Planck-Institut für Radioastronomie, Auf dem Hügel 69, D-53121 Bonn (Germany)

    2015-02-01

    Sh 2-174 is believed to be either a planetary nebula (PN) or ionized, ambient interstellar medium (ISM). We present in this paper 1420 MHz polarization, 1420 MHz total intensity (Stokes-I), and neutral hydrogen (H I) images of the region around Sh 2-174. The radio images address not only the nature of the object, but also the history of the relationship between Sh 2-174 and its surrounding environment. The H I images show that Sh 2-174 sits presently at the center of a ∼1.°2 × ∼0.°4 cloud (with peak hydrogen density n {sub H} = 4 ± 2 cm{sup –3}). The Stokes-I image shows thermal-emission peaks (with electron densities n{sub e} = 11 ± 3 cm{sup –3}) coincident with the R-band optical nebula, as well as low-surface-brightness emission from an ionized ''halo'' around Sh 2-174 and from an ionized ''plateau'' extending southeast from the cloud. The polarization images reveal Faraday-rotation structures along the projected trajectory of Sh 2-174, including a high-contrast structure with ''arms'' that run precisely along the eastern edge of the H I cloud and a wide central region that merges with the downstream edge of Sh 2-174. The high-contrast structure is consistent with an ionized tail that has both early-epoch (before Sh 2-174 entered the cloud) and present-epoch (after Sh 2-174 entered the cloud) components. Furthermore, our rotation-measure analysis indicates that the ISM magnetic field is deflected at the leading edge of Sh 2-174. The downstream tail and upstream field deflection point to a PN-ISM interaction. Our estimated space velocity for the host white dwarf (GD 561) demonstrates that Sh 2-174 entered the cloud ∼27,000 yr ago, and gives a PN-ISM interaction timescale ≲ 2.0 × 10{sup 5} yr. We estimate an ambient magnetic field in the cloud of 11 ± 3 μG.

  15. Automatic Assignment of Non-Leaf MeSH Terms to Biomedical Articles.

    Science.gov (United States)

    Kavuluru, Ramakanth; Rios, Anthony

    2015-01-01

    Assigning labels from a hierarchical vocabulary is a well known special case of multi-label classification, often modeled to maximize micro F1-score. However, building accurate binary classifiers for poorly performing labels in the hierarchy can improve both micro and macro F1-scores. In this paper, we propose and evaluate classification strategies involving descendant node instances to build better binary classifiers for non-leaf labels with the use-case of assigning Medical Subject Headings (MeSH) to biomedical articles. Librarians at the National Library of Medicine tag each biomedical article to be indexed by their PubMed information system with terms from the MeSH terminology, a biomedical conceptual hierarchy with over 27,000 terms. Human indexers look at each article's full text to assign a set of most suitable MeSH terms for indexing it. Several recent automated attempts focused on using the article title and abstract text to identify MeSH terms for the corresponding article. Despite these attempts, it is observed that assigning MeSH terms corresponding to certain non-leaf nodes of the MeSH hierarchy is particularly challenging. Non-leaf nodes are very important as they constitute one third of the total number of MeSH terms. Here, we demonstrate the effectiveness of exploiting training examples of descendant terms of non-leaf nodes in improving the performance of conventional classifiers for the corresponding non-leaf MeSH terms. Specifically, we focus on reducing the false positives (FPs) caused due to descendant instances in traditional classifiers. Our methods are able to achieve a relative improvement of 7.5% in macro-F1 score while also increasing the micro-F1 score by 1.6% for a set of 500 non-leaf terms in the MeSH hierarchy. These results strongly indicate the critical role of incorporating hierarchical information in MeSH term prediction. To our knowledge, our effort is the first to demonstrate the role of hierarchical information in improving

  16. Impairment by hypoxia or hypoxia/reoxygenation of nitric oxide-mediated relaxation in isolated monkey coronary artery: the role of intracellular superoxide.

    Science.gov (United States)

    Tawa, Masashi; Yamamizu, Kohei; Geddawy, Ayman; Shimosato, Takashi; Imamura, Takeshi; Ayajiki, Kazuhide; Okamura, Tomio

    2011-01-01

    To investigate the effect of hypoxia or hypoxia/reoxygenation on vascular smooth muscle function, mechanical response of monkey coronary artery without endothelium was studied under normoxia, hypoxia, and hypoxia/reoxygenation. Hypoxia or hypoxia/reoxygenation impaired the relaxation by nitroglycerin or isosorbide dinitrate but not that by 8-bromoguanosine-3',5'-cyclic monophosphate or isoproterenol. Tempol restored the impaired relaxation by nitroglycerin or isosorbide dinitrate, but superoxide dismutase had no effect. Apocynin, an NADPH oxidase inhibitor, improved the nitroglycerin-induced relaxation under hypoxia, but not under reoxygenation. Under combined treatment of apocynin with oxypurinol (xanthine oxidase inhibitor), rotenone (mitochondria electron transport inhibitor), or both, hypoxic impairment of vasorelaxation was restored more effectively. Similarly, impairment of the nitroglycerin-induced vasorelaxation under hypoxia/reoxygenation was restored by combined treatment with three inhibitors, apocynin, oxypurinol, and rotenone. Increase in superoxide production under hypoxia tended to be inhibited by apocynin and that under hypoxia/reoxygenation was abolished by combined treatment with three inhibitors. These findings suggest that increased intracellular superoxide production under hypoxia or hypoxia/reoxygenation attenuates vasodilation mediated with a nitric oxide/soluble guanylyl cyclase, but not adenylyl cyclase, signaling pathway. The main source of superoxide production under hypoxia seems to be different from that under reoxygenation: superoxide is produced by NADPH oxidase during hypoxia, whereas it is produced by xanthine oxidase, mitochondria, or both during reoxygenation.[Supplementary Figure: available only at http://dx.doi.org/10.1254/jphs.11031FP].

  17. Measuring hypoxia induced metal release from highly contaminated estuarine sediments during a 40 day laboratory incubation experiment

    Energy Technology Data Exchange (ETDEWEB)

    Banks, Joanne L., E-mail: jlbanks@student.unimelb.edu.au [Department of Zoology, University of Melbourne, Victoria, 3010 Australia (Australia); Ross, D. Jeff, E-mail: Jeff.Ross@utas.edu.au [Institute of Marine and Antarctic Studies, Nubeena Crescent, Taroona, Tasmania, 7053 Australia (Australia); Keough, Michael J., E-mail: mjkeough@unimelb.edu.au [Department of Zoology, University of Melbourne, Victoria, 3010 Australia (Australia); Eyre, Bradley D., E-mail: bradley.eyre@scu.edu.au [Centre for Coastal Biogeochemistry, School of Environmental Science and Management, Southern Cross University, PO Box 157, Lismore, NSW, 2480 Australia (Australia); Macleod, Catriona K., E-mail: Catriona.Macleod@utas.edu.au [Institute of Marine and Antarctic Studies, Nubeena Crescent, Taroona, Tasmania, 7053 Australia (Australia)

    2012-03-15

    Nutrient inputs to estuarine and coastal waters worldwide are increasing and this in turn is increasing the prevalence of eutrophication and hypoxic and anoxic episodes in these systems. Many urbanised estuaries are also subject to high levels of anthropogenic metal contamination. Environmental O{sub 2} levels may influence whether sediments act as sinks or sources of metals. In this study we investigated the effect of an extended O{sub 2} depletion event (40 days) on fluxes of trace metals (and the metalloid As) across the sediment-water interface in sediments from a highly metal contaminated estuary in S.E. Tasmania, Australia. We collected sediments from three sites that spanned a range of contamination and measured total metal concentration in the overlying water using sealed core incubations. Manganese and iron, which are known to regulate the release of other divalent cations from sub-oxic sediments, were released from sediments at all sites as hypoxia developed. In contrast, the release of arsenic, cadmium, copper and zinc was comparatively low, most likely due to inherent stability of these elements within the sediments, perhaps as a result of their refractory origin, their association with fine-grained sediments or their being bound in stable sulphide complexes. Metal release was not sustained due to the powerful effect of metal-sulphide precipitation of dissolved metals back into sediments. The limited mobilisation of sediment bound metals during hypoxia is encouraging, nevertheless the results highlight particular problems for management in areas where hypoxia might occur, such as the release of metals exacerbating already high loads or resulting in localised toxicity. - Highlights: Black-Right-Pointing-Pointer Metal contaminated sediments exposed to long-term hypoxia released Mn and Fe pulses. Black-Right-Pointing-Pointer As flux increased under anoxic conditions Cd, Cu and Zn fluxes occurred only during the first week of hypoxia. Black

  18. Cold collisions of SH- with He: Potential energy surface and rate coefficients

    Science.gov (United States)

    Bop, C. T.; Trabelsi, T.; Hammami, K.; Mogren Al Mogren, M.; Lique, F.; Hochlaf, M.

    2017-09-01

    Collisional energy transfer under cold conditions is of great importance from the fundamental and applicative point of view. Here, we investigate low temperature collisions of the SH- anion with He. We have generated a three-dimensional potential energy surface (PES) for the SH-(X1Σ+)-He(1S) van der Waals complex. The ab initio multi-dimensional interaction PES was computed using the explicitly correlated coupled cluster approach with simple, double, and perturbative triple excitation in conjunction with the augmented-correlation consistent-polarized valence triple zeta Gaussian basis set. The PES presents two minima located at linear geometries. Then, the PES was averaged over the ground vibrational wave function of the SH- molecule and the resulting two-dimensional PES was incorporated into exact quantum mechanical close coupling calculations to study the collisional excitation of SH- by He. We have computed inelastic cross sections among the 11 first rotational levels of SH- for energies up to 2500 cm-1. (De-)excitation rate coefficients were deduced for temperatures ranging from 1 to 300 K by thermally averaging the cross sections. We also performed calculations using the new PES for a fixed internuclear SH- distance. Both sets of results were found to be in reasonable agreement despite differences existing at low temperatures confirming that accurate predictions require the consideration of all internal degrees of freedom in the case of molecular hydrides. The rate coefficients presented here may be useful in interpreting future experimental work on the SH- negative ion colliding with He as those recently done for the OH--He collisional system as well as for possible astrophysical applications in case SH- would be detected in the interstellar medium.

  19. Dental size variation in the Atapuerca-SH Middle Pleistocene hominids.

    Science.gov (United States)

    Bermúdez de Castro, J M; Sarmiento, S; Cunha, E; Rosas, A; Bastir, M

    2001-09-01

    The Middle Pleistocene Atapuerca-Sima de los Huesos (SH) site in Spain has yielded the largest sample of fossil hominids so far found from a single site and belonging to the same biological population. The SH dental sample includes a total of 452 permanent and deciduous teeth, representing a minimum of 27 individuals. We present a study of the dental size variation in these hominids, based on the analysis of the mandibular permanent dentition: lateral incisors, n=29; canines, n=27; third premolars, n=30; fourth premolars, n=34; first molars, n=38; second molars, n=38. We have obtained the buccolingual diameter and the crown area (measured on occlusal photographs) of these teeth, and used the bootstrap method to assess the amount of variation in the SH sample compared with the variation of a modern human sample from the Museu Antropologico of the Universidade of Coimbra (Portugal). The SH hominids have, in general terms, a dental size variation higher than that of the modern human sample. The analysis is especially conclusive for the canines. Furthermore, we have estimated the degree of sexual dimorphism of the SH sample by obtaining male and female dental subsamples by means of sexing the large sample of SH mandibular specimens. We obtained the index of sexual dimorphism (ISD=male mean/female mean) and the values were compared with those obtained from the sexed modern human sample from Coimbra, and with data found in the literature concerning several recent human populations. In all tooth classes the ISD of the SH hominids was higher than that of modern humans, but the differences were generally modest, except for the canines, thus suggesting that canine size sexual dimorphism in Homo heidelbergensis was probably greater than that of modern humans. Since the approach of sexing fossil specimens has some obvious limitations, these results should be assessed with caution. Additional data from SH and other European Middle Pleistocene sites would be necessary to test

  20. Examining transition metal hydrosulfides: The pure rotational spectrum of ZnSH (X ˜ 2A')

    Science.gov (United States)

    Bucchino, M. P.; Adande, G. R.; Halfen, D. T.; Ziurys, L. M.

    2017-10-01

    The pure rotational spectrum of the ZnSH (X ˜ 2A') radical has been measured using millimeter-wave direct absorption and Fourier transform microwave (FTMW) methods across the frequency range 18-468 GHz. This work is the first gas-phase detection of ZnSH by any spectroscopic technique. Spectra of the 66ZnSH, 68ZnSH, and 64ZnSD isotopologues were also recorded. In the mm-wave study, ZnSH was synthesized in a DC discharge by the reaction of zinc vapor, generated by a Broida-type oven, with H2S; for FTMW measurements, the radical was made in a supersonic jet expansion by the same reactants but utilizing a discharge-assisted laser ablation source. Between 7 and 9 rotational transitions were recorded for each isotopologue. Asymmetry components with Ka = 0 through 6 were typically measured in the mm-wave region, each split into spin-rotation doublets. In the FTMW spectra, hyperfine interactions were also resolved, arising from the hydrogen or deuterium nuclear spins of I = 1/2 or I = 1, respectively. The data were analyzed using an asymmetric top Hamiltonian, and rotational, spin-rotation, and magnetic hyperfine parameters were determined for ZnSH, as well as the quadrupole coupling constant for ZnSD. The observed spectra clearly indicate that ZnSH has a bent geometry. The rm(1) structure was determined to be rZn-S = 2.213(5) Å, rS-H = 1.351(3) Å, and θZn-S-H = 90.6(1)°, suggesting that the bonding occurs primarily through sulfur p orbitals, analogous to H2S. The hyperfine constants indicate that the unpaired electron in ZnSH primarily resides on the zinc nucleus.

  1. Examining transition metal hydrosulfides: The pure rotational spectrum of ZnSH (X̃(2)A').

    Science.gov (United States)

    Bucchino, M P; Adande, G R; Halfen, D T; Ziurys, L M

    2017-10-21

    The pure rotational spectrum of the ZnSH (X̃(2)A') radical has been measured using millimeter-wave direct absorption and Fourier transform microwave (FTMW) methods across the frequency range 18-468 GHz. This work is the first gas-phase detection of ZnSH by any spectroscopic technique. Spectra of the (66)ZnSH, (68)ZnSH, and (64)ZnSD isotopologues were also recorded. In the mm-wave study, ZnSH was synthesized in a DC discharge by the reaction of zinc vapor, generated by a Broida-type oven, with H2S; for FTMW measurements, the radical was made in a supersonic jet expansion by the same reactants but utilizing a discharge-assisted laser ablation source. Between 7 and 9 rotational transitions were recorded for each isotopologue. Asymmetry components with Ka = 0 through 6 were typically measured in the mm-wave region, each split into spin-rotation doublets. In the FTMW spectra, hyperfine interactions were also resolved, arising from the hydrogen or deuterium nuclear spins of I = 1/2 or I = 1, respectively. The data were analyzed using an asymmetric top Hamiltonian, and rotational, spin-rotation, and magnetic hyperfine parameters were determined for ZnSH, as well as the quadrupole coupling constant for ZnSD. The observed spectra clearly indicate that ZnSH has a bent geometry. The rm((1)) structure was determined to be rZn-S = 2.213(5) Å, rS-H = 1.351(3) Å, and θZn-S-H = 90.6(1)°, suggesting that the bonding occurs primarily through sulfur p orbitals, analogous to H2S. The hyperfine constants indicate that the unpaired electron in ZnSH primarily resides on the zinc nucleus.

  2. Spectral theory of differential operators M. Sh. Birman 80th anniversary collection

    CERN Document Server

    Suslina, T

    2009-01-01

    This volume is dedicated to Professor M. Sh. Birman in honor of his eightieth birthday. It contains original articles in spectral and scattering theory of differential operators, in particular, Schrodinger operators, and in homogenization theory. All articles are written by members of M. Sh. Birman's research group who are affiliated with different universities all over the world. A specific feature of the majority of the papers is a combination of traditional methods with new modern ideas.

  3. Engineered regulation of lysozyme by the SH3-CB1 binding interaction.

    Science.gov (United States)

    Pham, Elizabeth; Truong, Kevin

    2012-06-01

    The ability to design proteins with desired properties by using protein structural information will allow us to create high-value therapeutic and diagnostic products. Using the protein structures of lambda lysozyme and the SH3 domain of human Crk, we designed a synthetic protein switch that controls the activity of lysozyme by sterically hindering its active cleft through the binding of SH3 to its CB1 peptide-binding partner. First, several fusion protein designs with lysozyme and CB1 were modeled to determine the one with greatest steric effect in the presence of SH3. Next, the selected fusion protein was created and tested in vitro. In the absence of SH3, the lysozyme-CB1 fusion protein functioned normally. In the presence of SH3, the lysozyme activity was inhibited and with the addition of excess CB1 peptides to compete for SH3 binding, the lysozyme activity was restored. Lastly, this structure-based strategy can be used to engineer synthetic regulation by peptide-domain-binding interfaces into a variety of proteins.

  4. Mutations of the SH3BP2 gene in 2 families of cherubism.

    Science.gov (United States)

    Tuna, Elif Bahar; Shimizu, Takehiko; Seymen, Figen; Yildirim, Mine; Gencay, Koray; Maeda, Takahide

    2012-01-01

    Cherubism is a rare autosomal dominant syndrome characterized by abnormal bone tissue in the lower part of the face. Mutations in the gene coding for SH3BP2 have been identified in about 80% of people with cherubism. The aim of this study was to determine whether a mutation in the SH3BP2 gene was the molecular basis of cherubism in two unrelated families. Two cases of the aggressive form of Cherubism were described in two Turkish families with extensive bilateral swelling in the mandible, typical pathological features and familial history. Genomic DNA was extracted from six affected and three unaffected individuals from two families, and mutations in the SH3BP2 were detected by PCR, and direct DNA sequencing was carried out. In the first family, a missense mutation Arg415Gln was found in exon 9 of the SH3BP2 in all affected individuals. The unaffected individuals did not have this mutation. In the second family, another missense mutation Pro418Thr was identified in exon 9 of the SH3BP2 in the patient and his mother with cherubism. We detected the point mutations in the SH3BP2 gene in the patients with multiple affected individuals. Genotype-phenotype association studies in individuals with cherubism are necessary to provide important knowledge about molecular mechanisms of the disease.

  5. Identification of novel cancer therapeutic targets using a designed and pooled shRNA library screen

    Science.gov (United States)

    Oliver, David; Ji, Hao; Liu, Piaomu; Gasparian, Alexander; Gardiner, Ellen; Lee, Samuel; Zenteno, Adrian; Perinskaya, Lillian O.; Chen, Mengqian; Buckhaults, Phillip; Broude, Eugenia; Wyatt, Michael D.; Valafar, Homayoun; Peña, Edsel; Shtutman, Michael

    2017-01-01

    Targeted cancer therapeutics aim to exploit tumor-specific, genetic vulnerabilities specifically affecting neoplastic cells without similarly affecting normal cells. Here we performed sequencing-based screening of an shRNA library on a panel of cancer cells of different origins as well as normal cells. The shRNA library was designed to target a subset of genes previously identified using a whole genome screening approach. This focused shRNA library was infected into cells followed by analysis of enrichment and depletion of the shRNAs over the course of cell proliferation. We developed a bootstrap likelihood ratio test for the interpretation of the effects of multiple shRNAs over multiple cell line passages. Our analysis identified 44 genes whose depletion preferentially inhibited the growth of cancer cells. Among these genes ribosomal protein RPL35A, putative RNA helicase DDX24, and coatomer complex I (COPI) subunit ARCN1 most significantly inhibited growth of multiple cancer cell lines without affecting normal cell growth and survival. Further investigation revealed that the growth inhibition caused by DDX24 depletion is independent of p53 status underlining its value as a drug target. Overall, our study establishes a new approach for the analysis of proliferation-based shRNA selection strategies and identifies new targets for the development of cancer therapeutics. PMID:28223711

  6. Analysis and Simulation of the Transmission Distortions of the Mobile Digital Television DVB-SH Part 1: Terrestrial Mode DVB-SH-A with OFDM

    Directory of Open Access Journals (Sweden)

    L. Polak

    2011-12-01

    Full Text Available This paper deals with the latest digital TV standard DVB-SH (Digital Video Broadcasting - Satellite to Handhelds with focus on utilization of its advantages for the next generation of mobile TV broadcasting. The whole paper consists of two parts. In this first part, after the brief introduction to DVB-SH and related last works review, the simulation model of DVB-SH-A, which is using terrestrial configuration with OFDM transmission mode, is presented. The work is especially focused on the description of new type of forward error correction and system configuration of the DVB-SH-A mode. For the analysis and simulation of the transmission, the original scheme of turbo encoder was modified in this paper. Application for simulation of the transmission in mobile and portable fading transmission channels was developed in MATLAB. Dependences of BER on C/N ratio for all types of payload modulation are compared with focus on mobile TV services availability. Finally, the achieved results are evaluated and clearly discussed.

  7. MeSH Speller + askMEDLINE: auto-completes MeSH terms then searches MEDLINE/PubMed via free-text, natural language queries.

    Science.gov (United States)

    Fontelo, Paul; Liu, Fang; Ackerman, Michael

    2005-01-01

    Medical terminology is challenging even for healthcare personnel. Spelling errors can make searching MEDLINE/PubMed ineffective. We developed a utility that provides MeSH term and Specialist Lexicon Vocabulary suggestions as it is typed on a search page. The correctly spelled term can be incorporated into a free-text, natural language search or used as a clinical queries search.

  8. Bone marrow transplantation improves autoinflammation and inflammatory bone loss in SH3BP2 knock-in cherubism mice.

    Science.gov (United States)

    Yoshitaka, Teruhito; Kittaka, Mizuho; Ishida, Shu; Mizuno, Noriyoshi; Mukai, Tomoyuki; Ueki, Yasuyoshi

    2015-02-01

    Cherubism (OMIM#118400) is a genetic disorder in children characterized by excessive jawbone destruction with proliferation of fibro-osseous lesions containing a large number of osteoclasts. Mutations in the SH3-domain binding protein 2 (SH3BP2) are responsible for cherubism. Analysis of the knock-in (KI) mouse model of cherubism showed that homozygous cherubism mice (Sh3bp2(KI/KI)) spontaneously develop systemic autoinflammation and inflammatory bone loss and that cherubism is a TNF-α-dependent hematopoietic disorder. In this study, we investigated whether bone marrow transplantation (BMT) is effective for the treatment of inflammation and bone loss in Sh3bp2(KI/KI) mice. Bone marrow (BM) cells from wild-type (Sh3bp2(+/+)) mice were transplanted to 6-week-old Sh3bp2(KI/KI) mice with developing inflammation and to 10-week-old Sh3bp2(KI/KI) mice with established inflammation. Six-week-old Sh3bp2(KI/KI) mice transplanted with Sh3bp2(+/+) BM cells exhibited improved body weight loss, facial swelling, and survival rate. Inflammatory lesions in the liver and lung as well as bone loss in calvaria and mandibula were ameliorated at 10weeks after BMT compared to Sh3bp2(KI/KI) mice transplanted with Sh3bp2(KI/KI) BM cells. Elevation of serum TNF-α levels was not detected after BMT. BMT was effective for up to 20weeks in 6-week-old Sh3bp2(KI/KI) mice transplanted with Sh3bp2(+/+) BM cells. BMT also ameliorated the inflammation and bone loss in 10-week-old Sh3bp2(KI/KI) mice. Thus our study demonstrates that BMT improves the inflammation and bone loss in cherubism mice. BMT may be effective for the treatment of cherubism patients. Copyright © 2013. Published by Elsevier Inc.

  9. Sustainable consumption

    DEFF Research Database (Denmark)

    Prothero, Andrea; Dobscha, Susan; Freund, Jim

    2011-01-01

    This essay explores sustainable consumption and considers possible roles for marketing and consumer researchers and public policy makers in addressing the many sustainability challenges that pervade our planet. Future research approaches to this interdisciplinary topic need to be comprehensive...... and systematic and will benefit from a variety of different perspectives. There are a number of opportunities for future research, and three areas are explored in detail. First, the essay considers the inconsistency between the attitudes and behaviors of consumers with respect to sustainability; next, the agenda...... is broadened to explore the role of individual citizens in society; and finally, a macro institutional approach to fostering sustainability is explored. Each of these areas is examined in detail and possible research avenues and public policy initiatives are considered within each of these separate...

  10. Stabilizing Sustainability

    DEFF Research Database (Denmark)

    Reitan Andersen, Kirsti

    The publication of the Brundtland Report in 1987 put the topic of sustainable development on the political and corporate agenda. Defining sustainable development as “a development that meets the needs of the future without compromising the ability of future generations to meet their own needs......” (WCED, 1987, p. 43), the Report also put a positive spin on the issue of sustainability by upholding capitalist beliefs in the possibility of infinite growth in a world of finite resources. While growth has delivered benefits, however, it has done so unequally and unsustainably. This thesis focuses...... on the textile and fashion industry, one of the world’s most polluting industries and an industry to some degree notorious for leading the ‘race to the bottom’ in global labour standards. Despite being faced with increasing demands to practise sustainability, most textile and fashion companies continue to fail...

  11. Sustainability reporting

    NARCIS (Netherlands)

    Kolk, A.

    2005-01-01

    This article gives an overview of developments in sustainability (also sometimes labelled corporate social responsibility) reporting. The article will first briefly indicate how accountability on social and environmental issues started, already in the 1970s when social reports were published.

  12. Sustainable Cities

    DEFF Research Database (Denmark)

    Georg, Susse; Garza de Linde, Gabriela Lucía

    Judging from the number of communities and cities striving or claiming to be sustainable and how often eco-development is invoked as the means for urban regeneration, it appears that sustainable and eco-development have become “the leading paradigm within urban development” (Whitehead 2003......), urban design competitions are understudied mechanisms for bringing about field level changes. Drawing on actor network theory, this paper examines how urban design competitions may bring about changes within the professional field through the use of intermediaries such as a sustainable planning....../assessment tool. The context for our study is urban regeneration in one Danish city, which had been suffering from industrial decline and which is currently investing in establishing a “sustainable city”. Based on this case study we explore how the insights and inspiration evoked in working with the tool...

  13. Sustainable responsibilities?

    DEFF Research Database (Denmark)

    Lystbæk, Christian Tang

    2015-01-01

    This working paper analyzes the conceptions of corporate responsibility for sustainable development in EU policies on CSR. The notion of corporate responsibility has until recently been limited to economical and legal responsibilities. Based on this narrow conception of corporate responsibility.......e. a combination of destruction and construction, this chapter will deconstruct conceptions of responsibility for sustainable development in these EU documents on CSR. A deconstructive conceptual analysis involves destructing dominant interpretations of a text and allowing for constructions of alternative...... such as sustainability actually means, but on what the concept says and does not say. A deconstructive analysis of EU policies on CSR, then, pinpoints that such policies are sites of conceptual struggles. This kind of analysis is suitable for studying conceptions of corporate responsibility for sustainable development...

  14. Agriculture: Sustainability

    Science.gov (United States)

    Sustainability creates and maintains the conditions under which humans and nature can exist in productive harmony, that permit fulfilling the food, feed, and fiber needs of our country and the social, economic and other requirements.

  15. Sustainable finance

    OpenAIRE

    Boersma-de Jong, Margreet F.

    2012-01-01

    Presentation for Springschool of Strategy, University of Groningen, 10 October 2012. The role of CSR is to stimulate ethical behaviour, and as a result, mutual trust in society. Advantage of CSR for the company and the evolution of CSR. From CSR to Sustainable Finance: how does CSR influence Sustainable Business Administration & Management Accounting, Financial Leadership and what is the importance of CSR in the financial sector

  16. Myocardial metabolism during hypoxia: Maintained lactate oxidation during increased glycolysis

    Energy Technology Data Exchange (ETDEWEB)

    Mazer, C.D.; Stanley, W.C.; Hickey, R.F.; Neese, R.A.; Cason, B.A.; Demas, K.A.; Wisneski, J.A.; Gertz, E.W. (Univ. of California, San Francisco (USA))

    1990-09-01

    In the intact animal, myocardial lactate utilization and oxidation during hypoxia are not well understood. Nine dogs were chronically instrumented with flow probes on the left anterior descending coronary artery and with a coronary sinus sampling catheter. ({sup 14}C)lactate and ({sup 13}C)glucose tracers, or ({sup 13}C)lactate and ({sup 14}C)glucose were administered to quantitate lactate and glucose oxidation, lactate conversion to glucose, and simultaneous lactate extraction and release. The animals were anesthetized and exposed to 90 minutes of severe hypoxia (PO2 = 25 +/- 4 torr). Hypoxia resulted in significant increases in heart rate, cardiac output and myocardial blood flow, but no significant change in myocardial oxygen consumption. The arterial/coronary sinus differences for glucose and lactate did not change from normoxia to hypoxia; however, the rate of glucose uptake increased significantly due to the increase in myocardial blood flow. Tracer-measured lactate extraction did not decrease with hypoxia, despite a 250% increase in lactate release. During hypoxia, 90% +/- 4% of the extracted {sup 14}C-lactate was accounted for by the appearance of {sup 14}CO{sub 2} in the coronary sinus, compared with 88% +/- 4% during normoxia. Thus, in addition to the expected increase in glucose uptake and lactate production, we observed an increase in lactate oxidation during hypoxia.

  17. Tumor hypoxia and reoxygenation: the yin and yang for radiotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Hong, Beom Ju; Kim, Jong Woo; Jeong, Hoi Bin; Bok, Seo Yeon; Kim, Young Eun; Ahn, G One [Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang (Korea, Republic of)

    2016-12-15

    Tumor hypoxia, a common feature occurring in nearly all human solid tumors is a major contributing factor for failures of anticancer therapies. Because ionizing radiation depends heavily on the presence of molecular oxygen to produce cytotoxic effect, the negative impact of tumor hypoxia had long been recognized. In this review, we will highlight some of the past attempts to overcome tumor hypoxia including hypoxic radiosensitizers and hypoxia-selective cytotoxin. Although they were (still are) a very clever idea, they lacked clinical efficacy largely because of ‘reoxygenation’ phenomenon occurring in the conventional low dose hyperfractionation radiotherapy prevented proper activation of these compounds. Recent meta-analysis and imaging studies do however indicate that there may be a significant clinical benefit in lowering the locoregional failures by using these compounds. Latest technological advancement in radiotherapy has allowed to deliver high doses of radiation conformally to the tumor volume. Although this technology has brought superb clinical responses for many types of cancer, recent modeling studies have predicted that tumor hypoxia is even more serious because ‘reoxygenation’ is low thereby leaving a large portion of hypoxic tumor cells behind. Wouldn’t it be then reasonable to combine hypoxic radiosensitizers and/or hypoxia-selective cytotoxin with the latest radiotherapy? We will provide some preclinical and clinical evidence to support this idea hoping to revamp an enthusiasm for hypoxic radiosensitizers or hypoxia-selective cytotoxins as an adjunct therapy for radiotherapy.

  18. SUSTAINABLE TRANSPORTATION

    Directory of Open Access Journals (Sweden)

    Linda STEG

    2007-01-01

    Full Text Available This paper discusses possible contributions of psychologists to sustainable transportation. It is argued that in order to reach sustainable transportation, among others, behaviour changes of individual car users are needed. As transport policies will be more effective if they target important antecedents of travel behaviour, first, factors influencing such behaviour are discussed. It is argued that car use is very attractive and sometimes even necessary for many different reasons. This implies that a combination of policies is called for, each targeting different factors that support car use and hinder the use of more sustainable modes of transport. Next, the paper elaborates on policy strategies that may be employed to achieve sustainable transportation by changing car use. Increasing the attractiveness of sustainable transport modes by means of pull measures seems not sufficient to reduce the level of car use. Besides, car use should be made less attractive by means of push measures to force drivers to reconsider their travel behaviour. The acceptability of such policies may be increased by clearly communicating the aim of these policies, and the expected positive consequences (e.g., less congestion, improved environmental quality. Moreover, possible negative effects for individual freedom may be compensated by implementing additional policies aimed at facilitating the use of sustainable transport modes.

  19. Optimization of duplex stability and terminal asymmetry for shRNA design.

    Directory of Open Access Journals (Sweden)

    Olga V Matveeva

    Full Text Available Prediction of efficient oligonucleotides for RNA interference presents a serious challenge, especially for the development of genome-wide RNAi libraries which encounter difficulties and limitations due to ambiguities in the results and the requirement for significant computational resources. Here we present a fast and practical algorithm for shRNA design based on the thermodynamic parameters. In order to identify shRNA and siRNA features universally associated with high silencing efficiency, we analyzed structure-activity relationships in thousands of individual RNAi experiments from publicly available databases (ftp://ftp.ncbi.nlm.nih.gov/pub/shabalin/siRNA/si_shRNA_selector/. Using this statistical analysis, we found free energy ranges for the terminal duplex asymmetry and for fully paired duplex stability, such that shRNAs or siRNAs falling in both ranges have a high probability of being efficient. When combined, these two parameters yield a approximately 72% success rate on shRNAs from the siRecords database, with the target RNA levels reduced to below 20% of the control. Two other parameters correlate well with silencing efficiency: the stability of target RNA and the antisense strand secondary structure. Both parameters also correlate with the short RNA duplex stability; as a consequence, adding these parameters to our prediction scheme did not substantially improve classification accuracy. To test the validity of our predictions, we designed 83 shRNAs with optimal terminal asymmetry, and experimentally verified that small shifts in duplex stability strongly affected silencing efficiency. We showed that shRNAs with short fully paired stems could be successfully selected by optimizing only two parameters: terminal duplex asymmetry and duplex stability of the hypothetical cleavage product, which also relates to the specificity of mRNA target recognition. Our approach performs at the level of the best currently utilized algorithms that take

  20. Sustainable markets for sustainable energy

    Energy Technology Data Exchange (ETDEWEB)

    Millan, J.; Smyser, C.

    1997-12-01

    The author discusses how the Inter-American Development Bank (IDB) is involved in sustainable energy development. It presently has 50 loans and grants for non conventional renewable energy projects and ten grants for efficiency programs for $600 and $17 million respectively, representing 100 MW of power. The IDB is concerned with how to create a sustainable market for sustainable energy projects. The IDB is trying to work with government, private sector, NGOs, trading allies, credit sources, and regulators to find proper roles for such projects. He discusses how the IDB is working to expand its vision and objectives in renewable energy projects in Central and South America.

  1. Hypoxia-regulated MicroRNAs in Gastroesophageal Cancer

    DEFF Research Database (Denmark)

    Winther, Mette; Alsner, Jan; Sørensen, Brita Singers

    2016-01-01

    BACKGROUND/AIM: The present study aimed to identify hypoxia-regulated microRNAs (HRMs) in vitro and investigate the clinical role of candidate HRMs in patients with gastroesophageal cancer (GEC). MATERIALS AND METHODS: microRNA expression changes induced by hypoxia in human GEC cell lines were...... associations of HRMs and clinical outcome in patients with GEC were identified. CONCLUSION: This study supports the involvement of hypoxia on miRNAs in vitro and confirms the role of miR-210 as being a universal HRM....

  2. From Binding-Induced Dynamic Effects in SH3 Structures to Evolutionary Conserved Sectors.

    Directory of Open Access Journals (Sweden)

    Ana Zafra Ruano

    2016-05-01

    Full Text Available Src Homology 3 domains are ubiquitous small interaction modules known to act as docking sites and regulatory elements in a wide range of proteins. Prior experimental NMR work on the SH3 domain of Src showed that ligand binding induces long-range dynamic changes consistent with an induced fit mechanism. The identification of the residues that participate in this mechanism produces a chart that allows for the exploration of the regulatory role of such domains in the activity of the encompassing protein. Here we show that a computational approach focusing on the changes in side chain dynamics through ligand binding identifies equivalent long-range effects in the Src SH3 domain. Mutation of a subset of the predicted residues elicits long-range effects on the binding energetics, emphasizing the relevance of these positions in the definition of intramolecular cooperative networks of signal transduction in this domain. We find further support for this mechanism through the analysis of seven other publically available SH3 domain structures of which the sequences represent diverse SH3 classes. By comparing the eight predictions, we find that, in addition to a dynamic pathway that is relatively conserved throughout all SH3 domains, there are dynamic aspects specific to each domain and homologous subgroups. Our work shows for the first time from a structural perspective, which transduction mechanisms are common between a subset of closely related and distal SH3 domains, while at the same time highlighting the differences in signal transduction that make each family member unique. These results resolve the missing link between structural predictions of dynamic changes and the domain sectors recently identified for SH3 domains through sequence analysis.

  3. Towards Antiviral shRNAs Based on the AgoshRNA Design.

    Directory of Open Access Journals (Sweden)

    Ying Poi Liu

    Full Text Available RNA interference (RNAi can be induced by intracellular expression of a short hairpin RNA (shRNA. Processing of the shRNA requires the RNaseIII-like Dicer enzyme to remove the loop and to release the biologically active small interfering RNA (siRNA. Dicer is also involved in microRNA (miRNA processing to liberate the mature miRNA duplex, but recent studies indicate that miR-451 is not processed by Dicer. Instead, this miRNA is processed by the Argonaute 2 (Ago2 protein, which also executes the subsequent cleavage of a complementary mRNA target. Interestingly, shRNAs that structurally resemble miR-451 can also be processed by Ago2 instead of Dicer. The key determinant of these "AgoshRNA" molecules is a relatively short basepaired stem, which avoids Dicer recognition and consequently allows alternative processing by Ago2. AgoshRNA processing yields a single active RNA strand, whereas standard shRNAs produce a duplex with guide and passenger strands and the latter may cause adverse off-target effects. In this study, we converted previously tested active anti-HIV-1 shRNA molecules into AgoshRNA. We tested several designs that could potentially improve AgoshRNA activity, including extension of the complementarity between the guide strand and the mRNA target and reduction of the thermodynamic stability of the hairpins. We demonstrate that active AgoshRNAs can be generated. However, the RNAi activity is reduced compared to the matching shRNAs. Despite reduced RNAi activity, comparison of an active AgoshRNA and the matching shRNA in a sensitive cell toxicity assay revealed that the AgoshRNA is much less toxic.

  4. Propagation of SH waves in an infinite/semi-infinite piezoelectric/piezomagnetic periodically layered structure.

    Science.gov (United States)

    Pang, Yu; Liu, Yu-Shan; Liu, Jin-Xi; Feng, Wen-Jie

    2016-04-01

    In this paper, SH bulk/surface waves propagating in the corresponding infinite/semi-infinite piezoelectric (PE)/piezomagnetic (PM) and PM/PE periodically layered composites are investigated by two methods, the stiffness matrix method and the transfer matrix method. For a semi-infinite PE/PM or PM/PE medium, the free surface is parallel to the layer interface. Both PE and PM materials are assumed to be transversely isotropic solids. Dispersion equations are derived by the stiffness/transfer matrix methods, respectively. The effects of electric-magnetic (ME) boundary conditions at the free surface and the layer thickness ratios on dispersion curves are considered in detail. Numerical examples show that the results calculated by the two methods are the same. The dispersion curves of SH surface waves are below the bulk bands or inside the frequency gaps. The ratio of the layer thickness has an important effect not only on the bulk bands but also on the dispersion curves of SH surface waves. Electric and magnetic boundary conditions, respectively, determine the dispersion curves of SH surface waves for the PE/PM and PM/PE semi-infinite structures. The band structures of SH bulk waves are consistent for the PE/PM and PM/PE structures, however, the dispersive behaviors of SH surface waves are indeed different for the two composites. The realization of the above-mentioned characteristics of SH waves will make it possible to design PE/PM acoustic wave devices with periodical structures and achieve the better performance. Copyright © 2016 Elsevier B.V. All rights reserved.

  5. Cherubism gene Sh3bp2 is important for optimal bone formation, osteoblast differentiation, and function.

    Science.gov (United States)

    Mukherjee, Padma M; Wang, Chiachien J; Chen, I-Ping; Jafarov, Toghrul; Olsen, Bjorn R; Ueki, Yasuyoshi; Reichenberger, Ernst J

    2010-08-01

    Cherubism is a human genetic disorder that causes bilateral symmetrical enlargement of the maxilla and the mandible in children. It is caused by mutations in SH3BP2. The exact pathogenesis of the disorder is an area of active research. Sh3bp2 knock-in mice were developed by introducing a Pro416Arg mutation (Pro418Arg in humans) in the mouse genome. The osteoclast phenotype of this mouse model was recently described. We examined the bone phenotype of the cherubism mouse model, the role of Sh3bp2 during bone formation, osteoblast differentiation, and osteoblast function. We observed delays in early postnatal development of homozygous Sh3bp2(KI/KI) mice, which exhibited increased growth plate thickness and significantly decreased trabecular bone thickness and bone mineral density. Histomorphometric and microcomputed tomography analyses showed bone loss in the cranial and appendicular skeletons. Sh3bp2(KI/KI) mice also exhibited a significant decrease in osteoid formation that indicated a defect in osteoblast function. Calvarial osteoblast cell cultures had decreased alkaline phosphatase expression and mineralization, suggesting reduced differentiation potential. Gene expression of osteoblast differentiation markers such as collagen type I, alkaline phosphatase, and osteocalcin were decreased in osteoblast cultures from Sh3bp2(KI/KI) mice. These data suggest that Sh3bp2 regulates bone homeostasis through not only osteoclast-specific effects, but also through effects on osteoblast differentiation and function. Copyright (c) 2010 American Association of Orthodontists. Published by Mosby, Inc. All rights reserved.

  6. Medical Subject Heading (MeSH) annotations illuminate maize genetics and evolution.

    Science.gov (United States)

    Beissinger, Timothy M; Morota, Gota

    2017-01-01

    High-density marker panels and/or whole-genome sequencing, coupled with advanced phenotyping pipelines and sophisticated statistical methods, have dramatically increased our ability to generate lists of candidate genes or regions that are putatively associated with phenotypes or processes of interest. However, the speed with which we can validate genes, or even make reasonable biological interpretations about the principles underlying them, has not kept pace. A promising approach that runs parallel to explicitly validating individual genes is analyzing a set of genes together and assessing the biological similarities among them. This is often achieved via gene ontology analysis, a powerful tool that involves evaluating publicly available gene annotations. However, additional resources such as Medical Subject Headings (MeSH) can also be used to evaluate sets of genes to make biological interpretations. In this manuscript, we describe utilizing MeSH terms to make biological interpretations in maize. MeSH terms are assigned to PubMed-indexed manuscripts by the National Library of Medicine, and can be directly mapped to genes to develop gene annotations. Once mapped, these terms can be evaluated for enrichment in sets of genes or similarity between gene sets to provide biological insights. Here, we implement MeSH analyses in five maize datasets to demonstrate how MeSH can be leveraged by the maize and broader crop-genomics community. We demonstrate that MeSH terms can be effectively leveraged to generate hypotheses and make biological interpretations in maize, and we provide a pipeline that enables the use of MeSH terms in other plant species.

  7. Hypoxia-Inducible Factor 3 Is an Oxygen-Dependent Transcription Activator and Regulates a Distinct Transcriptional Response to Hypoxia

    Directory of Open Access Journals (Sweden)

    Peng Zhang

    2014-03-01

    Full Text Available Hypoxia-inducible factors (HIFs play key roles in the cellular response to hypoxia. It is widely accepted that whereas HIF-1 and HIF-2 function as transcriptional activators, HIF-3 inhibits HIF-1/2α action. Contrary to this idea, we show that zebrafish Hif-3α has strong transactivation activity. Hif-3α is degraded under normoxia. Mutation of P393, P493, and L503 inhibits this oxygen-dependent degradation. Transcriptomics and chromatin immunoprecipitation analyses identify genes that are regulated by Hif-3α, Hif-1α, or both. Under hypoxia or when overexpressed, Hif-3α binds to its target gene promoters and upregulates their expression. Dominant-negative inhibition and knockdown of Hif-3α abolish hypoxia-induced Hif-3α-promoter binding and gene expression. Hif-3α not only mediates hypoxia-induced growth and developmental retardation but also possesses hypoxia-independent activities. Importantly, transactivation activity is conserved and human HIF-3α upregulates similar genes in human cells. These findings suggest that Hif-3 is an oxygen-dependent transcription factor and activates a distinct transcriptional response to hypoxia.

  8. Climate-Forced Variability of Ocean Hypoxia

    Science.gov (United States)

    Deutsch, Curtis; Brix, Holger; Ito, Taka; Frenzel, Hartmut; Thompson, LuAnne

    2011-07-01

    Oxygen (O2) is a critical constraint on marine ecosystems. As oceanic O2 falls to hypoxic concentrations, habitability for aerobic organisms decreases rapidly. We show that the spatial extent of hypoxia is highly sensitive to small changes in the ocean’s O2 content, with maximum responses at suboxic concentrations where anaerobic metabolisms predominate. In model-based reconstructions of historical oxygen changes, the world’s largest suboxic zone, in the Pacific Ocean, varies in size by a factor of 2. This is attributable to climate-driven changes in the depth of the tropical and subtropical thermocline that have multiplicative effects on respiration rates in low-O2 water. The same mechanism yields even larger fluctuations in the rate of nitrogen removal by denitrification, creating a link between decadal climate oscillations and the nutrient limitation of marine photosynthesis.

  9. [Modeling of functional working state in hypoxia].

    Science.gov (United States)

    Kravchenko, Iu V

    2003-01-01

    The given method automatically allows us to watch functional working states of the brain (FWSB) in dependence on the neurodynamic loading (first-signal positive and brake stimuli). It defines main properties of nervous processes, wave frame of the sensomotor loading (WFSL) at implementation of three following FWSB: hard work of a brain, a prestressful mode with maximal mobilization of forces and stressful mode. It defines a level of function mobility of nervous processes, force of nervous processes, efficiency of a brain, balance of nervous processes by a method of the parametrical spectral analysis WFSL. The given model allows defining a level of men training who operate in extreme conditions of information processing and hypoxia.

  10. Hypoxia in models of lung cancer

    DEFF Research Database (Denmark)

    Graves, Edward E; Vilalta, Marta; Cecic, Ivana K

    2010-01-01

    PURPOSE: To efficiently translate experimental methods from bench to bedside, it is imperative that laboratory models of cancer mimic human disease as closely as possible. In this study, we sought to compare patterns of hypoxia in several standard and emerging mouse models of lung cancer...... to establish the appropriateness of each for evaluating the role of oxygen in lung cancer progression and therapeutic response. EXPERIMENTAL DESIGN: Subcutaneous and orthotopic human A549 lung carcinomas growing in nude mice as well as spontaneous K-ras or Myc-induced lung tumors grown in situ......H2AX foci in vitro and in vivo. Finally, our findings were compared with oxygen electrode measurements of human lung cancers. RESULTS: Minimal fluoroazomycin arabinoside and pimonidazole accumulation was seen in tumors growing within the lungs, whereas subcutaneous tumors showed substantial trapping...

  11. [18F]-FMISO PET study of hypoxia in gliomas before surgery: correlation with molecular markers of hypoxia and angiogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Bekaert, Lien [CHU de Caen, Department of Neurology, Caen (France); Normandie Univ, UNICAEN, CEA, CNRS, ISTCT/CERVOxy Group, Caen (France); CHU de Caen, Department of Neurosurgery, Caen (France); CHU de Caen, Service de Neurochirurgie, Caen (France); Valable, Samuel; Collet, Solene; Bordji, Karim; Petit, Edwige; Bernaudin, Myriam [Normandie Univ, UNICAEN, CEA, CNRS, ISTCT/CERVOxy Group, Caen (France); Lechapt-Zalcman, Emmanuele [Normandie Univ, UNICAEN, CEA, CNRS, ISTCT/CERVOxy Group, Caen (France); CHU de Caen, Department of Pathology, Caen (France); Ponte, Keven [CHU de Caen, Department of Neurosurgery, Caen (France); Normandie Univ, UNICAEN, CEA, CNRS, ISTCT/CERVOxy Group, Caen (France); Constans, Jean-Marc [Normandie Univ, UNICAEN, CEA, CNRS, ISTCT/CERVOxy Group, Caen (France); CHU de Caen, Department of Neuroradiology, Caen (France); Levallet, Guenaelle [CHU de Caen, Department of Pathology, Caen (France); Branger, Pierre [CHU de Caen, Department of Neurology, Caen (France); Emery, Evelyne [CHU de Caen, Department of Neurosurgery, Caen (France); Manrique, Alain [CHU de Caen, Department of Nuclear Medicine, Caen (France); Barre, Louisa [Normandie Univ, UNICAEN, CEA, CNRS, ISTCT/LDM-TEP group, Caen (France); Guillamo, Jean-Sebastien [CHU de Caen, Department of Neurology, Caen (France); Normandie Univ, UNICAEN, CEA, CNRS, ISTCT/CERVOxy Group, Caen (France); CHU de Nimes, Department of Neurology, Nimes (France)

    2017-08-15

    Hypoxia in gliomas is associated with tumor resistance to radio- and chemotherapy. However, positron emission tomography (PET) imaging of hypoxia remains challenging, and the validation of biological markers is, therefore, of great importance. We investigated the relationship between uptake of the PET hypoxia tracer [18F]-FMISO and other markers of hypoxia and angiogenesis and with patient survival. In this prospective single center clinical study, 33 glioma patients (grade IV: n = 24, III: n = 3, and II: n = 6) underwent [18F]-FMISO PET and MRI including relative cerebral blood volume (rCBV) maps before surgery. Maximum standardized uptake values (SUVmax) and hypoxic volume were calculated, defining two groups of patients based on the presence or absence of [18F]-FMISO uptake. After surgery, molecular quantification of CAIX, VEGF, Ang2 (rt-qPCR), and HIF-1α (immunohistochemistry) were performed on tumor specimens. [18F]-FMISO PET uptake was closely linked to tumor grade, with high uptake in glioblastomas (GB, grade IV). Expression of biomarkers of hypoxia (CAIX, HIF-1α), and angiogenesis markers (VEGF, Ang2, rCBV) were significantly higher in the [18F]-FMISO uptake group. We found correlations between the degree of hypoxia (hypoxic volume and SUVmax) and expression of HIF-1α, CAIX, VEGF, Ang2, and rCBV (p < 0.01). Patients without [18F]-FMISO uptake had a longer survival time than uptake positive patients (log-rank, p < 0.005). Tumor hypoxia as evaluated by [18F]-FMISO PET is associated with the expression of hypoxia markers on a molecular level and is related to angiogenesis. [18F]-FMISO uptake is a mark of an aggressive tumor, almost always a glioblastoma. Our results underline that [18F]-FMISO PET could be useful to guide glioma treatment, and in particular radiotherapy, since hypoxia is a well-known factor of resistance. (orig.)

  12. Chronic Hypoxia Accentuates Dysanaptic Lung Growth.

    Science.gov (United States)

    Llapur, Conrado J; Martínez, Myriam R; Grassino, Pedro T; Stok, Ana; Altieri, Héctor H; Bonilla, Federico; Caram, María M; Krowchuk, Natasha M; Kirby, Miranda; Coxson, Harvey O; Tepper, Robert S

    2016-08-01

    Adults born and raised at high altitudes have larger lung volumes and greater pulmonary diffusion capacity compared with adults at low altitude; however, it remains unclear whether the air and tissue volumes have comparable increases and whether there is a difference in airway size. To assess the effect of chronic hypoxia on lung growth using in vivo high-resolution computed tomography measurements. Healthy adults born and raised at moderate altitude (2,000 m above sea level; n = 19) and at low altitude (400 m above sea level; n = 23) underwent high-resolution computed tomography. Differences in total lung, air, and tissue volume, mean lung density, as well as airway lumen and wall areas in anatomically matched airways were compared between groups. No significant differences for age, sex, weight, or height were found between the two groups (P > 0.05). In a multivariate regression model, altitude was a significant contributor for total lung volume (P = 0.02), air volume (P = 0.03), and tissue volume (P = 0.03), whereby the volumes were greater for the moderate- versus the low-altitude group. However, altitude was not a significant contributor for mean lung density (P = 0.35) or lumen and wall areas in anatomically matched segmental, subsegmental, and subsubsegmental airways. Our findings suggest that the adult lung did not increase lung volume later in life by expansion of an existing number of alveoli, but rather from increased alveolarization early in life. In addition, chronic hypoxia accentuates dysanaptic lung growth by increasing the lung parenchyma but not the airways.

  13. A preclinical model for noninvasive imaging of hypoxia-induced gene expression; comparison with an exogenous marker of tumor hypoxia

    Energy Technology Data Exchange (ETDEWEB)

    Wen Bixiu; Burgman, Paul; Zanzonico, Pat; O' Donoghue, Joseph; Li, Gloria C.; Ling, C. Clifton [Memorial Sloan-Kettering Cancer Center, Department of Medical Physics, New York (United States); Cai Shangde; Finn, Ron [Memorial Sloan-Kettering Cancer Center, Department of Radiology, New York (United States); Serganova, Inna [Memorial Sloan-Kettering Cancer Center, Department of Neurology, New York (United States); Blasberg, Ronald; Gelovani, Juri [Memorial Sloan-Kettering Cancer Center, Department of Radiology, New York (United States); Memorial Sloan-Kettering Cancer Center, Department of Neurology, New York (United States)

    2004-11-01

    Hypoxia is associated with tumor aggressiveness and is an important cause of resistance to radiation therapy and chemotherapy. Assays of tumor hypoxia could provide selection tools for hypoxia-modifying treatments. The purpose of this study was to develop and characterize a rodent tumor model with a reporter gene construct that would be transactivated by the hypoxia-inducible molecular switch, i.e., the upregulation of HIF-1. The reporter gene construct is the herpes simplex virus 1-thymidine kinase (HSV1-tk) fused with the enhanced green fluorescent protein (eGFP) under the regulation of an artificial hypoxia-responsive enhancer/promoter. In this model, tumor hypoxia would up-regulate HIF-1, and through the hypoxia-responsive promoter transactivate the HSV1-tkeGFPfusion gene. The expression of this reporter gene can be assessed with the {sup 124}I-labeled reporter substrate 2'-fluoro-2'-deoxy-1-{beta}-d-arabinofuranosyl-5-iodouracil ({sup 124}I-FIAU), which is phosphorylated by the HSV1-tk enzyme and trapped in the hypoxic cells. Animal positron emission tomography (microPET) and phosphor plate imaging (PPI) were used in this study to visualize the trapped {sup 124}I-FIAU, providing a distribution of the hypoxia-induced molecular events. The distribution of {sup 124}I-FIAU was also compared with that of an exogenous hypoxic cell marker, {sup 18}F-fluoromisonidazole (FMISO). Our results showed that {sup 124}I-FIAU microPET imaging of the hypoxia-induced reporter gene expression is feasible, and that the intratumoral distributions of {sup 124}I-FIAU and {sup 18}F-FMISO are similar. In tumor sections, detailed radioactivity distributions were obtained with PPI which also showed similarity between {sup 124}I-FIAU and {sup 18}F-FMISO. This reporter system is sufficiently sensitive to detect hypoxia-induced transcriptional activation by noninvasive imaging and might provide a valuable tool in studying tumor hypoxia and in validating existing and future

  14. 96 shRNAs designed for maximal coverage of HIV-1 variants

    Directory of Open Access Journals (Sweden)

    Shen Sylvie

    2009-06-01

    Full Text Available Abstract Background The RNA interference (RNAi pathway is a mechanism of gene-suppression with potential gene therapy applications for treating viral disease such as HIV-1. The most suitable inducer of RNAi for this application is short hairpin RNA (shRNA although it is limited to suppressing a single target. A successful anti-HIV-1 therapy will require combinations of multiple highly active, highly conserved shRNAs to adequately counter the emergence of resistant strains. Results We calculated the percentage conservations of 8, 846 unique 19 nucleotide HIV-1 targets amongst 37, 949 HIV-1 gene sequence fragments containing 24.8 million 19 mers. We developed a novel method of determining conservation in 'profile' sets of 5 overlapping 19 mer sequences (covering 23 nucleotides in total to ensure that the intended conservation of each shRNA would be unaffected by possible variations in shRNA processing. Ninety six of the top ranking targets from 22 regions were selected based on conservation profiles, predicted activities, targets and specific nucleotide inclusion/exclusion criteria. We constructed 53 shRNAs with 20 bp stems and 43 shRNAs with 21 bp stems which we tested and ranked using fluorescent reporter and HIV-1 expression assays. Average suppressive activities ranged from 71 – 75%, with 65 hairpins classed as highly active (> 75% activity. Overall we found little difference in activities from minor changes in stem length (20 cf. 21, or between neighboring targets differing by a single nucleotide in start position. However, there were several exceptions which suggest that all sequences, irrespective of similarities in target site or design, may be useful candidates. We encountered technical limitations with GFP reporter assays when the target domain was long and or when the distance between the target site and fusion junction was large. Assay performance was improved by dividing large targets into several shorter domains. Conclusion In

  15. Roundtabling Sustainability

    DEFF Research Database (Denmark)

    Ponte, Stefano

    2014-01-01

    The willingness of public authority to delegate social and environmental regulation to the private sector has varied from sector to sector, but has often led to the establishment of ‘voluntary’ standards and certifications on sustainability. Many of these have taken the form of ‘stewardship...... councils’ and ‘sustainability roundtables’ and have been designed around a set of institutional features seeking to establish legitimacy, fend off possible criticism, and ‘sell’ certifications to potential users. The concept of ‘roundtabling’ emphasizes the fitting a variety of commodity......-specific sustainability situations into a form that not only ‘hears more voices’ (as in ‘multi-stakeholder’), but also portrays to give them equal standing at the table of negotiations (roundtable), thus raising higher expectations on accountability, transparency and inclusiveness. In this article, I examine to what...

  16. Structural Basis for Activation of ZAP-70 by Phosphorylation of the SH2-Kinase Linker

    Science.gov (United States)

    Yan, Qingrong; Barros, Tiago; Visperas, Patrick R.; Deindl, Sebastian; Kadlecek, Theresa A.; Weiss, Arthur

    2013-01-01

    Serial activation of the tyrosine kinases Lck and ZAP-70 initiates signaling downstream of the T cell receptor. We previously reported the structure of an autoinhibited ZAP-70 variant in which two regulatory tyrosine residues (315 and 319) in the SH2-kinase linker were replaced by phenylalanine. We now present a crystal structure of ZAP-70 in which Tyr 315 and Tyr 319 are not mutated, leading to the recognition of a five-residue sequence register error in the SH2-kinase linker of the original crystallographic model. The revised model identifies distinct roles for these two tyrosines. As seen in a recently reported structure of the related tyrosine kinase Syk, Tyr 315 of ZAP-70 is part of a hydrophobic interface between the regulatory apparatus and the kinase domain, and the integrity of this interface would be lost upon engagement of doubly phosphorylated peptides by the SH2 domains. Tyr 319 is not necessarily dislodged by SH2 engagement, which activates ZAP-70 only ∼5-fold in vitro. In contrast, phosphorylation by Lck activates ZAP-70 ∼100-fold. This difference is due to the ability of Tyr 319 to suppress ZAP-70 activity even when the SH2 domains are dislodged from the kinase domain, providing stringent control of ZAP-70 activity downstream of Lck. PMID:23530057

  17. Design and cloning strategies for constructing shRNA expression vectors

    Directory of Open Access Journals (Sweden)

    McIntyre Glen J

    2006-01-01

    Full Text Available Abstract Background Short hairpin RNA (shRNA encoded within an expression vector has proven an effective means of harnessing the RNA interference (RNAi pathway in mammalian cells. A survey of the literature revealed that shRNA vector construction can be hindered by high mutation rates and the ensuing sequencing is often problematic. Current options for constructing shRNA vectors include the use of annealed complementary oligonucleotides (74 % of surveyed studies, a PCR approach using hairpin containing primers (22 % and primer extension of hairpin templates (4 %. Results We considered primer extension the most attractive method in terms of cost. However, in initial experiments we encountered a mutation frequency of 50 % compared to a reported 20 – 40 % for other strategies. By modifying the technique to be an isothermal reaction using the DNA polymerase Phi29, we reduced the error rate to 10 %, making primer extension the most efficient and cost-effective approach tested. We also found that inclusion of a restriction site in the loop could be exploited for confirming construct integrity by automated sequencing, while maintaining intended gene suppression. Conclusion In this study we detail simple improvements for constructing and sequencing shRNA that overcome current limitations. We also compare the advantages of our solutions against proposed alternatives. Our technical modifications will be of tangible benefit to researchers looking for a more efficient and reliable shRNA construction process.

  18. SH1 leaf rust and bacterial halo blight coffee resistances are genetically independent

    Directory of Open Access Journals (Sweden)

    Lucas Mateus Rivero Rodrigues

    Full Text Available ABSTRACT Coffee resistance to Pseudomonas syringae pv. garcae has been associated to pleiotropic effect of SH1 allele, present in coffee plants resistant to certain races of Hemileia vastatrix, the causal agent of leaf rust, or genetic linkage between resistance alleles to both pathogens. To validate this hypothesis, 63 coffee plants in F2 generation were evaluated for resistance to 2 isolates of H. vastatrix carriers of alleles, respectively, v2, v5 (isolate I/2015 and v1; v2; v5 (isolate II/2015 with the objective to confirm presence of SH1 allele in resistant plants to isolate I/2015. The same coffee plants were evaluated for resistance to a mixture of P. syringae pv. garcae strains highly pathogenic to coffee. Results showed that, among F2 coffee allele SH1 carriers, resistant to isolate I/2015, resistant and susceptible plants to bacterial halo blight were found; the same segregation occurs between F2 homozygous for SH1 allele, susceptible to the same isolate (I/2015 of H. vastatrix. Results also indicate that there is no pleiotropic effect of gene or allele SH1 connection between genes conferring resistance to leaf rust caused by H. vastatrix and bacterial halo blight caused by P. syringae pv. garcae.

  19. Medical Subject Headings (MeSH) for indexing and retrieving open-source healthcare data.

    Science.gov (United States)

    Marc, David T; Khairat, Saif S

    2014-01-01

    The US federal government initiated the Open Government Directive where federal agencies are required to publish high value datasets so that they are available to the public. Data.gov and the community site Healthdata.gov were initiated to disperse such datasets. However, data searches and retrieval for these sites are keyword driven and severely limited in performance. The purpose of this paper is to address the issue of extracting relevant open-source data by proposing a method of adopting the MeSH framework for indexing and data retrieval. A pilot study was conducted to compare the performance of traditional keywords to MeSH terms for retrieving relevant open-source datasets related to "mortality". The MeSH framework resulted in greater sensitivity with comparable specificity to the keyword search. MeSH showed promise as a method for indexing and retrieving data, yet future research should conduct a larger scale evaluation of the performance of the MeSH framework for retrieving relevant open-source healthcare datasets.

  20. Solution structure, dynamics and thermodynamics of the three SH3 domains of CD2AP

    Energy Technology Data Exchange (ETDEWEB)

    Roldan, Jose L. Ortega [Universidad de Granada, Departamento de Quimica Fisica e Instituto de Biotecnologia, Facultad de Ciencias (Spain); Blackledge, Martin [Institut de Biologie Structurale Jean-Pierre Ebel, CEA, CNRS, UJF UMR 5075, Protein Dynamics and Flexibility by NMR (France); Nuland, Nico A. J. van, E-mail: nvnuland@vub.ac.be [Vrije Universiteit Brussel, Structural Biology Brussels (Belgium); Azuaga, Ana I. [Universidad de Granada, Departamento de Quimica Fisica e Instituto de Biotecnologia, Facultad de Ciencias (Spain)

    2011-06-15

    CD2 associated protein (CD2AP) is an adaptor protein that plays an important role in cell to cell union needed for the kidney function. It contains three N-terminal SH3 domains that are able to interact among others with CD2, ALIX, c-Cbl and Ubiquitin. To understand the role of the individual SH3 domains of this adaptor protein we have performed a complete structural, thermodynamic and dynamic characterization of the separate domains using NMR and DSC. The energetic contributions to the stability and the backbone dynamics have been related to the structural features of each domain using the structure-based FoldX algorithm. We have found that the N-terminal SH3 domain of both adaptor proteins CD2AP and CIN85 are the most stable SH3 domains that have been studied until now. This high stability is driven by a more extensive network of intra-molecular interactions. We believe that this increased stabilization of N-terminal SH3 domains in adaptor proteins is crucial to maintain the necessary conformation to establish the proper interactions critical for the recruitment of their natural targets.

  1. Comparative analysis of duckweed cultivation with sewage water and SH media for production of fuel ethanol.

    Directory of Open Access Journals (Sweden)

    Changjiang Yu

    Full Text Available Energy crises and environmental pollution have caused considerable concerns; duckweed is considered to be a promising new energy plant that may relieve such problems. Lemna aequinoctialis strain 6000, which has a fast growth rate and the ability to accumulate high levels of starch was grown in both Schenk & Hildebrandt medium (SH and in sewage water (SW. The maximum growth rates reached 10.0 g DW m(-2 day(-1 and 4.3 g DW m(-2 day(-1, respectively, for the SH and SW cultures, while the starch content reached 39% (w/w and 34% (w/w. The nitrogen and phosphorus removal rate reached 80% (SH and 90% (SW during cultivation, and heavy metal ions assimilation was observed. About 95% (w/w of glucose was released from duckweed biomass hydrolysates, and then fermented by Angel yeast with ethanol yield of 0.19 g g(-1 (SH and 0.17 g g(-1 (SW. The amylose/amylopectin ratios of the cultures changed as starch content increased, from 0.252 to 0.155 (SH and from 0.252 to 0.174 (SW. Lemna aequinoctialis strain 6000 could be considered as valuable feedstock for bioethanol production and water resources purification.

  2. Comparative analysis of duckweed cultivation with sewage water and SH media for production of fuel ethanol.

    Science.gov (United States)

    Yu, Changjiang; Sun, Changjiang; Yu, Li; Zhu, Ming; Xu, Hua; Zhao, Jinshan; Ma, Yubin; Zhou, Gongke

    2014-01-01

    Energy crises and environmental pollution have caused considerable concerns; duckweed is considered to be a promising new energy plant that may relieve such problems. Lemna aequinoctialis strain 6000, which has a fast growth rate and the ability to accumulate high levels of starch was grown in both Schenk & Hildebrandt medium (SH) and in sewage water (SW). The maximum growth rates reached 10.0 g DW m(-2) day(-1) and 4.3 g DW m(-2) day(-1), respectively, for the SH and SW cultures, while the starch content reached 39% (w/w) and 34% (w/w). The nitrogen and phosphorus removal rate reached 80% (SH) and 90% (SW) during cultivation, and heavy metal ions assimilation was observed. About 95% (w/w) of glucose was released from duckweed biomass hydrolysates, and then fermented by Angel yeast with ethanol yield of 0.19 g g(-1) (SH) and 0.17 g g(-1) (SW). The amylose/amylopectin ratios of the cultures changed as starch content increased, from 0.252 to 0.155 (SH) and from 0.252 to 0.174 (SW). Lemna aequinoctialis strain 6000 could be considered as valuable feedstock for bioethanol production and water resources purification.

  3. Enhancing MEDLINE document clustering by incorporating MeSH semantic similarity.

    Science.gov (United States)

    Zhu, Shanfeng; Zeng, Jia; Mamitsuka, Hiroshi

    2009-08-01

    Clustering MEDLINE documents is usually conducted by the vector space model, which computes the content similarity between two documents by basically using the inner-product of their word vectors. Recently, the semantic information of MeSH (Medical Subject Headings) thesaurus is being applied to clustering MEDLINE documents by mapping documents into MeSH concept vectors to be clustered. However, current approaches of using MeSH thesaurus have two serious limitations: first, important semantic information may be lost when generating MeSH concept vectors, and second, the content information of the original text has been discarded. Our new strategy includes three key points. First, we develop a sound method for measuring the semantic similarity between two documents over the MeSH thesaurus. Second, we combine both the semantic and content similarities to generate the integrated similarity matrix between documents. Third, we apply a spectral approach to clustering documents over the integrated similarity matrix. Using various 100 datasets of MEDLINE records, we conduct extensive experiments with changing alternative measures and parameters. Experimental results show that integrating the semantic and content similarities outperforms the case of using only one of the two similarities, being statistically significant. We further find the best parameter setting that is consistent over all experimental conditions conducted. We finally show a typical example of resultant clusters, confirming the effectiveness of our strategy in improving MEDLINE document clustering. Supplementary data are available at Bioinformatics online.

  4. Inhibition and Promotion of Pyrolysis by Hydrogen Sulfide (H2S) and Sulfanyl Radical (SH).

    Science.gov (United States)

    Zeng, Zhe; Altarawneh, Mohammednoor; Oluwoye, Ibukun; Glarborg, Peter; Dlugogorski, Bogdan Z

    2016-11-17

    This study resolves the interaction of sulfanyl radical (SH) with aliphatic (C1-C4) hydrocarbons, using CBS-QB3 based calculations. We obtained the C-H dissociation enthalpies and located the weakest link in each hydrocarbon. Subsequent computations revealed that, H abstraction by SH from the weakest C-H sites in alkenes and alkynes, except for ethylene, appears noticeably exothermic. Furthermore, abstraction of H from propene, 1-butene, and iso-butene displays pronounced spontaneity (i.e., ΔrG° hydrogen bond. However, an alkyl radical readily abstracts H atom from H2S, with H2S acting as a potent scavenger for alkyl radicals in combustion processes. That is, these reactions proceed in the opposite direction than those involving SH and alkene or alkyne species, exhibiting shallow barriers and strong spontaneity. Our findings demonstrate that the documented inhibition effect of hydrogen sulfide (H2S) on pyrolysis of alkanes does not apply to alkenes and alkynes. During interaction with hydrocarbons, the inhibitive effect of H2S and promoting interaction of SH radical depend on the reversibility of the H abstraction processes. For the three groups of hydrocarbon, Evans-Polanyi plots display linear correlations between the bond dissociation enthalpies of the abstracted hydrogens and the relevant activation energies. In the case of methane, we demonstrated that the reactivity of SH radicals toward abstracting H atoms exceeds that of HO2 but falls below those of OH and NH2 radicals.

  5. Cytotoxicity induced by cypermethrin in Human Neuroblastoma Cell Line SH-SY5Y

    Directory of Open Access Journals (Sweden)

    Grzegorz Raszewski

    2015-12-01

    Full Text Available The purpose of this study was to evaluate the cytotoxic potential of Cypermethrin (CM on cultured human Neuroblastoma SH-SY5Y cells. SH-SY5Y cells were treated with CM at 0–200µM for 24, 48, and 72 h, [i]in vitro[/i]. It was found that CM induced the cell death of Neuroblastoma cells in a dose- and time-dependent manner, as shown by LDH assays. Next, some aspects of the process of cell death triggered by CM in the human SH-SY5Y cell line were investigated. It was revealed that the pan-caspase inhibitor Q-VD-OPh, sensitizes SH-SY5Y cells to necroptosis caused by CM. Furthermore, signal transduction inhibitors PD98059, SL-327, SB202190, SP600125 failed to attenuate the effect of the pesticide. Finally, it was shown that inhibition of TNF-a by Pomalidomide (PLD caused statistically significant reduction in CM-induced cytotoxicity. Overall, the data obtained suggest that CM induces neurotoxicity in SH-SY5Y cells by necroptosis.

  6. Pomegranate inhibits neuroinflammation and amyloidogenesis in IL-1β-stimulated SK-N-SH cells.

    Science.gov (United States)

    Velagapudi, Ravikanth; Baco, Gina; Khela, Sunjeet; Okorji, Uchechukwu; Olajide, Olumayokun

    2016-06-01

    Pomegranate fruit, Punica granatum L. (Punicaceae), and its constituents have been shown to inhibit inflammation. In this study, we aimed to assess the effects of freeze-dried pomegranate (PWE) on PGE2 production in IL-1β-stimulated SK-N-SH cells. An enzyme immunoassay (EIA) was used to measure prostaglandin E2 (PGE2) production from supernatants of IL-1β-stimulated SK-N-SH cells. Expression of COX-2, phospho-IκB, and phospho-IKK proteins was evaluated, while NF-κB reporter gene assay was carried out in TNFα-stimulated HEK293 cells to determine the effect of PWE on NF-κB transactivation. Levels of BACE-1 and Aβ in SK-N-SH cells stimulated with IL-1β were measured with an in cell ELISA. PWE (25-200 μg/ml) dose dependently reduced COX-2-dependent PGE2 production in SK-N-SH cells stimulated with IL-1β. Phosphorylation of IκB and IKK was significantly (p pomegranate inhibits inflammation, as well as amyloidogenesis in IL-1β-stimulated SK-N-SH cells. We propose that pomegranate is a potential nutritional strategy in slowing the progression of neurodegenerative disorders such as Alzheimer's disease.

  7. Sustainability Evaluation.

    Science.gov (United States)

    Stichnothe, Heinz

    2017-03-17

    The long-term substitution of fossil resources can only be achieved through a bio-based economy, with biorefineries and bio-based products playing a major role. However, it is important to assess the implications of the transition to a bio-based economy. Life cycle-based sustainability assessment is probably the most suitable approach to quantify impacts and to identify trade-offs at multiple levels. The extended utilisation of biomass can cause land use change and affect food security of the most vulnerable people throughout the world. Although this is mainly a political issue and governments should be responsible, the responsibility is shifted to companies producing biofuels and other bio-based products. Organic wastes and lignocellulosic biomass are considered to be the preferred feedstock for the production of bio-based products. However, it is unlikely that a bio-based economy can rely only on organic wastes and lignocellulosic biomass.It is crucial to identify potential problems related to socio-economic and environmental issues. Currently there are many approaches to the sustainability of bio-based products, both quantitative and qualitative. However, results of different calculation methods are not necessarily comparable and can cause confusion among decision-makers, stakeholders and the public.Hence, a harmonised, globally agreed approach would be the best solution to secure sustainable biomass/biofuels/bio-based chemicals production and trade, and to avoid indirect effects (e.g. indirect land use change). However, there is still a long way to go.Generally, the selection of suitable indicators that serve the purpose of sustainability assessment is very context-specific. Therefore, it is recommended to use a flexible and modular approach that can be adapted to various purposes. A conceptual model for the selection of sustainability indicators is provided that facilitates identifying suitable sustainability indicators based on relevance and significance in a

  8. Ethanol-induced lowering of arterial oxyhemoglobin saturation during hypoxia.

    Science.gov (United States)

    Hansen, J E; Claybaugh, J R

    1975-09-01

    Nine fasting, healthy, adult male volunteers were given oral carbohydrate before exposures to normoxia (PIO2 = 149 torr) and mild hypoxia (PIO2 = 98 torr). Following recovery, they were given oral ethanol before similar exposure to normoxia and mild hypoxia. Repeated measures of arterial blood and expired gases were made. Ethanol diminished respiratory gas exchange (R), causing lower alveolar and arterial oxygen pressures during normoxia and mild hypoxia and a reduction in arterial oxygen saturation from 89.9 to 87.4% during mild hypoxia. It is suggested that carbohydrates are preferable to ethanol and fats as nutrients during limited oxygen transport situations, such as high-altitude, carbon monoxide exposure, or during heavy exertion, and for patients with cardiovascular or pulmonary disease.

  9. Exercise performed at hypoxia influences mood state and anxiety symptoms

    Directory of Open Access Journals (Sweden)

    Jorge Fernando Tavares de Souza

    2015-06-01

    Full Text Available During hypoxia conditions, psychological states can be worsened. However, little information is available regarding the effect of physical exercise performed in hypoxia conditions on mood state and anxiety symptoms. The aim of the present study was to elucidate the acute effect of moderate physical exercise performed at hypoxia on mood states and anxiety symptoms in healthy young subjects. Ten volunteers were subjected to the following conditions: a normoxic condition (NC and a hypoxic condition (HC. They performed 45 min of physical exercise. Their anxiety symptoms and mood states were evaluated at the initial time point as well as immediately following and 30 and 60 min after the exercise session. Our results showed a significant increase in post-exercise anxiety symptoms and a significant decrease in mood scores immediately after and 30 min after exercise performed in the HC. Moderate physical activity performed at hypoxia condition increased post-exercise anxiety and worsened mood state.

  10. 2010 Summer Hypoxia Watch Bottom CTD Station Locations

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The NOAA Hypoxia Watch project provides near-real-time, web-based maps of dissolved oxygen near the sea floor over the Texas-Louisiana continental shelf during a...

  11. 2012 Summer Hypoxia Watch Bottom CTD Station Locations

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The NOAA Hypoxia Watch project provides near-real-time, web-based maps of dissolved oxygen near the sea floor over the Texas-Louisiana continental shelf during a...

  12. DUBs, new members in the hypoxia signaling clUb

    Directory of Open Access Journals (Sweden)

    Amelie S Schober

    2016-03-01

    Full Text Available Cellular protein homeostasis is tightly regulated by ubiquitination. Responsible for target protein ubiquitination is a class of enzymes, the so-called ubiquitin (Ub E3-ligases. They are opposed to a second class of enzymes, called DeUBiquitinating enzymes (DUBs, which can remove polyubiquitin chains from their specific target proteins. The coaction of the two sets of enzymes allow the cell to adapt its overall protein content and the abundance of particular proteins to a variety of cellular and environmental stresses, including hypoxia. In recent years, DUBs have been highlighted to play major roles in many diseases, including cancer, both as tumor suppressors and oncogenes. Therefore, DUBs are emerging as promising targets for cancer-cell specific treatment. Here, we will review the current understanding of DUBs implicated in the control of hypoxia-inducible factor (HIF, the regulation of DUBs by hypoxia and the use of DUB-specific drugs to target tumor hypoxia signaling.

  13. 2009 Summer Hypoxia Watch Bottom CTD Station Locations

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The NOAA Hypoxia Watch project provides near-real-time, web-based maps of dissolved oxygen near the sea floor over the Texas-Louisiana continental shelf during a...

  14. ROE Long Island Sound Hypoxia Data Web Service 2012

    Data.gov (United States)

    U.S. Environmental Protection Agency — Point data of collection sites overlayed on raster of hypoxia water data. The raster is broken out into 5 color-coded categories of oxygen level. This map is an...

  15. Short-term hypoxia/reoxygenation activates the angiogenic pathway ...

    Indian Academy of Sciences (India)

    PCR and ELISA. For vessel labelling, lectin location and expression were analysed using histochemical and image processing techniques (fractal dimension). Expression of Hif-1, Vegf, Adm and Tgf- 1 mRNA rose immediately after hypoxia ...

  16. 2008 Summer Hypoxia Watch Bottom CTD Station Locations

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The NOAA Hypoxia Watch project provides near-real-time, web-based maps of dissolved oxygen near the sea floor over the Texas-Louisiana continental shelf during a...

  17. 2011 Summer Hypoxia Watch Bottom CTD Station Locations

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The NOAA Hypoxia Watch project provides near-real-time, web-based maps of dissolved oxygen near the sea floor over the Texas-Louisiana continental shelf during a...

  18. 2013 Summer Hypoxia Watch Bottom CTD Station Locations

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The NOAA Hypoxia Watch project provides near-real-time, web-based maps of dissolved oxygen near the sea floor over the Texas-Louisiana continental shelf during a...

  19. An insight into tumoral hypoxia: the radiomarkers and clinical applications

    Directory of Open Access Journals (Sweden)

    Ana Margarida Abrantes

    2011-12-01

    Full Text Available Tumoral hypoxia is related to severe structural abnormalities of tumor microvessels, leading to deteriorated O2 diffusion. This decreased O2 concentration in cancer cells compromises cellular functions, besides being responsible for resistance to radiation therapy. Consequently, it is very important to know the hypoxic status of a tumor. In this review, the different methodologies available for evaluating cellular hypoxia in vivo are discussed, particularly those in which the hypoxia information is obtained through imaging. Among these the nuclear medicine approach uses ligands to complex with radionuclides. The resulting radioactive complexes which may be single photon or positron emitters, are very useful as imaging probes. The nature of ligands and their corresponding complexes, with application or potential application as hypoxia detectors, will be described. A summary of the most significant results so far obtained in clinical or preclinical applications will also be discussed.

  20. 2008 (Summer) Hypoxia Watch Bottom CTD Station Locations

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The NOAA Hypoxia Watch project provides near-real-time, web-based maps of dissolved oxygen near the sea floor over the Texas-Louisiana continental shelf during a...

  1. 2015 Summer Hypoxia Watch Bottom CTD Station Locations

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The NOAA Hypoxia Watch project provides near-real-time, web-based maps of dissolved oxygen near the sea floor over the Texas-Louisiana continental shelf during a...

  2. Hypoxia promotes tumor growth in linking angiogenesis to immune escape

    Directory of Open Access Journals (Sweden)

    Salem eCHOUAIB

    2012-02-01

    Full Text Available Despite the impressive progress over the past decade, in the field of tumor immunology, such as the identification of tumor antigens and antigenic peptides as potential targets, there are still many obstacles in eliciting an effective immune response to eradicate cancer. It has become increasingly clear that tumor microenvironment plays a crucial role in the control of immune protection and contains many overlapping mechanisms to evade antigen specific immunotherapy. Obviously, tumors have evolved to utilize hypoxic stress to their own advantage by activating key biochemical and cellular pathways that are important in progression, survival and metastasis. Among the hypoxia-induced genes, hypoxia-inducible factor (HIF-1 and vascular endothelial growth factor (VEGF play a determinant role in promoting tumor cell growth and survival. In this regard, hypoxia is emerging as an attractive target for cancer therapy. How the microenvironmental hypoxia poses both obstacles and opportunities for new therapeutic immune interventions will be discussed.

  3. Quality of pharmacy-specific Medical Subject Headings (MeSH) assignment in pharmacy journals indexed in MEDLINE.

    Science.gov (United States)

    Minguet, Fernando; Salgado, Teresa M; van den Boogerd, Lucienne; Fernandez-Llimos, Fernando

    2015-01-01

    The Medical Subject Headings (MeSH) is the National Library of Medicine (NLM) controlled vocabulary for indexing articles. Inaccuracies in the MeSH thesaurus have been reported for several areas including pharmacy. To assess the quality of pharmacy-specific MeSH assignment to articles indexed in pharmacy journals. The 10 journals containing the highest number of articles published in 2012 indexed under the MeSH 'Pharmacists' were identified. All articles published over a 5-year period (2008-2012) in the 10 previously selected journals were retrieved from PubMed. MeSH terms used to index these articles were extracted and pharmacy-specific MeSH terms were identified. The frequency of use of pharmacy-specific MeSH terms was calculated across journals. A total of 6989 articles were retrieved from the 10 pharmacy journals, of which 328 (4.7%) were articles not fully indexed and therefore did not contain any MeSH terms assigned. Among the 6661 articles fully indexed, the mean number of MeSH terms was 10.1 (SD = 4.0), being 1.0 (SD = 1.3) considered as Major MeSH. Both values significantly varied across journals. The mean number of pharmacy-specific MeSH terms per article was 0.9 (SD = 1.2). A total of 3490 (52.4%) of the 6661 articles were indexed in pharmacy journals without a single pharmacy-specific MeSH. Of the total 67193 MeSH terms assigned to articles, on average 10.5% (SD = 13.9) were pharmacy-specific MeSH. A statistically significant different pattern of pharmacy-specific MeSH assignment was identified across journals (Kruskal-Wallis P MeSH terms to articles indexed in pharmacy journals can be improved to further enhance evidence gathering in pharmacy. Over half of the articles published in the top-10 journals publishing pharmacy literature were indexed without a single pharmacy-specific MeSH. Copyright © 2015 Elsevier Inc. All rights reserved.

  4. Management of renal dysfunction following term perinatal hypoxia-ischaemia.

    LENUS (Irish Health Repository)

    Sweetman, Deirdre U

    2013-03-01

    Acute kidney injury frequently develops following the term perinatal hypoxia-ischaemia. Quantifying the degree of acute kidney injury is difficult, however, as the methods currently in use are suboptimal. Acute kidney injury management is largely supportive with little evidence basis for many interventions. This review discusses management strategies and novel biomarkers that may improve diagnosis and management of renal injury following perinatal hypoxia-ischaemia.

  5. Prenatal Hypoxia Induced Dysfunction in Cerebral Arteries of Offspring Rats.

    Science.gov (United States)

    Tang, Jiaqi; Li, Na; Chen, Xueyi; Gao, Qinqin; Zhou, Xiuwen; Zhang, Yingying; Liu, Bailin; Sun, Miao; Xu, Zhice

    2017-10-03

    Hypoxia during pregnancy could cause abnormal development and lead to increased risks of vascular diseases in adults. This study determined angiotensin II (AII)-mediated vascular dysfunction in offspring middle cerebral arteries (MCA). Pregnant rats were subjected to hypoxia. Vascular tension in offspring MCA by AII with or without inhibitors, calcium channel activities, and endoplasmic reticulum calcium stores were tested. Whole-cell patch clamping was used to investigate voltage-dependent calcium channel currents. mRNA expression was tested using quantitative real-time polymerase chain reaction. AII-mediated MCA constriction was greater in male offspring exposed to prenatal hypoxia. AT1 and AT2 receptors were involved in the altered AII-mediated vasoconstriction. Prenatal hypoxia increased baseline activities of L-type calcium channel currents in MCA smooth muscle cells. However, calcium currents stimulated by AII were not significantly changed, whereas nifedipine inhibited AII-mediated vasoconstrictions in the MCA. Activities of IP3/ryanodine receptor-operated calcium channels, endoplasmic reticulum calcium stores, and sarcoendoplasmic reticulum membrane Ca(2+)-ATPase were increased. Prenatal hypoxia also caused dysfunction of vasodilatation via the endothelium NO synthase. The mRNA expressions of AT1A, AT1B, AT2R, Cav1.2α1C, Cav3.2α1H, and ryanodine receptor RyR2 were increased in the prenatal-hypoxia group. Hypoxia in pregnancy could induce dysfunction in both contraction and dilation in the offspring MCA. AII-increased constriction in the prenatal-hypoxia group was not mainly dependent on the L-type and T-type calcium channels; it might predominantly rely on the AII receptors, IP3/ryanodine receptors, and the endoplasmic reticulum calcium store as well as calcium ATPase. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

  6. Upregulated copper transporters in hypoxia-induced pulmonary hypertension.

    Directory of Open Access Journals (Sweden)

    Adriana M Zimnicka

    Full Text Available Pulmonary vascular remodeling and increased arterial wall stiffness are two major causes for the elevated pulmonary vascular resistance and pulmonary arterial pressure in patients and animals with pulmonary hypertension. Cellular copper (Cu plays an important role in angiogenesis and extracellular matrix remodeling; increased Cu in vascular smooth muscle cells has been demonstrated to be associated with atherosclerosis and hypertension in animal experiments. In this study, we show that the Cu-uptake transporter 1, CTR1, and the Cu-efflux pump, ATP7A, were both upregulated in the lung tissues and pulmonary arteries of mice with hypoxia-induced pulmonary hypertension. Hypoxia also significantly increased expression and activity of lysyl oxidase (LOX, a Cu-dependent enzyme that causes crosslinks of collagen and elastin in the extracellular matrix. In vitro experiments show that exposure to hypoxia or treatment with cobalt (CoCl2 also increased protein expression of CTR1, ATP7A, and LOX in pulmonary arterial smooth muscle cells (PASMC. In PASMC exposed to hypoxia or treated with CoCl2, we also confirmed that the Cu transport is increased using 64Cu uptake assays. Furthermore, hypoxia increased both cell migration and proliferation in a Cu-dependent manner. Downregulation of hypoxia-inducible factor 1α (HIF-1α with siRNA significantly attenuated hypoxia-mediated upregulation of CTR1 mRNA. In summary, the data from this study indicate that increased Cu transportation due to upregulated CTR1 and ATP7A in pulmonary arteries and PASMC contributes to the development of hypoxia-induced pulmonary hypertension. The increased Cu uptake and elevated ATP7A also facilitate the increase in LOX activity and thus the increase in crosslink of extracellular matrix, and eventually leading to the increase in pulmonary arterial stiffness.

  7. Hypoxia enhances the angiogenic potential of human dental pulp cells.

    Science.gov (United States)

    Aranha, Andreza M F; Zhang, Zhaocheng; Neiva, Kathleen G; Costa, Carlos A S; Hebling, Josimeri; Nör, Jacques E

    2010-10-01

    Trauma can result in the severing of the dental pulp vessels, leading to hypoxia and ultimately to pulp necrosis. Improved understanding of mechanisms underlying the response of dental pulp cells to hypoxic conditions might lead to better therapeutic alternatives for patients with dental trauma. The purpose of this study was to evaluate the effect of hypoxia on the angiogenic response mediated by human dental pulp stem cells (DPSCs) and human dental pulp fibroblasts (HDPFs). DPSCs and HDPFs were exposed to experimental hypoxic conditions. Hypoxia-inducible transcription factor-1alpha (HIF-1alpha) was evaluated by Western blot and immunocytochemistry, whereas vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) expression was evaluated by enzyme-linked immunosorbent assay. YC-1, an inhibitor of HIF-1alpha, was used to evaluate the functional effect of this transcriptional factor on hypoxia-induced VEGF expression. Conditioned medium from hypoxic and normoxic pulp cells was used to stimulate human dermal microvascular endothelial cells (HDMECs). HDMEC proliferation was measured by WST-1 assay, and angiogenic potential was evaluated by a capillary sprouting assay in 3-dimensional collagen matrices. Hypoxia enhanced HIF-1alpha and VEGF expression in DPSCs and HDPFs. In contrast, hypoxia did not induce bFGF expression in pulp cells. YC-1 partially inhibited hypoxia-induced HIF-1alpha and VEGF in these cells. The growth factor milieu of hypoxic HDPFs (but not hypoxic DPSCs) induced endothelial cell proliferation and sprouting as compared with medium from normoxic cells. Collectively, these data demonstrate that hypoxia induces complex and cell type-specific pro-angiogenic responses and suggest that VEGF (but not bFGF) participates in the revascularization of hypoxic dental pulps. Copyright © 2010 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

  8. MeSHSim: An R/Bioconductor package for measuring semantic similarity over MeSH headings and MEDLINE documents.

    Science.gov (United States)

    Zhou, Jing; Shui, Yuxuan; Peng, Shengwen; Li, Xuhui; Mamitsuka, Hiroshi; Zhu, Shanfeng

    2015-12-01

    Currently, all MEDLINE documents are indexed by medical subject headings (MeSH). Computing semantic similarity between two MeSH headings as well as two documents has become very important for many biomedical text mining applications. We develop an R package, MeSHSim, which can compute nine similarity measures between MeSH nodes, by which similarity between MeSH headings as well as MEDLINE documents can be easily computed. Also, MeSHSim supports querying hierarchy information of a MeSH heading and retrieving MeSH headings of a query document, and can be easily integrated into pipelines for any biomedical text analysis tasks. MeSHSim is released under general public license (GPL), and available through Bioconductor and from Github at https://github.com/JingZhou2015/MeSHSim.

  9. Genome-Wide Prediction of SH2 Domain Targets Using Structural Information and the FoldX Algorithm

    DEFF Research Database (Denmark)

    Sanchez, Ignacio E.; Beltrao, Pedro; Stricher, Francois

    2008-01-01

    Current experiments likely cover only a fraction of all protein-protein interactions. Here, we developed a method to predict SH2-mediated protein-protein interactions using the structure of SH2-phosphopeptide complexes and the FoldX algorithm. We show that our approach performs similarly to exper......Current experiments likely cover only a fraction of all protein-protein interactions. Here, we developed a method to predict SH2-mediated protein-protein interactions using the structure of SH2-phosphopeptide complexes and the FoldX algorithm. We show that our approach performs similarly...... to experimentally derived consensus sequences and substitution matrices at predicting known in vitro and in vivo targets of SH2 domains. We use our method to provide a set of high-confidence interactions for human SH2 domains with known structure filtered on secondary structure and phosphorylation state. We...

  10. Targeting Hypoxia-Inducible Factor-1α/Pyruvate Dehydrogenase Kinase 1 Axis by Dichloroacetate Suppresses Bleomycin-induced Pulmonary Fibrosis.

    Science.gov (United States)

    Goodwin, Justin; Choi, Hyunsung; Hsieh, Meng-Hsiung; Neugent, Michael L; Ahn, Jung-Mo; Hayenga, Heather N; Singh, Pankaj K; Shackelford, David B; Lee, In-Kyu; Shulaev, Vladimir; Dhar, Shanta; Takeda, Norihiko; Kim, Jung-Whan

    2018-02-01

    Hypoxia has long been implicated in the pathogenesis of fibrotic diseases. Aberrantly activated myofibroblasts are the primary pathological driver of fibrotic progression, yet how various microenvironmental influences, such as hypoxia, contribute to their sustained activation and differentiation is poorly understood. As a defining feature of hypoxia is its impact on cellular metabolism, we sought to investigate how hypoxia-induced metabolic reprogramming affects myofibroblast differentiation and fibrotic progression, and to test the preclinical efficacy of targeting glycolytic metabolism for the treatment of pulmonary fibrosis. Bleomycin-induced pulmonary fibrotic progression was evaluated in two independent, fibroblast-specific, promoter-driven, hypoxia-inducible factor (Hif) 1A knockout mouse models and in glycolytic inhibitor, dichloroacetate-treated mice. Genetic and pharmacological approaches were used to explicate the role of metabolic reprogramming in myofibroblast differentiation. Hypoxia significantly enhanced transforming growth factor-β-induced myofibroblast differentiation through HIF-1α, whereas overexpression of the critical HIF-1α-mediated glycolytic switch, pyruvate dehydrogenase kinase 1 (PDK1) was sufficient to activate glycolysis and potentiate myofibroblast differentiation, even in the absence of HIF-1α. Inhibition of the HIF-1α/PDK1 axis by genomic deletion of Hif1A or pharmacological inhibition of PDK1 significantly attenuated bleomycin-induced pulmonary fibrosis. Our findings suggest that HIF-1α/PDK1-mediated glycolytic reprogramming is a critical metabolic alteration that acts to promote myofibroblast differentiation and fibrotic progression, and demonstrate that targeting glycolytic metabolism may prove to be a potential therapeutic strategy for the treatment of pulmonary fibrosis.

  11. Identification of a novel mutation of SH3BP2 in cherubism and demonstration that SH3BP2 mutations lead to increased NFAT activation.

    Science.gov (United States)

    Lietman, Steven A; Kalinchinko, Natasha; Deng, Xichao; Kohanski, Ronald; Levine, Michael A

    2006-07-01

    We describe a novel missense mutation (Aspartic acid to Asparagine, p.D419N (g.1371G>A, c.1255G>A) within exon 9 of SH3BP2 in a patient with cherubism, an autosomal dominant syndrome characterized by excessive osteoclastic bone resorption of the jaw. Two siblings and the father were carriers but lacked phenotypic features. Transient expression of p.D419N (c.1255G>A), as well as three previously described exon 9 mutations from cherubism patients (p.R415Q (c.1244G>A), p.D420E (c.1259G>A), and p.P418R (c.1253C>G)) increased activity of NFAT (nuclear factor of activated T-cells), an osteoclastogenic mediator, indicating that cherubism results from gain of function mutations in SH3BP2.

  12. Hypoxia in the changing marine environment

    Digital Repository Service at National Institute of Oceanography (India)

    Zhang, J.; Cowie, G.; Naqvi, S.W.A.

    The predicted future of the global marine environment, as a combined result of forcing due to climate change (e.g. warming and acidification) and other anthropogenic perturbation (e.g. eutrophication), presents a challenge to the sustainability...

  13. Advances in Hypoxia-Mediated Mechanisms in Hepatocellular Carcinoma.

    Science.gov (United States)

    Xiong, Xin Xin; Qiu, Xin Yao; Hu, Dian Xing; Chen, Xiao Qian

    2017-09-01

    Hepatocellular carcinoma (HCC) is the fifth most common and the third most deadly malignant tumor worldwide. Hypoxia and related oxidative stress are heavily involved in the process of HCC development and its therapies. However, direct and accurate measurement of oxygen concentration and evaluation of hypoxic effects in HCC prove difficult. Moreover, the hypoxia-mediated mechanisms in HCC remain elusive. Here, we summarize recent major evidence of hypoxia in HCC lesions shown by measuring partial pressure of oxygen (pO2), the clinical importance of hypoxic markers in HCC, and recent advances in hypoxia-related mechanisms and therapies in HCC. For the mechanisms, we focus mainly on the roles of oxygen-sensing proteins (i.e., hypoxia-inducible factor and neuroglobin) and hypoxia-induced signaling proteins (e.g., matrix metalloproteinases, high mobility group box 1, Beclin 1, glucose metabolism enzymes, and vascular endothelial growth factor). With respect to therapies, we discuss mainly YQ23, sorafenib, 2-methoxyestradiol, and celastrol. This review focuses primarily on the results of clinical and animal studies. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

  14. NITRIC OXIDE INTERFERES WITH HYPOXIA SIGNALING DURING COLONIC INFLAMMATION

    Directory of Open Access Journals (Sweden)

    Cintia Rabelo e Paiva CARIA

    2014-12-01

    Full Text Available Context Intestinal inflammation can induce a local reduction in oxygen levels that triggers an adaptive response centered on the expression of hypoxia-inducible factors (HIFs. Nitric oxide, a well-described inflammatory mediator, may interfere with hypoxia signaling. Objectives We aimed to evaluate the role of nitric oxide in hypoxia signaling during colonic inflammation. Methods Colitis was induced by single (acute or repeated (reactivated colitis trinitrobenzenosulfonic acid administration in rats. In addition, one group of rats with reactivated colitis was also treated with Nw-Nitro-L-arginine methyl ester hydrochloride to block nitric oxide synthase. Colitis was assessed by macroscopic score and myeloperoxidase activity in the colon samples. Hypoxia was determined using the oxygen-dependent probe, pimonidazole. The expression of HIF-1α and HIF-induced factors (vascular endothelial growth factor - VEGF and apelin was assessed using Western blotting. Results The single or repeated administration of trinitrobenzenosulfonic acid to rats induced colitis which was characterized by a high macroscopic score and myeloperoxidase activity. Hypoxia was observed with both protocols. During acute colitis, HIF-1α expression was not increased, but VEGF and apelin were increased. HIF-1α expression was inhibited during reactivated colitis, and VEGF and apelin were not increased. Nw-Nitro-L-arginine methyl ester hydrochloride blockade during reactivated colitis restored HIF-1α, VEGF and apelin expression. Conclusions Nitric oxide could interfere with hypoxia signaling during reactivated colitis inflammation modifying the expression of proteins regulated by HIF-1α.

  15. Nitric oxide interferes with hypoxia signaling during colonic inflammation.

    Science.gov (United States)

    Caria, Cintia Rabelo e Paiva; Moscato, Camila Henrique; Tomé, Renata Bortolin Guerra; Pedrazzoli, José; Ribeiro, Marcelo Lima; Gambero, Alessandra

    2014-01-01

    Intestinal inflammation can induce a local reduction in oxygen levels that triggers an adaptive response centered on the expression of hypoxia-inducible factors (HIFs). Nitric oxide, a well-described inflammatory mediator, may interfere with hypoxia signaling. We aimed to evaluate the role of nitric oxide in hypoxia signaling during colonic inflammation. Colitis was induced by single (acute) or repeated (reactivated colitis) trinitrobenzenosulfonic acid administration in rats. In addition, one group of rats with reactivated colitis was also treated with Nw-Nitro-L-arginine methyl ester hydrochloride to block nitric oxide synthase. Colitis was assessed by macroscopic score and myeloperoxidase activity in the colon samples. Hypoxia was determined using the oxygen-dependent probe, pimonidazole. The expression of HIF-1α and HIF-induced factors (vascular endothelial growth factor - VEGF and apelin) was assessed using Western blotting. The single or repeated administration of trinitrobenzenosulfonic acid to rats induced colitis which was characterized by a high macroscopic score and myeloperoxidase activity. Hypoxia was observed with both protocols. During acute colitis, HIF-1α expression was not increased, but VEGF and apelin were increased. HIF-1α expression was inhibited during reactivated colitis, and VEGF and apelin were not increased. Nw-Nitro-L-arginine methyl ester hydrochloride blockade during reactivated colitis restored HIF-1α, VEGF and apelin expression. Nitric oxide could interfere with hypoxia signaling during reactivated colitis inflammation modifying the expression of proteins regulated by HIF-1α.

  16. Hypoxia inhibits colonic ion transport via activation of AMP kinase.

    LENUS (Irish Health Repository)

    Collins, Danielle

    2012-02-01

    BACKGROUND AND AIMS: Mucosal hypoxia is a common endpoint for many pathological processes including ischemic colitis, colonic obstruction and anastomotic failure. Previous studies suggest that hypoxia modulates colonic mucosal function through inhibition of chloride secretion. However, the molecular mechanisms underlying this observation are poorly understood. AMP-activated protein kinase (AMPK) is a metabolic energy regulator found in a wide variety of cells and has been linked to cystic fibrosis transmembrane conductance regulator (CFTR) mediated chloride secretion in several different tissues. We hypothesized that AMPK mediates many of the acute effects of hypoxia on human and rat colonic electrolyte transport. METHODS: The fluorescent chloride indicator dye N-(ethoxycarbonylmethyl)-6-methoxyquinolinium bromide was used to measure changes in intracellular chloride concentrations in isolated single rat colonic crypts. Ussing chamber experiments in human colonic mucosa were conducted to evaluate net epithelial ion transport. RESULTS: This study demonstrates that acute hypoxia inhibits electrogenic chloride secretion via AMPK mediated inhibition of CFTR. Pre-treatment of tissues with the AMPK inhibitor 6-[4-(2-piperidin-1-yl-ethoxy)-phenyl)]-3-pyridin-4-yl-pyyrazolo [1,5-a] pyrimidine (compound C) in part reversed the effects of acute hypoxia on chloride secretion. CONCLUSION: We therefore suggest that AMPK is a key component of the adaptive cellular response to mucosal hypoxia in the colon. Furthermore, AMPK may represent a potential therapeutic target in diseased states or in prevention of ischemic intestinal injury.

  17. Hypoxia-Induced Oxidative Stress Modulation with Physical Activity

    Science.gov (United States)

    Debevec, Tadej; Millet, Grégoire P.; Pialoux, Vincent

    2017-01-01

    Increased oxidative stress, defined as an imbalance between prooxidants and antioxidants, resulting in molecular damage and disruption of redox signaling, is associated with numerous pathophysiological processes and known to exacerbate chronic diseases. Prolonged systemic hypoxia, induced either by exposure to terrestrial altitude or a reduction in ambient O2 availability is known to elicit oxidative stress and thereby alter redox balance in healthy humans. The redox balance modulation is also highly dependent on the level of physical activity. For example, both high-intensity exercise and inactivity, representing the two ends of the physical activity spectrum, are known to promote oxidative stress. Numerous to-date studies indicate that hypoxia and exercise can exert additive influence upon redox balance alterations. However, recent evidence suggests that moderate physical activity can attenuate altitude/hypoxia-induced oxidative stress during long-term hypoxic exposure. The purpose of this review is to summarize recent findings on hypoxia-related oxidative stress modulation by different activity levels during prolonged hypoxic exposures and examine the potential mechanisms underlying the observed redox balance changes. The paper also explores the applicability of moderate activity as a strategy for attenuating hypoxia-related oxidative stress. Moreover, the potential of such moderate intensity activities used to counteract inactivity-related oxidative stress, often encountered in pathological, elderly and obese populations is also discussed. Finally, future research directions for investigating interactive effects of altitude/hypoxia and exercise on oxidative stress are proposed. PMID:28243207

  18. Wnt pathway activation increases hypoxia tolerance during development.

    Directory of Open Access Journals (Sweden)

    Merril Gersten

    Full Text Available Adaptation to hypoxia, defined as a condition of inadequate oxygen supply, has enabled humans to successfully colonize high altitude regions. The mechanisms attempted by organisms to cope with short-term hypoxia include increased ATP production via anaerobic respiration and stabilization of Hypoxia Inducible Factor 1α (HIF-1α. However, less is known about the means through which populations adapt to chronic hypoxia during the process of development within a life time or over generations. Here we show that signaling via the highly conserved Wnt pathway impacts the ability of Drosophila melanogaster to complete its life cycle under hypoxia. We identify this pathway through analyses of genome sequencing and gene expression of a Drosophila melanogaster population adapted over >180 generations to tolerate a concentration of 3.5-4% O2 in air. We then show that genetic activation of the Wnt canonical pathway leads to increased rates of adult eclosion in low O2. Our results indicate that a previously unsuspected major developmental pathway, Wnt, plays a significant role in hypoxia tolerance.

  19. Macrophage-mediated response to hypoxia in disease

    Directory of Open Access Journals (Sweden)

    Tazzyman S

    2014-11-01

    Full Text Available Simon Tazzyman,1 Craig Murdoch,2 James Yeomans,1 Jack Harrison,1 Munitta Muthana3 1Department of Oncology, 2School of Clinical Dentistry, 3Department of Infection and Immunity, University of Sheffield, Sheffield, UK Abstract: Hypoxia plays a critical role in the pathobiology of various inflamed, diseased tissues, including malignant tumors, atherosclerotic plaques, myocardial infarcts, the synovia of rheumatoid arthritic joints, healing wounds, and sites of bacterial infection. These areas of hypoxia form when the blood supply is occluded and/or the oxygen supply is unable to keep pace with cell growth and/or infiltration of inflammatory cells. Macrophages are ubiquitous in all tissues of the body and exhibit great plasticity, allowing them to perform divergent functions, including, among others, patrolling tissue, combating invading pathogens and tumor cells, orchestrating wound healing, and restoring homeostasis after an inflammatory response. The number of tissue macrophages increases markedly with the onset and progression of many pathological states, with many macrophages accumulating in avascular and necrotic areas, where they are exposed to hypoxia. Recent studies show that these highly versatile cells then respond rapidly to the hypoxia present by altering their expression of a wide array of genes. Here we review the evidence for hypoxia-driven macrophage inflammatory responses in various disease states, and how this influences disease progression and treatment. Keywords: macrophage, hypoxia, inflammation, cytokine

  20. Mild hypoxia affects synaptic connectivity in cultured neuronal networks.

    Science.gov (United States)

    Hofmeijer, Jeannette; Mulder, Alex T B; Farinha, Ana C; van Putten, Michel J A M; le Feber, Joost

    2014-04-04

    Eighty percent of patients with chronic mild cerebral ischemia/hypoxia resulting from chronic heart failure or pulmonary disease have cognitive impairment. Overt structural neuronal damage is lacking and the precise cause of neuronal damage is unclear. As almost half of the cerebral energy consumption is used for synaptic transmission, and synaptic failure is the first abrupt consequence of acute complete anoxia, synaptic dysfunction is a candidate mechanism for the cognitive deterioration in chronic mild ischemia/hypoxia. Because measurement of synaptic functioning in patients is problematic, we use cultured networks of cortical neurons from new born rats, grown over a multi-electrode array, as a model system. These were exposed to partial hypoxia (partial oxygen pressure of 150Torr lowered to 40-50Torr) during 3 (n=14) or 6 (n=8) hours. Synaptic functioning was assessed before, during, and after hypoxia by assessment of spontaneous network activity, functional connectivity, and synaptically driven network responses to electrical stimulation. Action potential heights and shapes and non-synaptic stimulus responses were used as measures of individual neuronal integrity. During hypoxia of 3 and 6h, there was a statistically significant decrease of spontaneous network activity, functional connectivity, and synaptically driven network responses, whereas direct responses and action potentials remained unchanged. These changes were largely reversible. Our results indicate that in cultured neuronal networks, partial hypoxia during 3 or 6h causes isolated disturbances of synaptic connectivity. Copyright © 2014 Elsevier B.V. All rights reserved.

  1. HRGFish: A database of hypoxia responsive genes in fishes

    Science.gov (United States)

    Rashid, Iliyas; Nagpure, Naresh Sahebrao; Srivastava, Prachi; Kumar, Ravindra; Pathak, Ajey Kumar; Singh, Mahender; Kushwaha, Basdeo

    2017-02-01

    Several studies have highlighted the changes in the gene expression due to the hypoxia response in fishes, but the systematic organization of the information and the analytical platform for such genes are lacking. In the present study, an attempt was made to develop a database of hypoxia responsive genes in fishes (HRGFish), integrated with analytical tools, using LAMPP technology. Genes reported in hypoxia response for fishes were compiled through literature survey and the database presently covers 818 gene sequences and 35 gene types from 38 fishes. The upstream fragments (3,000 bp), covered in this database, enables to compute CG dinucleotides frequencies, motif finding of the hypoxia response element, identification of CpG island and mapping with the reference promoter of zebrafish. The database also includes functional annotation of genes and provides tools for analyzing sequences and designing primers for selected gene fragments. This may be the first database on the hypoxia response genes in fishes that provides a workbench to the scientific community involved in studying the evolution and ecological adaptation of the fish species in relation to hypoxia.

  2. Hypoxia-Induced Oxidative Stress Modulation with Physical Activity.

    Science.gov (United States)

    Debevec, Tadej; Millet, Grégoire P; Pialoux, Vincent

    2017-01-01

    Increased oxidative stress, defined as an imbalance between prooxidants and antioxidants, resulting in molecular damage and disruption of redox signaling, is associated with numerous pathophysiological processes and known to exacerbate chronic diseases. Prolonged systemic hypoxia, induced either by exposure to terrestrial altitude or a reduction in ambient O2 availability is known to elicit oxidative stress and thereby alter redox balance in healthy humans. The redox balance modulation is also highly dependent on the level of physical activity. For example, both high-intensity exercise and inactivity, representing the two ends of the physical activity spectrum, are known to promote oxidative stress. Numerous to-date studies indicate that hypoxia and exercise can exert additive influence upon redox balance alterations. However, recent evidence suggests that moderate physical activity can attenuate altitude/hypoxia-induced oxidative stress during long-term hypoxic exposure. The purpose of this review is to summarize recent findings on hypoxia-related oxidative stress modulation by different activity levels during prolonged hypoxic exposures and examine the potential mechanisms underlying the observed redox balance changes. The paper also explores the applicability of moderate activity as a strategy for attenuating hypoxia-related oxidative stress. Moreover, the potential of such moderate intensity activities used to counteract inactivity-related oxidative stress, often encountered in pathological, elderly and obese populations is also discussed. Finally, future research directions for investigating interactive effects of altitude/hypoxia and exercise on oxidative stress are proposed.

  3. Mutation of SH2B3 (LNK), a GWAS candidate for hypertension, attenuates Dahl SS hypertension via inflammatory modulation

    Science.gov (United States)

    Rudemiller, Nathan P.; Lund, Hayley; Priestley, Jessica R. C.; Endres, Bradley T.; Prokop, Jeremy W.; Jacob, Howard J.; Geurts, Aron M.; Cohen, Eric P.; Mattson, David L.

    2015-01-01

    Human genome wide association studies (GWAS) have linked SH2B3 (LNK) to hypertension and renal disease, though little experimental investigation has been done to verify a role for SH2B3 in these pathologies. SH2B3, a member of the SH2B adaptor protein family, is an intracellular adaptor protein that functions as a negative regulator in many signaling pathways, including inflammatory signaling processes. To explore a mechanistic link between SH2B3 and hypertension, we targeted the SH2B3 gene for mutation on the Dahl salt-sensitive (SS) rat genetic background with zinc-finger nucleases (ZFN). The resulting mutation was a 6 base-pair, in-frame deletion within a highly-conserved region of the Src Homology 2 (SH2) domain of SH2B3. This mutation significantly attenuated Dahl salt-sensitive (SS) hypertension and renal disease. Also, infiltration of leukocytes into the kidneys, a key mediator of Dahl SS pathology, was significantly blunted in the Sh2b3em1Mcwi mutant rats. To determine if this was due to differences in immune signaling, bone marrow transplant studies were performed in which Dahl SS and Sh2b3em1Mcwi mutants underwent total body irradiation and were then transplanted with Dahl SS or Sh2b3em1Mcwi mutant bone marrow. Rats that received Sh2b3em1Mcwi mutant bone marrow had a significant reduction in mean arterial pressure and kidney injury when placed on a high salt diet (4% NaCl). These data further support a role for the immune system as a modulator of disease severity in the pathogenesis of hypertension and provide insight into inflammatory mechanisms at play in human hypertension and renal disease. PMID:25776069

  4. An assessment of the visibility of MeSH-indexed medical web catalogs through search engines.

    Science.gov (United States)

    Zweigenbaum, P; Darmoni, S J; Grabar, N; Douyère, M; Benichou, J

    2002-01-01

    Manually indexed Internet health catalogs such as CliniWeb or CISMeF provide resources for retrieving high-quality health information. Users of these quality-controlled subject gateways are most often referred to them by general search engines such as Google, AltaVista, etc. This raises several questions, among which the following: what is the relative visibility of medical Internet catalogs through search engines? This study addresses this issue by measuring and comparing the visibility of six major, MeSH-indexed health catalogs through four different search engines (AltaVista, Google, Lycos, Northern Light) in two languages (English and French). Over half a million queries were sent to the search engines; for most of these search engines, according to our measures at the time the queries were sent, the most visible catalog for English MeSH terms was CliniWeb and the most visible one for French MeSH terms was CISMeF.

  5. A novel mutation in the SH3BP2 gene causes cherubism: case report

    Directory of Open Access Journals (Sweden)

    Yu Shi-Feng

    2006-12-01

    Full Text Available Abstract Background Cherubism is a rare hereditary multi-cystic disease of the jaws, characterized by its typical appearance in early childhood, and stabilization and remission after puberty. It is genetically transmitted in an autosomal dominant fashion and the gene coding for SH3-binding protein 2 (SH3BP2 may be involved. Case presentation We investigated a family consisting of 21 members with 3 female affected individuals with cherubism from Northern China. Of these 21 family members, 17 were recruited for the genetic analysis. We conducted the direct sequence analysis of the SH3BP2 gene among these 17 family members. A disease-causing mutation was identified in exon 9 of the gene. It was an A1517G base change, which leads to a D419G amino acid substitution. Conclusion To our knowledge, the A1517G mutation has not been reported previously in cherubism. This finding is novel.

  6. Strong SH-to-Love wave scattering off the Southern California Continental Borderland

    Science.gov (United States)

    Yu, Chunquan; Zhan, Zhongwen; Hauksson, Egill; Cochran, Elizabeth S.

    2017-01-01

    Seismic scattering is commonly observed and results from wave propagation in heterogeneous medium. Yet, deterministic characterization of scatterers associated with lateral heterogeneities remains challenging. In this study, we analyze broadband waveforms recorded by the Southern California Seismic Network and observe strongly scattered Love waves following the arrival of teleseismic SH wave. These scattered Love waves travel approximately in the same (azimuthal) direction as the incident SH wave at a dominant period of ~10 s but at an apparent velocity of ~3.6 km/s as compared to the ~11 km/s for the SH wave. Back-projection suggests that this strong scattering is associated with pronounced bathymetric relief in the Southern California Continental Borderland, in particular the Patton Escarpment. Finite-difference simulations using a simplified 2-D bathymetric and crustal model are able to predict the arrival times and amplitudes of major scatterers. The modeling suggests a relatively low shear wave velocity in the Continental Borderland.

  7. Strong SH-to-Love Wave Scattering off the Southern California Continental Borderland

    Science.gov (United States)

    Yu, Chunquan; Zhan, Zhongwen; Hauksson, Egill; Cochran, Elizabeth S.

    2017-10-01

    Seismic scattering is commonly observed and results from wave propagation in heterogeneous medium. Yet deterministic characterization of scatterers associated with lateral heterogeneities remains challenging. In this study, we analyze broadband waveforms recorded by the Southern California Seismic Network and observe strongly scattered Love waves following the arrival of teleseismic SH wave. These scattered Love waves travel approximately in the same (azimuthal) direction as the incident SH wave at a dominant period of 10 s but at an apparent velocity of 3.6 km/s as compared to the 11 km/s for the SH wave. Back projection suggests that this strong scattering is associated with pronounced bathymetric relief in the Southern California Continental Borderland, in particular the Patton Escarpment. Finite-difference simulations using a simplified 2-D bathymetric and crustal model are able to predict the arrival times and amplitudes of major scatterers. The modeling suggests a relatively low shear wave velocity in the Continental Borderland.

  8. A novel mutation in the SH3BP2 gene causes cherubism: case report.

    Science.gov (United States)

    Li, Cui-Ying; Yu, Shi-Feng

    2006-12-05

    Cherubism is a rare hereditary multi-cystic disease of the jaws, characterized by its typical appearance in early childhood, and stabilization and remission after puberty. It is genetically transmitted in an autosomal dominant fashion and the gene coding for SH3-binding protein 2 (SH3BP2) may be involved. We investigated a family consisting of 21 members with 3 female affected individuals with cherubism from Northern China. Of these 21 family members, 17 were recruited for the genetic analysis. We conducted the direct sequence analysis of the SH3BP2 gene among these 17 family members. A disease-causing mutation was identified in exon 9 of the gene. It was an A1517G base change, which leads to a D419G amino acid substitution. To our knowledge, the A1517G mutation has not been reported previously in cherubism. This finding is novel.

  9. Annotating patents with Medline MeSH codes via citation mapping.

    Science.gov (United States)

    Griffin, Thomas D; Boyer, Stephen K; Councill, Isaac G

    2010-01-01

    Both patents and Medline are important document collections for discovering new relationships between chemicals and biology, searching for prior art for patent applications and retrieving background knowledge for current research activities. Finding relevance to a topic within patents is often made difficult by poor categorization, badly written descriptions, and even intentional obfuscation. Unlike patents, the Medline corpus has Medical Subject Heading (MeSH) keywords manually added to their articles, giving a medically relevant taxonomy to the 18 million article abstracts. Our work attempts to accurately recognize the citations made in patents to Medline-indexed articles, linking them to their corresponding PubMed ID and exploiting the associated MeSH to enhance patent search by annotating the referencing patents with their Medline citations' MeSH codes. The techniques, system features, and benefits are explained.

  10. Identification of Tyrosine Phosphorylated Proteins by SH2 Domain Affinity Purification and Mass Spectrometry.

    Science.gov (United States)

    Buhs, Sophia; Gerull, Helwe; Nollau, Peter

    2017-01-01

    Phosphotyrosine signaling plays a major role in the control of many important biological functions such as cell proliferation and apoptosis. Deciphering of phosphotyrosine-dependent signaling is therefore of great interest paving the way for the understanding of physiological and pathological processes of signal transduction. On the basis of the specific binding of SH2 domains to phosphotyrosine residues, we here present an experimental workflow for affinity purification and subsequent identification of tyrosine phosphorylated proteins by mass spectrometry. In combination with SH2 profiling, a broadly applicable platform for the characterization of phosphotyrosine profiles in cell extracts, our pull down strategy enables researchers by now to identify proteins in signaling cascades which are differentially phosphorylated and selectively recognized by distinct SH2 domains.

  11. Hydrogen Peroxide Toxicity Induces Ras Signaling in Human Neuroblastoma SH-SY5Y Cultured Cells

    Directory of Open Access Journals (Sweden)

    Jirapa Chetsawang

    2010-01-01

    Full Text Available It has been reported that overproduction of reactive oxygen species occurs after brain injury and mediates neuronal cells degeneration. In the present study, we examined the role of Ras signaling on hydrogen peroxide-induced neuronal cells degeneration in dopaminergic neuroblastoma SH-SY5Y cells. Hydrogen peroxide significantly reduced cell viability in SH-SY5Y cultured cells. An inhibitor of the enzyme that catalyzes the farnesylation of Ras proteins, FTI-277, and a competitive inhibitor of GTP-binding proteins, GDP-beta-S significantly decreased hydrogen peroxide-induced reduction in cell viability in SH-SY5Y cultured cells. The results of this study might indicate that a Ras-dependent signaling pathway plays a role in hydrogen peroxide-induced toxicity in neuronal cells.

  12. SH-wave seismic reflection at a landslide (Patigno, NW Italy) integrated with P-wave

    Science.gov (United States)

    Stucchi, E.; Tognarelli, A.; Ribolini, A.

    2017-11-01

    The aim of this paper is to present the acquisition and processing up to the depth migrated section of an SH-wave reflection seismic profile. This experience is conducted on a deep-seated gravitational slope deformation located in the Northern Apennines in Italy. The SH-wave depth-migrated image in the investigated area provides a detailed description of the small reactivation slip surfaces delineating minor landslides at shallow depths, which are responsible for the major damages observed. These results are integrated with a recently acquired P-wave seismic reflection profile investigating the same slope and delineating the highly deformed layer at depth, liable for the deep-seated gravitational slope deformation. The combined use of P-waves and SH-waves allows to gain a deeper knowledge of the landslide internal setting that is necessary to mitigate the risk associated with the mass movement.

  13. Sustainable Soesterkwartier

    NARCIS (Netherlands)

    Abrahams, H.; Goosen, H.; Jong, de F.; Sickmann, J.; Prins, D.

    2010-01-01

    The municipality of Amersfoort wants to construct an endurable and sustainable eco-town in the Soesterkwartier neighbourhood, by taking future climate change into account. The impact of climate change at the location of the proposed eco-town was studied by a literature review.

  14. Sustainable agriculture

    International Development Research Centre (IDRC) Digital Library (Canada)

    New farming techniques, better food security. Since 1970, IDRC-supported research has introduced sustainable agricultural practices to farmers and communities across the devel- oping world. The result: higher productivity, less poverty, greater food security, and a healthier environment. Opportunities grow on trees in ...

  15. Sustainable Development

    African Journals Online (AJOL)

    Tsegai Berhane Ghebretekle

    Abstract. This article examines the concept of sustainable development after the Post-. 2015 Paris Climate Change Agreement with particular emphasis on Ethiopia. Various African countries are vulnerable to climate change, as is evidenced by recent droughts. Ethiopia is selected as a case study in light of its pace in.

  16. Sustainable machining

    CERN Document Server

    2017-01-01

    This book provides an overview on current sustainable machining. Its chapters cover the concept in economic, social and environmental dimensions. It provides the reader with proper ways to handle several pollutants produced during the machining process. The book is useful on both undergraduate and postgraduate levels and it is of interest to all those working with manufacturing and machining technology.

  17. Architecture Sustainability

    NARCIS (Netherlands)

    Avgeriou, Paris; Stal, Michael; Hilliard, Rich

    2013-01-01

    Software architecture is the foundation of software system development, encompassing a system's architects' and stakeholders' strategic decisions. A special issue of IEEE Software is intended to raise awareness of architecture sustainability issues and increase interest and work in the area. The

  18. Sustainability reporting

    NARCIS (Netherlands)

    Kolk, A.

    2005-01-01

    This article gives an overview of developments in sustainability (also sometimes labelled corporate social responsibility) reporting. It The article will first briefly indicate how accountability on social and environmental issues started, already in the 1970s when social reports were published.

  19. Exergy sustainability.

    Energy Technology Data Exchange (ETDEWEB)

    Robinett, Rush D. III (.; ); Wilson, David Gerald; Reed, Alfred W.

    2006-05-01

    Exergy is the elixir of life. Exergy is that portion of energy available to do work. Elixir is defined as a substance held capable of prolonging life indefinitely, which implies sustainability of life. In terms of mathematics and engineering, exergy sustainability is defined as the continuous compensation of irreversible entropy production in an open system with an impedance and capacity-matched persistent exergy source. Irreversible and nonequilibrium thermodynamic concepts are combined with self-organizing systems theories as well as nonlinear control and stability analyses to explain this definition. In particular, this paper provides a missing link in the analysis of self-organizing systems: a tie between irreversible thermodynamics and Hamiltonian systems. As a result of this work, the concept of ''on the edge of chaos'' is formulated as a set of necessary and sufficient conditions for stability and performance of sustainable systems. This interplay between exergy rate and irreversible entropy production rate can be described as Yin and Yang control: the dialectic synthesis of opposing power flows. In addition, exergy is shown to be a fundamental driver and necessary input for sustainable systems, since exergy input in the form of power is a single point of failure for self-organizing, adaptable systems.

  20. Sustainable processing

    DEFF Research Database (Denmark)

    Kristensen, Niels Heine

    2004-01-01

    Kristensen_NH and_Beck A: Sustainable processing. In Otto Schmid, Alexander Beck and Ursula Kretzschmar (Editors) (2004): Underlying Principles in Organic and "Low-Input Food" Processing - Literature Survey. Research Institute of Organic Agriculture FiBL, CH-5070 Frick, Switzerland. ISBN 3-906081-58-3...

  1. Sustainable finance

    NARCIS (Netherlands)

    dr. Margreet F. Boersma-de Jong

    2012-01-01

    Presentation for Springschool of Strategy, University of Groningen, 10 October 2012. The role of CSR is to stimulate ethical behaviour, and as a result, mutual trust in society. Advantage of CSR for the company and the evolution of CSR. From CSR to Sustainable Finance: how does CSR influence

  2. Spectroscopic and Electrochemical Detection of Thrombin/5'-SH or 3'-SH Aptamer Immobilized on (porous) Gold Substrates

    Energy Technology Data Exchange (ETDEWEB)

    Park, Buem Jin; Sa, Young Seung; Kim, Yong Hwan; Kim, Young Hun [Kwangwoon University, Seoul (Korea, Republic of)

    2012-01-15

    Thrombin is a serine protease that catalyzes the conversion of soluble fibrinogen to insoluble fibrin, and thus induces physiological and pathological blood coagulation. Therefore, it is important to detect thrombin in blood serum for purposes of diagnosis. To achieve this goal, it has been suggested that a 15-mer aptamer strongly binds with thrombin to form a G-quartet structure of the aptamer. Generally, 5'-end thiol-functionalized aptamer has been used as an anti-thrombin binder. Herein, we evaluate the possibility of utilizing a 3'-SH aptasensor for thrombin detection using SPR spectroscopy, and compare the enhancement of the electrochemical signal of the thrombin-aptamer bound on a porous gold substrate. Although the two aptamers have similar configurations, in SPR analysis, the 3'-SH aptamer was a effective aptasensor as well as 5'-SH aptamer. Results from electrochemical analysis showed that the porous gold substrate acted as a good substrate for an aptasensor and demonstrated 5-fold enhancement of current change, as compared to gold thin film.

  3. High frequency of SH3TC2 mutations in Czech HMSN I patients.

    Science.gov (United States)

    Laššuthová, P; Mazanec, R; Vondráček, P; Sišková, D; Haberlová, J; Sabová, J; Seeman, P

    2011-10-01

    Charcot-Marie-Tooth (CMT) neuropathy type 4C (CMT4C) is an autosomal recessive (AR), demyelinating neuropathy with early spine deformities caused by mutations in the SH3TC2 gene. To determine the spectrum of SH3TC2 mutations in the Czech population, the entire coding region of SH3TC2 was sequenced in 60 unrelated Czech patients. The prevalent mutation was shown to be the p.Arg954Stop. Therefore, 412 additional patients referred for CMT testing were tested for the presence of p.Arg954Stop only. Of 60 patients in whom the SH3TC2 gene was sequenced, at least one mutation was detected in 13 (21.7%) patients and biallelic pathogenic mutations were detected in 7 (11.6%) patients. Of the 412 patients tested for p.Arg954Stop, the mutation was found in 8 patients (1.94%), 6 were homozygous and 2 were heterozygous. The second causative mutation was detected by sequencing in one of the patients but not in the other. Nine novel sequence variants were detected. Their pathogenicity was further tested in silico and in control samples. Mutations in the SH3TC2 gene are a frequent cause of demyelinating hereditary neuropathy among Czech patients. In total, at least one mutation was found in 21 unrelated patients. CMT4C seems to be the most frequent type of AR CMT and one of the most frequent of all CMT types. Mutation p.Arg954Stop is highly prevalent in the Czech population. Patients with demyelinating neuropathy along with non-dominant mode of inheritance and negative for CMT1A/hereditary neuropathy with liability to pressure palsy should be tested for the presence of the p.Arg954Stop mutation or other mutations in the SH3TC2 gene. © 2011 John Wiley & Sons A/S.

  4. Hypoxia-inducible factor-1α activation improves renal oxygenation and mitochondrial function in early chronic kidney disease.

    Science.gov (United States)

    Thomas, Joanna L; Pham, Hai; Li, Ying; Hall, Elanore; Perkins, Guy A; Ali, Sameh S; Patel, Hemal H; Singh, Prabhleen

    2017-08-01

    The pathophysiology of chronic kidney disease (CKD) is driven by alterations in surviving nephrons to sustain renal function with ongoing nephron loss. Oxygen supply-demand mismatch, due to hemodynamic adaptations, with resultant hypoxia, plays an important role in the pathophysiology in early CKD. We sought to investigate the underlying mechanisms of this mismatch. We utilized the subtotal nephrectomy (STN) model of CKD to investigate the alterations in renal oxygenation linked to sodium (Na) transport and mitochondrial function in the surviving nephrons. Oxygen delivery was significantly reduced in STN kidneys because of lower renal blood flow. Fractional oxygen extraction was significantly higher in STN. Tubular Na reabsorption was significantly lower per mole of oxygen consumed in STN. We hypothesized that decreased mitochondrial bioenergetic capacity may account for this and uncovered significant mitochondrial dysfunction in the early STN kidney: higher oxidative metabolism without an attendant increase in ATP levels, elevated superoxide levels, and alterations in mitochondrial morphology. We further investigated the effect of activation of hypoxia-inducible factor-1α (HIF-1α), a master regulator of cellular hypoxia response. We observed significant improvement in renal blood flow, glomerular filtration rate, and tubular Na reabsorption per mole of oxygen consumed with HIF-1α activation. Importantly, HIF-1α activation significantly lowered mitochondrial oxygen consumption and superoxide production and increased mitochondrial volume density. In conclusion, we report significant impairment of renal oxygenation and mitochondrial function at the early stages of CKD and demonstrate the beneficial role of HIF-1α activation on renal function and metabolism.

  5. Is TNF-a-targeted short hairpin RNA (shRNA) a novel potential therapeutic tool in psoriasis treatment?

    DEFF Research Database (Denmark)

    Stenderup, Karin; Jakobsen, Maria; Rosada, Cecilia

    2008-01-01

    the efficiency of targeting TNF-a with specific short hairpin RNA (shRNA) and explores its potential in treating psoriasis. ShRNAs targeting human TNF-α mRNA were generated. Their efficiency in down-regulating TNF-a protein expression was evaluated using a Renilla luciferase screening-assay and a transient co......-transfection assay. The expression cassette encoding the most efficient TNF-a shRNA was inserted into a lentiviral vector, allowing proficient gene delivery. The lentiviral vector is integrated into the host genome and establishes life-long infection and persistent shRNA expression. The lentiviral vector expressing...

  6. Effects of exercise training on tumor hypoxia and vascular function in the rodent preclinical orthotopic prostate cancer model

    Science.gov (United States)

    McCullough, Danielle J.; Nguyen, Linda M.-D.; Siemann, Dietmar W.

    2013-01-01

    Regular physical exercise is considered to be an integral component of cancer care strategies. However, the effect of exercise training on tumor microvascular oxygenation, hypoxia, and vascular function, all of which can affect the tumor microenvironment, remains unknown. Using an orthotopic preclinical model of prostate cancer, we tested the hypotheses that, after exercise training, in the tumor, there would be an enhanced microvascular Po2, increased number of patent vessels, and reduced hypoxia. We also investigated tumor resistance artery contractile properties. Dunning R-3327 AT-1 tumor cells (104) were injected into the ventral prostate of 4–5-mo-old male Copenhagen or Nude rats, which were randomly assigned to tumor-bearing exercise trained (TB-Ex trained; n = 15; treadmill exercise for 5–7 wk) or sedentary groups (TB-Sedentary; n = 12). Phosphorescence quenching was used to measure tumor microvascular Po2, and Hoechst-33342 and EF-5 were used to measure patent vessels and tumor hypoxia, respectively. Tumor resistance artery function was assessed in vitro using the isolated microvessel technique. Compared with sedentary counterparts, tumor microvascular Po2 increased ∼100% after exercise training (TB-Sedentary, 6.0 ± 0.3 vs. TB-Ex Trained, 12.2 ± 1.0 mmHg, P Exercise training did not affect the number of patent vessels but did significantly reduce tumor hypoxia in the conscious, resting condition from 39 ± 12% of the tumor area in TB-Sedentary to 4 ± 1% in TB-Ex Trained. Exercise training did not affect vessel contractile function. These results demonstrate that after exercise training, there is a large increase in the driving force of O2 from the tumor microcirculation, which likely contributes to the considerable reduction in tumor hypoxia. These results suggest that exercise training can modulate the microenvironment of the tumor, such that a sustained reduction in tumor hypoxia occurs, which may lead to a less aggressive phenotype and improve

  7. Envisioning the Shôjo Aesthetic in Illustrations of Miyazawa Kenji’s Literature.

    OpenAIRE

    Helen Claire Kilpatrick

    2013-01-01

    Despite an ever-growing body of scholarship on the shôjo (girl) in manga and anime, little has been written about representations of the ‘girl’ in Japanese picture books. Shôjo literature and culture have grown exponentially in Japan since about the 1980s, but there has been a tendency in popular media to overemphasise the 'cute', disempowering aspects of the ‘girl’. By using Takahara Eiri's (1999) concept of “girl consciousness” and Honda Masuko's (1992) envisioning of the girl’s imagined fr...

  8. MEDLINE MeSH Indexing: Lessons Learned from Machine Learning and Future Directions

    DEFF Research Database (Denmark)

    Jimeno-Yepes, Antonio; Mork, James G.; Wilkowski, Bartlomiej

    2012-01-01

    Map and a k-NN approach called PubMed Related Citations (PRC). Our motivation is to improve the quality of MTI based on machine learning. Typical machine learning approaches fit this indexing task into text categorization. In this work, we have studied some Medical Subject Headings (MeSH) recommended by MTI...... and analyzed the issues when using standard machine learning algorithms. We show that in some cases machine learning can improve the annotations already recommended by MTI, that machine learning based on low variance methods achieves better performance and that each MeSH heading presents a different behavior...

  9. Envisioning the Shôjo Aesthetic in Illustrations of Miyazawa Kenji’s Literature.

    Directory of Open Access Journals (Sweden)

    Helen Claire Kilpatrick

    2013-01-01

    Full Text Available Despite an ever-growing body of scholarship on the shôjo (girl in manga and anime, little has been written about representations of the ‘girl’ in Japanese picture books. Shôjo literature and culture have grown exponentially in Japan since about the 1980s, but there has been a tendency in popular media to overemphasise the 'cute', disempowering aspects of the ‘girl’. By using Takahara Eiri's (1999 concept of “girl consciousness” and Honda Masuko's (1992 envisioning of the girl’s imagined freedom through a hirahira (fluttering aesthetic, notions of the powerless or mindlessly consuming shôjo can be dispelled. Such concepts help demonstrate that the girl ‘has her own creative, critical and cultural, if not social or political, power’ (Aoyama 2008: 286. This paper examines the shôjo tropes in contemporary illustrations that were produced to accompany two tales by the renowned author Miyazawa Kenji (1896-1933, Futago no Hoshi (Twin Stars and Ginga Tetsudô no Yoru (Night of the Milky Way Railway. Although Kenji (as he is known is not generally considered a shôjo author, some of his works incorporate gently transgressive shôjo themes reminiscent of, for example, Yoshiya Nobuko’s Hana Monogatari (Flower Tales from the 1920s. I argue that the current artwork of two award-winning artists, Makino Suzuko and Azuma Itsuko, reflects and enhances Kenji’s ‘girlish’ verbal images, bringing them to the fore in their accompanying imagery for Futago and Ginga by drawing on shôjo art, manga and literature. The artists thus bring into play intertextual references that occur not only across different historical temporalities but also through relations between the author, the artist, the text(s, the protagonists and the reading/viewing audience. The analysis of their striking artwork shows how they bring Kenji’s 1920s’ works firmly into the arena of the contemporary ‘girl’, expanding the abstract consciousness of the shôjo to

  10. High-intensity interval training in hypoxia does not affect muscle HIF responses to acute hypoxia in humans.

    Science.gov (United States)

    De Smet, Stefan; D'Hulst, Gommaar; Poffé, Chiel; Van Thienen, Ruud; Berardi, Emanuele; Hespel, Peter

    2018-02-08

    The myocellular response to hypoxia is primarily regulated by hypoxia-inducible factors (HIFs). HIFs thus conceivably are implicated in muscular adaptation to altitude training. Therefore, we investigated the effect of hypoxic versus normoxic training during a period of prolonged hypoxia ('living high') on muscle HIF activation during acute ischaemia. Ten young male volunteers lived in normobaric hypoxia for 5 weeks (5 days per week, ~ 15.5 h per day, FiO2: 16.4-14.0%). One leg was trained in hypoxia (TRHYP, 12.3% FiO2) whilst the other leg was trained in normoxia (TRNOR, 20.9% FiO2). Training sessions (3 per week) consisted of intermittent unilateral knee extensions at 20-25% of the 1-repetition maximum. Before and after the intervention, a 10-min arterial occlusion and reperfusion of the leg was performed. Muscle oxygenation status was continuously measured by near-infrared spectroscopy. Biopsies were taken from m. vastus lateralis before and at the end of the occlusion. Irrespective of training, occlusion elevated the fraction of HIF-1α expressing myonuclei from ~ 54 to ~ 64% (P Training in both TRNOR and TRHYP raised muscular oxygen extraction rate upon occlusion by ~ 30%, whilst muscle hyperperfusion immediately following the occlusion increased by ~ 25% in either group (P training during 'living high' altered muscle HIF translocation, stabilisation, or transcription in response to acute hypoxia induced by arterial occlusion.

  11. Synovial tissue hypoxia and inflammation in vivo.

    LENUS (Irish Health Repository)

    Ng, C T

    2012-02-01

    INTRODUCTION: Hypoxia is a microenvironmental feature in the inflamed joint, which promotes survival advantage for cells. The aim of this study was to examine the relationship of partial oxygen pressure in the synovial tissue (tPO(2)) in patients with inflammatory arthritis with macroscopic\\/microscopic inflammation and local levels of proinflammatory mediators. METHODS: Patients with inflammatory arthritis underwent full clinical assessment and video arthroscopy to quantify macroscopic synovitis and measure synovial tPO(2) under direct visualisation. Cell specific markers (CD3 (T cells), CD68 (macrophages), Ki67 (cell proliferation) and terminal deoxynucleotidyl transferase dUTP nick end labelling (cell apoptosis)) were quantified by immunohistology. In vitro migration was assessed in primary and normal synoviocytes (synovial fibroblast cells (SFCs)) using a wound repair scratch assay. Levels of tumour necrosis factor alpha (TNFalpha), interleukin 1beta (IL1beta), interferon gamma (IFNgamma), IL6, macrophage inflammatory protein 3alpha (MIP3alpha) and IL8 were quantified, in matched serum and synovial fluid, by multiplex cytokine assay and ELISA. RESULTS: The tPO(2) was 22.5 (range 3.2-54.1) mm Hg and correlated inversely with macroscopic synovitis (r=-0.421, p=0.02), sublining CD3 cells (-0.611, p<0.01) and sublining CD68 cells (r=-0.615, p<0.001). No relationship with cell proliferation or apoptosis was found. Primary and normal SFCs exposed to 1% and 3% oxygen (reflecting the median tPO(2) in vivo) induced cell migration. This was coupled with significantly higher levels of synovial fluid tumour necrosis factor alpha (TNFalpha), IL1beta, IFNgamma and MIP3alpha in patients with tPO(2) <20 mm Hg (all p values <0.05). CONCLUSIONS: This is the first study to show a direct in vivo correlation between synovial tPO(2), inflammation and cell migration, thus it is proposed that hypoxia is a possible primary driver of inflammatory processes in the arthritic joint.

  12. SUSTAINABLE CORPORATE AND SUSTAINABLE DEVELOPMENT

    Directory of Open Access Journals (Sweden)

    DORU CÎRNU

    2017-06-01

    Full Text Available In recent decades, the image of the international business environment has changed significantly. Studies conducted by UNCTAD shows that corporate phenomenon developments in the world economy is growing. Without claiming to present an exhaustive topic so vast we tried to capture some "facets" of sustainable development from the perspective of multinational corporations, given the expansion of these economic entities and strengthening their power in the global economy. We present more negative aspects of the actions of multinational corporations in terms of sustainable development, it is very important to know both sides of the coin, which will not only help transnational giants including release. Based on issues such as corporate social responsibility, environmental pollution and workers' rights, we sought to counter official statements. The conclusion is that these economic entities are real forces that can not be ignored in today's world and the obvious problem of sustainable development can not be addressed independently of the phenomenon, context we also identified some possible solutions to conflict of corporations and essence of the concept of sustainable development.

  13. Proteomic analysis reveals that proteasome subunit beta 6 is involved in hypoxia-induced pulmonary vascular remodeling in rats.

    Directory of Open Access Journals (Sweden)

    Jian Wang

    Full Text Available Chronic hypoxia (CH is known to be one of the major causes of pulmonary hypertension (PH, which is characterized by sustained elevation of pulmonary vascular resistance resulting from vascular remodeling. In this study, we investigated whether the ubiquitin proteasome system (UPS was involved in the mechanism of hypoxia-induced pulmonary vascular remodeling. We isolated the distal pulmonary artery (PA from a previously defined chronic hypoxic pulmonary hypertension (CHPH rat model, performed proteomic analyses in search of differentially expressed proteins belonging to the UPS, and subsequently identified their roles in arterial remodeling.Twenty-two proteins were differently expressed between the CH and normoxic group. Among them, the expression of proteasome subunit beta (PSMB 1 and PSMB6 increased after CH exposure. Given that PSMB1 is a well-known structural subunit and PSMB6 is a functional subunit, we sought to assess whether PSMB6 could be related to the multiple functional changes during the CHPH process. We confirmed the proteomic results by real-time PCR and Western blot. With the increase in quantity of the active subunit, proteasome activity in both cultured pulmonary artery smooth muscle cells (PASMCs and isolated PA from the hypoxic group increased. An MTT assay revealed that the proteasome inhibitor MG132 was able to attenuate the hypoxia-induced proliferation of PASMC in a dose-dependent manner. Knockdown of PSMB6 using siRNA also prevented hypoxia-induced proliferation.The present study revealed the association between increased PSMB6 and CHPH. CH up-regulated proteasome activity and the proliferation of PASMCs, which may have been related to increased PSMB6 expression and the subsequently enhanced functional catalytic sites of the proteasome. These results suggested an essential role of the proteasome during CHPH development, a novel finding requiring further study.

  14. Effects of growth hormone transgenesis on metabolic rate, exercise performance and hypoxia tolerance in tilapia hybrids

    DEFF Research Database (Denmark)

    McKenzie, DJ; Martinez, R; Morales, A

    2003-01-01

    Swimming respirometry was employed to compare inactive metabolic rate (Rr), maximum metabolic rate (Rmax), resultant aerobic scope and maximum sustainable (critical) swimming speed (Ucrit), in growth hormone transgenic (GHT) and wild-type (W) tilapia Oreochromis sp. hybrids. Although the Rr of GHT...... tilapia was significantly (58%) higher than their W conspecifics, there were no significant differences in their net aerobic scope because GHT tilapia exhibited a compensatory increase in Rmax that was equal to their net increase in Rr. As a consequence, the two groups had the same Ucrit. The GHT and W...... tilapia also exhibited the same capacity to regulate oxygen uptake during progressive hypoxia, despite the fact that the GHT fish were defending a higher demand for O2. The results indicate that ectopic expression of GH raises metabolic rate in tilapia, but the fish compensate for this metabolic load...

  15. MeSH key terms for validation and annotation of gene expression clusters

    Energy Technology Data Exchange (ETDEWEB)

    Rechtsteiner, A. (Andreas); Rocha, L. M. (Luis Mateus)

    2004-01-01

    Integration of different sources of information is a great challenge for the analysis of gene expression data, and for the field of Functional Genomics in general. As the availability of numerical data from high-throughput methods increases, so does the need for technologies that assist in the validation and evaluation of the biological significance of results extracted from these data. In mRNA assaying with microarrays, for example, numerical analysis often attempts to identify clusters of co-expressed genes. The important task to find the biological significance of the results and validate them has so far mostly fallen to the biological expert who had to perform this task manually. One of the most promising avenues to develop automated and integrative technology for such tasks lies in the application of modern Information Retrieval (IR) and Knowledge Management (KM) algorithms to databases with biomedical publications and data. Examples of databases available for the field are bibliographic databases c ntaining scientific publications (e.g. MEDLINE/PUBMED), databases containing sequence data (e.g. GenBank) and databases of semantic annotations (e.g. the Gene Ontology Consortium and Medical Subject Headings (MeSH)). We present here an approach that uses the MeSH terms and their concept hierarchies to validate and obtain functional information for gene expression clusters. The controlled and hierarchical MeSH vocabulary is used by the National Library of Medicine (NLM) to index all the articles cited in MEDLINE. Such indexing with a controlled vocabulary eliminates some of the ambiguity due to polysemy (terms that have multiple meanings) and synonymy (multiple terms have similar meaning) that would be encountered if terms would be extracted directly from the articles due to differing article contexts or author preferences and background. Further, the hierarchical organization of the MeSH terms can illustrate the conceptuallfunctional relationships of genes

  16. Sustainable Consumption

    DEFF Research Database (Denmark)

    Røpke, Inge

    2015-01-01

    in wider social, economic and technological frameworks is emphasised. In particular, the chapter is inspired by practice theory and transition theory. First, various trends in consumption are outlined to highlight some of the challenges for sustainability transitions. Then, it is discussed how consumption...... patterns are shaped over time and what should be considered in sustainability strategies. While discussions on consumption often take their point of departure in the perspective of the individual and then zoom to the wider context, the present approach is the opposite. The outline starts with the basic...... biophysical, distributional and economic conditions for high consumption in rich countries and then zooms in on the coevolution of provision systems and consumption, and how consumption is shaped by practices and projects in everyday life. Furthermore, the paper discusses whether and how transition...

  17. Sustainable Buildings

    DEFF Research Database (Denmark)

    Tommerup, Henrik M.; Elle, Morten

    The scientific community agrees that: all countries must drastically and rapidly reduce their CO2 emissions and that energy efficient houses play a decisive role in this. The general attitude at the workshop on Sustainable Buildings was that we face large and serious climate change problems that ...... that need urgent action. The built environment is an obvious area to put effort into because of the large and cost-effective energy saving potential and potential for Renewable Energy-based supply systems for buildings.......The scientific community agrees that: all countries must drastically and rapidly reduce their CO2 emissions and that energy efficient houses play a decisive role in this. The general attitude at the workshop on Sustainable Buildings was that we face large and serious climate change problems...

  18. Quantifying hypoxia in human cancers using static PET imaging

    Science.gov (United States)

    Taylor, Edward; Yeung, Ivan; Keller, Harald; Wouters, Bradley G.; Milosevic, Michael; Hedley, David W.; Jaffray, David A.

    2016-11-01

    Compared to FDG, the signal of 18F-labelled hypoxia-sensitive tracers in tumours is low. This means that in addition to the presence of hypoxic cells, transport properties contribute significantly to the uptake signal in static PET images. This sensitivity to transport must be minimized in order for static PET to provide a reliable standard for hypoxia quantification. A dynamic compartmental model based on a reaction-diffusion formalism was developed to interpret tracer pharmacokinetics and applied to static images of FAZA in twenty patients with pancreatic cancer. We use our model to identify tumour properties—well-perfused without substantial necrosis or partitioning—for which static PET images can reliably quantify hypoxia. Normalizing the measured activity in a tumour voxel by the value in blood leads to a reduction in the sensitivity to variations in ‘inter-corporal’ transport properties—blood volume and clearance rate—as well as imaging study protocols. Normalization thus enhances the correlation between static PET images and the FAZA binding rate K 3, a quantity which quantifies hypoxia in a biologically significant way. The ratio of FAZA uptake in spinal muscle and blood can vary substantially across patients due to long muscle equilibration times. Normalized static PET images of hypoxia-sensitive tracers can reliably quantify hypoxia for homogeneously well-perfused tumours with minimal tissue partitioning. The ideal normalizing reference tissue is blood, either drawn from the patient before PET scanning or imaged using PET. If blood is not available, uniform, homogeneously well-perfused muscle can be used. For tumours that are not homogeneously well-perfused or for which partitioning is significant, only an analysis of dynamic PET scans can reliably quantify hypoxia.

  19. Hypoxia inhibits hypertrophic differentiation and endochondral ossification in explanted tibiae.

    Directory of Open Access Journals (Sweden)

    Jeroen C H Leijten

    Full Text Available Hypertrophic differentiation of growth plate chondrocytes induces angiogenesis which alleviates hypoxia normally present in cartilage. In the current study, we aim to determine whether alleviation of hypoxia is merely a downstream effect of hypertrophic differentiation as previously described or whether alleviation of hypoxia and consequent changes in oxygen tension mediated signaling events also plays an active role in regulating the hypertrophic differentiation process itself.Fetal mouse tibiae (E17.5 explants were cultured up to 21 days under normoxic or hypoxic conditions (21% and 2.5% oxygen respectively. Tibiae were analyzed on growth kinetics, histology, gene expression and protein secretion.The oxygen level had a strong influence on the development of explanted fetal tibiae. Compared to hypoxia, normoxia increased the length of the tibiae, length of the hypertrophic zone, calcification of the cartilage and mRNA levels of hypertrophic differentiation-related genes e.g. MMP9, MMP13, RUNX2, COL10A1 and ALPL. Compared to normoxia, hypoxia increased the size of the cartilaginous epiphysis, length of the resting zone, calcification of the bone and mRNA levels of hyaline cartilage-related genes e.g. ACAN, COL2A1 and SOX9. Additionally, hypoxia enhanced the mRNA and protein expression of the secreted articular cartilage markers GREM1, FRZB and DKK1, which are able to inhibit hypertrophic differentiation.Collectively our data suggests that oxygen levels play an active role in the regulation of hypertrophic differentiation of hyaline chondrocytes. Normoxia stimulates hypertrophic differentiation evidenced by the expression of hypertrophic differentiation related genes. In contrast, hypoxia suppresses hypertrophic differentiation of chondrocytes, which might be at least partially explained by the induction of GREM1, FRZB and DKK1 expression.

  20. RIG-I Resists Hypoxia-Induced Immunosuppression and Dedifferentiation.

    Science.gov (United States)

    Engel, Christina; Brügmann, Grethe; Lambing, Silke; Mühlenbeck, Larissa H; Marx, Samira; Hagen, Christian; Horváth, Dorottya; Goldeck, Marion; Ludwig, Janos; Herzner, Anna-Maria; Drijfhout, Jan W; Wenzel, Daniela; Coch, Christoph; Tüting, Thomas; Schlee, Martin; Hornung, Veit; Hartmann, Gunther; Van den Boorn, Jasper G

    2017-06-01

    A hypoxic tumor microenvironment is linked to poor prognosis. It promotes tumor cell dedifferentiation and metastasis and desensitizes tumor cells to type-I IFN, chemotherapy, and irradiation. The cytoplasmic immunoreceptor retinoic acid-inducible gene-I (RIG-I) is ubiquitously expressed in tumor cells and upon activation by 5'-triphosphate RNA (3pRNA) drives the induction of type I IFN and immunogenic cell death. Here, we analyzed the impact of hypoxia on the expression of RIG-I in various human and murine tumor and nonmalignant cell types and further investigated its function in hypoxic murine melanoma. 3pRNA-inducible RIG-I-expression was reduced in hypoxic melanoma cells compared with normoxic controls, a phenomenon that depended on the hypoxia-associated transcription factor HIF1α. Still, RIG-I functionality was conserved in hypoxic melanoma cells, whereas responsiveness to recombinant type-I IFN was abolished, due to hypoxia-induced loss of type I IFN receptor expression. Likewise, RIG-I activation in hypoxic melanoma cells, but not exposure to recombinant IFNα, provoked melanocyte antigen-specific CD8+ T-cell and NK-cell attack. Scavenging of hypoxia-induced reactive oxygen species by vitamin C restored the inducible expression of RIG-I under hypoxia in vitro, boosted in vitro anti-melanoma NK- and CD8+ T-cell attack, and augmented 3pRNA antitumor efficacy in vivo These results demonstrate that RIG-I remains operational under hypoxia and that RIG-I function is largely insensitive to lower cell surface expression of the IFNα receptor. RIG-I function could be fortified under hypoxia by the combined use of 3pRNA with antioxidants. Cancer Immunol Res; 5(6); 455-67. ©2017 AACR. ©2017 American Association for Cancer Research.

  1. Nutritional status in chronic obstructive pulmonary disease: role of hypoxia.

    Science.gov (United States)

    Raguso, Comasia A; Luthy, Christophe

    2011-02-01

    In patients with chronic obstructive pulmonary disease (COPD), malnutrition and limited physical activity are very common and contribute to disease prognosis, whereas a balance between caloric intake and exercise allows body weight stability and muscle mass preservation. The goal of this review is to analyze the implications of chronic hypoxia on three key elements involved in energy homeostasis and its role in COPD cachexia. The first one is energy intake. Body weight loss, often observed in patients with COPD, is related to lack of appetite. Inflammatory cytokines are known to be involved in anorexia and to be correlated to arterial partial pressure of oxygen. Recent studies in animals have investigated the role of hypoxia in peptides involved in food consumption such as leptin, ghrelin, and adenosine monophosphate activated protein kinase. The second element is muscle function, which is strongly related to energy use. In COPD, muscle atrophy and muscle fiber shift to the glycolytic type might be an adaptation to chronic hypoxia to preserve the muscle from oxidative stress. Muscle atrophy could be the result of a marked activation of the ubiquitin-proteasome pathway as found in muscle of patients with COPD. Hypoxia, via hypoxia inducible factor-1, is implicated in mitochondrial biogenesis and autophagy. Third, hormonal control of energy balance seems to be affected in patients with COPD. Insulin resistance has been described in this group of patients as well as a sort of "growth hormone resistance." Hypoxia, by hypoxia inducible factor-1, accelerates the degradation of tri-iodothyronine and thyroxine, decreasing cellular oxygen consumption, suggesting an adaptive mechanism rather than a primary cause of COPD cachexia. COPD rehabilitation aimed at maintaining function and quality of life needs to address body weight stabilization and, in particular, muscle mass preservation. Copyright © 2011 Elsevier Inc. All rights reserved.

  2. Phosphorylation of xanthine dehydrogenase/oxidase in hypoxia.

    Science.gov (United States)

    Kayyali, U S; Donaldson, C; Huang, H; Abdelnour, R; Hassoun, P M

    2001-04-27

    The enzyme xanthine oxidase (XO) has been implicated in the pathogenesis of several disease processes, such as ischemia-reperfusion injury, because of its ability to generate reactive oxygen species. The expression of XO and its precursor xanthine dehydrogenase (XDH) is regulated at pre- and posttranslational levels by agents such as lipopolysaccharide and hypoxia. Posttranslational modification of the protein, for example through thiol oxidation or proteolysis, has been shown to be important in converting XDH to XO. The possibility of posttranslational modification of XDH/XO through phosphorylation has not been adequately investigated in mammalian cells, and studies have reported conflicting results. The present report demonstrates that XDH/XO is phosphorylated in rat pulmonary microvascular endothelial cells (RPMEC) and that phosphorylation is greatly increased ( approximately 50-fold) in response to acute hypoxia (4 h). XDH/XO phosphorylation appears to be mediated, at least in part, by casein kinase II and p38 kinase as inhibitors of these kinases partially prevent XDH/XO phosphorylation. In addition, the results indicate that p38 kinase, a stress-activated kinase, becomes activated in response to hypoxia (an approximately 4-fold increase after 1 h of exposure of RPMEC to hypoxia) further supporting a role for this kinase in hypoxia-stimulated XDH/XO phosphorylation. Finally, hypoxia-induced XDH/XO phosphorylation is accompanied by a 2-fold increase in XDH/XO activity, which is prevented by inhibitors of phosphorylation. In summary, this study shows that XDH/XO is phosphorylated in hypoxic RPMEC through a mechanism involving p38 kinase and casein kinase II and that phosphorylation is necessary for hypoxia-induced enzymatic activation.

  3. Hypoxia Adjacent to the Mississippi River Plume

    Science.gov (United States)

    Rabalais, N. N.; Turner, R. E.

    2005-05-01

    The northern Gulf of Mexico receives the freshwater and constituent flux from the Mississippi River, which integrates 40% of the lower 48 United States. In the last half of the 20th century, the flux of nitrogen tripled, phosphorus concentration appears to have increased, and silicate concentration decreased. These changes result from landscape alterations over two centuries with an intensification of human activities that increased the flux of nitrogen and phosphorus particularly in the 1960s to 1980s. Evidence for eutrophication in the coastal ecosystem includes an increase in algal biomass, carbon accumulation from nutrient-enhanced production, worsening oxygen deficiency in the lower water column, and shifts in food web structure. The extent of the oxygen deficiency reaches 20,000 km2 of the inner continental shelf over long periods in summer with the potential for affecting commercially important fisheries in the Gulf. There is daily, weekly and seasonal variability in currents and stratification on the shelf and, therefore, no simple description of the couplings between nutrient delivery, carbon production in surface waters and delivery to and cycling in bottom waters. There are, however, multiple lines of evidence to implicate changes in riverine nutrient loads with overall primary and secondary production, carbon accumulation at the seabed, and low oxygen conditions on the shelf. The change in nutrient loads and responses of the northern Gulf coastal ecosystem, including widespread, severe seasonal hypoxia, parallel similar conditions in the coastal ocean on a global scale.

  4. Sab (Sh3bp5) dependence of JNK mediated inhibition of mitochondrial respiration in palmitic acid induced hepatocyte lipotoxicity.

    Science.gov (United States)

    Win, Sanda; Than, Tin Aung; Le, Bao Han Allison; García-Ruiz, Carmen; Fernandez-Checa, Jose C; Kaplowitz, Neil

    2015-06-01

    Sustained c-Jun N-terminal kinase (JNK) activation by saturated fatty acids plays a role in lipotoxicity and the pathogenesis of non-alcoholic steatohepatitis (NASH). We have reported that the interaction of JNK with mitochondrial Sab leads to inhibition of respiration, increased reactive oxygen species (ROS), cell death and hepatotoxicity. We tested whether this pathway underlies palmitic acid (PA)-induced lipotoxicity in hepatocytes. Primary mouse hepatocytes (PMH) from adeno-shlacZ or adeno-shSab treated mice and HuH7 cells were used. In PMH, PA dose-dependently up to 1mM stimulated oxygen consumption rate (OCR) due to mitochondrial β-oxidation. At ⩾1.5mM, PA gradually reduced OCR, followed by cell death. Inhibition of JNK, caspases or treatment with antioxidant butylated hydroxyanisole (BHA) protected PMH against cell death. Sab knockdown or a membrane permeable Sab blocking peptide prevented PA-induced mitochondrial impairment, but inhibited only the late phase of both JNK activation (beyond 4h) and cell death. In PMH, PA increased p-PERK and its downstream target CHOP, but failed to activate the IRE-1α arm of the UPR. However, Sab silencing did not affect PA-induced PERK activation. Conversely, specific inhibition of PERK prevented JNK activation and cell death, indicating a major role upstream of JNK activation. The effect of p-JNK on mitochondria plays a key role in PA-mediated lipotoxicity. The interplay of p-JNK with mitochondrial Sab leads to impaired respiration, ROS production, sustained JNK activation, and apoptosis. Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  5. Challenges and Opportunities for Mainstreaming Climate Change Adaptation into WaSH Development Planning in Ghana.

    Science.gov (United States)

    Alhassan, Salley; Hadwen, Wade L

    2017-07-10

    Climate change threatens water, sanitation and hygiene (WaSH) facilities and services, as these are intimately linked to the water cycle and are vulnerable to changes in the quantity and quality of available water resources. Floods and droughts, which pollute and reduce water delivery respectively, have now become a perennial issue to deal with in the northern regions of Ghana. This study aimed to assess the degree to which climate change adaptation measures are mainstreamed into the water, sanitation and hygiene (WaSH) development planning process in Ghana. Stakeholders from government and non-government agencies were interviewed to gain perspectives on the threat of climate change, the inclusion of climate change in WaSH planning and the barriers preventing mainstreaming. Despite awareness of climate change, adaptation measures have not been considered, and the immediate WaSH needs remain the priority. Overall, stakeholders felt the adaptive capacity of the Municipality was low and that mainstreaming has not yet occurred. Despite the lack of progress, there are great opportunities for mainstreaming climate change adaptation into planning through increasing awareness and capacity, legislative and institutional changes and the development of participatory systems to provide early warning systems and disaster risk analyses that will inform future planning.

  6. Fast evaluation of complete synthetic SH seismograms based on asymptotic mode theory

    NARCIS (Netherlands)

    Bastians, M.W.J.M.

    1986-01-01

    In this thesis we have developed an asymptotic mode theory with the following features. 1) Complete synthetic SH seismograms can be evaluated for both realistic models of Earth and crust. 2) The method is of practical value and can be used even on small computers wi th reasonable computation

  7. Fast evaluation of complete synthetic SH seismograms based on asymptotic mode theory

    NARCIS (Netherlands)

    Bastians, M.W.J.M.

    1986-01-01

    In this thesis we have developed an asymptotic mode theory with the following features. 1) Complete synthetic SH seismograms can be evaluated for both realistic models of Earth and crust. 2) The method is of practical value and can be used even on small computers wi th reasonable computation times

  8. Silencing effect of shRNA expression vectors with stem length of 21 ...

    African Journals Online (AJOL)

    AJL

    2011-02-14

    Feb 14, 2011 ... In this study, shRNA vectors having different stem length were constructed and their silencing effect was tested in mouse embryonic fibroblast and in vivo. Interfering RNAs were designed with stems of. 21, 27, and 29 bp. The enhanced green fluorescent protein gene was used as target gene. The.

  9. On the Performance of Medical Information Retrieval using MeSH Terms – A Survey

    Directory of Open Access Journals (Sweden)

    Swetha S

    2014-09-01

    Full Text Available Internet users have increased everywhere. Searching and retrieving documents is a common thing nowadays. Retrieving related documents from the search engines are difficult task. To retrieve correct documents, knowledge about the search topic is essential. Even though separate search engines are there to retrieve medical documents the users are not familiar with MeSH terms (Medical Subject Heading. So, both the search browser and the MeSH terms have to be integrated to make the search effective and efficient. To implement this integration, SimpleMed and MeSHMed were introduced. The MeSH terms have to be ranked to know how frequently it has been used and to know the importance of the MeSH terms. To rank it a semi – automated tool called MeSHy was developed. The terms were extracted, filtered, ranked and displayed to the user. Classifiers have to be constructed to label the documents as health and non – health. Three strategies were used to classify them. The errors that are commonly done by the users have to be found out. It was calculated based on the queries presented by the user to the search browser.

  10. Silencing effect of shRNA expression vectors with stem length of 21 ...

    African Journals Online (AJOL)

    In this study, shRNA vectors having different stem length were constructed and their silencing effect was tested in mouse embryonic fibroblast and in vivo. Interfering RNAs were designed with stems of 21, 27, and 29 bp. The enhanced green fluorescent protein gene was used as target gene. The synthesized single strands ...

  11. An shRNA barcode screen provides insight into cancer cell vulnerability to MDM2 inhibitors

    NARCIS (Netherlands)

    Bernards, R.A.; Brummelkamp, T.R.; Fabius, A.W.M.; Mullenders, J.; Madiredjo, M.; Velds, A.; Kerkhoven, R.M.; Beijersbergen, R.L.

    The identification of the cellular targets of small molecules with anticancer activity is crucial to their further development as drug candidates. Here, we present the application of a large-scale RNA interference–based short hairpin RNA (shRNA) barcode screen to gain insight in the mechanism of

  12. Comparing CλaSH and VHDL by implementing a dataflow processor

    NARCIS (Netherlands)

    Niedermeier, A.; Wester, Rinse; Wester, Rinse; Baaij, C.P.R.; Kuper, Jan; Smit, Gerardus Johannes Maria

    2010-01-01

    As embedded systems are becoming increasingly complex, the design process and verification have become very time-consuming. Additionally, specifying hardware manually in a low-level hardware description language like VHDL is usually an error-prone task. In our group, a tool (the ClaSH compiler) was

  13. Disturbance of SH-type waves due to moving stress discontinuity in ...

    Indian Academy of Sciences (India)

    The disturbance and propagation of SH-type waves in an anisotropic soil layer overlying an inhomogeneous elastic half-space by a moving stress discontinuity is considered. Stress discontinuity moves with non-uniform velocity and is impulsive in nature. The displacements are obtained in exact form by themethod due to ...

  14. Disturbance of SH-type waves due to moving stress discontinuity in ...

    Indian Academy of Sciences (India)

    Disturbance of SH-type waves due to moving stress discontinuity in an anisotropic soil layer overlying an inhomogeneous elastic half-space. D MANDAL1,2∗, P C PAL2 and S KUMAR2. 1Government Engineering College, Chaibasa 833 215, India. 2Department of Applied Mathematics, Indian School of Mines,. Dhanbad ...

  15. Mapping proteins to disease terminologies: from UniProt to MeSH

    Directory of Open Access Journals (Sweden)

    Ruch Patrick

    2008-04-01

    Full Text Available Abstract Background Although the UniProt KnowledgeBase is not a medical-oriented database, it contains information on more than 2,000 human proteins involved in pathologies. However, these annotations are not standardized, which impairs the interoperability between biological and clinical resources. In order to make these data easily accessible to clinical researchers, we have developed a procedure to link diseases described in the UniProtKB/Swiss-Prot entries to the MeSH disease terminology. Results We mapped disease names extracted either from the UniProtKB/Swiss-Prot entry comment lines or from the corresponding OMIM entry to the MeSH. Different methods were assessed on a benchmark set of 200 disease names manually mapped to MeSH terms. The performance of the retained procedure in term of precision and recall was 86% and 64% respectively. Using the same procedure, more than 3,000 disease names in Swiss-Prot were mapped to MeSH with comparable efficiency. Conclusions This study is a first attempt to link proteins in UniProtKB to the medical resources. The indexing we provided will help clinicians and researchers navigate from diseases to genes and from genes to diseases in an efficient way. The mapping is available at: http://research.isb-sib.ch/unimed.

  16. Challenges and Opportunities for Mainstreaming Climate Change Adaptation into WaSH Development Planning in Ghana

    Science.gov (United States)

    2017-01-01

    Climate change threatens water, sanitation and hygiene (WaSH) facilities and services, as these are intimately linked to the water cycle and are vulnerable to changes in the quantity and quality of available water resources. Floods and droughts, which pollute and reduce water delivery respectively, have now become a perennial issue to deal with in the northern regions of Ghana. This study aimed to assess the degree to which climate change adaptation measures are mainstreamed into the water, sanitation and hygiene (WaSH) development planning process in Ghana. Stakeholders from government and non-government agencies were interviewed to gain perspectives on the threat of climate change, the inclusion of climate change in WaSH planning and the barriers preventing mainstreaming. Despite awareness of climate change, adaptation measures have not been considered, and the immediate WaSH needs remain the priority. Overall, stakeholders felt the adaptive capacity of the Municipality was low and that mainstreaming has not yet occurred. Despite the lack of progress, there are great opportunities for mainstreaming climate change adaptation into planning through increasing awareness and capacity, legislative and institutional changes and the development of participatory systems to provide early warning systems and disaster risk analyses that will inform future planning. PMID:28698518

  17. The Janus Kinase (JAK) FERM and SH2 Domains: Bringing Specificity to JAK–Receptor Interactions

    Science.gov (United States)

    Ferrao, Ryan; Lupardus, Patrick J.

    2017-01-01

    The Janus kinases (JAKs) are non-receptor tyrosine kinases essential for signaling in response to cytokines and interferons and thereby control many essential functions in growth, development, and immune regulation. JAKs are unique among tyrosine kinases for their constitutive yet non-covalent association with class I and II cytokine receptors, which upon cytokine binding bring together two JAKs to create an active signaling complex. JAK association with cytokine receptors is facilitated by N-terminal FERM and SH2 domains, both of which are classical mediators of peptide interactions. Together, the JAK FERM and SH2 domains mediate a bipartite interaction with two distinct receptor peptide motifs, the proline-rich “Box1” and hydrophobic “Box2,” which are present in the intracellular domain of cytokine receptors. While the general sidechain chemistry of Box1 and Box2 peptides is conserved between receptors, they share very weak primary sequence homology, making it impossible to posit why certain JAKs preferentially interact with and signal through specific subsets of cytokine receptors. Here, we review the structure and function of the JAK FERM and SH2 domains in light of several recent studies that reveal their atomic structure and elucidate interaction mechanisms with both the Box1 and Box2 receptor motifs. These crystal structures demonstrate how evolution has repurposed the JAK FERM and SH2 domains into a receptor-binding module that facilitates interactions with multiple receptors possessing diverse primary sequences. PMID:28458652

  18. The Janus Kinase (JAK) FERM and SH2 Domains: Bringing Specificity to JAK-Receptor Interactions.

    Science.gov (United States)

    Ferrao, Ryan; Lupardus, Patrick J

    2017-01-01

    The Janus kinases (JAKs) are non-receptor tyrosine kinases essential for signaling in response to cytokines and interferons and thereby control many essential functions in growth, development, and immune regulation. JAKs are unique among tyrosine kinases for their constitutive yet non-covalent association with class I and II cytokine receptors, which upon cytokine binding bring together two JAKs to create an active signaling complex. JAK association with cytokine receptors is facilitated by N-terminal FERM and SH2 domains, both of which are classical mediators of peptide interactions. Together, the JAK FERM and SH2 domains mediate a bipartite interaction with two distinct receptor peptide motifs, the proline-rich "Box1" and hydrophobic "Box2," which are present in the intracellular domain of cytokine receptors. While the general sidechain chemistry of Box1 and Box2 peptides is conserved between receptors, they share very weak primary sequence homology, making it impossible to posit why certain JAKs preferentially interact with and signal through specific subsets of cytokine receptors. Here, we review the structure and function of the JAK FERM and SH2 domains in light of several recent studies that reveal their atomic structure and elucidate interaction mechanisms with both the Box1 and Box2 receptor motifs. These crystal structures demonstrate how evolution has repurposed the JAK FERM and SH2 domains into a receptor-binding module that facilitates interactions with multiple receptors possessing diverse primary sequences.

  19. Computational anharmonic force fields of CuSH and CuSD

    Science.gov (United States)

    Zhao, Yanliang; Wang, Meishan; Yang, Chuanlu; Ma, Xiaoguang; Yu, Yongjiang

    2017-08-01

    The anharmonic force fields and spectroscopy constants for the ground electronic state (\\tilde{{{X}}}{}1{{A}}\\prime ) of copper hydrosulfide (CuSH) have been investigated using various theoretical methods (MP2, B3LYP, B3P86, B3PW91) and basis sets (cc-pVDZ, cc-pVTZ). It turns out that the MP2/cc-pVTZ theoretical level is reasonable to study the molecular spectroscopic properties of CuSH. The calculated molecular structure, rotational constants, vibrational frequencies, centrifugal distortion constants, vibration-rotation interaction constants, force constants and Coriolis coupling constants of CuSH can be utilized to provide theoretical predictions of the spectroscopic properties and can be conducive to chemical applications such as the hydrodesulfurisation of fossil feed-stocks. Besides, the calculated force constants, evaluated in mass-weighted normal coordinates using a finite-difference approach, can be used to analyze the potential energy surface of CuSH. In addition, the anharmonic force fields of CuSD have been also investigated using the MP2 method.

  20. Publication trends in the medical informatics literature: 20 years of "Medical Informatics" in MeSH

    Science.gov (United States)

    2009-01-01

    Background The purpose of this study is to identify publication output, and research areas, as well as descriptively and quantitatively characterize the field of medical informatics through publication trend analysis over a twenty year period (1987–2006). Methods A bibliometric analysis of medical informatics citations indexed in Medline was performed using publication trends, journal frequency, impact factors, MeSH term frequencies and characteristics of citations. Results There were 77,023 medical informatics articles published during this 20 year period in 4,644 unique journals. The average annual article publication growth rate was 12%. The 50 identified medical informatics MeSH terms are rarely assigned together to the same document and are almost exclusively paired with a non-medical informatics MeSH term, suggesting a strong interdisciplinary trend. Trends in citations, journals, and MeSH categories of medical informatics output for the 20-year period are summarized. Average impact factor scores and weighted average impact factor scores increased over the 20-year period with two notable growth periods. Conclusion There is a steadily growing presence and increasing visibility of medical informatics literature over the years. Patterns in research output that seem to characterize the historic trends and current components of the field of medical informatics suggest it may be a maturing discipline, and highlight specific journals in which the medical informatics literature appears most frequently, including general medical journals as well as informatics-specific journals. PMID:19159472

  1. Silencing of HIV-1 with RNA interference: a multiple shRNA approach

    NARCIS (Netherlands)

    ter Brake, Olivier; Konstantinova, Pavlina; Ceylan, Mustafa; Berkhout, Ben

    2006-01-01

    Double-stranded RNA can induce gene silencing via a process known as RNA interference (RNAi). Previously, we have shown that stable expression of a single shRNA targeting the HIV-1 Nef gene strongly inhibits HIV-1 replication. However, this was not sufficient to maintain inhibition. One of the

  2. Polymorphisms in sh2b1 and spns1 loci are associated with ...

    Indian Academy of Sciences (India)

    Dag Hammarskjölds väg 20, 751 85, Uppsala, Sweden. [Västermark Å., Jacobsson J. A., Johansson Å., Fredriksson R., Gyllensten U. and Schiöth H. B. 2012 Polymorphisms in sh2b1 and spns1 loci are associated with triglyceride levels in a healthy population in northern Sweden. J. Genet. 91, 237–240]. Introduction.

  3. Publication trends in the medical informatics literature: 20 years of "Medical Informatics" in MeSH

    Directory of Open Access Journals (Sweden)

    LaVallie Donna L

    2009-01-01

    Full Text Available Abstract Background The purpose of this study is to identify publication output, and research areas, as well as descriptively and quantitatively characterize the field of medical informatics through publication trend analysis over a twenty year period (1987–2006. Methods A bibliometric analysis of medical informatics citations indexed in Medline was performed using publication trends, journal frequency, impact factors, MeSH term frequencies and characteristics of citations. Results There were 77,023 medical informatics articles published during this 20 year period in 4,644 unique journals. The average annual article publication growth rate was 12%. The 50 identified medical informatics MeSH terms are rarely assigned together to the same document and are almost exclusively paired with a non-medical informatics MeSH term, suggesting a strong interdisciplinary trend. Trends in citations, journals, and MeSH categories of medical informatics output for the 20-year period are summarized. Average impact factor scores and weighted average impact factor scores increased over the 20-year period with two notable growth periods. Conclusion There is a steadily growing presence and increasing visibility of medical informatics literature over the years. Patterns in research output that seem to characterize the historic trends and current components of the field of medical informatics suggest it may be a maturing discipline, and highlight specific journals in which the medical informatics literature appears most frequently, including general medical journals as well as informatics-specific journals.

  4. Creatures of Myth and Modernity: Representations of Shōjō in the Meiji Era

    Directory of Open Access Journals (Sweden)

    Daniel J. Wyatt

    2017-06-01

    Full Text Available This study investigates the multiple representations of shōjō in the translated literature and print media of Japan’s Meiji era. It explores the origins of the shōjō as a yōkai, or mythical being of traditional folklore and Noh theatre, through to its unveiling as a real-life creature of the modern world, as an orangutan, initially at misemono sideshows, before its introduction to the Tokyo public at the Ueno Zoo, in 1898. The zoo, as a new framework for ordering the relationship between people and the natural world, is one of the cultural systems through which knowledge of the shōjō was constructed, circulated and experienced in this period. Examining such materials, the paper reveals contesting knowledge systems that contributed to modern experience. Translation also plays an important role in this process, and the translated literature of this era is explored and foregrounded here as an active contributor to the creation and transition of knowledge of exotic animals like the shōjō in late nineteenth- and early twentieth-century Japan.

  5. Application of short hairpin RNAs (shRNAs) to study gene function in ...

    African Journals Online (AJOL)

    Yomi

    2010-12-29

    Dec 29, 2010 ... effect involve small interfering RNA (siRNA) and short hairpin RNA (shRNA). In various applications,. RNAi has been used to create model systems, to identify novel molecular targets, to study gene function in a genome-wide fashion, and to create new avenues for clinical therapeutics. This article reviews ...

  6. Comparative Genomics and Disorder Prediction Identify Biologically Relevant SH3 Protein Interactions.

    Directory of Open Access Journals (Sweden)

    2005-08-01

    Full Text Available Protein interaction networks are an important part of the post-genomic effort to integrate a part-list view of the cell into system-level understanding. Using a set of 11 yeast genomes we show that combining comparative genomics and secondary structure information greatly increases consensus-based prediction of SH3 targets. Benchmarking of our method against positive and negative standards gave 83% accuracy with 26% coverage. The concept of an optimal divergence time for effective comparative genomics studies was analyzed, demonstrating that genomes of species that diverged very recently from Saccharomyces cerevisiae(S. mikatae, S. bayanus, and S. paradoxus, or a long time ago (Neurospora crassa and Schizosaccharomyces pombe, contain less information for accurate prediction of SH3 targets than species within the optimal divergence time proposed. We also show here that intrinsically disordered SH3 domain targets are more probable sites of interaction than equivalent sites within ordered regions. Our findings highlight several novel S. cerevisiae SH3 protein interactions, the value of selection of optimal divergence times in comparative genomics studies, and the importance of intrinsic disorder for protein interactions. Based on our results we propose novel roles for the S. cerevisiae proteins Abp1p in endocytosis and Hse1p in endosome protein sorting.

  7. Comparative genomics and disorder prediction identify biologically relevant SH3 protein interactions.

    Directory of Open Access Journals (Sweden)

    Pedro Beltrao

    2005-08-01

    Full Text Available Protein interaction networks are an important part of the post-genomic effort to integrate a part-list view of the cell into system-level understanding. Using a set of 11 yeast genomes we show that combining comparative genomics and secondary structure information greatly increases consensus-based prediction of SH3 targets. Benchmarking of our method against positive and negative standards gave 83% accuracy with 26% coverage. The concept of an optimal divergence time for effective comparative genomics studies was analyzed, demonstrating that genomes of species that diverged very recently from Saccharomyces cerevisiae(S. mikatae, S. bayanus, and S. paradoxus, or a long time ago (Neurospora crassa and Schizosaccharomyces pombe, contain less information for accurate prediction of SH3 targets than species within the optimal divergence time proposed. We also show here that intrinsically disordered SH3 domain targets are more probable sites of interaction than equivalent sites within ordered regions. Our findings highlight several novel S. cerevisiae SH3 protein interactions, the value of selection of optimal divergence times in comparative genomics studies, and the importance of intrinsic disorder for protein interactions. Based on our results we propose novel roles for the S. cerevisiae proteins Abp1p in endocytosis and Hse1p in endosome protein sorting.

  8. A two step hardware design method using CλaSH

    NARCIS (Netherlands)

    Wester, Rinse; Baaij, C.P.R.; Kuper, Jan

    2012-01-01

    In order to effectively utilize the growing number of resources available on FPGAs, higher level abstraction mechanisms are needed to deal with increasing complexity resulting from large designs. Functional hardware description languages, like the CλaSH HDL, offer adequate abstraction mechanisms

  9. PubMed in progress: latest changes in MeSH and MyNCBI.

    Science.gov (United States)

    Giglia, E

    2011-09-01

    PubMed interface re-engineering has moved further steps with the latest changes in the MeSH - Medical Subject Headings database and in the MyNCBI homepage. Aim of this contribution is to present the most relevant added feature in order to improve your query efficiency.

  10. PubMed in progress: latest changes in MeSH and MyNCBI

    OpenAIRE

    Giglia, Elena

    2011-01-01

    PubMed interface re-engineering has moved further steps with the latest changes in the MeSH – Medical Subject Headings database and in the MyNCBI homepage. Aim of thi socntributon is to present the most relevant added feature in order to improve your query efficiency

  11. Effects of prolonged hypobaric hypoxia on human skeletal muscle function and electromyographic events.

    Science.gov (United States)

    Caquelard, F; Burnet, H; Tagliarini, F; Cauchy, E; Richalet, J P; Jammes, Y

    2000-03-01

    This study tested the hypothesis that a prolonged decrease in arterial oxygen pressure in resting or contracting skeletal muscles alters their ability to develop force through an impairment of energy-dependent metabolic processes and also through an alteration of electrophysiological events. The experiment was conducted during a 32-day simulated ascent of Mt. Everest (8848 m altitude) (Everest III Comex '97), which also allowed testing of the effects of re-oxygenation on muscle function. Maximal voluntary contractions (MVCs) of the flexor digitorum, and static handgrips sustained at 60% of MVC, were performed by eight subjects before the ascent (control), then during the stays at simulated altitudes of 5000 m, 6000 m and 7000 m, and finally 1 day after the return to 0 m. The evoked muscle compound action potential (M-wave) was recorded at rest and during the manoeuvres at 60% of MVC. The changes in median frequency of electromyographic (EMG) power spectra were also studied during the contraction at 60% of MVC. In four individuals, transient re-oxygenation during the ascent allowed us to test the reversibility of hypoxia-induced MVC and M-wave changes. At rest, a significant decrease in M-wave amplitude was noted at 5000 m. This effect was associated with a prolonged M-wave conduction time at 6000 m and an increased M-wave duration at 7000 m, and persisted after the return to 0 m. Re-oxygenation did not modify the changes in M-wave characteristics. A significant decrease in MVC was measured only during the ascent (-10 to -24%) in the non-dominant forearm of subjects who underwent re-oxygenation; this intervention slightly improved muscle strength at 6000 m and 7000 m. During the ascent and after the return to 0 m, there was a significant reduction of the median frequency decrease throughout contraction at 60% of MVC compared with the EMG changes measured before the ascent. It is concluded that prolonged exposure to hypoxia slows the propagation of myopotentials and

  12. Are floating algal mats a refuge from hypoxia for estuarine invertebrates?

    Directory of Open Access Journals (Sweden)

    Michael R.S. Coffin

    2017-03-01

    Full Text Available Eutrophic aquatic habitats are characterized by the proliferation of vegetation leading to a large standing biomass that upon decomposition may create hypoxic (low-oxygen conditions. This is indeed the case in nutrient impacted estuaries of Prince Edward Island, Canada, where macroalgae, from the genus Ulva, form submerged ephemeral mats. Hydrological forces and gases released from photosynthesis and decomposition lead to these mats occasionally floating to the water’s surface, henceforth termed floating mats. Here, we explore the hypothesis that floating mats are refugia during periods of sustained hypoxia/anoxia and examine how the invertebrate community responds to it. Floating mats were not always present, so in the first year (2013 sampling was attempted monthly and limited to when both floating and submerged mats occurred. In the subsequent year sampling was weekly, but at only one estuary due to logistical constraints from increased sampling frequency, and was not limited to when both mat types occurred. Water temperature, salinity, and pH were monitored bi-weekly with dissolved oxygen concentration measured hourly. The floating and submerged assemblages shared many of the same taxa but were statistically distinct communities; submerged mats tended to have a greater proportion of benthic animals and floating mats had more mobile invertebrates and insects. In 2014, sampling happened to occur in the weeks before the onset of anoxia, during 113 consecutive hours of sustained anoxia, and for four weeks after normoxic conditions returned. The invertebrate community on floating mats appeared to be unaffected by anoxia, indicating that these mats may be refugia during times of oxygen stress. Conversely, there was a dramatic decrease in animal abundances that remained depressed on submerged mats for two weeks. Cluster analysis revealed that the submerged mat communities from before the onset of anoxia and four weeks after anoxia were highly

  13. The Linkage between Breast Cancer, Hypoxia, and Adipose Tissue

    Directory of Open Access Journals (Sweden)

    Linda K. Rausch

    2017-09-01

    Full Text Available ObjectiveThe development of breast cancer cells is linked to hypoxia. The hypoxia-induced factor HIF-1α influences metastasis through neovascularization. Hypoxia seems to decrease the responsiveness to hormonal treatment due to loss of estrogen receptors (ERs. Obesity is discussed to increase hypoxia in adipocytes, which promotes a favorable environment for tumor cells in mammary fat tissue, whereas, tumor cells profit from good oxygen supply and are influenced by its deprivation as target regions within tumors show. This review gives an overview of the current state on research of hypoxia and breast cancer in human adipose tissue.MethodsA systematic literature search was conducted on PubMed (2000–2016 by applying hypoxia and/or adipocytes and breast cancer as keywords. Review articles were excluded as well as languages other than English or German. There was no restriction regarding the study design or type of breast cancer. A total of 35 papers were found. Eight studies were excluded due to missing at least two of the three keywords. One paper was removed due to Russian language, and one was dismissed due to lack of adherence. Seven papers were identified as reviews. After applying exclusion criteria, 18 articles were eligible for inclusion.ResultsTwo articles describe the impairment of mammary epithelial cell polarization through hypoxic preconditioning. A high amount of adipocytes enhances cancer progression due to the increased expression of HIF-1α which causes the loss of ER α protein as stated in four articles. Four articles analyzed that increased activation of HIF’s induces a series of transcriptions resulting in tumor angiogenesis. HIF inhibition, especially when combined with cytotoxic chemotherapy, holds strong potential for tumor suppression as stated in further four articles. In two articles there is evidence of a strong connection between hypoxia, oxidative stress and a poor prognosis for breast cancer via HIF regulated

  14. DNA analysis of the SH3BP2 gene in patients with aggressive central giant cell granuloma

    NARCIS (Netherlands)

    de Lange, Jan; van Maarle, Merel C.; van den Akker, Hans P.; Redeker, Egbert J. W.

    2007-01-01

    A mutation of the SH3BP2 gene is known to cause cherubism. As there are clinical and histopathological similarities between central giant cell granuloma and cherubism, we made a constitutional DNA analysis of the SH3BP2 gene in four patients with aggressive giant cell granuloma (having one or more

  15. Hypoxia promotes adipose-derived stem cell proliferation via VEGF

    Directory of Open Access Journals (Sweden)

    Phuc Van Pham

    2016-01-01

    Full Text Available Adipose-derived stem cells (ADSCs are a promising mesenchymal stem cell source with therapeutic applications. Recent studies have shown that ADSCs could be expanded in vitro without phenotype changes. This study aimed to evaluate the effect of hypoxia on ADSC proliferation in vitro and to determine the role of vascular endothelial growth factor (VEGF in ADSC proliferation. ADSCs were selectively cultured from the stromal vascular fraction obtained from adipose tissue in DMEM/F12 medium supplemented with 10% fetal bovine serum and 1% antibiotic-antimycotic. ADSCs were cultured under two conditions: hypoxia (5% O2 and normal oxygen (21% O2. The effects of the oxygen concentration on cell proliferation were examined by cell cycle and doubling time. The expression of VEGF was evaluated by the ELISA assay. The role of VEGF in ADSC proliferation was studied by neutralizing VEGF with anti-VEGF monoclonal antibodies. We found that the ADSC proliferation rate was significantly higher under hypoxia compared with normoxia. In hypoxia, ADSCs also triggered VEGF expression. However, neutralizing VEGF with anti-VEGF monoclonal antibodies significantly reduced the proliferation rate. These results suggest that hypoxia stimulated ADSC proliferation in association with VEGF production. [Biomed Res Ther 2016; 3(1.000: 476-482

  16. Insights into the cellular responses to hypoxia in filamentous fungi.

    Science.gov (United States)

    Hillmann, Falk; Shekhova, Elena; Kniemeyer, Olaf

    2015-08-01

    Most eukaryotes require molecular oxygen for growth. In general, oxygen is the terminal electron acceptor of the respiratory chain and represents an important substrate for the biosynthesis of cellular compounds. However, in their natural environment, such as soil, and also during the infection, filamentous fungi are confronted with low levels of atmospheric oxygen. Transcriptome and proteome studies on the hypoxic response of filamentous fungi revealed significant alteration of the gene expression and protein synthesis upon hypoxia. These analyses discovered not only common but also species-specific responses to hypoxia with regard to NAD(+) regeneration systems and other metabolic pathways. A surprising outcome was that the induction of oxidative and nitrosative stress defenses during oxygen limitation represents a general trait of adaptation to hypoxia in many fungi. The interplay of these different stress responses is poorly understood, but recent studies have shown that adaptation to hypoxia contributes to virulence of pathogenic fungi. In this review, results on metabolic changes of filamentous fungi during adaptation to hypoxia are summarized and discussed.

  17. Structural and functional analysis of coral Hypoxia Inducible Factor.

    Directory of Open Access Journals (Sweden)

    Didier Zoccola

    Full Text Available Tissues of symbiotic Cnidarians are exposed to wide, rapid and daily variations of oxygen concentration. Indeed, during daytime, intracellular O2 concentration increases due to symbiont photosynthesis, while during night, respiration of both host cells and symbionts leads to intra-tissue hypoxia. The Hypoxia Inducible Factor 1 (HIF-1 is a heterodimeric transcription factor used for maintenance of oxygen homeostasis and adaptation to hypoxia. Here, we carried out a mechanistic study of the response to variations of O2 concentrations of the coral model Stylophora pistillata. In silico analysis showed that homologs of HIF-1 α (SpiHIF-1α and HIF-1β (SpiHIF-1β exist in coral. A specific SpiHIF-1 DNA binding on mammalian Hypoxia Response Element (HRE sequences was shown in extracts from coral exposed to dark conditions. Then, we cloned the coral HIF-1α and β genes and determined their expression and transcriptional activity. Although HIF-1α has an incomplete Oxygen-dependent Degradation Domain (ODD relative to its human homolog, its protein level is increased under hypoxia when tested in mammalian cells. Moreover, co-transfection of SpiHIF-1α and β in mammalian cells stimulated an artificial promoter containing HRE only in hypoxic conditions. This study shows the strong conservation of molecular mechanisms involved in adaptation to O2 concentration between Cnidarians and Mammals whose ancestors diverged about 1,200-1,500 million years ago.

  18. SUSTAINABLE CHEMISTRY FOR SUSTAINABLE INDUSTRY

    Directory of Open Access Journals (Sweden)

    G. Rizzuto

    2015-01-01

    Full Text Available Foundry Alfe Chem is an industrial reality working in the field of lubrication and chemical auxiliaries for industrial processes, which falls within the framework of the emerging and increasingly important «green chemistry». The goal of the company is to develop products that are more environmentally friendly by using raw materials from renewable sources; specifically, Foundry Alfe Chem has a program of self-sustainability that contemplates, for the foreseeable future, the direct production of renewable raw materials. The company has developed a new dedicated product line, Olitema, whose purpose is to offer highly technological solutions with complete environmental sustainability. In this context, Foundry Alfe CHEM has created a new product which represents a breakthrough in the class of HFC hydraulic fluids: Ecosafe Plus is a biodegradable fire-resistant hydraulic fluid with high engineering and technological performances, high environmental sustainability and the best security guarantees in workplaces. Its formulation is glycols-free, and it allows for easier disposal of the exhausted fluid, compared to a traditional water/ glycol-based HFC hydraulic fluid. For what concern the technological properties, Ecosafe Plus has been tested by accredited laboratories with tribological trials (4 Ball wear test ASTM D 4172, Ball on disc test ASTM 6425, Brugger test DIN 51347, Vickers test ASTM D 2882, with elastomer compatibility test (ASTM D 471 and biodegradability test (OECD 310 F.

  19. Quantifying information transfer by protein domains: analysis of the Fyn SH2 domain structure.

    Science.gov (United States)

    Lenaerts, Tom; Ferkinghoff-Borg, Jesper; Stricher, Francois; Serrano, Luis; Schymkowitz, Joost W H; Rousseau, Frederic

    2008-10-08

    Efficient communication between distant sites within a protein is essential for cooperative biological response. Although often associated with large allosteric movements, more subtle changes in protein dynamics can also induce long-range correlations. However, an appropriate formalism that directly relates protein structural dynamics to information exchange between functional sites is still lacking. Here we introduce a method to analyze protein dynamics within the framework of information theory and show that signal transduction within proteins can be considered as a particular instance of communication over a noisy channel. In particular, we analyze the conformational correlations between protein residues and apply the concept of mutual information to quantify information exchange. Mapping out changes of mutual information on the protein structure then allows visualizing how distal communication is achieved. We illustrate the approach by analyzing information transfer by the SH2 domain of Fyn tyrosine kinase, obtained from Monte Carlo dynamics simulations. Our analysis reveals that the Fyn SH2 domain forms a noisy communication channel that couples residues located in the phosphopeptide and specificity binding sites and a number of residues at the other side of the domain near the linkers that connect the SH2 domain to the SH3 and kinase domains. We find that for this particular domain, communication is affected by a series of contiguous residues that connect distal sites by crossing the core of the SH2 domain. As a result, our method provides a means to directly map the exchange of biological information on the structure of protein domains, making it clear how binding triggers conformational changes in the protein structure. As such it provides a structural road, next to the existing attempts at sequence level, to predict long-range interactions within protein structures.

  20. Sustainable Procurement

    DEFF Research Database (Denmark)

    Telles, Pedro; Ølykke, Grith Skovgaard

    2017-01-01

    and within it how sustainable requirements have increased the level of compliance required, particularly regulatory compliance. Compliance was already present in previous EU public procurement frameworks, but its extent on Directive 2014/24/EU leads the authors to consider the current legal framework...... as subject to substantial regulatory compliance obligations external to the process of procurement. In short, procurement has been transformed in a way to enforce regulatory obligations that are not intrinsic to the process of buying. This leads to the conclusion that questions such as the cost and trade...

  1. Silencing of reversion-inducing cysteine-rich protein with Kazal motifs stimulates hyperplastic phenotypes through activation of epidermal growth factor receptor and hypoxia-inducible factor-2α.

    Directory of Open Access Journals (Sweden)

    You Mie Lee

    Full Text Available Reversion-inducing cysteine-rich protein with Kazal motifs (RECK, a tumor suppressor is down-regulated by the oncogenic signals and hypoxia, but the biological function of RECK in early tumorigenic hyperplastic phenotypes is largely unknown. Knockdown of RECK by small interfering RNA (siRECK or hypoxia significantly promoted cell proliferation in various normal epithelial cells. Hypoxia as well as knockdown of RECK by siRNA increased the cell cycle progression, the levels of cyclin D1 and c-Myc, and the phosphorylation of Rb protein (p-pRb, but decreased the expression of p21(cip1, p27(kip1, and p16(ink4A. HIF-2α was upregulated by knockdown of RECK, indicating HIF-2α is a downstream target of RECK. As knockdown of RECK induced the activation of epidermal growth factor receptor (EGFR and treatment of an EGFR kinase inhibitor, gefitinib, suppressed HIF-2α expression induced by the silencing of RECK, we can suggest that the RECK silenicng-EGFR-HIF-2α axis might be a key molecular mechanism to induce hyperplastic phenotype of epithelial cells. It was also found that shRNA of RECK induced larger and more numerous colonies than control cells in an anchorage-independent colony formation assay. Using a xenograft assay, epithelial cells with stably transfected with shRNA of RECK formed a solid mass earlier and larger than those with control cells in nude mice. In conclusion, the suppression of RECK may promote the development of early tumorigenic hyperplastic characteristics in hypoxic stress.

  2. Structural recognition mechanisms between human Src homology domain 3 (SH3) and ALG-2-interacting protein X (Alix).

    Science.gov (United States)

    Shi, Xiaoli; Betzi, Stephane; Lugari, Adrien; Opi, Sandrine; Restouin, Audrey; Parrot, Isabelle; Martinez, Jean; Zimmermann, Pascale; Lecine, Patrick; Huang, Mingdong; Arold, Stefan T; Collette, Yves; Morelli, Xavier

    2012-06-21

    The functions of Src family kinases are tightly regulated through Src homology (SH) domain-mediated protein-protein interactions. We previously reported the biophysical characteristics of the apoptosis-linked gene 2-interacting protein X (Alix) in complex with the haemopoietic cell kinase (Hck) SH3 domain. In the current study, we have combined ITC, NMR, SAXS and molecular modeling to determine a 3D model of the complex. We demonstrate that Hck SH3 recognizes an extended linear proline-rich region of Alix. This particular binding mode enables Hck SH3 to sense a specific non-canonical residue situated in the SH3 RT-loop of the kinase. The resulting model helps clarify the mechanistic insights of Alix-Hck interaction. Copyright © 2012 Federation of European Biochemical Societies. All rights reserved.

  3. Use of NLM medical subject headings with the MeSH2010 thesaurus in the PORTAL-DOORS system.

    Science.gov (United States)

    Taswell, Carl

    2010-01-01

    The NLM MeSH Thesaurus has been incorporated for use in the PORTAL-DOORS System (PDS) for resource metadata management on the semantic web. All 25588 descriptor records from the NLM 2010 MeSH Thesaurus have been exposed as web accessible resources by the PDS MeSH2010 Thesaurus implemented as a PDS PORTAL Registry operating as a RESTful web service. Examples of records from the PDS MeSH2010 PORTAL are demonstrated along with their use by records in other PDS PORTAL Registries that reference the concepts from the MeSH2010 Thesaurus. Use of this important biomedical terminology will greatly enhance the quality of metadata content of other PDS records thus improving cross-domain searches between different problem oriented domains and amongst different clinical specialty fields.

  4. Sustainable consumption and marketing

    NARCIS (Netherlands)

    Dam, van Y.K.

    2016-01-01

    Sustainable development in global food markets is hindered by the discrepancy between positive consumer attitudes towards sustainable development or sustainability and the lack of corresponding sustainable consumption by a majority of consumers. Apparently for many (light user) consumers the

  5. The effects of diel-cycling hypoxia acclimation on the hypoxia tolerance, swimming capacity and growth performance of southern catfish (Silurus meridionalis).

    Science.gov (United States)

    Yang, Han; Cao, Zhen-Dong; Fu, Shi-Jian

    2013-06-01

    To investigate the effects of diel-cycling hypoxia acclimation on the hypoxia tolerance, swimming and growth performance of juvenile southern catfish, we initially measured the critical oxygen tension (P(crit)), oxygen thresholds of aquatic surface respiration (ASR) and loss of equilibrium (LOE) of diel-cycling hypoxia-acclimated (15 d, 7:00-21:00, dissolved oxygen level (DO) = 7.0 ± 0.2 mg L(-1); 21:00-7:00, DO = 3.0 ± 0.2 mg L(-1)) and non-acclimated (15 d, DO = 7.0 ± 0.2 mg L(-1)) southern catfish at 25 °C. We then measured the critical swimming speed (U(crit)) and metabolic rate (MR) of hypoxia-acclimated and non-acclimated fish (under both hypoxic and normoxic conditions). The feeding rate (FR), feeding efficiency (FE) and specific growth rate (SGR) of fish in hypoxia-acclimated and non-acclimated groups were also measured. The P(crit), ASR and LOE of hypoxia-acclimated fish were significantly lower than those of non-acclimated fish. Hypoxia acclimation resulted in a significantly higher U(crit) when the individuals swam in hypoxia. The U(crit), maximum metabolic rate (MMR) and metabolic scope (MS) of both the hypoxia-acclimated and non-acclimated fish all decreased with the decrease of DO. However, the U(crit), MMR and MS decreased by 31, 43 and 54%, respectively, in non-acclimated fish, whereas these values decreased by 15, 28 and 29%, respectively, in hypoxia-acclimated fish, which suggests that hypoxia-acclimated fish were less sensitive to the DO decrease. The FR, FE and SGR all decreased by 21, 20 and 45%, respectively, in the hypoxia-acclimated group compared to the non-acclimated group. This result suggests that diel-cycling hypoxia acclimation improved the hypoxia tolerance and aerobic swimming performance of southern catfish, whereas impaired the growth performance. The high hypoxia tolerance and physiological plasticity to hypoxia-acclimated southern catfish may be related to its lower maintenance energy expenditure, sit-and-wait lifestyle and

  6. Proliferative and Synthetic Activity of Nerve Cells after Combined or Individual Exposure to Hypoxia and Hypercapnia.

    Science.gov (United States)

    Tregub, P P; Kulikov, V P; Rucheikin, N Yu; Belova, E V; Motin, Yu G

    2015-07-01

    We compared synthetic and proliferative activity of brain cells in rats exposed hypoxia, hypercapnia, or both prior to experimental focal stroke. The mean number of nucleolus organizer regions in penumbra neurons did not change after normobaric hypoxia, but increased after permissive hypercapnia or hypercapnic hypoxia. These data attest to activation of proliferative and synthetic functions in nerve cells, which plays an important role in the neuroprotective mechanisms under conditions of combined exposure to hypoxia and hypercapnia.

  7. Cardiac atria are the primary source of ANP release in hypoxia-adapted rats.

    Science.gov (United States)

    Casserly, Brian; Pietras, Linda; Schuyler, Joy; Wang, Richard; Hill, Nicholas S; Klinger, James R

    2010-09-11

    atrial natriuretic peptide (ANP) is released from the heart in response to hypoxia and helps mitigate the development of pulmonary hypertension. However, the mechanism of hypoxia-induced ANP release is not clear. The cardiac atria are the primary source of ANP secretion under normal conditions, but right ventricular ANP expression is markedly up-regulated during adaptation to hypoxia. We sought to better understand mechanisms of cardiac ANP release during adaptation to hypoxia. we measured hypoxia-induced ANP release from isolated perfused rat hearts obtained from normoxia and hypoxia-adapted rats before and after removal of the atria. in both normoxia- and hypoxia-adapted hearts, ANP levels in the perfusate increased within 15 min of hypoxia. Hypoxia-induced ANP release was greater from hypoxia-adapted than normoxia-adapted hearts. Baseline and hypoxia-induced ANP release were considerably greater with the atria intact (213±29 to 454±62 and 281±26 to 618±87 pg/ml for normoxia- and hypoxia-adapted hearts respectively, PANP release was reduced over 80% by removing the atria in both normoxia- and in hypoxia-adapted hearts. Acute hypoxia caused a transient increase in lactate release and reductions in pH and left ventricular generated force, but no differences in pH or left ventricular generated force were seen between normoxia- and hypoxia-adapted rats. we conclude that the right ventricle is not a major source of cardiac ANP release in normoxia- or hypoxia-adapted rats. 2010 Elsevier Inc. All rights reserved.

  8. Global Gene Expression Profiling in Three Tumor Cell Lines Subjected to Experimental Cycling and Chronic Hypoxia

    Science.gov (United States)

    Olbryt, Magdalena; Habryka, Anna; Student, Sebastian; Jarząb, Michał; Tyszkiewicz, Tomasz; Lisowska, Katarzyna Marta

    2014-01-01

    Hypoxia is one of the most important features of the tumor microenvironment, exerting an adverse effect on tumor aggressiveness and patient prognosis. Two types of hypoxia may occur within the tumor mass, chronic (prolonged) and cycling (transient, intermittent) hypoxia. Cycling hypoxia has been shown to induce aggressive tumor cell phenotype and radioresistance more significantly than chronic hypoxia, though little is known about the molecular mechanisms underlying this phenomenon. The aim of this study was to delineate the molecular response to both types of hypoxia induced experimentally in tumor cells, with a focus on cycling hypoxia. We analyzed in vitro gene expression profile in three human cancer cell lines (melanoma, ovarian cancer, and prostate cancer) exposed to experimental chronic or transient hypoxia conditions. As expected, the cell-type specific variability in response to hypoxia was significant. However, the expression of 240 probe sets was altered in all 3 cell lines. We found that gene expression profiles induced by both types of hypoxia were qualitatively similar and strongly depend on the cell type. Cycling hypoxia altered the expression of fewer genes than chronic hypoxia (6,132 vs. 8,635 probe sets, FDR adjusted pcycling hypoxia than by prolonged hypoxia, such as IL8, PLAU, and epidermal growth factor (EGF) pathway-related genes (AREG, HBEGF, and EPHA2). These transcripts were, in most cases, validated by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Our results indicate that experimental cycling hypoxia exerts similar, although less intense effects, on the examined cancer cell lines than its chronic counterpart. Nonetheless, we identified genes and molecular pathways that seem to be preferentially regulated by cyclic hypoxia. PMID:25122487

  9. Three new shRNA expression vectors targeting the CYP3A4 coding sequence to inhibit its expression

    Directory of Open Access Journals (Sweden)

    Siyun Xu

    2014-10-01

    Full Text Available RNA interference (RNAi is useful for selective gene silencing. Cytochrome P450 3A4 (CYP3A4, which metabolizes approximately 50% of drugs in clinical use, plays an important role in drug metabolism. In this study, we aimed to develop a short hairpin RNA (shRNA to modulate CYP3A4 expression. Three new shRNAs (S1, S2 and S3 were designed to target the coding sequence (CDS of CYP3A4, cloned into a shRNA expression vector, and tested in different cells. The mixture of three shRNAs produced optimal reduction (55% in CYP3A4 CDS-luciferase activity in both CHL and HEK293 cells. Endogenous CYP3A4 expression in HepG2 cells was decreased about 50% at both mRNA and protein level after transfection of the mixture of three shRNAs. In contrast, CYP3A5 gene expression was not altered by the shRNAs, supporting the selectivity of CYP3A4 shRNAs. In addition, HepG2 cells transfected with CYP3A4 shRNAs were less sensitive to Ginkgolic acids, whose toxic metabolites are produced by CYP3A4. These results demonstrate that vector-based shRNAs could modulate CYP3A4 expression in cells through their actions on CYP3A4 CDS, and CYP3A4 shRNAs may be utilized to define the role of CYP3A4 in drug metabolism and toxicity.

  10. Functional analysis of SH3 domain containing ring finger 2 during the myogenic differentiation of quail myoblast cells

    Directory of Open Access Journals (Sweden)

    Si Won Kim

    2017-08-01

    Full Text Available Objective Owing to the public availability of complete genome sequences, including avian species, massive bioinformatics analyses may be conducted for computational gene prediction and the identification of gene regulatory networks through various informatics tools. However, to evaluate the biofunctional activity of a predicted target gene, in vivo and in vitro functional genomic analyses should be a prerequisite. Methods Due to a lack of quail genomic sequence information, we first identified the partial genomic structure and sequences of the quail SH3 domain containing ring finger 2 (SH3RF2 gene. Subsequently, SH3RF2 was knocked out using clustered regularly interspaced short palindromic repeat/Cas9 technology and single cell-derived SH3RF2 mutant sublines were established to study the biofunctional activity of SH3RF2 in quail myoblast (QM7 cells during muscle differentiation. Results Through a T7 endonuclease I assay and genotyping analysis, we established an SH3RF2 knockout (KO QM7#4 subline with 61 and 155 nucleotide deletion mutations in SH3RF2. After the induction of myotube differentiation, the expression profiles were analyzed and compared between regular QM7 and SH3RF2 KO QM7#4 cells by global RNA sequencing and bioinformatics analysis. Conclusion We did not detect any statistically significant role of SH3RF2 during myotube differentiation in QM7 myoblast cells. However, additional experiments are necessary to examine the biofunctional activity of SH3RF2 in cell proliferation and muscle growth.

  11. Lentivirus mediated shRNA interference targeting MAT2B induces growth-inhibition and apoptosis in hepatocelluar carcinoma.

    Science.gov (United States)

    Wang, Qun; Liu, Quan-Yan; Liu, Zhi-Su; Qian, Qun; Sun, Quan; Pan, Ding-Yu

    2008-08-07

    To investigate the effects of lentivirus vector mediated short hairpin RNA interference targeting methionine adenosyltransferase 2beta gene (LV-shMAT2B) on hepatocelluar carcinoma (HCC) cells. We constructed four plasmids of RNA interference targeting the MAT2B gene. After LV-shMAT2B was transfected with L-02 cells and two kinds of HCC cells, cell viability and proliferation were measured with MTT and [3H]thymidine assays respectively. Flow cytometry was used to assess cell apoptosis. The level of S-adenosyl methionine (SAMe) in HepG2 cells was evaluated. The expressions of cyclin D1, cyclin D2, bcl-x(L) and bcl-x(S) were detected with western blot. We constructed LV-shMAT2B successfully. LV-shMAT2B was safe for human normal liver cells. LV-shMAT2B caused dramatic reduction in proliferation compared with controls in HCC cells Bel-7402 (P = 0.054) and HepG2 (P = 0.031). Flow cytometry analysis showed that cell apoptosis caused by LV-shMAT2B was greater in HCC cells Bel-7402 and HepG2 than in control induced by scrambled siRNA (P = 0.047), but apoptosis rates in L-02 induced by LV-shMAT2B and scrambled siRNA respectively had no significant difference. Moreover, LV-shMAT2B significantly suppressed expression of MAT2B leading to growth-inhibition effect on HCC cells by down-regulating cyclin D1. Apoptosis induced by LV-shMAT2B was involved in down-regulating bcl-x(L) and up- regulating bcl-x(S). LV-shMAT2B can induce cell apoptosis and growth-inhibition in HCC cells. MAT2B may be a therapy target in HCC in the future.

  12. Doxycycline protects human intestinal cells from hypoxia/reoxygenation injury: Implications from an in-vitro hypoxia model.

    Science.gov (United States)

    Hummitzsch, Lars; Zitta, Karina; Berndt, Rouven; Kott, Matthias; Schildhauer, Christin; Parczany, Kerstin; Steinfath, Markus; Albrecht, Martin

    2017-04-15

    Intestinal ischemia/reperfusion (I/R) injury is a grave clinical emergency and associated with high morbidity and mortality rates. Based on the complex underlying mechanisms, a multimodal pharmacological approach seems necessary to prevent intestinal I/R injury. The antibiotic drug doxycycline, which exhibits a wide range of pleiotropic therapeutic properties, might be a promising candidate for also reducing I/R injury in the intestine. To investigate possible protective effects of doxycycline on intestinal I/R injury, human intestinal CaCo-2 cells were exposed to doxycycline at clinically relevant concentrations. In order to mimic I/R injury, CaCo-2 were thereafter subjected to hypoxia/reoxygenation by using our recently described two-enzyme in-vitro hypoxia model. Investigations of cell morphology, cell damage, apoptosis and hydrogen peroxide formation were performed 24h after the hypoxic insult. Hypoxia/reoxygenation injury resulted in morphological signs of cell damage, elevated LDH concentrations in the respective culture media (Pdoxycycline (5µM, 10µM, 50µM) reduced the hypoxia induced signs of cell damage and LDH release (Pdoxycycline protects human intestinal cells from hypoxia/reoxygenation injury in-vitro. Further animal and clinical studies are required to prove the protective potential of doxycycline on intestinal I/R injury under in-vivo conditions. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. Hypoxia-induced retinopathy model in adult zebrafish

    DEFF Research Database (Denmark)

    Cao, Ziquan; Jensen, Lasse D.; Rouhi, Pegah

    2010-01-01

    Hypoxia-induced vascular responses, including angiogenesis, vascular remodeling and vascular leakage, significantly contribute to the onset, development and progression of retinopathy. However, until recently there were no appropriate animal disease models recapitulating adult retinopathy available....... In this article, we describe protocols that create hypoxia-induced retinopathy in adult zebrafish. Adult fli1: EGFP zebrafish are placed in hypoxic water for 3-10 d and retinal neovascularization is analyzed using confocal microscopy. It usually takes 11 d to obtain conclusive results using the hypoxia......-induced retinopathy model in adult zebrafish. This model provides a unique opportunity to study kinetically the development of retinopathy in adult animals using noninvasive protocols and to assess therapeutic efficacy of orally active antiangiogenic drugs....

  14. Management of renal dysfunction following term perinatal hypoxia-ischaemia.

    Science.gov (United States)

    Sweetman, Deirdre U; Riordan, Michael; Molloy, Eleanor J

    2013-03-01

    Acute kidney injury frequently develops following the term perinatal hypoxia-ischaemia. Quantifying the degree of acute kidney injury is difficult, however, as the methods currently in use are suboptimal. Acute kidney injury management is largely supportive with little evidence basis for many interventions. This review discusses management strategies and novel biomarkers that may improve diagnosis and management of renal injury following perinatal hypoxia-ischaemia. Following perinatal hypoxia-ischaemia, acute kidney injury is common. Management of neonatal acute kidney injury is largely supportive. Novel acute kidney injury biomarkers may play a role in optimizing new categorical definitions of renal injury. Studies are needed to investigate the impact of neonatal acute kidney injury on long-term outcome. ©2012 The Author(s)/Acta Paediatrica ©2012 Foundation Acta Paediatrica.

  15. Mild hypoxia is associated with quantitative EEG changes, but not with dissociative symptoms

    Directory of Open Access Journals (Sweden)

    H W Smith

    2006-06-01

    Full Text Available Backround and aims. Hypoxia at altitude may lead to mental changes resembling dissociative symptoms. This study examined whether hypoxia precipitates dissociative states in normal subjects and whether quantitative electro- encephalographic (EEG changes occur. Methods. Dissociative symptoms and EEG changes were examined in a hypobaric chamber. Results. No dissociation was noted. EEG slowing accompanied hypoxia, replicating previous findings.

  16. [Effect of intermittent hypoxia of sleep apnea on embryonic rat cortical neurons in vitro].

    Science.gov (United States)

    Zhang, Chanjuan; Li, Yanzhong; Wang, Yan

    2015-05-01

    To investigate the effects of different pattens of intermittent hypoxia on the activity and apoptosis of primary cultured rat embryonic cortical neurons, and to evaluate the role of intermittent hypoxia in the mechanism of obstructive sleep syndrom induced cognitive function loss. The embryonic cerebral cortical neurons were cultured in vitro and were identified by immunofluorescence. Cultured neurons were randomly divided into intermittent hypoxia group, intermittent normal oxygen group, persistent hypoxia group and the control group, and intermittent hypoxia group was divided into five subgroups according to different frequency and time-bound. Neurons were exposed in different modes of hypoxia. MTT colorimetry was used to detect the viability of the neurons, and DAPI colorated measurement was used to calculate the percentages of neuron apoptosis. There were significantly different effects between all subgroups of intermittent hypoxia and the continued hypoxia group on neuronal activity and apoptosis (P Intermittent hypoxia groups with different frequency and time had no difference in neuronal activity and apoptosis (P > 0.05). The effect of intermittent hypoxia was more serious than that of continued hypoxia on neuronal activity and apoptosis; The impact of intermittent hypoxia on neuronal activity and apoptosis may be an important factor in obstructive sleep apnea related cognitive impairment.

  17. Hypoxia Impacts on Food Web Linkages in a Pelagic Ecosystem

    Science.gov (United States)

    Sato, M.; Horne, J. K.; Parker-Stetter, S. L.; Essington, T.; Keister, J. E.; Moriarty, P.; Li, L.

    2016-02-01

    Low dissolved oxygen (DO), or hypoxia, causes significant disturbances on aquatic organisms, but the consequences for key food web linkages is not well understood. Here, we tested how the intensity of low DO events governs the degree of spatial overlap between pelagic zooplanktivorous fish and their zooplankton prey, fish feeding rates, and community compositions of zooplankton. We hypothesized that the greater sensitivity of fish to DO compared to zooplankton would lead to diminished spatial overlap at moderate DO and reduced feeding rates of fish, while severe hypoxia would amplify spatial overlap by preventing zooplankton from using deep refuge habitats leading to increased fish feeding rates. We also hypothesized shifts in zooplankton community composition towards less energetically profitable taxa such as small copepods and gelatinous species. We used a combination of multifrequency acoustic and net sampling for detecting distributions and abundance of zooplankton and pelagic fish in Hood Canal, WA, a seasonally hypoxic fjord. We employed a sampling design which paired hypoxic regions of Hood Canal with normoxic regions sampled prior to, during, and after the onset of hypoxia in two years. Contrary to our hypotheses, we found that fish and zooplankton did not change their horizontal and vertical distributions during periods and in locations with low DO levels. Consequently, the vertical overlap between fish and zooplankton did not change with DO. Fish feeding rates and the dominant zooplankton prey did not change with hypoxia events. The apparent resilience of fish to low DO in our system may be explained by decreased metabolic oxygen demand due to cool temperatures, increased availability and accessibility to their prey in low DO waters, or potential increase in predation risk at shallower depth. This study highlights the importance of both temperature and DO, instead of hypoxia threshold alone, in evaluating the impacts of hypoxia on pelagic communities.

  18. Peak heart rate decreases with increasing severity of acute hypoxia

    DEFF Research Database (Denmark)

    Lundby, C; Araoz, M; Van Hall, Gerrit

    2001-01-01

    The purpose of the present study was to investigate the degree to which peak heart rate is reduced during exhaustive exercise in acute hypoxia. Five sea-level lowlanders performed maximal exercise at normobaric normoxia and at three different levels of hypobaric hypoxia (barometric pressures of 518......, 459, and 404 mmHg) in a hypobaric chamber and while breathing 9% O(2) in N(2). These conditions were equivalent to altitudes of 3300, 4300, 5300, and 6300 m above sea level, respectively. At 4300 m, maximal exercise was also repeated after 4 and 8 h. Peak heart rate (HR) decreased from 191 (182...

  19. Past Occurrences of Hypoxia in the Baltic Sea

    Science.gov (United States)

    Zillen, L.; Conley, D. J.; Bjorck, S.

    2007-12-01

    The hypoxic zone in the Baltic Sea has increased in area by about four times since 1950. Widespread oxygen deficiency below the halocline has severely reduced macro benthic communities in the Baltic Proper and the Gulf of Finland over the past decades and negatively effected food chain dynamics, fish habitats and fisheries in the entire Baltic Sea. In addition, hypoxia alters nutrient biogeochemical cycles. The cause of the increased hypoxia is believed to be enhanced eutrophication through increased anthropogenic input of nutrients, such as phosphorous and nitrogen. Conditions prior to the 1950s are considered as the benchmark and some authors suggest that the earlier Baltic Sea was an oligothrophic, clear-water body with oxygenated deep waters. By contrast, studies of short sediment cores reveal that hypoxia has been present in some of the deepest basins for at least the last 100-200 years. In addition, long sediment cores suggest that hypoxia in the Baltic Sea has occurred intermittently in deep basins over the last c. 8500 years. Thus, the occurrence of present day hypoxia in the deeper basins need not necessarily be attributed to human activity but rather to natural oceanographic, geologic and climate conditions. We present a compilation of previous publications that reported the occurrence of laminated sediments (i.e. a palaeo-proxy for hypoxia) in the Baltic Sea. This review shows that the deeper parts of the Baltic Sea have experienced either intermittent or more regular hypoxia during most of the Holocene and that more continuous laminations started to form c. 7800-8500 cal. yr BP ago, in association with the establishment of a permanent halocline during the transition from the Ancylus Lake to the Littorina Sea. Laminated sediments were more common during the early and late Holocene and coincided with intervals of high organic productivity (high TOC content) and high salinity during the Holocene Thermal Maximum and the Medieval Climate Optimum. This study

  20. Hypoxia signaling pathways: modulators of oxygen-related organelles

    OpenAIRE

    Schönenberger, Miriam J.; Kovacs, Werner J.

    2015-01-01

    Oxygen (O2) is an essential substrate in cellular metabolism, bioenergetics, and signaling and as such linked to the survival and normal function of all metazoans. Low O2 tension (hypoxia) is a fundamental feature of physiological processes as well as pathophysiological conditions such as cancer and ischemic diseases. Central to the molecular mechanisms underlying O2 homeostasis are the hypoxia-inducible factors-1 and -2 alpha (HIF-1α and EPAS1/HIF-2α) that function as master regulators of th...

  1. Nutrients, hypoxia and mass fishkill events in Tapi estuary, India.

    Digital Repository Service at National Institute of Oceanography (India)

    Ram, A.; JiyalalRam, M.J.; Rokade, M.A.; Bharti, S.; Vishwasrao, C.; Majithiya, D.

    , or approximately 30% saturation) is emerging as a major threat to coastal ecosystems globally. More than 600 coastal and estuarine sites globally have developed hypoxia (Nixon, 2009; Diaz et al., 2010; Conley et al., 2011) which is an increase of approximately 5.... Several factors are known to cause fish kills such as hypoxia/anoxia, or the build up of high concentrations of ammonia or nitrite (Diaz and Rosenberg, 1995; Wetzel, 2001; Anderson et al., 2002; Breitburg, 2002, Camargo and Alonso, 2006). Our long term...

  2. Influence of hypoxia on protoplast structure in the plant cell

    Directory of Open Access Journals (Sweden)

    Maria Podbielkowska

    2015-01-01

    Full Text Available An influence of hypoxia on the protoplast’s structure in the root tips meristematic cells of onion (Allium cepa L. and of Tradescantia bracteata Small has been investigated. Hypoxia was caused either by respiratory inhibitors (sodium azide, 2,4-dinitrophenol, phosfon-D or by anaeroibic conditions. In both cases characteristic membranization of cytoplasm was observed. It appeared as spherical and parallel structures of rough endoplasmic reticulum. The observed hypertrophy was not connected with the increase of nucleic acids and proteins synthesis. In the examined cells the membranization was accompanied by an increase of the lipids content.

  3. Determinants of maximal oxygen uptake in severe acute hypoxia

    DEFF Research Database (Denmark)

    Calbet, J A L; Boushel, Robert Christopher; Rådegran, G

    2003-01-01

    level). With hypoxia, exercise PaO2 dropped to 31-34 mmHg and arterial O2 content (CaO2) was reduced by 35% (P exchange......, as reflected by the higher alveolar-arterial O2 difference in hypoxia (P rate and stroke VOlume (P ...: 1) reduction of PiO2, 2) impairment of pulmonary gas exchange, and 3) reduction of maximal cardiac output and peak leg blood flow, each explaining about one-third of the loss in VO2 max....

  4. Improving MeSH classification of biomedical articles using citation contexts.

    Science.gov (United States)

    Aljaber, Bader; Martinez, David; Stokes, Nicola; Bailey, James

    2011-10-01

    Medical Subject Headings (MeSH) are used to index the majority of databases generated by the National Library of Medicine. Essentially, MeSH terms are designed to make information, such as scientific articles, more retrievable and assessable to users of systems such as PubMed. This paper proposes a novel method for automating the assignment of biomedical publications with MeSH terms that takes advantage of citation references to these publications. Our findings show that analysing the citation references that point to a document can provide a useful source of terms that are not present in the document. The use of these citation contexts, as they are known, can thus help to provide a richer document feature representation, which in turn can help improve text mining and information retrieval applications, in our case MeSH term classification. In this paper, we also explore new methods of selecting and utilising citation contexts. In particular, we assess the effect of weighting the importance of citation terms (found in the citation contexts) according to two aspects: (i) the section of the paper they appear in and (ii) their distance to the citation marker. We conduct intrinsic and extrinsic evaluations of citation term quality. For the intrinsic evaluation, we rely on the UMLS Metathesaurus conceptual database to explore the semantic characteristics of the mined citation terms. We also analyse the "informativeness" of these terms using a class-entropy measure. For the extrinsic evaluation, we run a series of automatic document classification experiments over MeSH terms. Our experimental evaluation shows that citation contexts contain terms that are related to the original document, and that the integration of this knowledge results in better classification performance compared to two state-of-the-art MeSH classification systems: MeSHUP and MTI. Our experiments also demonstrate that the consideration of Section and Distance factors can lead to statistically

  5. PLC-β2 is modulated by low oxygen availability in breast tumor cells and plays a phenotype dependent role in their hypoxia-related malignant potential.

    Science.gov (United States)

    Brugnoli, Federica; Grassilli, Silvia; Al-Qassab, Yasamin; Capitani, Silvano; Bertagnolo, Valeria

    2016-12-01

    Limited oxygen availability plays a critical role in the malignant progression of breast cancer by orchestrating a complex modulation of the gene transcription largely dependent on the tumor phenotype. Invasive breast tumors belonging to different molecular subtypes are characterized by over-expression of PLC-β2, whose amount positively correlates with the malignant evolution of breast neoplasia and supports the invasive potential of breast tumor cells. Here we report that hypoxia modulates the expression of PLC-β2 in breast tumor cells in a phenotype-related manner, since a decrease of the protein was observed in the BT-474 and MCF7 cell lines while an increase was revealed in MDA-MB-231 cells as a consequence of low oxygen availability. Under hypoxia, the down-modulation of PLC-β2 was mainly correlated with the decrease of the EMT marker E-cadherin in the BT-474 cells and with the up-regulation of the stem cell marker CD133 in MCF7 cells. The increase of PLC-β2 induced by low oxygen in MDA-MB-231 cells supports the hypoxia-related reorganization of actin cytoskeleton and sustains invasion capability. In all examined cell lines, but with an opposite role in the ER-positive and ER-negative cells, PLC-β2 was involved in the hypoxia-induced increase of HIF-1α, known to affect both EMT and CD133 expression. Our data include PLC-β2 in the complex and interconnected signaling pathways induced by low oxygen availability in breast tumor cells and suggest that the forced modulation of PLC-β2 programmed on the basis of tumor phenotype may prevent the malignant progression of breast neoplasia as a consequence of intra-tumoral hypoxia. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  6. Virtual Sustainability

    Directory of Open Access Journals (Sweden)

    William Sims Bainbridge

    2010-09-01

    Full Text Available In four ways, massively multiplayer online role-playing games may serve as tools for advancing sustainability goals, and as laboratories for developing alternatives to current social arrangements that have implications for the natural environment. First, by moving conspicuous consumption and other usually costly status competitions into virtual environments, these virtual worlds might reduce the need for physical resources. Second, they provide training that could prepare individuals to be teleworkers, and develop or demonstrate methods for using information technology to replace much transportation technology, notably in commuting. Third, virtual worlds and online games build international cooperation, even blending national cultures, thereby inching us toward not only the world consciousness needed for international agreements about the environment, but also toward non-spatial government that cuts across archaic nationalisms. Finally, realizing the potential social benefits of this new technology may urge us to reconsider a number of traditional societal institutions.

  7. Sustainability; Sustentabilidade

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2009-10-15

    This chapter analyses the production chain of ethanol, considering the impacts on the quality of the air, water supplies, soil occupation and biodiversity, and the efforts for the soil preservation. It is pointed out the activities of the production cycle and use of bio ethanol due to great uncertainties as far the environmental impacts is concerning and that will deserve more attention in future evaluations. At same time, the chapter highlights another activities where the present acknowledge is sufficient to assure the control and/or prediction of consequences of the desired intervention on the environment media to accommodate the sugar and ethanol production expansion. The consideration is not conservative but to promote the sustainable development.

  8. Sustainability Science Needs Sustainable Data!

    Science.gov (United States)

    Downs, R. R.; Chen, R. S.

    2013-12-01

    Sustainability science (SS) is an 'emerging field of research dealing with the interactions between natural and social systems, and with how those interactions affect the challenge of sustainability: meeting the needs of present and future generations while substantially reducing poverty and conserving the planet's life support systems' (Kates, 2011; Clark, 2007). Bettencourt & Kaur (2011) identified more than 20,000 scientific papers published on SS topics since the 1980s with more than 35,000 distinct authors. They estimated that the field is currently growing exponentially, with the number of authors doubling approximately every 8 years. These scholars are undoubtedly using and generating a vast quantity and variety of data and information for both SS research and applications. Unfortunately we know little about what data the SS community is actually using, and whether or not the data that SS scholars generate are being preserved for future use. Moreover, since much SS research is conducted by cross-disciplinary, multi-institutional teams, often scattered around the world, there could well be increased risks of data loss, reduced data quality, inadequate documentation, and poor long-term access and usability. Capabilities and processes therefore need to be established today to support continual, reliable, and efficient preservation of and access to SS data in the future, especially so that they can be reused in conjunction with future data and for new studies not conceived in the original data collection activities. Today's long-term data stewardship challenges include establishing sustainable data governance to facilitate continuing management, selecting data to ensure that limited resources are focused on high priority SS data holdings, securing sufficient rights to allow unforeseen uses, and preparing data to enable use by future communities whose specific research and information needs are not yet known. Adopting sustainable models for archival

  9. Induction of gastrin expression in gastrointestinal cells by hypoxia or cobalt is independent of hypoxia-inducible factor (HIF).

    Science.gov (United States)

    Xiao, Lin; Kovac, Suzana; Chang, Mike; Shulkes, Arthur; Baldwin, Graham S; Patel, Oneel

    2012-07-01

    Gastrin and its precursors have been shown to promote mitogenesis and angiogenesis in gastrointestinal tumors. Hypoxia stimulates tumor growth, but its effect on gastrin gene regulation has not been examined in detail. Here we have investigated the effect of hypoxia on the transcription of the gastrin gene in human gastric cancer (AGS) cells. Gastrin mRNA was measured by real-time PCR, gastrin peptides were measured by RIA, and gastrin promoter activity was measured by dual-luciferase reporter assay. Exposure to a low oxygen concentration (1%) increased gastrin mRNA concentrations in wild-type AGS cells (AGS) and in AGS cells overexpressing the gastrin receptor (AGS-cholecystokinin receptor 2) by 2.1 ± 0.4- and 4.1 ± 0.3-fold (P gastrin promoter activity in AGS cells by 2.4 ± 0.3-fold (P gastrin promoter of the putative binding sites for the transcription factor hypoxia-inducible factor 1 (HIF-1) or knockdown of either the HIF-1α or HIF-1β subunit did not affect gastrin promoter inducibility under hypoxia indicated that the hypoxic activation of the gastrin gene is likely HIF independent. Mutational analysis of previously identified Sp1 regulatory elements in the gastrin promoter also failed to abrogate the induction of promoter activity by hypoxia. The observations that hypoxia up-regulates the gastrin gene in AGS cells by HIF-independent mechanisms, and that this effect is enhanced by the presence of gastrin receptors, provide potential targets for gastrointestinal cancer therapy.

  10. ATR controls cellular adaptation to hypoxia through positive regulation of hypoxia-inducible factor 1 (HIF-1) expression.

    Science.gov (United States)

    Fallone, F; Britton, S; Nieto, L; Salles, B; Muller, C

    2013-09-12

    Tumor cells adaptation to severe oxygen deprivation (hypoxia) plays a major role in tumor progression. The transcription factor HIF-1 (hypoxia-inducible factor 1), whose α-subunit is stabilized under hypoxic conditions is a key component of this process. Recent studies showed that two members of the phosphoinositide 3-kinase-related kinases (PIKKs) family, ATM (ataxia telangiectasia mutated) and DNA-PK (DNA-dependent protein kinase), regulate the hypoxic-dependent accumulation of HIF-1. These proteins initiate cellular stress responses when DNA damage occurs. In addition, it has been demonstrated that extreme hypoxia induces a replicative stress resulting in regions of single-stranded DNA at stalled replication forks and the activation of ATR (ataxia telangiectasia and Rad3 related protein), another member of the PIKKs family. Here, we show that even less severe hypoxia (0.1% O2) also induces activation of ATR through replicative stress. Importantly, in using either transiently silenced ATR cells, cells expressing an inactive form of ATR or cells exposed to an ATR inhibitor (CGK733), we demonstrate that hypoxic ATR activation positively regulates the key transcription factor HIF-1 independently of the checkpoint kinase Chk1. We show that ATR kinase activity regulates HIF-1α at the translational level and we find that the elements necessary for the regulation of HIF-1α translation are located within the coding region of HIF-1α mRNA. Finally, by using three independent cellular models, we clearly show that the loss of ATR expression and/or kinase activity results in the decrease of HIF-1 DNA binding under hypoxia and consequently affects protein expression levels of two HIF-1 target genes, GLUT-1 and CAIX. Taken together, our data show a new function for ATR in cellular adaptation to hypoxia through regulation of HIF-1α translation. Our work offers new prospect for cancer therapy using ATR inhibitors with the potential to decrease cellular adaptation in hypoxic

  11. Exposure of mice to chronic hypoxia attenuates pulmonary arterial contractile responses to acute hypoxia by increases in extracellular hydrogen peroxide.

    Science.gov (United States)

    Patel, Dhara; Alhawaj, Raed; Wolin, Michael S

    2014-08-15

    Exposing mice to a chronic hypoxic treatment (10% oxygen, 21 days) that promotes pulmonary hypertension was observed to attenuate the pulmonary vasoconstriction response to acute hypoxia (HPV) both in vivo and in isolated pulmonary arteries. Since catalase restored the HPV response in isolated arteries, it appeared to be attenuated by extracellular hydrogen peroxide. Chronic hypoxia promoted the detection of elevated lung superoxide, extracellular peroxide, extracellular SOD expression, and protein kinase G (PKG) activation [based on PKG dimerization and vasodilator-stimulated phosphoprotein (VASP) phosphorylation], suggesting increased generation of extracellular peroxide and PKG activation may contribute to the suppression of HPV. Aorta from mice exposed to 21 days of hypoxia also showed evidence for extracellular hydrogen peroxide, suppressing the relaxation response to acute hypoxia. Peroxide appeared to partially suppress contractions to phenylephrine used in the study of in vitro hypoxic responses. Treatment of mice with the heme precursor δ-aminolevulinic acid (ALA; 50 mg·kg(-1)·day(-1)) during exposure to chronic hypoxia was examined as a pulmonary hypertension therapy because it could potentially activate beneficial cGMP-mediated effects through promoting a prolonged protoporphyrin IX (PpIX)-elicited activation of soluble guanylate cyclase. ALA attenuated pulmonary hypertension, increases in both superoxide and peroxide, and the suppression of in vitro and in vivo HPV responses. ALA generated prolonged detectible increases in PpIX and PKG-associated phosphorylation of VASP, suggesting PKG activation may contribute to suppression of pulmonary hypertension and prevention of alterations in extracellular peroxide that appear to be attenuating HPV responses caused by chronic hypoxia. Copyright © 2014 the American Physiological Society.

  12. Vagal activity and oxygen saturation response to hypoxia: Effects of aerobic fitness and rating of hypoxia tolerance

    OpenAIRE

    Tomáš Macoun; Michal Botek; Jakub Krejčí; McKune, Andrew J.

    2017-01-01

    Background: A reduction in the inspired oxygen fraction (FiO2) induces a decline in arterial oxygen saturation (SpO2) and changes of heart rate variability (HRV). It has been shown that SpO2 and HRV responses to similar levels of acute normobaric hypoxia are inter-individual variable. Variable response may be influenced by normoxia reached maximal oxygen uptake (VO2max) value. Objective: The primary aim was to assess HRV and the SpO2 response to hypoxia, and examine the association with normo...

  13. BAR-SH3 sorting nexins are conserved interacting proteins of Nervous wreck that organize synapses and promote neurotransmission.

    Science.gov (United States)

    Ukken, Fiona P; Bruckner, Joseph J; Weir, Kurt L; Hope, Sarah J; Sison, Samantha L; Birschbach, Ryan M; Hicks, Lawrence; Taylor, Kendra L; Dent, Erik W; Gonsalvez, Graydon B; O'Connor-Giles, Kate M

    2016-01-01

    Nervous wreck (Nwk) is a conserved F-BAR protein that attenuates synaptic growth and promotes synaptic function in Drosophila. In an effort to understand how Nwk carries out its dual roles, we isolated interacting proteins using mass spectrometry. We report a conserved interaction between Nwk proteins and BAR-SH3 sorting nexins, a family of membrane-binding proteins implicated in diverse intracellular trafficking processes. In mammalian cells, BAR-SH3 sorting nexins induce plasma membrane tubules that localize NWK2, consistent with a possible functional interaction during the early stages of endocytic trafficking. To study the role of BAR-SH3 sorting nexins in vivo, we took advantage of the lack of genetic redundancy in Drosophila and employed CRISPR-based genome engineering to generate null and endogenously tagged alleles of SH3PX1. SH3PX1 localizes to neuromuscular junctions where it regulates synaptic ultrastructure, but not synapse number. Consistently, neurotransmitter release was significantly diminished in SH3PX1 mutants. Double-mutant and tissue-specific-rescue experiments indicate that SH3PX1 promotes neurotransmitter release presynaptically, at least in part through functional interactions with Nwk, and might act to distinguish the roles of Nwk in regulating synaptic growth and function. © 2016. Published by The Company of Biologists Ltd.

  14. Giant-Planet Chemistry: Ammonium Hydrosulfide (NH4SH), Its IR Spectra and Thermal and Radiolytic Stabilities

    Science.gov (United States)

    Loeffler, Mark J.; Hudson, Reggie L.; Chanover, Nancy J.; Simon, Amy A.

    2015-01-01

    Here we present our recent studies of proton-irradiated and unirradiated ammonium hydrosulfide, NH4SH, a compound predicted to be an important tropospheric cloud component of Jupiter and other giant planets. We irradiated both crystalline and amorphous NH4SH at 10-160 K and used IR spectroscopy to observe and identify reaction products in the ice, specifically NH3 and long-chained sulfur-containing ions. Crystalline NH4SH was amorphized during irradiation at all temperatures studied with the rate being the fastest at the lowest temperatures. Irradiation of amorphous NH4SH at approximately 10-75 K showed that 60-80% of the NH4 + remained when equilibrium was reached, and that NH4SH destruction rates were relatively constant within this temperature range. Irradiations at higher temperatures produced different dose dependence and were accompanied by pressure outbursts that, in some cases, fractured the ice. The thermal stability of irradiated NH4SH was found to be greater than that of unirradiated NH4SH, suggesting that an irradiated giant-planet cloud precipitate can exist at temperatures and altitudes not previously considered.

  15. Multi-resistance strategy for viral diseases and in vitro shRNA verification method in pigs.

    Science.gov (United States)

    Oh, Jong-Nam; Choi, Kwang-Hwan; Lee, C K

    2017-12-19

    Foot and mouth disease (FMD) and porcine reproductive and respiratory syndrome (PRRS) are major diseases that interrupt porcine production. Because they are viral diseases, vaccinations are of only limited effectiveness in preventing outbreaks. To establish an alternative multi-resistant strategy against FMD virus (FMDV) and PRRS virus (PRRSV), the present study introduced two genetic modification techniques to porcine cells. First, CD163, the PRRSV viral receptor, was edited with the CRISPR-Cas9 technique. The CD163 gene sequences of edited cells and control cells differed. Second, shRNAs were integrated into the cells. The shRNAs, targeting the 3D gene of FMDV and the ORF7 gene of PRRSV, were transferred into fibroblasts. We also developed an in vitro shRNA verification method with a target gene expression vector. shRNA activity was confirmed in vitro with vectors that expressed the 3D and ORF7 genes in the cells. Cells containing shRNAs showed lower transcript levels than cells with only the expression vectors. The shRNAs were integrated into CD163-edited cells to combine the two techniques, and the viral genes were suppressed in these cells. We established a multi-resistant strategy against viral diseases and an in vitro shRNA verification method.

  16. Effects of chronic hypoxia on maternal vasodilation and vascular reactivity in guinea pig and ovine pregnancy.

    Science.gov (United States)

    White, Margueritte M; Zhang, Lubo

    2003-01-01

    During pregnancy, exposure to chronic hypoxia is thought to be associated with an increased risk of preeclampsia and fetal intrauterine growth restriction (IUGR). While some studies suggest that this process may be mediated through effects of chronic hypoxia on uterine artery vasodilation and growth, these observations are likely to be species specific and may represent genetic variability in maternal adaptation to hypoxia. This review is a comparative analysis of the effects of chronic hypoxia on vascular reactivity in pregnant and nonpregnant guinea pig and sheep. Data suggest that exposure to chronic hypoxia is associated with enhanced uterine artery blood flow in the sheep, whereas, in the guinea pig, blood flow is decreased.

  17. Desiderata for an authoritative Representation of MeSH in RDF.

    Science.gov (United States)

    Winnenburg, Rainer; Bodenreider, Olivier

    2014-01-01

    The Semantic Web provides a framework for the integration of resources on the web, which facilitates information integration and interoperability. RDF is the main representation format for Linked Open Data (LOD). However, datasets are not always made available in RDF by their producers and the Semantic Web community has had to convert some of these datasets to RDF in order for these datasets to participate in the LOD cloud. As a result, the LOD cloud sometimes contains outdated, partial and even inaccurate RDF datasets. We review the LOD landscape for one of these resources, MeSH, and analyze the characteristics of six existing representations in order to identify desirable features for an authoritative version, for which we create a prototype. We illustrate the suitability of this prototype on three common use cases. NLM intends to release an authoritative representation of MeSH in RDF (beta version) in the Fall of 2014.

  18. Inhibition and Promotion of Pyrolysis by Hydrogen Sulfide (H2S) and Sulfanyl Radical (SH)

    DEFF Research Database (Denmark)

    Zeng, Zhe; Altarawneh, Mohammednoor; Oluwoye, Ibukun

    2016-01-01

    the weakest C–H sites in alkenes and alkynes, except for ethylene, appears noticeably exothermic. Furthermore, abstraction of H from propene, 1-butene, and iso-butene displays pronounced spontaneity (i.e., ΔrG° hydrogen bond. However...... findings demonstrate that the documented inhibition effect of hydrogen sulfide (H2S) on pyrolysis of alkanes does not apply to alkenes and alkynes. During interaction with hydrocarbons, the inhibitive effect of H2S and promoting interaction of SH radical depend on the reversibility of the H abstraction...... processes. For the three groups of hydrocarbon, Evans–Polanyi plots display linear correlations between the bond dissociation enthalpies of the abstracted hydrogens and the relevant activation energies. In the case of methane, we demonstrated that the reactivity of SH radicals toward abstracting H atoms...

  19. Investigation of the SH3BP2 gene mutation in cherubism.

    Science.gov (United States)

    Lee, Ji-Young; Jung, Yang-Seok; Kim, Soo-A; Lee, Sang-Ho; Ahn, Sang-Gun; Yoon, Jung-Hoon

    2008-06-01

    Cherubism is a rare developmental lesion of the jaw that is generally inherited as an autosomal dominant trait. Recent studies have revealed point mutations in the SH3BP2 gene in cherubism patients. In this study, we examined a 6-year-old Korean boy and his family. We found a Pro418Arg mutation in the SH3BP2 gene of the patient and his mother. A father and his 30-month-old younger brother had no mutations. Immunohistochemically, the multinucleated giant cells proved positive for CD68 and tartrate-resistant acid phosphatase (TRAP). Numerous spindle-shaped stromal cells expressed a ligand for receptor activator of nuclear factor kB (RANKL), but not in multinucleated giant cells. These results provide evidence that RANKL plays a critical role in the differentiation of osteoclast precursor cells to multinucleated giant cells in cherubism. Additionally, genetic analysis may be a useful method for differentiation of cherubism.

  20. Thermal performance evaluation of the Suncatcher SH-11 (liquid) solar collector

    Science.gov (United States)

    1980-01-01

    The procedures used and the results obtained during the evaluation test program on the Solar Unlimited, Inc., Suncatcher SH-11 (liquid) solar collector are presented. The flat-plate collector case assembly is made of .08 inch aluminum 3003 H14 riveted with fiberglass board insulation. The absorber consists of collared aluminum fins mechanically bonded to 3/8 inch copper tubing and coated with 3M Nextel black. Water is used as the working fluid. The glazing is made of a single glass, 1/8 inch water white, tempered and antireflective. The collector weight is 85 pounds with overall external dimensions of about 35.4 in x 82.0 in x 4.0 in. Thermal performance data on the Solar Unlimited Suncatcher SH-11 solar collector under simulated conditions were conducted using the MSFC Solar Simulator.

  1. Quantifying information transfer by protein domains: Analysis of the Fyn SH2 domain structure

    DEFF Research Database (Denmark)

    Lenaerts, Tom; Ferkinghoff-Borg, Jesper; Stricher, Francois

    2008-01-01

    Background: Efficient communication between distant sites within a protein is essential for cooperative biological response. Although often associated with large allosteric movements, more subtle changes in protein dynamics can also induce long-range correlations. However, an appropriate formalism...... that directly relates protein structural dynamics to information exchange between functional sites is still lacking. Results: Here we introduce a method to analyze protein dynamics within the framework of information theory and show that signal transduction within proteins can be considered as a particular...... distal communication is achieved. We illustrate the approach by analyzing information transfer by the SH2 domain of Fyn tyrosine kinase, obtained from Monte Carlo dynamics simulations. Our analysis reveals that the Fyn SH2 domain forms a noisy communication channel that couples residues located...

  2. PubMedMiner: Mining and Visualizing MeSH-based Associations in PubMed.

    Science.gov (United States)

    Zhang, Yucan; Sarkar, Indra Neil; Chen, Elizabeth S

    2014-01-01

    The exponential growth of biomedical literature provides the opportunity to develop approaches for facilitating the identification of possible relationships between biomedical concepts. Indexing by Medical Subject Headings (MeSH) represent high-quality summaries of much of this literature that can be used to support hypothesis generation and knowledge discovery tasks using techniques such as association rule mining. Based on a survey of literature mining tools, a tool implemented using Ruby and R - PubMedMiner - was developed in this study for mining and visualizing MeSH-based associations for a set of MEDLINE articles. To demonstrate PubMedMiner's functionality, a case study was conducted that focused on identifying and comparing comorbidities for asthma in children and adults. Relative to the tools surveyed, the initial results suggest that PubMedMiner provides complementary functionality for summarizing and comparing topics as well as identifying potentially new knowledge.

  3. Loss of Sh3gl2/Endophilin A1 Is a Common Event in Urothelial Carcinoma that Promotes Malignant Behavior

    Directory of Open Access Journals (Sweden)

    Shyama Majumdar

    2013-07-01

    Full Text Available Urothelial carcinoma (UC causes substantial morbidity and mortality worldwide. However, the molecular mechanisms underlying urothelial cancer development and tumor progression are still largely unknown. Using informatics analysis, we identified Sh3gl2 (endophilin A1 as a bladder urothelium-enriched transcript. The gene encoding Sh3gl2 is located on chromosome 9p, a region frequently altered in UC. Sh3gl2 is known to regulate endocytosis of receptor tyrosine kinases implicated in oncogenesis, such as the epidermal growth factor receptor (EGFR and c-Met. However, its role in UC pathogenesis is unknown. Informatics analysis of expression profiles as well as immunohistochemical staining of tissue microarrays revealed Sh3gl2 expression to be decreased in UC specimens compared to nontumor tissues. Loss of Sh3gl2 was associated with increasing tumor grade and with muscle invasion, which is a reliable predictor of metastatic disease and cancer-derived mortality. Sh3gl2 expression was undetectable in 19 of 20 human UC cell lines but preserved in the low-grade cell line RT4. Stable silencing of Sh3gl2 in RT4 cells by RNA interference 1 enhanced proliferation and colony formation in vitro, 2 inhibited EGF-induced EGFR internalization and increased EGFR activation, 3 stimulated phosphorylation of Src family kinases and STAT3, and 4 promoted growth of RT4 xenografts in subrenal capsule tissue recombination experiments. Conversely, forced re-expression of Sh3gl2 in T24 cells and silenced RT4 clones attenuated oncogenic behaviors, including growth and migration. Together, these findings identify loss of Sh3gl2 as a frequent event in UC development that promotes disease progression.

  4. Loss of Sh3gl2/endophilin A1 is a common event in urothelial carcinoma that promotes malignant behavior.

    Science.gov (United States)

    Majumdar, Shyama; Gong, Edward M; Di Vizio, Dolores; Dreyfuss, Jonathan; Degraff, David J; Hager, Martin H; Park, Peter J; Bellmunt, Joaquim; Matusik, Robert J; Rosenberg, Jonathan E; Adam, Rosalyn M

    2013-07-01

    Urothelial carcinoma (UC) causes substantial morbidity and mortality worldwide. However, the molecular mechanisms underlying urothelial cancer development and tumor progression are still largely unknown. Using informatics analysis, we identified Sh3gl2 (endophilin A1) as a bladder urothelium-enriched transcript. The gene encoding Sh3gl2 is located on chromosome 9p, a region frequently altered in UC. Sh3gl2 is known to regulate endocytosis of receptor tyrosine kinases implicated in oncogenesis, such as the epidermal growth factor receptor (EGFR) and c-Met. However, its role in UC pathogenesis is unknown. Informatics analysis of expression profiles as well as immunohistochemical staining of tissue microarrays revealed Sh3gl2 expression to be decreased in UC specimens compared to nontumor tissues. Loss of Sh3gl2 was associated with increasing tumor grade and with muscle invasion, which is a reliable predictor of metastatic disease and cancer-derived mortality. Sh3gl2 expression was undetectable in 19 of 20 human UC cell lines but preserved in the low-grade cell line RT4. Stable silencing of Sh3gl2 in RT4 cells by RNA interference 1) enhanced proliferation and colony formation in vitro, 2) inhibited EGF-induced EGFR internalization and increased EGFR activation, 3) stimulated phosphorylation of Src family kinases and STAT3, and 4) promoted growth of RT4 xenografts in subrenal capsule tissue recombination experiments. Conversely, forced re-expression of Sh3gl2 in T24 cells and silenced RT4 clones attenuated oncogenic behaviors, including growth and migration. Together, these findings identify loss of Sh3gl2 as a frequent event in UC development that promotes disease progression.

  5. Transcriptomic changes triggered by hypoxia: evidence for HIF-1α-independent, [Na+]i/[K+]i-mediated, excitation-transcription coupling.

    Directory of Open Access Journals (Sweden)

    Svetlana V Koltsova

    Full Text Available This study examines the relative impact of canonical hypoxia-inducible factor-1alpha- (HIF-1α and Na+i/K+i-mediated signaling on transcriptomic changes evoked by hypoxia and glucose deprivation. Incubation of RASMC in ischemic conditions resulted in ∼3-fold elevation of [Na+]i and 2-fold reduction of [K+]i. Using global gene expression profiling we found that Na+,K+-ATPase inhibition by ouabain or K+-free medium in rat aortic vascular smooth muscle cells (RASMC led to the differential expression of dozens of genes whose altered expression was previously detected in cells subjected to hypoxia and ischemia/reperfusion. For further investigations, we selected Cyp1a1, Fos, Atf3, Klf10, Ptgs2, Nr4a1, Per2 and Hes1, i.e. genes possessing the highest increments of expression under sustained Na+,K+-ATPase inhibition and whose implication in the pathogenesis of hypoxia was proved in previous studies. In ouabain-treated RASMC, low-Na+, high-K+ medium abolished amplification of the [Na+]i/[K+]i ratio as well as the increased expression of all tested genes. In cells subjected to hypoxia and glucose deprivation, dissipation of the transmembrane gradient of Na+ and K+ completely eliminated increment of Fos, Atf3, Ptgs2 and Per2 mRNAs and sharply diminished augmentation expression of Klf10, Edn1, Nr4a1 and Hes1. In contrast to low-Na+, high-K+ medium, RASMC transfection with Hif-1a siRNA attenuated increments of Vegfa, Edn1, Klf10 and Nr4a1 mRNAs triggered by hypoxia but did not impact Fos, Atf3, Ptgs2 and Per2 expression. Thus, our investigation demonstrates, for the first time, that Na+i/K+i-mediated, Hif-1α- -independent excitation-transcription coupling contributes to transcriptomic changes evoked in RASMC by hypoxia and glucose deprivation.

  6. NMR characterizations of an amyloidogenic conformational ensemble of the PI3K SH3 domain

    OpenAIRE

    Ahn, Hee-Chul; Le, Yen T.H.; Nagchowdhuri, Partha S.; DeRose, Eugene F.; Putnam-Evans, Cindy; London, Robert E.; Markley, John L.; Lim, Kwang Hun

    2006-01-01

    Amyloid formation is associated with structural changes of native polypeptides to monomeric intermediate states and their self-assembly into insoluble aggregates. Characterizations of the amyloidogenic intermediate state are, therefore, of great importance in understanding the early stage of amyloidogenesis. Here, we present NMR investigations of the structural and dynamic properties of the acid-unfolded amyloidogenic intermediate state of the phosphatidylinositol 3-kinase (PI3K) SH3 domain—a...

  7. Regulation of lifespan, metabolism, and stress responses by the Drosophila SH2B protein, Lnk.

    Directory of Open Access Journals (Sweden)

    Cathy Slack

    2010-03-01

    Full Text Available Drosophila Lnk is the single ancestral orthologue of a highly conserved family of structurally-related intracellular adaptor proteins, the SH2B proteins. As adaptors, they lack catalytic activity but contain several protein-protein interaction domains, thus playing a critical role in signal transduction from receptor tyrosine kinases to form protein networks. Physiological studies of SH2B function in mammals have produced conflicting data. However, a recent study in Drosophila has shown that Lnk is an important regulator of the insulin/insulin-like growth factor (IGF-1 signaling (IIS pathway during growth, functioning in parallel to the insulin receptor substrate, Chico. As this pathway also has an evolutionary conserved role in the determination of organism lifespan, we investigated whether Lnk is required for normal lifespan in Drosophila. Phenotypic analysis of mutants for Lnk revealed that loss of Lnk function results in increased lifespan and improved survival under conditions of oxidative stress and starvation. Starvation resistance was found to be associated with increased metabolic stores of carbohydrates and lipids indicative of impaired metabolism. Biochemical and genetic data suggest that Lnk functions in both the IIS and Ras/Mitogen activated protein Kinase (MapK signaling pathways. Microarray studies support this model, showing transcriptional feedback onto genes in both pathways as well as indicating global changes in both lipid and carbohydrate metabolism. Finally, our data also suggest that Lnk itself may be a direct target of the IIS responsive transcription factor, dFoxo, and that dFoxo may repress Lnk expression. We therefore describe novel functions for a member of the SH2B protein family and provide the first evidence for potential mechanisms of SH2B regulation. Our findings suggest that IIS signaling in Drosophila may require the activity of a second intracellular adaptor, thereby yielding fundamental new insights into the

  8. Sexual dimorphism in the Atapuerca-SH hominids: the evidence from the mandibles.

    Science.gov (United States)

    Rosas, Antonio; Bastir, Markus; Martínez-Maza, Cayetana; Bermúdez de Castro, Jose María

    2002-04-01

    The pattern of sexual dimorphism in 15 mandibles from the Atapuerca-SH Middle Pleistocene site, attributed to Homo heidelbergensis, is explored. Two modern human samples of known sex are used as a baseline for establishing sexing criteria. The mandible was divided for analysis into seven study regions and differential expression of sexual dimorphism in these regions is analysed. A total of 40 continuous and 32 discrete variables were scored on the mandibles. The means method given in Regh & Leigh (Am. J. phys. Anthrop.110, 95-104, 1999) was followed for evaluating the potential of correct sex attribution for each variable. On average, the mandibles from the Atapuerca-SH site present a degree of sexual dimorphism about eight points higher than in H. sapiens samples. However, mandibular anatomy of the European Middle Pleistocene hominid records sexual dimorphism differentially. Different areas of the Atapuerca-SH mandibles exhibit quite distinct degrees of sexual dimorphism. For instance, variables of the alveolar arcade present very low or practically no sexual dimorphism. Variables related to overall size of the mandible and symphysis region present a medium degree of sex differences. Finally, ramus height, and gonion and coronoid process present a high degree of sexual dimorphism (indexes of sexual dimorphism are all above 130%). Whether this marked sexual dimorphism in specific anatomical systems affects sexual differences in body size is not completely clear and further studies are needed. Sexual differences detected in the mandible of modern humans have at least two components: differences related to musculo-skeletal development and differences related to a different growth trajectory in males and females (relative development of some of the basal border features). The Atapuerca-SH mandibles display little variation in the basal border, however. The limited variation of this mandibular region may indicate that the pattern of sexual variation in H

  9. Improving image retrieval effectiveness via query expansion using MeSH hierarchical structure.

    Science.gov (United States)

    Crespo Azcárate, Mariano; Mata Vázquez, Jacinto; Maña López, Manuel

    2013-01-01

    We explored two strategies for query expansion utilizing medical subject headings (MeSH) ontology to improve the effectiveness of medical image retrieval systems. In order to achieve greater effectiveness in the expansion, the search text was analyzed to identify which terms were most amenable to being expanded. To perform the expansions we utilized the hierarchical structure by which the MeSH descriptors are organized. Two strategies for selecting the terms to be expanded in each query were studied. The first consisted of identifying the medical concepts using the unified medical language system metathesaurus. In the second strategy the text of the query was divided into n-grams, resulting in sequences corresponding to MeSH descriptors. For the evaluation of the system, we used the collection made available by the ImageCLEF organization in its 2011 medical image retrieval task. The main measure of efficiency employed for evaluating the techniques developed was the mean average precision (MAP). Both strategies exceeded the average MAP score in the ImageCLEF 2011 competition (0.1644). The n-gram expansion strategy achieved a MAP of 0.2004, which represents an improvement of 21.89% over the average MAP score in the competition. On the other hand, the medical concepts expansion strategy scored 0.2172 in the MAP, representing a 32.11% improvement. This run won the text-based medical image retrieval task in 2011. Query expansion exploiting the hierarchical structure of the MeSH descriptors achieved a significant improvement in image retrieval systems.

  10. Expression of CD38 in human neuroblastoma SH-SY5Y cells.

    Science.gov (United States)

    Orciani, M; Trubiani, O; Cavaletti, G; Guarnieri, S; Salvolini, E; Tredici, G; Di Primio, R

    2008-01-01

    Human CD38 antigen is a 42-45 kDa type II transmembrane glycoprotein with a short N-terminal cytoplasmic domain and a long C-terminal extracellular region. It is widely expressed in different cell types including thymocytes, activated T cells, and terminally differentiated B cells (plasma cells) and it is involved in cellular proliferation and adhesion. CD38 acts as an ectocyclase that converts NAD+ to the Ca2+ -releasing second messenger cyclic ADP-ribose (cADPR). It has been also demonstrated that increased extracellular levels of NAD+ and cADPR are involved in inflammatory diseases and in cellular damage, such as ischemia. In the present study, we have characterized the expression of CD38 in human neuroblastoma SH-SY5Y cell line. All-trans-retinoic acid (ATRA) treatment was used to induce cell differentiation. Our results indicate that: a) even if SH-SY5Y cells have a negative phenotype express CD38 at nuclear level, ATRA treatment does not influence this pattern; b) CD38 localizing to the nucleus may co-localize with p80-coilin positive nuclear-coiled bodies; c) purified nuclei, by Western blot determinations using anti-CD38 antibodies, display a band with a molecular mass of approximately 42 kDa; d) SH-SY5Y cells show nuclear ADP-ribosyl cyclase due to CD38 activity; e) the basal level of CD38 mRNA shows a time-dependent increase after treatment with ATRA. These results suggest that the presence of constitutive fully functional CD38 in the SH-SY5Y nucleus has some important implications for intracellular generation of cADP-ribose and subsequent nucleoplasmic calcium release.

  11. BabelMeSH: development of a cross-language tool for MEDLINE/PubMed.

    Science.gov (United States)

    Liu, Fang; Ackerman, Michael; Fontelo, Paul

    2006-01-01

    BabelMeSH is a cross-language tool for searching MEDLINE/PubMed. Queries can be submitted as single terms or complex phrases in French, Spanish and Portuguese. Citations will be sent to the user in English. It uses a smart parser interface with a medical terms database in MySQL. Preliminary evaluation using compound key words in foreign language medical journals showed an accuracy of 68%, 60% and 51% for French, Spanish and Portuguese, respectively. Development is continuing.

  12. Haplotype-specific modulation of a SOX10/CREB response element at the Charcot-Marie-Tooth disease type 4C locus SH3TC2

    NARCIS (Netherlands)

    Brewer, Megan Hwa; Ma, Ki Hwan; Beecham, Gary W.; Gopinath, Chetna; Baas, Frank; Choi, Byung-Ok; Reilly, Mary M.; Shy, Michael E.; Züchner, Stephan; Svaren, John; Antonellis, Anthony

    2014-01-01

    Loss-of-function mutations in the Src homology 3 (SH3) domain and tetratricopeptide repeats 2 (SH3TC2) gene cause autosomal recessive demyelinating Charcot-Marie-Tooth neuropathy. The SH3TC2 protein has been implicated in promyelination signaling through axonal neuregulin-1 and the ERBB2 Schwann

  13. Expression of Hypoxia-Inducible Factor-1α and Myoglobin in Rat Heart as Adaptive Response to Intermittent Hypobaric Hypoxia Exposure

    Directory of Open Access Journals (Sweden)

    Margaretha Herawati

    2017-07-01

    Full Text Available The aim of this study was to investigate the influence of intermittent hypobaric hypoxia on the expression hypoxia adaptation proteins, namely hypoxia inducibla factor-1a (HIF-1a and myoglobin (Mb. Twenty five male Sprague-Dawley rats were exposed to intermittent hypobaric hypoxia in a hypobaric chamber in Indonesian Air Force Institute of Aviation Medicine, for 49.5 minutes at various low pressure, 1 week interval for 4 times (day 1, 8, 15 and 22. HIF-1α and Mb protein were measured with ELISA. mRNA expression of Mb was measured with one step real time RT-PCR. HIF-1α protein levels increased after induction of hypobaric hypoxia and continues to decrease after induction of intermittent hypobaric hypoxia 3 times (ANOVA, p = 0.0437. mRNA expression and protein of Mb increased after induction of hypobaric hypoxia and continues to decrease after induction of intermittent hypobaric hypoxia 3 times (ANOVA, p = 0.0283; 0.0170, and both are strongly correlated (Pearson, r = 0.6307. The heart of rats adapted to intermittent hypoxia conditions by upregulation the expression of HIF-1a and myoglobin and then both return to normal level.

  14. Assessment of hypoxia-inducible factor-1α mRNA expression in mantis shrimp as a biomarker of environmental hypoxia exposure.

    Science.gov (United States)

    Kodama, Keita; Rahman, Md Saydur; Horiguchi, Toshihiro; Thomas, Peter

    2012-04-23

    Efforts to assess the ecological impacts of the marked increase in coastal hypoxia worldwide have been hampered by a lack of biomarkers of hypoxia exposure in marine benthic organisms. Here, we show that hypoxia-inducible factor-1α (HIF-1α) transcript levels in the heart and cerebral ganglion of mantis shrimp (Oratosquilla oratoria) collected from hypoxic sites in Tokyo Bay are elevated several-fold over those in shrimp collected from normoxic sites. Upregulation of HIF-1α mRNA levels in the heart after exposure to sub-lethal hypoxia was confirmed in controlled laboratory experiments. HIF-1α transcript levels were increased at approximately threefold after 7 and 14 days of hypoxia exposure and declined to control levels within 24 h of restoration to normoxic conditions. The results provide the first evidence for upregulation of HIF-1α transcript levels in two hypoxia-sensitive organs, heart and cerebral ganglion, in a marine invertebrate exposed to environmental hypoxia. These results suggest that upregulation of HIF-1α transcript levels is an important component in adaptation of mantis shrimp to chronic hypoxia and is a potentially useful biomarker of environmental hypoxia exposure.

  15. Holomorphic field realization of SH{sup c} and quantum geometry of quiver gauge theories

    Energy Technology Data Exchange (ETDEWEB)

    Bourgine, Jean-Emile [INFN Bologna, Università di Bologna,Via Irnerio 46, 40126 Bologna (Italy); Matsuo, Yutaka [Department of Physics, The University of Tokyo,Hongo 7-3-1, Bunkyo-ku, Tokyo (Japan); Zhang, Hong [Department of Physics and Center for Quantum Spacetime (CQUeST),Sogang University,35 Baekbeom-ro, Mapo-gu, Seoul 04107 (Korea, Republic of)

    2016-04-27

    In the context of 4D/2D dualities, SH{sup c} algebra, introduced by Schiffmann and Vasserot, provides a systematic method to analyse the instanton partition functions of N=2 supersymmetric gauge theories. In this paper, we rewrite the SH{sup c} algebra in terms of three holomorphic fields D{sub 0}(z), D{sub ±1}(z) with which the algebra and its representations are simplified. The instanton partition functions for arbitrary N=2 super Yang-Mills theories with A{sub n} and A{sub n}{sup (1)} type quiver diagrams are compactly expressed as a product of four building blocks, Gaiotto state, dilatation, flavor vertex operator and intertwiner which are written in terms of SH{sup c} and the orthogonal basis introduced by Alba, Fateev, Litvinov and Tarnopolskiy. These building blocks are characterized by new conditions which generalize the known ones on the Gaiotto state and the Carlsson-Okounkov vertex. Consistency conditions of the inner product give algebraic relations for the chiral ring generating functions defined by Nekrasov, Pestun and Shatashvili. In particular we show the polynomiality of the qq-characters which have been introduced as a deformation of the Yangian characters. These relations define a second quantization of the Seiberg-Witten geometry, and, accordingly, reduce to a Baxter TQ-equation in the Nekrasov-Shatashvili limit of the Omega-background.

  16. Concentration-dependent binding of CdSe quantum dots on the SH3 domain.

    Science.gov (United States)

    Bell, David R; Kang, Seung-Gu; Huynh, Tien; Zhou, Ruhong

    2017-12-21

    Quantum dots (QDs) are being used increasingly in applications for solar panels, consumer electronics, and biomedical imaging. For biomedical applications, QDs are typically coated with a biocompatible molecule for the system of interest. Experiments have indicated a QD dose-dependent and surface coating-dependent toxicity, with a portion of the toxicity being ascribed to interference with biomolecules. In this work, the interaction of trioctylphosphine oxide (TOPO) coated (CdSe) 13 QDs with the SRC homology 3 domain (SH3) protein domain are explored using molecular dynamics simulations. The results of this research agree well with experiments that show that at the lowest concentration, the QDs have little affinity for the native proline-rich motif (PRM) binding site of SH3. At higher concentrations, the QDs aggregate and increasingly prefer the PRM binding site, indicating that the normal SH3 function is impeded. This binding dependence is attributed to changes in the local density of the surface coated TOPO molecules upon aggregation. These results present possible interesting QD toxicity patterns and reveal the interdependence between dose and surface coating effects in QD toxicity.

  17. An S/H circuit with parasitics optimized for IF-sampling

    Science.gov (United States)

    Xuqiang, Zheng; Fule, Li; Zhijun, Wang; Weitao, Li; Wen, Jia; Zhihua, Wang; Shigang, Yue

    2016-06-01

    An IF-sampling S/H is presented, which adopts a flip-around structure, bottom-plate sampling technique and improved input bootstrapped switches. To achieve high sampling linearity over a wide input frequency range, the floating well technique is utilized to optimize the input switches. Besides, techniques of transistor load linearization and layout improvement are proposed to further reduce and linearize the parasitic capacitance. The S/H circuit has been fabricated in 0.18-μm CMOS process as the front-end of a 14 bit, 250 MS/s pipeline ADC. For 30 MHz input, the measured SFDR/SNDR of the ADC is 94.7 dB/68. 5dB, which can remain over 84.3 dB/65.4 dB for input frequency up to 400 MHz. The ADC presents excellent dynamic performance at high input frequency, which is mainly attributed to the parasitics optimized S/H circuit. Poject supported by the Shenzhen Project (No. JSGG20150512162029307).

  18. The role of SH3BP2 in the pathophysiology of cherubism.

    Science.gov (United States)

    Reichenberger, Ernst J; Levine, Michael A; Olsen, Bjorn R; Papadaki, Maria E; Lietman, Steven A

    2012-05-24

    Cherubism is a rare bone dysplasia that is characterized by symmetrical bone resorption limited to the jaws. Bone lesions are filled with soft fibrous giant cell-rich tissue that can expand and cause severe facial deformity. The disorder typically begins in children at ages of 2-5 years and the bone resorption and facial swelling continues until puberty; in most cases the lesions regress spontaneously thereafter. Most patients with cherubism have germline mutations in the gene encoding SH3BP2, an adapter protein involved in adaptive and innate immune response signaling. A mouse model carrying a Pro416Arg mutation in SH3BP2 develops osteopenia and expansile lytic lesions in bone and some soft tissue organs. In this review we discuss the genetics of cherubism, the biological functions of SH3BP2 and the analysis of the mouse model. The data suggest that the underlying cause for cherubism is a systemic autoinflammatory response to physiologic challenges despite the localized appearance of bone resorption and fibrous expansion to the jaws in humans.

  19. Ritual Pengikut Tarekat Shâdhilîyah di Tambak Beras, Jombang-Jawa Timur

    Directory of Open Access Journals (Sweden)

    Abdullah Safik

    2015-10-01

    Full Text Available This article tries to phenomenologically examines the existence of the Shâdhilîyah tarekat supervised by KH. Djamaluddin in Tambak Beras, Jombang. The Shâdhîlîyah tarekat, that had been initiated by Abû Hasan al-Shâdhilî, is an exceptional and consistent in holding and practicing its tawhid principle as well as dhikr rituals. In Indonesia, this tarekat has rapidly evolved. One of its murshid is KH. Abdul Jalil Mustaqim in Tulungagung, the murshid to KH. Djamaluddin. The tarekat has two main doctrines, are: firstly, ‘ubûdîyah realm where its followers are obliged to phisically and mentally obey Allah swt and His messenger, i.e. the prophet Muhammad, in all their sayings and deeds. Secondly, mu‘âmalah aspect where each follower is taught to interact with other people and creatures only for the sake of Allah. It means that the tarekat is a medium of self approaching to Allah. One of special rites (khusûsîyah conducted by this tarekat is an every-Tuesday agenda where dhikr, tawassul, tahlîl, and tahmîd activities are held. Technically, a sâlik when s/he recites dhikr should be followed by breathing in which is concentrated in the navel and going on top through thoracic cavity and coming out through the mouth then retracting it back to tongue.

  20. Laccase Gene Sh-lac Is Involved in the Growth and Melanin Biosynthesis of Scleromitrula shiraiana.

    Science.gov (United States)

    Lǚ, Zhiyuan; Kang, Xin; Xiang, Zhonghuai; He, Ningjia

    2017-03-01

    Scleromitrula shiraiana causes the popcorn disease in mulberry trees resulting in severe economic losses. Previous studies have shown that melanin may play a vital role in establishing the pathogenicity of fungi. In the present study, we identified the melanin produced in S. shiraiana belongs to DHN melanin by gas chromatography-mass spectrometry, and cloned the laccase Sh-lac, a potential DHN melanin biosynthesis gene from S. shiraiana. We obtained two stable Sh-lac silenced transformants using RNAi, ilac-4 and 8 to elucidate the DHN melanin biosynthetic pathway in S. shiraiana. The melanin production of ilac-4 and ilac-8 was significantly reduced, and their vegetative growth was also suppressed. Results such as these led to a proposal that Sh-lac played a key role in DHN melanin formation in S. shiraiana and may function differentially with other melanin biosynthetic genes. The inhibition of melanin was accompanied by the decrease of oxalic acid and the adhesion of hyphae was impaired. Our results indicated that laccase was an important enzyme in the synthesis of melanin and might play a critical role in the pathogenicity of S. shiraiana.

  1. Candida albicans SH3-domain proteins involved in hyphal growth, cytokinesis, and vacuolar morphology.

    Science.gov (United States)

    Reijnst, Patrick; Jorde, Sigyn; Wendland, Jürgen

    2010-08-01

    This report describes the analyses of three Candida albicans genes that encode Src Homology 3 (SH3)-domain proteins. Homologs in Saccharomyces cerevisiae are encoded by the SLA1, NBP2, and CYK3 genes. Deletion of CYK3 in C. albicans was not feasible, suggesting it is essential. Promoter shutdown experiments of CaCYK3 revealed cytokinesis defects, which are in line with the localization of GFP-tagged Cyk3 at septal sites. Deletion of SLA1 resulted in strains with decreased ability to form hyphal filaments. The number of cortical actin patches was strongly reduced in Deltasla1 strains during all growth stages. Sla1-GFP localizes in patches that are found concentrated at the hyphal tip. Deletion of the first two SH3-domains of Sla1 still resulted in cortical localization of the truncated protein. However, the actin cytoskeleton in this strain was aberrant like in the Deltasla1 deletion mutant indicating a function of these SH3 domains to recruit actin nucleation to sites of endocytosis. Deletion of NBP2 resulted in a defect in vacuolar fusion in hyphae. Germ cells of Deltanbp2 strains lacked a large vacuole but initiated several germ tubes. The mutant phenotypes of Deltanbp2 and Deltasla1 could be corrected by reintegration of the wild-type genes.

  2. Neuroprotective effect of Rosmarinus officinalis extract on human dopaminergic cell line, SH-SY5Y.

    Science.gov (United States)

    Park, Se-Eun; Kim, Seung; Sapkota, Kumar; Kim, Sung-Jun

    2010-07-01

    Hydrogen peroxide (H2O2) is a major Reactive Oxygen Species (ROS), which has been implicated in many neurodegenerative conditions including Parkinson's disease (PD). Rosmarinus officinalis (R. officinalis) has been reported to have various pharmacological properties including anti-oxidant activity. In this study, we investigated the neuroprotective effects of R. officinalis extract on H2O2-induced apoptosis in human dopaminergic cells, SH-SY5Y. Our results showed that H2O2-induced cytotoxicity in SH-SY5Y cells was suppressed by treatment with R. officinalis. Moreover, R. officinalis was very effective in attenuating the disruption of mitochondrial membrane potential and apoptotic cell death induced by H2O2. R. officinalis extract effectively suppressed the up-regulation of Bax, Bak, Caspase-3 and -9, and down-regulation of Bcl-2. Pretreatment with R. officinalis significantly attenuated the down-regulation of tyrosine hydroxylase (TH), and aromatic amino acid decarboxylase (AADC) gene in SH-SY5Y cells. These findings indicate that R. officinalis is able to protect the neuronal cells against H2O2-induced injury and suggest that R. officinalis might potentially serve as an agent for prevention of several human neurodegenerative diseases caused by oxidative stress and apoptosis.

  3. Emerging medical informatics research trends detection based on MeSH terms.

    Science.gov (United States)

    Lyu, Peng-Hui; Yao, Qiang; Mao, Jin; Zhang, Shi-Jing

    2015-01-01

    The aim of this study is to analyze the research trends of medical informatics over the last 12 years. A new method based on MeSH terms was proposed to identify emerging topics and trends of medical informatics research. Informetric methods and visualization technologies were applied to investigate research trends of medical informatics. The metric of perspective factor (PF) embedding MeSH terms was appropriately employed to assess the perspective quality for journals. The emerging MeSH terms have changed dramatically over the last 12 years, identifying two stages of medical informatics: the "medical imaging stage" and the "medical informatics stage". The focus of medical informatics has shifted from acquisition and storage of healthcare data by integrating computational, informational, cognitive and organizational sciences to semantic analysis for problem solving and clinical decision-making. About 30 core journals were determined by Bradford's Law in the last 3 years in this area. These journals, with high PF values, have relative high perspective quality and lead the trend of medical informatics.

  4. The role of SH3BP2 in the pathophysiology of cherubism

    Directory of Open Access Journals (Sweden)

    Reichenberger Ernst J

    2012-05-01

    Full Text Available Abstract Cherubism is a rare bone dysplasia that is characterized by symmetrical bone resorption limited to the jaws. Bone lesions are filled with soft fibrous giant cell-rich tissue that can expand and cause severe facial deformity. The disorder typically begins in children at ages of 2-5 years and the bone resorption and facial swelling continues until puberty; in most cases the lesions regress spontaneously thereafter. Most patients with cherubism have germline mutations in the gene encoding SH3BP2, an adapter protein involved in adaptive and innate immune response signaling. A mouse model carrying a Pro416Arg mutation in SH3BP2 develops osteopenia and expansile lytic lesions in bone and some soft tissue organs. In this review we discuss the genetics of cherubism, the biological functions of SH3BP2 and the analysis of the mouse model. The data suggest that the underlying cause for cherubism is a systemic autoinflammatory response to physiologic challenges despite the localized appearance of bone resorption and fibrous expansion to the jaws in humans.

  5. Hyperosmotic Stress Induces Tau Proteolysis by Caspase-3 Activation in SH-SY5Y Cells.

    Science.gov (United States)

    Olivera-Santa Catalina, Marta; Caballero-Bermejo, Montaña; Argent, Ricardo; Alonso, Juan C; Cuenda, Ana; Lorenzo, María J; Centeno, Francisco

    2016-12-01

    Tau is a microtubule-associated protein implicated in the pathogenesis of Alzheimer's disease and other related tauopathies. In this subset of neurodegenerative disorders, Tau auto-assembles into insoluble fibrils that accumulate in neurons as paired helical filaments (PHFs), promoting cellular dysfunction and cytotoxic effects. Growing evidence suggests that abnormal post-translational regulation, mainly hyperphosphorylation and aberrant cleavage, drives Tau to this pathological state. In this work we show that sorbitol-induced hyperosmotic stress promotes Tau proteolysis in SH-SY5Y neuroblastoma cells. The appearance of cleaved Tau was preceded by the activation of μ-calpain, the proteasome system and caspase-3. Tau proteolysis was completely prevented by caspase-3 inhibition but unaffected by neither the proteasome system nor μ-calpain activity blockade. Concomitantly, hyperosmotic stress induced apoptosis in SH-SY5Y cells, which was efficiently avoided by the inhibition of caspase-3 activity. Altogether, our results provide the first evidence that Tau protein is susceptible to caspase-3 proteolysis under hyperosmotic stress and suggest a positive relationship between Tau proteolysis and apoptosis in SH-SY5Y cells. J. Cell. Biochem. 117: 2781-2790, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  6. PTPN11 induces endoplasmic stress and apoptosis in SH-SY5Y cells.

    Science.gov (United States)

    Chitranshi, Nitin; Dheer, Yogita; Gupta, Veer; Abbasi, Mojdeh; Mirzaei, Mehdi; You, Yuyi; Chung, Roger; Graham, Stuart L; Gupta, Vivek

    2017-11-19

    PTPN11 is associated with regulation of growth factor signaling pathways in neuronal cells. Using SH-SY5Y neuroblastoma cells, we showed that adeno-associated virus (AAV)-mediated PTPN11 upregulation was associated with TrkB antagonism, reduced neuritogenesis and enhanced endoplasmic reticulum (ER) stress response leading to apoptotic changes. Genetic knock-down of PTPN11 on the other hand leads to increased TrkB phosphorylation in SH-SY5Y cells. ER stress response induced by PTPN11 upregulation was alleviated pharmacologically by a TrkB agonist. Conversely the enhanced ER stress response induced by TrkB receptor antagonism was ameliorated by PTPN11 suppression, providing evidence of cross-talk of PTPN11 effects with TrkB actions. BDNF treatment of neuronal cells with PTPN11 upregulation also resulted in reduced expression of ER stress protein markers. This study provides evidence of molecular interactions between PTPN11 and the TrkB receptor in SH-SY5Y cells. The results reinforce the role played by PTPN11 in regulating neurotrophin protective signaling in neuronal cells and highlight that PTPN11 dysregulation promotes apoptotic activation. Based on these findings we suggest that blocking PTPN11 could have potential beneficial effects to limit the progression of neuronal loss in neurodegenerative disorders. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

  7. Theoretical prediction of S-H bond rupture in methanethiol upon interaction with gold.

    Science.gov (United States)

    Askerka, Mikhail; Pichugina, Daria; Kuz'menko, Nikolay; Shestakov, Alexander

    2012-07-26

    Organic thiols are known to react with gold surface to form self-assembled monolayers (SAMs), which can be used to produce materials with highly attractive properties. Although the structure of various SAMs is widely investigated, some aspects of their formation still represent a matter of debate. One of these aspects is the mechanism of S-H bond dissociation in thiols upon interaction with gold. This work presents a new suggestion for this mechanism on the basis of DFT study of methanethiol interaction with a single gold atom and a Au(20) cluster. The reaction path of dissociation is found to be qualitatively independent of the model employed. However, the highest activation barrier of S-H bond dissociation on the single gold atom (12.9 kcal/mol) is considerably lower than that on the Au(20) cluster (28.9 kcal/mol), which can be attributed to the higher extent of gold unsaturation. The energy barrier of S-H cleavage decreases by 4.6 kcal/mol in the presence of the second methanethiol molecule at the same adsorption site on the model gold atom. In the case of the Au(20) cluster we have observed the phenomenon of hydrogen transfer from one methanethiol molecule to another, which allows reducing the energy barrier of dissociation by 9.1 kcal/mol. This indicates the possibility of the "relay" hydrogen transfer to be the key step of the thiol adsorption observed for the SAMs systems.

  8. Stochastic Gradient Descent and the Prediction of MeSH for PubMed Records.

    Science.gov (United States)

    Wilbur, W John; Kim, Won

    2014-01-01

    Stochastic Gradient Descent (SGD) has gained popularity for solving large scale supervised machine learning problems. It provides a rapid method for minimizing a number of loss functions and is applicable to Support Vector Machine (SVM) and Logistic optimizations. However SGD does not provide a convenient stopping criterion. Generally an optimal number of iterations over the data may be determined using held out data. Here we compare stopping predictions based on held out data with simply stopping at a fixed number of iterations and show that the latter works as well as the former for a number of commonly studied text classification problems. In particular fixed stopping works well for MeSH(®) predictions on PubMed(®) records. We also surveyed the published algorithms for SVM learning on large data sets, and chose three for comparison: PROBE, SVMperf, and Liblinear and compared them with SGD with a fixed number of iterations. We find SGD with a fixed number of iterations performs as well as these alternative methods and is much faster to compute. As an application we made SGD-SVM predictions for all MeSH terms and used the Pool Adjacent Violators (PAV) algorithm to convert these predictions to probabilities. Such probabilistic predictions lead to ranked MeSH term predictions superior to previously published results on two test sets.

  9. Assessment of Hypoxia in the Stroma of Patient-Derived Pancreatic Tumor Xenografts

    Energy Technology Data Exchange (ETDEWEB)

    Lohse, Ines; Lourenco, Corey; Ibrahimov, Emin; Pintilie, Melania [Ontario Cancer Institute and Campbell Family Cancer Research Institute, Princess Margaret Cancer Center, University Health Network, 610 University Ave., Toronto, ON M5G2M9 (Canada); Tsao, Ming-Sound [Ontario Cancer Institute and Campbell Family Cancer Research Institute, Princess Margaret Cancer Center, University Health Network, 610 University Ave., Toronto, ON M5G2M9 (Canada); Department of Pathology, University Health Network, 200 Elizabeth Street, Toronto, ON M5G2C4 (Canada); Department of Laboratory Medicine and Pathobiology, 27 King’s College Circle, University of Toronto, Toronto, ON M5S1A1 (Canada); Hedley, David W., E-mail: david.hedley@uhn.ca [Ontario Cancer Institute and Campbell Family Cancer Research Institute, Princess Margaret Cancer Center, University Health Network, 610 University Ave., Toronto, ON M5G2M9 (Canada); Departments of Medical Biophysics University of Toronto, 610 University Ave., Toronto, ON M5G2M9 (Canada); Departments of Medicine, University of Toronto, 610 University Ave., Toronto, ON M5G2M9 (Canada); Department of Medical Oncology and Hematology, Princess Margaret Cancer Center, 610 University Ave., Toronto, ON M5G2M9 (Canada)

    2014-02-26

    The unusually dense stroma of pancreatic cancers is thought to play an important role in their biological aggression. The presence of hypoxia is also considered an adverse prognostic factor. Although it is usually assumed that this is the result of effects of hypoxia on the epithelial component, it is possible that hypoxia exerts indirect effects via the tumor stroma. We therefore measured hypoxia in the stroma of a series of primary pancreatic cancer xenografts. Nine patient-derived pancreatic xenografts representing a range of oxygenation levels were labeled by immunohistochemistry for EF5 and analyzed using semi-automated pattern recognition software. Hypoxia in the tumor and stroma was correlated with tumor growth and metastatic potential. The extent of hypoxia varied from 1%–39% between the different models. EF5 labeling in the stroma ranged from 0–20% between models, and was correlated with the level of hypoxia in the tumor cell area, but not microvessel density. Tumor hypoxia correlated with spontaneous metastasis formation with the exception of one hypoxic model that showed disproportionately low levels of hypoxia in the stroma and was non-metastatic. Our results demonstrate that hypoxia exists in the stroma of primary pancreatic cancer xenografts and suggest that stromal hypoxia impacts the metastatic potential.

  10. Marine modification of terrestrial influences on Gulf hypoxia: Part II

    Directory of Open Access Journals (Sweden)

    2007-01-01

    Full Text Available This study examines potential marine modification of two classes of terrestrial influence on Gulf hypoxia: (1 the flow of nutrient-rich water from the Mississippi/Atchafalaya River Basin and (2 the massive physical, hydrological, chemical and biological change associated with the Atchafalaya’s partial capture of the Mississippi River. The latter involves repartitioning of a total flow of about 20 000 m3 sec−1, equal to that of 13 Nile Rivers, and a sediment load of 210 million metric tonnes yr−1,nearly 20 times that delivered by all of the rivers of the East Coast of the USA. Also involved is the loss of hundreds-to-thousands of years of stored nutrients and organic matter to the Gulf from enormous coastal wetland loss. This study found that the oceanography of the Gulf minimises the impact of both classes of terrestrial influence from the Mississippi River and its nearby estuaries on Gulf hypoxia. Oceanographic conditions give events associated with the Atchafalaya River a disproportionately large influence on Gulf hypoxia. A truly holistic environmental approach which includes the full effects of this highly dynamic coastal area is recommended to better understand and control Gulf hypoxia.

  11. Hypoxia stimulates invasion and migration of human cervical cancer ...

    Indian Academy of Sciences (India)

    Here we show that hypoxiaincreases tumour cell invasion and migration by the modulation of Rab11, an important molecule for vesicular trafficking.In our study, we found that Rab11, together with the activation of Rac1, could stimulate invasion and migration of cervicalcancer cell lines HeLa/SiHa in hypoxia. Activation of ...

  12. Hypoxia influences expression profile of Pleckstrin homology-like ...

    Indian Academy of Sciences (India)

    2014-05-01

    May 1, 2014 ... Furthermore, under normoxic conditions, CbPHLDA2 was constitutively expressed with varying levels in analysed tissues. Short- and long-term hypoxia exposure resulted in significant changes in the expression of CbPHLDA2 in liver, spleen, head kidney, brain and muscle in a time-dependent manner.

  13. Hypoxia as a Biomarker and for Personalized Radiation Oncology

    DEFF Research Database (Denmark)

    Vordermark, Dirk; Horsman, Michael R

    2016-01-01

    Tumor hypoxia is a clinically relevant cause of radiation resistance. Direct measurements of tumor oxygenation have been performed predominantly with the Eppendorf histograph and these have defined the reduced prognosis after radiotherapy in poorly oxygenated tumors, especially head-and-neck canc...

  14. Hypoxia stimulates invasion and migration of human cervical cancer ...

    Indian Academy of Sciences (India)

    Hao Xu

    2017-07-25

    Jul 25, 2017 ... 6Tumor Biological Therapy Institute, Xuzhou Medical University, Xuzhou, China. *Corresponding author ... Our results showed that in cervical cancer cell lines HeLa/SiHa, Rac1 activation in hypoxia could stimulate invasion and migration ..... determinant of cancer stem cell evolution. BioEssays 38 Suppl 1.

  15. Invited review: decoding the microRNA response to hypoxia

    DEFF Research Database (Denmark)

    Pocock, Roger

    2011-01-01

    into how these tiny RNA molecules function. miRNAs are 20-24 nucleotide non-coding RNA molecules that predominantly regulate transcripts of target genes through translational inhibition. Much recent interest has focused on the influence of miRNAs on homeostatic regulation, and in particular, hypoxic...... of hypoxia and discuss where future breakthroughs in this area may be made....

  16. Noninvasive monitoring of brain edema after hypoxia in newborn piglets.

    Science.gov (United States)

    Malaeb, Shadi N; Izzetoglu, Meltem; McGowan, Jane; Delivoria-Papadopoulos, Maria

    2017-12-06

    BackgroundDevelopment of cerebral edema after brain injury carries a high risk for brain damage and death. The present study tests the ability of a noninvasive cerebral edema monitoring system that uses near-infrared spectroscopy (NIRS) with water as the chromophore of interest to detect brain edema following hypoxia.MethodsVentilated piglets were exposed to hypoxia for 1 h, and then returned to normal oxygen levels for 4 h. An NIRS sensor was placed on the animal's head at baseline, and changes in light attenuation were converted to changes in H2O. Cerebral water content and aquaporin-4 protein (AQP4) expression were measured.ResultsThe system detected changes in NIRS-derived water signal as early as 2 h after hypoxia, and provided fivefold signal amplification, representing a 10% increase in brain water content and a sixfold increase in AQP4, 4 h after hypoxia. Changes in water signal correlated well with changes in cerebral water content (R=0.74) and AQP4 expression (R=0.97) in the piglet brain.ConclusionThe data show that NIRS can detect cerebral edema early in the injury process, thus providing an opportunity to initiate therapy at an earlier and more effective time-point after an insult than is available with current technology.Pediatric Research advance online publication, 6 December 2017; doi:10.1038/pr.2017.264.

  17. Flight Performance During Exposure to Acute Hypobaric Hypoxia

    NARCIS (Netherlands)

    Steinman, Yuval; van den Oord, Marieke H. A. H.; Frings-Dresen, Monique H. W.; Sluiter, Judith K.

    2017-01-01

    The purpose of the present study was to examine the influence of hypobaric hypoxia (HH) on a pilot's flight performance during exposure to simulated altitudes of 91, 3048, and 4572 m (300, 10,000, and 15,000 ft) and to monitor the pilot's physiological reactions. In a single-blinded counter-balanced

  18. Human skin hypoxia modulates cerebrovascular and autonomic functions.

    Directory of Open Access Journals (Sweden)

    Olivia Pucci

    Full Text Available Because the skin is an oxygen sensor in amphibians and mice, we thought to confirm this function also in humans. The human upright posture, however, introduces additional functional demands for the maintenance of oxygen homeostasis in which cerebral blood flow and autonomic nervous system (ANS function may also be involved. We examined nine males and three females. While subjects were breathing ambient air, at sea level, we changed gases in a plastic body-bag during two conditions of the experiment such as to induce skin hypoxia (with pure nitrogen or skin normoxia (with air. The subjects performed a test of hypoxic ventilatory drive during each condition of the experiment. We found no differences in the hypoxic ventilatory drive tests. However, ANS function and cerebral blood flow velocities were modulated by skin hypoxia and the effect was significantly greater on the left than right middle cerebral arteries. We conclude that skin hypoxia modulates ANS function and cerebral blood flow velocities and this might impact life styles and tolerance to ambient hypoxia at altitude. Thus the skin in normal humans, in addition to its numerous other functions, is also an oxygen sensor.

  19. Progressive hypoxia decouples activity and aerobic performance of skate embryos

    Science.gov (United States)

    Di Santo, Valentina; Tran, Anna H.; Svendsen, Jon C.

    2016-01-01

    Although fish population size is strongly affected by survival during embryonic stages, our understanding of physiological responses to environmental stressors is based primarily on studies of post-hatch fishes. Embryonic responses to acute exposure to changes in abiotic conditions, including increase in hypoxia, could be particularly important in species exhibiting long developmental time, as embryos are unable to select a different environment behaviourally. Given that oxygen is key to metabolic processes in fishes and aquatic hypoxia is becoming more severe and frequent worldwide, organisms are expected to reduce their aerobic performance. Here, we examined the metabolic and behavioural responses of embryos of a benthic elasmobranch fish, the little skate (Leucoraja erinacea), to acute progressive hypoxia, by measuring oxygen consumption and movement (tail-beat) rates inside the egg case. Oxygen consumption rates were not significantly affected by ambient oxygen levels until reaching 45% air saturation (critical oxygen saturation, Scrit). Below Scrit, oxygen consumption rates declined rapidly, revealing an oxygen conformity response. Surprisingly, we observed a decoupling of aerobic performance and activity, as tail-beat rates increased, rather than matching the declining metabolic rates, at air saturation levels of 55% and below. These results suggest a significantly divergent response at the physiological and behavioural levels. While skate embryos depressed their metabolic rates in response to progressive hypoxia, they increased water circulation inside the egg case, presumably to restore normoxic conditions, until activity ceased abruptly around 9.8% air saturation. PMID:27293746

  20. The problem of hypoxia, hyperoxia and hypercapnia in space physiology

    Science.gov (United States)

    Agadzhanyan, N. A.; Gramenitskiy, P. M.; Kovalenko, Y. A.; Dvorzhak, I. I.; Moravek, M.; Palash, L.

    1974-01-01

    The dynamics of basic functional systems and behavioral reactions depend on the oxygen regime of the human body when confined in pressurized compartments during space flight. Permissible concentrations of oxygen, carbon dioxide and other gases to avoid symptoms of hypoxia, hyperoxia and hypercapnia are discussed in relation to numerous human tolerance studies.