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Sample records for demonstrated significant inhibition

  1. Behaviorally inhibited individuals demonstrate significantly enhanced conditioned response acquisition under non-optimal learning conditions.

    Science.gov (United States)

    Holloway, J L; Allen, M T; Myers, C E; Servatius, R J

    2014-03-15

    Behavioral inhibition (BI) is an anxiety vulnerability factor associated with hypervigilance to novel stimuli, threat, and ambiguous cues. The progression from anxiety risk to a clinical disorder is unknown, although the acquisition of defensive learning and avoidance may be a critical feature. As the expression of avoidance is also central to anxiety development, the present study examined avoidance acquisition as a function of inhibited temperament using classical eyeblink conditioning. Individuals were classified as behaviorally inhibited (BI) or non-inhibited (NI) based on combined scores from the Adult and Retrospective Measures of Behavioural Inhibition (AMBI and RMBI, respectively). Acquisition was assessed using delay, omission, or yoked conditioning schedules of reinforcement. Omission training was identical to delay, except that the emission of an eyeblink conditioned response (CR) resulted in omission of the unconditioned airpuff stimulus (US) on that trial. Each subject in the yoked group was matched on total BI score to a subject in the omission group, and received the same schedule of CS and US delivery, resulting in a partial reinforcement training schedule. Delay conditioning elicited significantly more CRs compared to the omission and yoked contingencies, the latter two of which did not differ from each other. Thus, acquisition of an avoidance response was not apparent. BI individuals demonstrated enhanced acquisition overall, while partial reinforcement training significantly distinguished between BI and NI groups. Enhanced learning in BI may be a function of an increased defensive learning capacity, or sensitivity to uncertainty. Further work examining the influence of BI on learning acquisition is important for understanding individual differences in disorder etiology in anxiety vulnerable cohorts.

  2. [Significance of the demonstration of Actinomyces in cervical cytological smears].

    Science.gov (United States)

    Dybdahl, H; Baandrup, U

    1988-10-17

    In recent years there has been well documented evidence of a connection between adnexitis and the use of IUDs. It has also been reported that Actinomyces-caused adnexitis is often a serious precursor of tubo-ovarian abscesses which require surgical attention. The investigation included a total of 17,734 routine Pap smears taken in the pathology department over a 4-month period. The smears were screened for the presence of Actinomyces and information on type of IUD and gynecological symptoms was gathered from women testing positive for Actinomyces. Comparable information was gathered from 2 age-matched control groups. 1 group consisted of women with an IUD but without Actinomyces; the other group consisted of women without an IUD and without Actinomyces. Of the 180 patients with Actinomyces, 175 were IUD users and only 5 were nonusers. The incidence of gynecological symptoms among the patients showed increased frequency for women with Actinomyces only with regard to cervical discharge. The Nova-T IUD was found to be significantly less frequently associated with Actinomyces than the other IUDs.

  3. Coeliac disease autoantibodies mediate significant inhibition of tissue transglutaminase.

    LENUS (Irish Health Repository)

    Byrne, Greg

    2012-02-01

    The detection of antibodies directed against tissue transglutaminase (tTG) in serum is a sensitive and specific test for suspected coeliac disease. tTG is a ubiquitous, multifunctional enzyme that has been implicated in many important physiological processes as well as the site-specific deamidation of glutamine residues in gluten-derived peptides. This modification of gluten peptides facilitates their binding to HLA-DQ2, which results in amplification of the T-cell response to gluten. The purpose of this study was to investigate the possibility that patient IgA autoantibodies directed against tTG interfere with the crosslinking activity of the enzyme. IgA autoantibodies against tTG were isolated\\/depleted from patient serum and tested for their capacity to interfere with tTG activity in vitro using a sensitive fluorescence-based activity assay. We have demonstrated that autoantibodies cause significant inhibition of tTG-mediated crosslinking at equimolar and 2:1 ratios of antibody to enzyme.

  4. Selective IRAK4 Inhibition Attenuates Disease in Murine Lupus Models and Demonstrates Steroid Sparing Activity.

    Science.gov (United States)

    Dudhgaonkar, Shailesh; Ranade, Sourabh; Nagar, Jignesh; Subramani, Siva; Prasad, Durga Shiv; Karunanithi, Preethi; Srivastava, Ratika; Venkatesh, Kamala; Selvam, Sabariya; Krishnamurthy, Prasad; Mariappan, T Thanga; Saxena, Ajay; Fan, Li; Stetsko, Dawn K; Holloway, Deborah A; Li, Xin; Zhu, Jun; Yang, Wen-Pin; Ruepp, Stefan; Nair, Satheesh; Santella, Joseph; Duncia, John; Hynes, John; McIntyre, Kim W; Carman, Julie A

    2017-02-01

    The serine/threonine kinase IL-1R-associated kinase (IRAK)4 is a critical regulator of innate immunity. We have identified BMS-986126, a potent, highly selective inhibitor of IRAK4 kinase activity that demonstrates equipotent activity against multiple MyD88-dependent responses both in vitro and in vivo. BMS-986126 failed to inhibit assays downstream of MyD88-independent receptors, including the TNF receptor and TLR3. Very little activity was seen downstream of TLR4, which can also activate an MyD88-independent pathway. In mice, the compound inhibited cytokine production induced by injection of several different TLR agonists, including those for TLR2, TLR7, and TLR9. The compound also significantly suppressed skin inflammation induced by topical administration of the TLR7 agonist imiquimod. BMS-986126 demonstrated robust activity in the MRL/lpr and NZB/NZW models of lupus, inhibiting multiple pathogenic responses. In the MRL/lpr model, robust activity was observed with the combination of suboptimal doses of BMS-986126 and prednisolone, suggesting the potential for steroid sparing activity. BMS-986126 also demonstrated synergy with prednisolone in assays of TLR7- and TLR9-induced IFN target gene expression using human PBMCs. Lastly, BMS-986126 inhibited TLR7- and TLR9-dependent responses using cells derived from lupus patients, suggesting that inhibition of IRAK4 has the potential for therapeutic benefit in treating lupus. Copyright © 2017 by The American Association of Immunologists, Inc.

  5. Environmental Assessment and Finding of No Significant Impact: Kalina Geothermal Demonstration Project Steamboat Springs, Nevada

    Energy Technology Data Exchange (ETDEWEB)

    N/A

    1999-02-22

    The Department of Energy (DOE) has prepared an Environmental Assessment (EA) to provide the DOE and other public agency decision makers with the environmental documentation required to take informed discretionary action on the proposed Kalina Geothermal Demonstration project. The EA assesses the potential environmental impacts and cumulative impacts, possible ways to minimize effects associated with partial funding of the proposed project, and discusses alternatives to DOE actions. The DOE will use this EA as a basis for their decision to provide financial assistance to Exergy, Inc. (Exergy), the project applicant. Based on the analysis in the EA, DOE has determined that the proposed action is not a major Federal action significantly affecting the quality of the human or physical environment, within the meaning of the National Environmental Policy Act (NEPA) of 1969. Therefore, the preparation of an environmental impact statement is not required and DOE is issuing this Finding of No Significant Impact (FONSI).

  6. Pharmacological kynurenine 3-monooxygenase enzyme inhibition significantly reduces neuropathic pain in a rat model.

    Science.gov (United States)

    Rojewska, Ewelina; Piotrowska, Anna; Makuch, Wioletta; Przewlocka, Barbara; Mika, Joanna

    2016-03-01

    Recent studies have highlighted the involvement of the kynurenine pathway in the pathology of neurodegenerative diseases, but the role of this system in neuropathic pain requires further extensive research. Therefore, the aim of our study was to examine the role of kynurenine 3-monooxygenase (Kmo), an enzyme that is important in this pathway, in a rat model of neuropathy after chronic constriction injury (CCI) to the sciatic nerve. For the first time, we demonstrated that the injury-induced increase in the Kmo mRNA levels in the spinal cord and the dorsal root ganglia (DRG) was reduced by chronic administration of the microglial inhibitor minocycline and that this effect paralleled a decrease in the intensity of neuropathy. Further, minocycline administration alleviated the lipopolysaccharide (LPS)-induced upregulation of Kmo mRNA expression in microglial cell cultures. Moreover, we demonstrated that not only indirect inhibition of Kmo using minocycline but also direct inhibition using Kmo inhibitors (Ro61-6048 and JM6) decreased neuropathic pain intensity on the third and the seventh days after CCI. Chronic Ro61-6048 administration diminished the protein levels of IBA-1, IL-6, IL-1beta and NOS2 in the spinal cord and/or the DRG. Both Kmo inhibitors potentiated the analgesic properties of morphine. In summary, our data suggest that in neuropathic pain model, inhibiting Kmo function significantly reduces pain symptoms and enhances the effectiveness of morphine. The results of our studies show that the kynurenine pathway is an important mediator of neuropathic pain pathology and indicate that Kmo represents a novel pharmacological target for the treatment of neuropathy.

  7. Hits identified in library screening demonstrate selective CYP17A1 lyase inhibition.

    Science.gov (United States)

    Krug, Sebastian J; Hu, Qingzhong; Hartmann, Rolf W

    2013-03-01

    A screening of structurally different steroid hormone synthesis inhibitors was performed in order to find a starting point for the development of a new inhibitor of the bifunctional steroidogenic enzyme CYP17A1. Emphasis was placed on determination of selectivity between the two catalytic steps, namely 17α-hydroxylase and C(17,20)-lyase. For that purpose a new inhibition assay has been developed. Hits identified within this novel assay demonstrated selective inhibition of CYP17A1 lyase activity, and thus mark the basis for the development of selective C(17,20)-lyase inhibitors for the treatment of prostate cancer.

  8. Cross-species analysis of thyroperoxidase inhibition by xenobiotics demonstrates conservation of response between pig and rat.

    Science.gov (United States)

    Paul, Katie B; Hedge, Joan M; Macherla, Chitralekha; Filer, Dayne L; Burgess, Emily; Simmons, Steven O; Crofton, Kevin M; Hornung, Michael W

    2013-10-04

    Thyroperoxidase (TPO), the enzyme that catalyzes the synthesis of thyroid hormone, is a known target for thyroid-disrupting chemicals. In vivo toxicological evidence supporting TPO-inhibition as one molecular-initiating event that leads to thyroid disruption is derived largely from rat models; however, a significant fraction of research on the inhibition of TPO by xenobiotics has been conducted using porcine TPO. The current work tested the hypothesis that porcine and rat thyroid microsomes exposed to TPO-inhibiting chemicals would demonstrate different responses in a guaiacol oxidation assay. A primary objective of this work is to establish the degree of concordance between rat and porcine TPO inhibition data. Microsomes were isolated from both rat and pig thyroid glands, and the guaiacol oxidation assay was performed for a training set of 12 chemicals, including previously reported TPO inhibitors, thyroid-disrupting chemicals thought to perturb other targets, and several previously untested chemicals, to determine the relative TPO inhibition responses across species. Concentration-response curves were derived for methimazole (MMI), dibutylphthalate (DBP), diethylhexylphthalate (DEHP), diethylphthalate (DEP), 3,5-dimethylpyrazole-1-methanol (DPM), iopanoic acid (IOA), 2-mercaptobenzothiazole (MBT), sodium perchlorate (PERC), p-nonylphenol (PNP), 4-propoxyphenol (4POP), 6-propylthiouracil (PTU), and triclosan (TCS). MMI, PTU, MBT, DPM, 4POP, and at extremely high concentrations, PERC, inhibited TPO activity. Results demonstrated a strong qualitative concordance of response between the two species. All chemicals that inhibited TPO in porcine microsomes also inhibited TPO in rat microsomes. Hill model-derived IC50 values revealed approximate 1.5- to 50-fold differences in relative potency to MMI between species for positive chemicals. DPM, MBT, 4POP, and PTU exhibited greater relative potency to MMI using rat TPO versus porcine TPO, but rank order potency for

  9. Risperidone significantly inhibits interferon-gamma-induced microglial activation in vitro.

    Science.gov (United States)

    Kato, Takahiro; Monji, Akira; Hashioka, Sadayuki; Kanba, Shigenobu

    2007-05-01

    Microglia has recently been regarded to be a mediator of neuroinflammation via the release of proinflammatory cytokines, nitric oxide (NO) and reactive oxygen species (ROS) in the central nervous system (CNS). Microglia has thus been reported to play an important role in the pathology of neurodegenerative disease, such as Alzheimer's disease (AD) and Parkinson's disease (PD). The pathological mechanisms of schizophrenia remain unclear while some recent neuroimaging studies suggest even schizophrenia may be a kind of neurodegenerative disease. Risperidone has been reported to decrease the reduction of MRI volume during the clinical course of schizophrenia. Many recent studies have demonstrated that immunological mechanisms via such as interferon (IFN)-gamma and cytokines might be relevant to the pathophysiology of schizophrenia. In the present study, we thus investigated the effects of risperidone on the generation of nitric oxide, inducible NO synthase (iNOS) expression and inflammatory cytokines: interleukin (IL)-1beta, IL-6 and tumor necrosis factor (TNF)-alpha by IFN-gamma-activated microglia by using Griess assay, Western blotting and ELISA, respectively. In comparison with haloperidol, risperidone significantly inhibited the production of NO and proinflammatory cytokines by activated microglia. The iNOS levels of risperidone-treated cells were much lower than those of the haloperidol-treated cells. Antipsychotics, especially risperidone may have an anti-inflammatory effect via the inhibition of microglial activation, which is not only directly toxic to neurons but also has an inhibitory effect on neurogenesis and oligodendrogenesis, both of which have been reported to play a crucial role in the pathology of schizophrenia.

  10. The demonstration of significant ferroelectricity in epitaxial Y-doped HfO2 film

    OpenAIRE

    Takao Shimizu; Kiliha Katayama; Takanori Kiguchi; Akihiro Akama; Konno, Toyohiko J.; Osami Sakata; Hiroshi Funakubo

    2016-01-01

    Ferroelectricity and Curie temperature are demonstrated for epitaxial Y-doped HfO2 film grown on (110) yttrium oxide-stabilized zirconium oxide (YSZ) single crystal using Sn-doped In2O3 (ITO) as bottom electrodes. The XRD measurements for epitaxial film enabled us to investigate its detailed crystal structure including orientations of the film. The ferroelectricity was confirmed by electric displacement filed – electric filed hysteresis measurement, which revealed saturated polarization of 16...

  11. Significance of coronary artery calcification demonstrated by computed tomography in detecting coronary artery stenosis

    Energy Technology Data Exchange (ETDEWEB)

    Shiraki, Teruo; Akiyama, Yoko; Kita, Masahide [Iwakuni national Hospital, Yamaguchi (Japan)] [and others

    2002-02-01

    Serial 27 patients with angina attack were enrolled in this trial. Plain computed tomography (CT) of the chest and coronary angiogram were performed simultaneously. Calcification of main branch of coronary arteies (left main trunk, left anterior desending artery, left circumflex artery, right coronary artery) was judged visually. More than 50% stenosis was defined significant by quantitative coronary angiogram. Correlation between calcified lesions detected by CT and angiographic stenoses showed high specificity and negative predictive value was also high (sensitity=58%, specificity=80%, positive predictive value=27%, negative predictive value=94%, p<0.05). There was no significant correlation between patients with calcification of corornary artery and angiographic stenosis. The present study showed the low probability of significant stenosis without calcification and the high probability with multiple calcified lesions. (author)

  12. [Diagnostic significance of the spinal-brain stem polysynaptic reflex and the period of inhibition].

    Science.gov (United States)

    Ivanichev, G A

    1985-01-01

    Electrical stimulation of the radial nerve associated with voluntary contraction of the shoulder girdle inhibited bioelectrical activity not only in the muscles of the hypothenar but also in the proximal muscles. In resting muscles, such stimulation elicited a reflex response with a large latent period. With weak voluntary tension stimulation elicited a reflex response while in the presence of considerable contraction the reflex response merged with bioelectrical activity, with a clearly demonstrable subsequent period of inhibition. The current viewpoint about the antidromal blockade of the segmental motoneurons is debated. It is suggested that the polysynaptic reflex and the inhibition period are connected with the same level of realization -- the oral portions of the brain stem.

  13. The demonstration of significant ferroelectricity in epitaxial Y-doped HfO2 film

    Science.gov (United States)

    Shimizu, Takao; Katayama, Kiliha; Kiguchi, Takanori; Akama, Akihiro; Konno, Toyohiko J.; Sakata, Osami; Funakubo, Hiroshi

    2016-09-01

    Ferroelectricity and Curie temperature are demonstrated for epitaxial Y-doped HfO2 film grown on (110) yttrium oxide-stabilized zirconium oxide (YSZ) single crystal using Sn-doped In2O3 (ITO) as bottom electrodes. The XRD measurements for epitaxial film enabled us to investigate its detailed crystal structure including orientations of the film. The ferroelectricity was confirmed by electric displacement filed – electric filed hysteresis measurement, which revealed saturated polarization of 16 μC/cm2. Estimated spontaneous polarization based on the obtained saturation polarization and the crystal structure analysis was 45 μC/cm2. This value is the first experimental estimations of the spontaneous polarization and is in good agreement with the theoretical value from first principle calculation. Curie temperature was also estimated to be about 450 °C. This study strongly suggests that the HfO2-based materials are promising for various ferroelectric applications because of their comparable ferroelectric properties including polarization and Curie temperature to conventional ferroelectric materials together with the reported excellent scalability in thickness and compatibility with practical manufacturing processes.

  14. Novel stable isotope analyses demonstrate significant rates of glucose cycling in mouse pancreatic islets.

    Science.gov (United States)

    Wall, Martha L; Pound, Lynley D; Trenary, Irina; O'Brien, Richard M; Young, Jamey D

    2015-06-01

    A polymorphism located in the G6PC2 gene, which encodes an islet-specific glucose-6-phosphatase catalytic subunit, is the most important common determinant of variations in fasting blood glucose (FBG) levels in humans. Studies of G6pc2 knockout (KO) mice suggest that G6pc2 represents a negative regulator of basal glucose-stimulated insulin secretion (GSIS) that acts by hydrolyzing glucose-6-phosphate (G6P), thereby reducing glycolytic flux. However, this conclusion conflicts with the very low estimates for the rate of glucose cycling in pancreatic islets, as assessed using radioisotopes. We have reassessed the rate of glucose cycling in pancreatic islets using a novel stable isotope method. The data show much higher levels of glucose cycling than previously reported. In 5 mmol/L glucose, islets from C57BL/6J chow-fed mice cycled ∼16% of net glucose uptake. The cycling rate was further increased at 11 mmol/L glucose. Similar cycling rates were observed using islets from high fat-fed mice. Importantly, glucose cycling was abolished in G6pc2 KO mouse islets, confirming that G6pc2 opposes the action of the glucose sensor glucokinase by hydrolyzing G6P. The demonstration of high rates of glucose cycling in pancreatic islets explains why G6pc2 deletion enhances GSIS and why variants in G6PC2 affect FBG in humans. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

  15. Clinically significant CYP2C inhibition by noscapine but not by glucosamine.

    Science.gov (United States)

    Rosenborg, S; Stenberg, M; Otto, S; Ostervall, J; Masquelier, M; Yue, Q-Y; Bertilsson, L; Eliasson, E

    2010-09-01

    Noscapine and glucosamine reportedly interact with warfarin. We investigated the effects of these drugs on various cytochrome P450 (CYP) activity markers. Twelve healthy subjects were phenotyped at baseline and during separate treatments with noscapine and glucosamine. Whereas glucosamine had no significant effect on CYP activity, noscapine caused marked inhibition of CYP2C9 (4.9-fold increase in urinary losartan/E3174 ratio) and CYP2C19 (3.6-fold increase in the plasma omeprazole/5-hydroxyomeprazole ratio). Noscapine-dependent inhibition of CYP2C9 may explain the interaction with warfarin.

  16. Inhibition of human copper trafficking by a small molecule significantly attenuates cancer cell proliferation

    Science.gov (United States)

    Wang, Jing; Luo, Cheng; Shan, Changliang; You, Qiancheng; Lu, Junyan; Elf, Shannon; Zhou, Yu; Wen, Yi; Vinkenborg, Jan L.; Fan, Jun; Kang, Heebum; Lin, Ruiting; Han, Dali; Xie, Yuxin; Karpus, Jason; Chen, Shijie; Ouyang, Shisheng; Luan, Chihao; Zhang, Naixia; Ding, Hong; Merkx, Maarten; Liu, Hong; Chen, Jing; Jiang, Hualiang; He, Chuan

    2015-12-01

    Copper is a transition metal that plays critical roles in many life processes. Controlling the cellular concentration and trafficking of copper offers a route to disrupt these processes. Here we report small molecules that inhibit the human copper-trafficking proteins Atox1 and CCS, and so provide a selective approach to disrupt cellular copper transport. The knockdown of Atox1 and CCS or their inhibition leads to a significantly reduced proliferation of cancer cells, but not of normal cells, as well as to attenuated tumour growth in mouse models. We show that blocking copper trafficking induces cellular oxidative stress and reduces levels of cellular ATP. The reduced level of ATP results in activation of the AMP-activated protein kinase that leads to reduced lipogenesis. Both effects contribute to the inhibition of cancer cell proliferation. Our results establish copper chaperones as new targets for future developments in anticancer therapies.

  17. Inhibition of human copper trafficking by a small molecule significantly attenuates cancer cell proliferation.

    Science.gov (United States)

    Wang, Jing; Luo, Cheng; Shan, Changliang; You, Qiancheng; Lu, Junyan; Elf, Shannon; Zhou, Yu; Wen, Yi; Vinkenborg, Jan L; Fan, Jun; Kang, Heebum; Lin, Ruiting; Han, Dali; Xie, Yuxin; Karpus, Jason; Chen, Shijie; Ouyang, Shisheng; Luan, Chihao; Zhang, Naixia; Ding, Hong; Merkx, Maarten; Liu, Hong; Chen, Jing; Jiang, Hualiang; He, Chuan

    2015-12-01

    Copper is a transition metal that plays critical roles in many life processes. Controlling the cellular concentration and trafficking of copper offers a route to disrupt these processes. Here we report small molecules that inhibit the human copper-trafficking proteins Atox1 and CCS, and so provide a selective approach to disrupt cellular copper transport. The knockdown of Atox1 and CCS or their inhibition leads to a significantly reduced proliferation of cancer cells, but not of normal cells, as well as to attenuated tumour growth in mouse models. We show that blocking copper trafficking induces cellular oxidative stress and reduces levels of cellular ATP. The reduced level of ATP results in activation of the AMP-activated protein kinase that leads to reduced lipogenesis. Both effects contribute to the inhibition of cancer cell proliferation. Our results establish copper chaperones as new targets for future developments in anticancer therapies.

  18. Significance of bacterial flora in abdominal irradiation-induced inhibition of lung metastases

    Energy Technology Data Exchange (ETDEWEB)

    Matsumoto, T.; Ando, K.; Koike, S.

    1988-06-01

    We have previously reported that abdominal irradiation prior to i.v. injection of syngeneic tumor cells reduced metastases in lung. Our report described an investigation of the significance of intestinal organisms in the radiation effect. We found that eliminating intestinal organisms with antibiotics totally abolished the radiation effect. Monoassociation of germ-free mice revealed that the radiation effect was observable only for Enterobacter cloacae, never for Streptococcus faecium, Bifidobacterium adlesentis, or Escherichia coli. After abdominal irradiation of regular mice, E. cloacae multiplied in cecal contents, adhered to mucous membranes, invaded the cecal wall, and translocated to mesenteric lymph nodes. Intravenous administration of E. cloacae in place of abdominal irradiation inhibited metastases. E. cloacae-monoassociated mice developed fewer metastases than germ-free mice, and the reduction was further enhanced by abdominal irradiation. We concluded that abdominal irradiation caused the invasion of E. cloacae from the mucous membrane of the intestine and inhibited formation of lung metastases.

  19. Pioneers in CNS inhibition: 1. Ivan M. Sechenov, the first to clearly demonstrate inhibition arising in the brain.

    Science.gov (United States)

    Stuart, Douglas G; Schaefer, Andreas T; Massion, Jean; Graham, Brett A; Callister, Robert J

    2014-02-22

    This article reviews the contributions of Ivan Michailovich Sechenov [1829-1905] to the neurophysiological concept of central inhibition. He first studied this concept in the frog and on himself. Later his trainees extended the study of central inhibition to other mammalian species. Outside his own country, Sechenov is better known for his prescient contributions to physiological psychology. In Russia, however, he is also revered as "the father of Russian physiology," because of his contributions to neurophysiology and other aspects of physiology including blood gases and respiration, the physiology and biomechanics of movement, and general physiology concepts that appeared in his textbooks and later works he helped translate from largely German sources. After graduation from Moscow University Medical School in 1856 he spent 3½ years in Germany and Austria where he attended lectures and conducted research under the direction of several prominent physiologists and biochemists. In his subsequent academic career he held positions at universities in St. Petersburg (1860-1870; 1876-1888), Odessa (1871-1876) and Moscow (1890-1905). From 1860 onwards he was acclaimed as a physiologist in academic circles. He was also well known in Russian society for his public lectures on physiology and his views on physiological psychology. The latter resulted in him being branded "politically unreliable" by the tsarist bureaucracy from 1863 onwards. Sechenov's first (1862) study on central inhibition remains his most memorable. He delayed the withdrawal of a frog's foot from a weak acid solution by chemical or electrical stimulation of selected parts of the central nervous system. He also noted similar effects on his own hand during co-activation of other sensory inputs by tickling or teeth gnashing.

  20. Pinelliae Rhizoma, a Toxic Chinese Herb, Can Significantly Inhibit CYP3A Activity in Rats

    Directory of Open Access Journals (Sweden)

    Jinjun Wu

    2015-01-01

    Full Text Available Raw Pinelliae Rhizoma (RPR is a representative toxic herb that is widely used for eliminating phlegm or treating cough and vomiting. Given its irritant toxicity, its processed products, including Pinelliae Rhizoma Praeparatum (PRP and Pinelliae Rhizoma Praeparatum cum Zingibere et Alumine (PRPZA, are more commonly applied and administered concomitantly with other chemical drugs, such as cough medications. This study aimed to investigate the effects of RPR, PRP, and PRPZA on CYP3A activity. Testosterone (Tes and buspirone (BP were used as specific probe substrates ex vivo and in vivo, respectively. CYP3A activity was determined by the metabolite formation ratios from the substrates. Ex vivo results show that the metabolite formation ratios from Tes significantly decreased, indicating that RPR, PRP, and PRPZA could inhibit CYP3A activity in rats. CYP3A protein and mRNA levels were determined to explore the underlying mechanism. These levels showed marked and consistent down-regulation with CYP3A activity. A significant decrease in metabolite formation ratios from BP was also found in PRPZA group in vivo, implying that PRPZA could inhibit CYP3A activity. Conclusively, co-administration of PR with other CYP3A-metabolizing drugs may cause drug–drug interactions. Clinical use of PR-related formulae should be monitored carefully to avoid adverse interactions.

  1. Inhibition of class IIb histone deacetylase significantly improves cloning efficiency in mice.

    Science.gov (United States)

    Ono, Tetsuo; Li, Chong; Mizutani, Eiji; Terashita, Yukari; Yamagata, Kazuo; Wakayama, Teruhiko

    2010-12-01

    Since the first mouse clone was produced by somatic cell nuclear transfer, the success rate of cloning in mice has been extremely low. Some histone deacetylase inhibitors, such as trichostatin A and scriptaid, have improved the full-term development of mouse clones significantly, but the mechanisms allowing for this are unclear. Here, we found that two other specific inhibitors, suberoylanilide hydroxamic acid and oxamflatin, could also reduce the rate of apoptosis in blastocysts, improve the full-term development of cloned mice, and increase establishment of nuclear transfer-generated embryonic stem cell lines significantly without leading to obvious abnormalities. However, another inhibitor, valproic acid, could not improve cloning efficiency. Suberoylanilide hydroxamic acid, oxamflatin, trichostatin A, and scriptaid are inhibitors for classes I and IIa/b histone deacetylase, whereas valproic acid is an inhibitor for classes I and IIa, suggesting that inhibiting class IIb histone deacetylase is an important step for reprogramming mouse cloning efficiency.

  2. The CO2 inhibition of terrestrial isoprene emission significantly affects future ozone projections

    Directory of Open Access Journals (Sweden)

    J. A. Pyle

    2008-11-01

    Full Text Available Simulations of future tropospheric composition often include substantial increases in biogenic isoprene emissions arising from the Arrhenius-like leaf emission response and warmer surface temperatures, and from enhanced vegetation productivity in response to temperature and atmospheric CO2 concentration. However, a number of recent laboratory and field data have suggested a direct inhibition of leaf isoprene production by increasing atmospheric CO2 concentration, notwithstanding isoprene being produced from precursor molecules that include some of the primary products of carbon assimilation. The cellular mechanism that underlies the decoupling of leaf photosynthesis and isoprene production still awaits a full explanation but accounting for this observation in a dynamic vegetation model that contains a semi-mechanistic treatment of isoprene emissions has been shown to change future global isoprene emission estimates notably. Here we use these estimates in conjunction with a chemistry-climate model to compare the effects of isoprene simulations without and with a direct CO2-inhibition on late 21st century O3 and OH levels. The impact on surface O3 was significant. Including the CO2-inhibition of isoprene resulted in opposing responses in polluted (O3 decreases of up to 10 ppbv vs. less polluted (O3 increases of up to 10 ppbv source regions, due to isoprene nitrate and peroxy acetyl nitrate (PAN chemistry. OH concentration increased with relatively lower future isoprene emissions, decreasing methane lifetime by ~7 months. Our simulations underline the large uncertainties in future chemistry and climate studies due to biogenic emission patterns and emphasize the problems of using globally averaged climate metrics to quantify the atmospheric impact of reactive, heterogeneously distributed substances.

  3. The CO2 inhibition of terrestrial isoprene emission significantly affects future ozone projections

    Science.gov (United States)

    Young, P. J.; Arneth, A.; Schurgers, G.; Zeng, G.; Pyle, J. A.

    2009-04-01

    Simulations of future tropospheric composition often include substantial increases in biogenic isoprene emissions arising from the Arrhenius-like leaf emission response and warmer surface temperatures, and from enhanced vegetation productivity in response to temperature and atmospheric CO2 concentration. However, a number of recent laboratory and field data have suggested a direct inhibition of leaf isoprene production by increasing atmospheric CO2 concentration, notwithstanding isoprene being produced from precursor molecules that include some of the primary products of carbon assimilation. The cellular mechanism that underlies the decoupling of leaf photosynthesis and isoprene production still awaits a full explanation but accounting for this observation in a dynamic vegetation model that contains a semi-mechanistic treatment of isoprene emissions has been shown to change future global isoprene emission estimates notably. Here we use these estimates in conjunction with a chemistry-climate model to compare the effects of isoprene simulations without and with a direct CO2-inhibition on late 21st century O3 and OH levels. The impact on surface O3 was significant. Including the CO2-inhibition of isoprene resulted in opposing responses in polluted (O3 decreases of up to 10 ppbv) vs. less polluted (O3 increases of up to 10 ppbv) source regions, due to isoprene nitrate and peroxy acetyl nitrate (PAN) chemistry. OH concentration increased with relatively lower future isoprene emissions, decreasing methane lifetime by ~7 months (6.6%). Our simulations underline the large uncertainties in future chemistry and climate studies due to biogenic emission patterns and emphasize the problems of using globally averaged climate metrics (such as global radiative forcing) to quantify the atmospheric impact of reactive, heterogeneously distributed substances.

  4. Marine organism sulfated polysaccharides exhibiting significant antimalarial activity and inhibition of red blood cell invasion by Plasmodium.

    Science.gov (United States)

    Marques, Joana; Vilanova, Eduardo; Mourão, Paulo A S; Fernàndez-Busquets, Xavier

    2016-04-13

    The antimalarial activity of heparin, against which there are no resistances known, has not been therapeutically exploited due to its potent anticoagulating activity. Here, we have explored the antiplasmodial capacity of heparin-like sulfated polysaccharides from the sea cucumbers Ludwigothurea grisea and Isostichopus badionotus, from the red alga Botryocladia occidentalis, and from the marine sponge Desmapsamma anchorata. In vitro experiments demonstrated for most compounds significant inhibition of Plasmodium falciparum growth at low-anticoagulant concentrations. This activity was found to operate through inhibition of erythrocyte invasion by Plasmodium, likely mediated by a coating of the parasite similar to that observed for heparin. In vivo four-day suppressive tests showed that several of the sulfated polysaccharides improved the survival of Plasmodium yoelii-infected mice. In one animal treated with I. badionotus fucan parasitemia was reduced from 10.4% to undetectable levels, and Western blot analysis revealed the presence of antibodies against P. yoelii antigens in its plasma. The retarded invasion mediated by sulfated polysaccharides, and the ensuing prolonged exposure of Plasmodium to the immune system, can be explored for the design of new therapeutic approaches against malaria where heparin-related polysaccharides of low anticoagulating activity could play a dual role as drugs and as potentiators of immune responses.

  5. Marine organism sulfated polysaccharides exhibiting significant antimalarial activity and inhibition of red blood cell invasion by Plasmodium

    Science.gov (United States)

    Marques, Joana; Vilanova, Eduardo; Mourão, Paulo A. S.; Fernàndez-Busquets, Xavier

    2016-01-01

    The antimalarial activity of heparin, against which there are no resistances known, has not been therapeutically exploited due to its potent anticoagulating activity. Here, we have explored the antiplasmodial capacity of heparin-like sulfated polysaccharides from the sea cucumbers Ludwigothurea grisea and Isostichopus badionotus, from the red alga Botryocladia occidentalis, and from the marine sponge Desmapsamma anchorata. In vitro experiments demonstrated for most compounds significant inhibition of Plasmodium falciparum growth at low-anticoagulant concentrations. This activity was found to operate through inhibition of erythrocyte invasion by Plasmodium, likely mediated by a coating of the parasite similar to that observed for heparin. In vivo four-day suppressive tests showed that several of the sulfated polysaccharides improved the survival of Plasmodium yoelii-infected mice. In one animal treated with I. badionotus fucan parasitemia was reduced from 10.4% to undetectable levels, and Western blot analysis revealed the presence of antibodies against P. yoelii antigens in its plasma. The retarded invasion mediated by sulfated polysaccharides, and the ensuing prolonged exposure of Plasmodium to the immune system, can be explored for the design of new therapeutic approaches against malaria where heparin-related polysaccharides of low anticoagulating activity could play a dual role as drugs and as potentiators of immune responses. PMID:27071342

  6. Adaptive management of the Great Barrier Reef: a globally significant demonstration of the benefits of networks of marine reserves.

    Science.gov (United States)

    McCook, Laurence J; Ayling, Tony; Cappo, Mike; Choat, J Howard; Evans, Richard D; De Freitas, Debora M; Heupel, Michelle; Hughes, Terry P; Jones, Geoffrey P; Mapstone, Bruce; Marsh, Helene; Mills, Morena; Molloy, Fergus J; Pitcher, C Roland; Pressey, Robert L; Russ, Garry R; Sutton, Stephen; Sweatman, Hugh; Tobin, Renae; Wachenfeld, David R; Williamson, David H

    2010-10-26

    The Great Barrier Reef (GBR) provides a globally significant demonstration of the effectiveness of large-scale networks of marine reserves in contributing to integrated, adaptive management. Comprehensive review of available evidence shows major, rapid benefits of no-take areas for targeted fish and sharks, in both reef and nonreef habitats, with potential benefits for fisheries as well as biodiversity conservation. Large, mobile species like sharks benefit less than smaller, site-attached fish. Critically, reserves also appear to benefit overall ecosystem health and resilience: outbreaks of coral-eating, crown-of-thorns starfish appear less frequent on no-take reefs, which consequently have higher abundance of coral, the very foundation of reef ecosystems. Effective marine reserves require regular review of compliance: fish abundances in no-entry zones suggest that even no-take zones may be significantly depleted due to poaching. Spatial analyses comparing zoning with seabed biodiversity or dugong distributions illustrate significant benefits from application of best-practice conservation principles in data-poor situations. Increases in the marine reserve network in 2004 affected fishers, but preliminary economic analysis suggests considerable net benefits, in terms of protecting environmental and tourism values. Relative to the revenue generated by reef tourism, current expenditure on protection is minor. Recent implementation of an Outlook Report provides regular, formal review of environmental condition and management and links to policy responses, key aspects of adaptive management. Given the major threat posed by climate change, the expanded network of marine reserves provides a critical and cost-effective contribution to enhancing the resilience of the Great Barrier Reef.

  7. Inhibition of an aquatic rhabdovirus demonstrates promise of a broad-spectrum antiviral for use in aquaculture

    Science.gov (United States)

    Balmer, Bethany F.; Powers, Rachel L.; Zhang, Ting-Hu; Lee, Jihye; Vigant, Frederic; Lee, Benhur; Jung, Michael E.; Purcell, Maureen K.; Snekvik, Kevin; Aguilar, Hector C.

    2017-01-01

    Many enveloped viruses cause devastating disease in aquaculture, resulting in significant economic impact. LJ001 is a broad-spectrum antiviral compound that inhibits enveloped virus infections by specifically targeting phospholipids in the lipid bilayer via the production of singlet oxygen (1O2). This stabilizes positive curvature and decreases membrane fluidity, which inhibits virus-cell membrane fusion during viral entry. Based on data from previous mammalian studies and the requirement of light for the activation of LJ001, we hypothesized that LJ001 may be useful as a preventative and/or therapeutic agent for infections by enveloped viruses in aquaculture. Here, we report that LJ001 was more stable with a prolonged inhibitory half-life at relevant aquaculture temperatures (15°C), than in mammalian studies at 37°C. When LJ001 was preincubated with our model virus, infectious hematopoietic necrosis virus (IHNV), infectivity was significantly inhibited in vitro (using the epithelioma papulosum cyprini [EPC] fish cell line) and in vivo (using rainbow trout fry) in a dose-dependent and time-dependent manner. While horizontal transmission of IHNV in a static cohabitation challenge model was reduced by LJ001, transmission was not completely blocked at established antiviral doses. Therefore, LJ001 may be best suited as a therapeutic for aquaculture settings that include viral infections with lower virus-shedding rates than IHNV or where higher viral titers are required to initiate infection of naive fish. Importantly, our data also suggest that LJ001-inactivated IHNV elicited an innate immune response in the rainbow trout host, making LJ001 potentially useful for future vaccination approaches.

  8. Cycloartane-3,24,25-triol inhibits MRCKα kinase and demonstrates promising anti prostate cancer activity in vitro

    Directory of Open Access Journals (Sweden)

    Lowe Henry I C

    2012-11-01

    Full Text Available Abstract Background Given the high occurrence of prostate cancer worldwide and one of the major sources of the discovery of new lead molecules being medicinal plants, this research undertook to investigate the possible anti-cancer activity of two natural cycloartanes; cycloartane-3,24,25-diol (extracted in our lab from Tillandsia recurvata and cycloartane-3,24,25-triol (purchased. The inhibition of MRCKα kinase has emerged as a potential solution to restoring the tight regulation of normal cellular growth, the loss of which leads to cancer cell formation. Methods Kinase inhibition was investigated using competition binding (to the ATP sites assays which have been previously established and authenticated and cell proliferation was measured using the WST-1 assay. Results Cycloartane-3,24,25-triol demonstrated strong selectivity towards the MRCKα kinase with a Kd50 of 0.26 μM from a total of 451 kinases investigated. Cycloartane-3,24,25-triol reduced the viability of PC-3 and DU145 cell lines with IC50 values of 2.226 ± 0.28 μM and 1.67 ± 0.18 μM respectively. Conclusions These results will prove useful in drug discovery as Cycloartane-3,24,25-triol has shown potential for development as an anti-cancer agent against prostate cancer.

  9. Orienting response elicitation by personally significant information under subliminal stimulus presentation: demonstration using the concealed information test.

    Science.gov (United States)

    Maoz, Keren; Breska, Assaf; Ben-Shakhar, Gershon

    2012-12-01

    Considerable evidence suggests that subliminal information can trigger cognitive and neural processes. Here, we examined whether elicitation of orienting response by personally significant (PS) verbal information requires conscious awareness of the input. Subjects were exposed to the Concealed Information Test (CIT), in which autonomic responses for autobiographical items are typically larger than for control items. These items were presented subliminally using two different masking protocols: single or multiple presentation of the masked item. An objective test was used to verify unawareness to the stimuli. As predicted, PS items elicited significantly stronger skin conductance responses than the control items in both exposure conditions. The results extend previous findings showing that autonomic responses can be elicited following subliminal exposure to aversive information, and also may have implications on the applied usage of the CIT.

  10. A clip-based protocol for breast boost radiotherapy provides clear target visualisation and demonstrates significant volume reduction over time

    Energy Technology Data Exchange (ETDEWEB)

    Lewis, Lorraine [Department of Radiation Oncology, Northern Sydney Cancer Centre, Royal North Shore Hospital, Sydney, New South Wales (Australia); Cox, Jennifer [Department of Radiation Oncology, Northern Sydney Cancer Centre, Royal North Shore Hospital, Sydney, New South Wales (Australia); Faculty of Health Sciences, University of Sydney, Sydney, New South Wales (Australia); Morgia, Marita [Department of Radiation Oncology, Northern Sydney Cancer Centre, Royal North Shore Hospital, Sydney, New South Wales (Australia); Atyeo, John [Faculty of Health Sciences, University of Sydney, Sydney, New South Wales (Australia); Lamoury, Gillian [Department of Radiation Oncology, Northern Sydney Cancer Centre, Royal North Shore Hospital, Sydney, New South Wales (Australia)

    2015-09-15

    The clinical target volume (CTV) for early stage breast cancer is difficult to clearly identify on planning computed tomography (CT) scans. Surgical clips inserted around the tumour bed should help to identify the CTV, particularly if the seroma has been reabsorbed, and enable tracking of CTV changes over time. A surgical clip-based CTV delineation protocol was introduced. CTV visibility and its post-operative shrinkage pattern were assessed. The subjects were 27 early stage breast cancer patients receiving post-operative radiotherapy alone and 15 receiving post-operative chemotherapy followed by radiotherapy. The radiotherapy alone (RT/alone) group received a CT scan at median 25 days post-operatively (CT1rt) and another at 40 Gy, median 68 days (CT2rt). The chemotherapy/RT group (chemo/RT) received a CT scan at median 18 days post-operatively (CT1ch), a planning CT scan at median 126 days (CT2ch), and another at 40 Gy (CT3ch). There was no significant difference (P = 0.08) between the initial mean CTV for each cohort. The RT/alone cohort showed significant CTV volume reduction of 38.4% (P = 0.01) at 40 Gy. The Chemo/RT cohort had significantly reduced volumes between CT1ch: median 54 cm{sup 3} (4–118) and CT2ch: median 16 cm{sup 3}, (2–99), (P = 0.01), but no significant volume reduction thereafter. Surgical clips enable localisation of the post-surgical seroma for radiotherapy targeting. Most seroma shrinkage occurs early, enabling CT treatment planning to take place at 7 weeks, which is within the 9 weeks recommended to limit disease recurrence.

  11. Chemical-genetic inhibition of a sensitized mutant myosin Vb demonstrates a role in peripheral-pericentriolar membrane traffic

    OpenAIRE

    Provance, D. William; Gourley, Christopher R.; Silan, Colleen M.; Cameron, L. C.; Kevan M Shokat; Goldenring, James R.; Shah, Kavita; Gillespie, Peter G.; John A. Mercer

    2004-01-01

    Selective, in situ inhibition of individual unconventional myosins is a powerful approach to determine their specific physiological functions. Here, we report the engineering of a myosin Vb mutant that still hydrolyzes ATP, yet is selectively sensitized to an N6-substituted ADP analog that inhibits its activity, causing it to remain tightly bound to actin. Inhibition of the sensitized mutant causes inhibition of accumulation of transferrin in the cytoplasm and increases levels of plasma-membr...

  12. Chemical-genetic inhibition of a sensitized mutant myosin Vb demonstrates a role in peripheral-pericentriolar membrane traffic.

    Science.gov (United States)

    Provance, D William; Gourley, Christopher R; Silan, Colleen M; Cameron, L C; Shokat, Kevan M; Goldenring, James R; Shah, Kavita; Gillespie, Peter G; Mercer, John A

    2004-02-17

    Selective, in situ inhibition of individual unconventional myosins is a powerful approach to determine their specific physiological functions. Here, we report the engineering of a myosin Vb mutant that still hydrolyzes ATP, yet is selectively sensitized to an N(6)-substituted ADP analog that inhibits its activity, causing it to remain tightly bound to actin. Inhibition of the sensitized mutant causes inhibition of accumulation of transferrin in the cytoplasm and increases levels of plasma-membrane transferrin receptor, suggesting that myosin Vb functions in traffic between peripheral and pericentrosomal compartments.

  13. Nitration of Tyrosine Residue Y10 of Aβ1-42 Significantly Inhibits Its Aggregation and Cytotoxicity.

    Science.gov (United States)

    Zhao, Jie; Wu, Jinming; Yang, Zhen; Li, Hailing; Gao, Zhonghong

    2017-04-17

    Amyloid-β plaques and oxidative stress are the major hallmarks of Alzheimer's disease. Our previous study found that the heme-Aβ complex enhanced the catalytic effect of free heme on protein tyrosine nitration in the presence of hydrogen peroxide (H2O2) and nitrite (NO2(-)). Y10 in Aβ could be the first target to be nitrated. We also found that nitration of Aβ1-40 significantly decreased its aggregation. However, a contrary report showed that nitration of Aβ1-42 by peroxynitrite enhanced its aggregation. To rule out the interference of peroxynitrite caused Aβ oxidation, we used synthetic Y10 nitrated Aβ1-42 to study the influence of Y10 nitration on Aβ1-42's aggregation and cytotoxicity in this study. We confirmed that Aβ1-42 could be nitrated in the presence of H2O2, NO2(-), and heme by dot blotting. CD spectroscopy showed an increase of β-sheet structure of Aβ1-42 and its mutants. The thioflavin T (ThT) flourescence assay revealed that both nitration and chlorination significantly inhibited Aβ1-42 fibril formation. TEM and AFM observations of Aβ peptide aggregates further confirmed that Y10 modification inhibited Aβ1-42 fibril formation. The cytotoxicity study of native and modified Aβ peptides on SH-SY5Y cells revealed that nitration of Aβ1-42 remarkably decreased the neurotoxicity of Aβ1-42. On the basis of these results, we hypothesized that nitration of Y10 may block the π-π stacking interactions of Aβ1-42 so that it inhibit its aggregation and neurotoxicity. More importantly, considerable evidence suggested that the levels of nitrite plus nitrate significantly decreased in the brain of AD patients. Thus, we believe that these findings would be helpful for further understanding the function of Aβ in AD.

  14. [Biochemical demonstration of HCO3--und Cl--dependent ATPase activities in the rectum of larval dragonflies and inhibition of rectal chloride uptake by thiocyanate (author's transl)].

    Science.gov (United States)

    Komnick, H; Schmitz, M; Hinssen, H

    1980-02-01

    Hydrogencarbonate and chloride activated, ouabain-insensitive ATPase activities are demonstrated in the salt-absorbing rectum of larval dragonflies. Maximal activation is achieved at approx. 30 mM HCO3- and 20 mM Cl-, respectively. The stimulation of each anion obeys Michaelis-Menten kinetics Km values are 4.65 mM for HCO3-- and 10.25 mM for Cl--activation. The activating anion of one type of ATPase simultaneously exerts an inhibitory effect on the other. Cl--activation is also reduced by Mg.ATP in concentrations above 0.5 mM and by Tris-Hepes buffer exceeding 2.5 mM. Both anion-dependent ATPase activities are found enriched in subcellular membraneous fractions of the rectum. Thiocyanate inhibits both activities and causes a significant decrease in rectal uptake of radioactive chloride from hypo-osmotic external solution. In the case of HCO3- dependent ATPase a competitive inhibition as SCN- was found with an inhibitor constant of Ki=0.5 mM.

  15. Inhibition of Mycobacterium tuberculosis Glutamine Synthetase as a Novel Antibiotic Strategy against Tuberculosis: Demonstration of Efficacy In Vivo

    OpenAIRE

    2003-01-01

    Tuberculosis remains one of humankind's greatest killers, and new therapeutic strategies are needed to combat the causative agent, Mycobacterium tuberculosis, which is rapidly developing resistance to conventional antibiotics. Using the highly demanding guinea pig model of pulmonary tuberculosis, we have investigated the feasibility of inhibiting M. tuberculosis glutamine synthetase (GS), an enzyme that plays a key role in both nitrogen metabolism and cell wall biosynthesis, as a novel antibi...

  16. Compounds from Terminalia mantaly L. (Combretaceae Stem Bark Exhibit Potent Inhibition against Some Pathogenic Yeasts and Enzymes of Metabolic Significance

    Directory of Open Access Journals (Sweden)

    Marthe Aimée Tchuente Tchuenmogne

    2017-01-01

    Full Text Available Background: Pathogenic yeasts resistance to current drugs emphasizes the need for new, safe, and cost-effective drugs. Also, new inhibitors are needed to control the effects of enzymes that are implicated in metabolic dysfunctions such as cancer, obesity, and epilepsy. Methods: The anti-yeast extract from Terminalia mantaly (Combretaceae was fractionated and the structures of the isolated compounds established by means of spectroscopic analysis and comparison with literature data. Activity was assessed against Candida albicans, C. parapsilosis and C. krusei using the microdilution method, and against four enzymes of metabolic significance: glucose-6-phosphate dehydrogenase, human erythrocyte carbonic anhydrase I and II, and glutathione S-transferase. Results: Seven compounds, 3,3′-di-O-methylellagic acid 4′-O-α-rhamnopyranoside; 3-O-methylellagic acid; arjungenin or 2,3,19,23-tetrahydroxyolean-12-en-28-oïc acid; arjunglucoside or 2,3,19,23-tetrahydroxyolean-12-en-28-oïc acid glucopyranoside; 2α,3α,24-trihydroxyolean-11,13(18-dien-28-oïc acid; stigmasterol; and stigmasterol 3-O-β-d-glucopyranoside were isolated from the extract. Among those, 3,3′-di-O-methylellagic acid 4′-O-α-rhamnopyranoside, 3-O-methylellagic acid, and arjunglucoside showed anti-yeast activity comparable to that of reference fluconazole with minimal inhibitory concentrations (MIC below 32 µg/mL. Besides, Arjunglucoside potently inhibited the tested enzymes with 50% inhibitory concentrations (IC50 below 4 µM and inhibitory constant (Ki <3 µM. Conclusions: The results achieved indicate that further SAR studies will likely identify potent hit derivatives that should subsequently enter the drug development pipeline.

  17. Statistics Related Self-Efficacy A Confirmatory Factor Analysis Demonstrating a Significant Link to Prior Mathematics Experiences for Graduate Level Students

    Directory of Open Access Journals (Sweden)

    Karen Larwin

    2014-02-01

    Full Text Available The present study examined students' statistics-related self-efficacy, as measured with the current statistics self-efficacy (CSSE inventory developed by Finney and Schraw (2003. Structural equation modeling was used to check the confirmatory factor analysis of the one-dimensional factor of CSSE. Once confirmed, this factor was used to test whether a significant link to prior mathematics experiences exists. Additionally a new post-structural equation modeling (SEM application was employed to compute error-free latent variable score for CSSE in an effort to examine the ancillary effects of gender, age, ethnicity, department, degree level, hours completed, expected course grade, number of college-level math classes, current GPA on students' CSSE scores. Results support the one-dimensional construct and as expected, the model demonstrated a significant link between CSSE scores and prior mathematics experiences to CSSE. Additionally the students' department, expected grade, and number of prior math classes were found to have a significant effect on student's CSSE scores.

  18. Chick RGS2L demonstrates concentration-dependent selectivity for pertussis toxin-sensitive and -insensitive pathways that inhibit L-type Ca2+ channels.

    Science.gov (United States)

    Tosetti, Patrizia; Parente, Valeria; Taglietti, Vanni; Dunlap, Kathleen; Toselli, Mauro

    2003-05-15

    In neuronal cells, the influx of Ca2+ ions through voltage-dependent L-type calcium (L) channels couples excitation to multiple cellular functions. In addition to voltage, several neurotransmitters, hormones and cytokines regulate L channel gating via binding to G-protein-coupled receptors. Intracellular molecules that modify G-protein activity - such as regulator of G-protein-signalling (RGS) proteins - are therefore potential candidates for regulating Ca2+ influx through L channels. Here we show that a novel RGS2 splice variant from chick dorsal root ganglion (DRG) neurons, RGS2L, reduces bradykinin (BK)-mediated inhibition of neuronal L channels and accelerates recovery from inhibition. Chick RGS2 reduces the inhibition mediated by both the pertussis toxin (PTX)-sensitive (Gi/o-coupled) and the PTX-insensitive (presumably Gq/11-coupled) pathways. However, we demonstrate for the first time in a living cell that the extent of coupling to each pathway varies with RGS2L concentration. A low concentration of recombinant chick RGS2L (10 nM) preferentially reduces the inhibition mediated by the PTX-insensitive pathway, whereas a 100-fold higher concentration attenuates both PTX-sensitive- and PTX-insensitive-mediated components equally. Our data suggest that factors promoting RGS2L gene induction may regulate Ca2+ influx through L channels by recruiting low-affinity interactions with Gi/o that are absent at basal RGS2L levels.

  19. Significant reduction of the antiatherogenic effect of estrogen by long-term inhibition of nitric oxide synthesis in cholesterol-clamped rabbits.

    Science.gov (United States)

    Holm, P; Korsgaard, N; Shalmi, M; Andersen, H L; Hougaard, P; Skouby, S O; Stender, S

    1997-01-01

    The purpose of this study was to investigate whether endothelium-derived nitric oxide (NO) is involved in the plasma lipid-independent antiatherogenic effect of estrogen and levormeloxifene, a partial estrogen receptor agonist. 85 rabbits were ovariectomized and balloon-injured in the middle thoracic aorta. The rabbits were fed a cholesterol-enriched diet supplemented with 17beta-estradiol, levormeloxifene, or placebo, either alone, or together with 160 microg/ml NG-nitro- -arginine methyl ester (-NAME), an NO synthase inhibitor, in their drinking water for 12 wk. Plasma cholesterol was maintained at 25-30 mmol/liter by individualized cholesterol feeding. In the undamaged aorta, the extent of atherosclerosis in the estrogen group was only one-third that in the placebo group. Simultaneous administration of -NAME, however, significantly reduced the antiatherogenic effect of estrogen (P < 0.01). There was no significant difference between the placebo group given -NAME and the group treated with placebo alone. At the previously endothelium-denuded site, estrogen had no effect on atherosclerosis development, whereas -NAME combined with estrogen significantly increased atherogenesis (P < 0.05). The effects of levormeloxifene were almost similar to those of estrogen. Active vascular concentrations of -NAME were demonstrated in an additional study, in which maximal aortic/coronary endothelium-dependent relaxation was significantly inhibited in rabbits given -NAME. Thus, in this study a considerable part of the plasma lipid-independent antiatherogenic effect of estrogen was mediated through its effect on endothelial NO in cholesterol-fed rabbits. The results for levormeloxifene suggest a common mechanism of action for estrogen and partial estrogen receptor agonists on atherogenesis. PMID:9259581

  20. P-glycoprotein-170 inhibition significantly reduces cortisol and ciclosporin efflux from human intestinal epithelial cells and T lymphocytes.

    Science.gov (United States)

    Farrell, R J; Menconi, M J; Keates, A C; Kelly, C P

    2002-05-01

    To assess the role of P-glycoprotein-170 (P-gp) in transporting cortisol and ciclosporin from human intestinal epithelium and T lymphocytes. The effect of P-gp inhibitors (verapamil, 0-100 microM; PSC 833, 0-20 microM) on the intracellular accumulation of 3H-cortisol and 3H-ciclosporin was studied in confluent layers of human Caco-2 cells (n=6), a P-gp-dependent absorptive intestinal epithelial cell phenotype, and moderately resistant MDRhigh CEM/VBL 100 T cells (n=6). The transport of 3H-vinblastine, a strong multidrug resistance (MDR) substrate, and 3H-progesterone, a poor MDR substrate, was also studied. Caco-2 cells had a 2.4-, 6.6-, 6.7- and 1.03-fold higher net basal to apical transport (efflux) of 3H-cortisol, 3H-ciclosporin, 3H-vinblastine and 3H-progesterone, respectively. PSC 833 (20 microM) reduced cortisol efflux by 69% (0.23 +/- 0.04 to 0.07 +/- 0.01 pmol/cm2/h, P 0.1 microM) and verapamil (> 1 microM) restored the intracellular level of 3H-cortisol and 3H-ciclosporin in MDRhigh CEM/VBL 100 T cells to that of MDRlow CEM cells with little change in accumulation in the MDRlow parental cell line. P-gp inhibitors significantly increase intracellular cortisol and ciclosporin levels in human intestinal epithelium and T lymphocytes in a dose-dependent manner, demonstrating a potential mechanism for overcoming poor response to immunosuppressant therapy in refractory inflammatory bowel disease.

  1. Inhibition of basophil histamine release by gangliosides. Further studies on the significance of cell membrane sialic acid in the histamine release process

    DEFF Research Database (Denmark)

    Jensen, C; Norn, S; Thastrup, Ole

    1987-01-01

    with the glucolipid mixture increased the sialic acid content of the cells, and this increase was attributed to an insertion of gangliosides into the cell membrane. The inhibition of histamine release was abolished by increasing the calcium concentration, which substantiates our previous findings that cell membrane......Histamine release from human basophils was inhibited by preincubation of the cells with a glucolipid mixture containing sialic acid-containing gangliosides. This was true for histamine release induced by anti-IgE, Concanavalin A and the calcium ionophore A23187, whereas the release induced by S....... aureus Wood 46 was not affected. It was demonstrated that the inhibitory capacity of the glucolipid mixture could be attributed to the content of gangliosides, since no inhibition was obtained with cerebrosides or with gangliosides from which sialic acid was removed. Preincubation of the cells...

  2. Interactions outside the proteinase-binding loop contribute significantly to the inhibition of activated coagulation factor XII by its canonical inhibitor from corn.

    Science.gov (United States)

    Korneeva, Vera A; Trubetskov, Mikhail M; Korshunova, Alena V; Lushchekina, Sofya V; Kolyadko, Vladimir N; Sergienko, Olga V; Lunin, Vladimir G; Panteleev, Mikhail A; Ataullakhanov, Fazoil I

    2014-05-16

    Activated factor XII (FXIIa) is selectively inhibited by corn Hageman factor inhibitor (CHFI) among other plasma proteases. CHFI is considered a canonical serine protease inhibitor that interacts with FXIIa through its protease-binding loop. Here we examined whether the protease-binding loop alone is sufficient for the selective inhibition of serine proteases or whether other regions of a canonical inhibitor are involved. Six CHFI mutants lacking different N- and C-terminal portions were generated. CHFI-234, which lacks the first and fifth disulfide bonds and 11 and 19 amino acid residues at the N and C termini, respectively, exhibited no significant changes in FXIIa inhibition (Ki = 3.2 ± 0.4 nm). CHFI-123, which lacks 34 amino acid residues at the C terminus and the fourth and fifth disulfide bridges, inhibited FXIIa with a Ki of 116 ± 16 nm. To exclude interactions outside the FXIIa active site, a synthetic cyclic peptide was tested. The peptide contained residues 20-45 (Protein Data Bank code 1BEA), and a C29D substitution was included to avoid unwanted disulfide bond formation between unpaired cysteines. Surprisingly, the isolated protease-binding loop failed to inhibit FXIIa but retained partial inhibition of trypsin (Ki = 11.7 ± 1.2 μm) and activated factor XI (Ki = 94 ± 11 μm). Full-length CHFI inhibited trypsin with a Ki of 1.3 ± 0.2 nm and activated factor XI with a Ki of 5.4 ± 0.2 μm. Our results suggest that the protease-binding loop is not sufficient for the interaction between FXIIa and CHFI; other regions of the inhibitor also contribute to specific inhibition.

  3. Practical lesson of Photosynthesis: A demonstration of Hill reaction in chloroplasts with energy dissipation by fluorescence upon photosystems uncoupling or inhibition by Diuron herbicide

    Directory of Open Access Journals (Sweden)

    Vadim Ravara Viviani

    2016-05-01

    Full Text Available During photosynthesis, the photochemical electron transfer process is easily demonstrated by the Hill reaction, where artificial electron acceptors are reduced by active chloroplasts suspensions in the presence of light.  However, the destiny of luminous energy absorbed by chlorophyll molecules in uncoupled or damaged photosystems is not usually demonstrated. Here we provide an adaptation of the classical Hill reaction using intact spinach chloroplasts, which includes the visualization of energy dissipation by fluorescence in lysed chloroplasts, and a dose/effect response in photosystems inhibited by the herbicide DCMU. This laboratory lesson, which is aimed to biochemistry and biophysics for undergraduate courses of Chemistry, Biological, Environmental and Agricultural Sciences, provides the basic photochemical principles using the classical Hill reaction, and photophysical principles through the visualization of energy dissipation by chlorophyll fluorescence,  improving the understanding of the photosynthetic process, and introducing the concept of fluorescence and its applications as bioanalytical tool to monitor photosynthesis in plants and vegetal ecosystems.

  4. Inhibition of tumor progression during allergic airway inflammation in a murine model: significant role of TGF-β.

    Science.gov (United States)

    Tirado-Rodriguez, Belen; Baay-Guzman, Guillermina; Hernandez-Pando, Rogelio; Antonio-Andres, Gabriela; Vega, Mario I; Rocha-Zavaleta, Leticia; Bonifaz, Laura C; Huerta-Yepez, Sara

    2015-09-01

    TGF-β is an important mediator of pulmonary allergic inflammation, and it has been recently reported to be a potential inhibitor of lung tumor progression. The correlation between cancer and allergic inflammatory diseases remains controversial. Thus, the aim of the present study was to evaluate the effects of pulmonary allergic inflammation and in particular the role of TGF-β on cancer progression. Cancer cells were implanted in a BALB/c mice model of allergic airway inflammation, and tumor growth was measured. Apoptosis was evaluated by TUNEL assay, and TGF-β was measured by ELISA. Expression of proliferating cell nuclear antigen, TGF-β, TGF-β receptors I and II, phospho-Smad2 and phospho-Smad4 was evaluated by immunohistochemistry and quantified using digital pathology. The effect of a TGF-β activity inhibitor and recombinant TGF-β on tumor growth was analyzed. The effect of exogenous TGF-β on cell proliferation and apoptosis was evaluated in vitro. Mice with allergic airway inflammation exhibited decreased tumor volumes due to cell proliferation inhibition and increased apoptosis. TGF-β was increased in the sera and tumor tissues of allergic mice. TGF-β activity inhibition increased tumor progression in allergic mice by enhancing proliferation and decreasing apoptosis of tumor cells. The administration of TGF-β resulted in reduced tumor growth. This study is the first to establish an inverse relationship between allergic airway inflammation and tumor progression. This effect appears to be mediated by TGF-β, which is overexpressed in tumor cells during pulmonary allergic inflammation. This study indicates that TGF-β is a potential target for antitumor therapy.

  5. Fusion of protegrin-1 and plectasin to MAP30 shows significant inhibition activity against dengue virus replication.

    Directory of Open Access Journals (Sweden)

    Hussin A Rothan

    Full Text Available Dengue virus (DENV broadly disseminates in tropical and sub-tropical countries and there are no vaccine or anti-dengue drugs available. DENV outbreaks cause serious economic burden due to infection complications that requires special medical care and hospitalization. This study presents a new strategy for inexpensive production of anti-DENV peptide-fusion protein to prevent and/or treat DENV infection. Antiviral cationic peptides protegrin-1 (PG1 and plectasin (PLSN were fused with MAP30 protein to produce recombinant antiviral peptide-fusion protein (PG1-MAP30-PLSN as inclusion bodies in E. coli. High yield production of PG1-MAP30-PLSN protein was achieved by solubilization of inclusion bodies in alkaline buffer followed by the application of appropriate refolding techniques. Antiviral PG1-MAP30-PLSN protein considerably inhibited DENV protease (NS2B-NS3pro with half-maximal inhibitory concentration (IC50 0.5±0.1 μM. The real-time proliferation assay (RTCA and the end-point proliferation assay (MTT assay showed that the maximal-nontoxic dose of the peptide-fusion protein against Vero cells is approximately 0.67±0.2 μM. The cell-based assays showed considerable inhibition of the peptide-fusion protein against binding and proliferating stages of DENV2 into the target cells. The peptide-fusion protein protected DENV2-challeged mice with 100% of survival at the dose of 50 mg/kg. In conclusion, producing recombinant antiviral peptide-fusion protein by combining short antiviral peptide with a central protein owning similar activity could be useful to minimize the overall cost of short peptide production and take advantage of its synergistic antiviral activities.

  6. Inhibition of histamine-mediated signaling confers significant protection against severe malaria in mouse models of disease

    Science.gov (United States)

    Beghdadi, Walid; Porcherie, Adeline; Schneider, Bradley S.; Dubayle, David; Peronet, Roger; Huerre, Michel; Watanabe, Takeshi; Ohtsu, Hiroshi; Louis, Jacques; Mécheri, Salaheddine

    2008-01-01

    From the inoculation of Plasmodium sporozoites via Anopheles mosquito bites to the development of blood-stage parasites, a hallmark of the host response is an inflammatory reaction characterized by elevated histamine levels in the serum and tissues. Given the proinflammatory and immunosuppressive activities associated with histamine, we postulated that this vasoactive amine participates in malaria pathogenesis. Combined genetic and pharmacologic approaches demonstrated that histamine binding to H1R and H2R but not H3R and H4R increases the susceptibility of mice to infection with Plasmodium. To further understand the role of histamine in malaria pathogenesis, we used histidine decarboxylase–deficient (HDC−/−) mice, which are free of histamine. HDC−/− mice were highly resistant to severe malaria whether infected by mosquito bites or via injection of infected erythrocytes. HDC−/− mice displayed resistance to two lethal strains: Plasmodium berghei (Pb) ANKA, which triggers cerebral malaria (CM), and Pb NK65, which causes death without neurological symptoms. The resistance of HDC−/− mice to CM was associated with preserved blood–brain barrier integrity, the absence of infected erythrocyte aggregation in the brain vessels, and a lack of sequestration of CD4 and CD8 T cells. We demonstrate that histamine-mediated signaling contributes to malaria pathogenesis. Understanding the basis for these biological effects of histamine during infection may lead to novel therapeutic strategies to alleviate the severity of malaria. PMID:18227221

  7. Two new proanthocyanidin trimers isolated from Cistus incanus L. demonstrate potent anti-inflammatory activity and selectivity to cyclooxygenase isoenzymes inhibition.

    Science.gov (United States)

    Mansoor, K A; Matalka, K Z; Qa'dan, F S; Awad, R; Schmidt, M

    2016-09-01

    Two new proanthocyanidin trimers have been isolated from Cistus incanus herb; gallocatechin-(4α→6)-gallocatechin-(4α→8)-gallocatechin (compound 1) and epigallocatechin-3-O-gallate-(4ß→8)-epigallocatechin-3-O-gallate-(4ß→8)-gallocatechin (compound 2). The structures were determined on the basis of 1D- and 2D-NMR (HSQC, HMBC) of their peracetylated derivatives, MALDI-TOF-MS and by acid-catalysed degradation with phloroglucinol. A more abundant proanthocyanidin oligomer was also isolated, purified and its chemical constitution studied by (13)C-NMR and phloroglucinol degradation. The mean molecular weight of the polymer was estimated to be about 7 to 8 flavan-3-ol-units with a ratio of procyanidin : prodelphinidin units at 1:5, some of which are derivatised by gallic acid. Water extract and higher oligomeric proanthocyanidin fractions of C. incanus significantly inhibited TPA-induced oedema when applied topically at doses of 0.5 and 1 mg/ear in mice. Furthermore, the extracts and the pure compounds inhibited COX-1 and COX-2 activities. In addition, compound 2 exhibited an IC50 of 4.5 μM against COX-2 indicating its high selectivity towards COX-2.

  8. Targeting CXCR1/2 Significantly Reduces Breast Cancer Stem Cell Activity and Increases the Efficacy of Inhibiting HER2 via HER2-dependent and -independent Mechanisms

    Science.gov (United States)

    Singh, Jagdeep K.; Farnie, Gillian; Bundred, Nigel J.; Simões, Bruno M; Shergill, Amrita; Landberg, Göran; Howell, Sacha; Clarke, Robert B.

    2012-01-01

    Purpose Breast cancer stem-like cells (CSCs) are an important therapeutic target as they are predicted to be responsible for tumour initiation, maintenance and metastases. Interleukin-8 (IL-8) is upregulated in breast cancer and associated with poor prognosis. Breast cancer cell line studies indicate that IL-8 via its cognate receptors, CXCR1 and CXCR2, is important in regulating breast CSC activity. We investigated the role of IL-8 in the regulation of CSC activity using patient-derived breast cancers and determined the potential benefit of combining CXCR1/2 inhibition with HER2-targeted therapy. Experimental design CSC activity of metastatic and invasive human breast cancers (n=19) was assessed ex vivo using the mammosphere colony forming assay. Results Metastatic fluid IL-8 level correlated directly with mammosphere formation (r=0.652; P<0.05; n=10). Recombinant IL-8 directly increased mammosphere formation/self-renewal in metastatic and invasive breast cancers (n=17). IL-8 induced activation of EGFR/HER2 and downstream signalling pathways and effects were abrogated by inhibition of SRC, EGFR/HER2, PI3K or MEK. Furthermore, lapatinib inhibited the mammosphere-promoting effect of IL-8 in both HER2-positive and negative patient-derived cancers. CXCR1/2 inhibition also blocked the effect of IL-8 on mammosphere formation and added to the efficacy of lapatinib in HER2-positive cancers. Conclusions These studies establish a role for IL-8 in the regulation of patient-derived breast CSC activity and demonstrate that IL-8/CXCR1/2 signalling is partly mediated via a novel SRC and EGFR/HER2-dependent pathway. Combining CXCR1/2 inhibitors with current HER2-targeted therapies has potential as an effective therapeutic strategy to reduce CSC activity in breast cancer and improve the survival of HER2-positive patients. PMID:23149820

  9. Development of an in vitro assay and demonstration of Plasmodium berghei liver-stage inhibition by TRAP-specific CD8+ T cells.

    Directory of Open Access Journals (Sweden)

    Rhea J Longley

    Full Text Available The development of an efficacious vaccine against the Plasmodium parasite remains a top priority. Previous research has demonstrated the ability of a prime-boost virally vectored sub-unit vaccination regimen, delivering the liver-stage expressed malaria antigen TRAP, to produce high levels of antigen-specific T cells. The liver-stage of malaria is the main target of T cell-mediated immunity, yet a major challenge in assessing new T cell inducing vaccines has been the lack of a suitable pre-clinical assay. We have developed a flow-cytometry based in vitro T cell killing assay using a mouse hepatoma cell line, Hepa1-6, and Plasmodium berghei GFP expressing sporozoites. Using this assay, P. berghei TRAP-specific CD8+ T cell enriched splenocytes were shown to inhibit liver-stage parasites in an effector-to-target ratio dependent manner. Further development of this assay using human hepatocytes and P. falciparum would provide a new method to pre-clinically screen vaccine candidates and to elucidate mechanisms of protection in vitro.

  10. Arborvitae (Thuja plicata essential oil significantly inhibited critical inflammation- and tissue remodeling-related proteins and genes in human dermal fibroblasts

    Directory of Open Access Journals (Sweden)

    Xuesheng Han

    2017-06-01

    Full Text Available Arborvitae (Thuja plicata essential oil (AEO is becoming increasingly popular in skincare, although its biological activity in human skin cells has not been investigated. Therefore, we sought to study AEO's effect on 17 important protein biomarkers that are closely related to inflammation and tissue remodeling by using a pre-inflamed human dermal fibroblast culture model. AEO significantly inhibited the expression of vascular cell adhesion molecule 1 (VCAM-1, intracellular cell adhesion molecule 1 (ICAM-1, interferon gamma-induced protein 10 (IP-10, interferon-inducible T-cell chemoattractant (I-TAC, monokine induced by interferon gamma (MIG, and macrophage colony-stimulating factor (M-CSF. It also showed significant antiproliferative activity and robustly inhibited collagen-I, collagen-III, plasminogen activator inhibitor-1 (PAI-1, and tissue inhibitor of metalloproteinase 1 and 2 (TIMP-1 and TIMP-2. The inhibitory effect of AEO on increased production of these protein biomarkers suggests it has anti-inflammatory property. We then studied the effect of AEO on the genome-wide expression of 21,224 genes in the same cell culture. AEO significantly and diversely modulated global gene expression. Ingenuity pathway analysis (IPA showed that AEO robustly affected numerous critical genes and signaling pathways closely involved in inflammatory and tissue remodeling processes. The findings of this study provide the first evidence of the biological activity and beneficial action of AEO in human skin cells.

  11. Small molecule inhibition of polo-like kinase 1 by volasertib (BI 6727) causes significant melanoma growth delay and regression in vivo.

    Science.gov (United States)

    Cholewa, Brian D; Ndiaye, Mary A; Huang, Wei; Liu, Xiaoqi; Ahmad, Nihal

    2017-01-28

    The objective of this study was to determine the therapeutic potential of polo-like kinase 1 (Plk1) inhibition in melanoma, in vivo. Employing Vectra technology, we assessed the Plk1 expression profile in benign nevi, malignant (stages I-IV) and metastatic melanomas. We found a significant elevation of Plk1 immunostaining in melanoma tissues. Further, a second generation small molecule Plk1 inhibitor, BI 6727, resulted in reductions in growth, viability and clonogenic survival, as well as an increase in apoptosis of A375 and Hs 294T melanoma cells. BI 6727 treatment also resulted in a G2/M-as well as S-phase cell cycle arrest in melanoma cells. Importantly, BI 6727 (intravenous injection; 10 and 25 mg/kg body weight) treatment resulted in significant tumor growth delay and regression in vivo in A375-and Hs 294T-implanted xenografts in athymic nude mice. These anti-melanoma effects were accompanied with a decreased cellular proliferation (Ki-67 staining) and induction of apoptosis (caspase 3 activation). In addition, BI 6727 treatment caused a marked induction of p53 and p21 in vitro as well as in vivo. Overall, we suggest that Plk1 inhibition may be a useful approach as a monotherapy as well as in combination with other existing therapeutics, for melanoma management. Published by Elsevier Ireland Ltd.

  12. Significant enhancement of (R)-mandelic acid production by relieving substrate inhibition of recombinant nitrilase in toluene-water biphasic system.

    Science.gov (United States)

    Zhang, Zhi-Jun; Pan, Jiang; Liu, Jun-Feng; Xu, Jian-He; He, Yu-Cai; Liu, You-Yan

    2011-03-10

    The enantioselective hydrolysis of mandelonitrile with whole cells of a recombinant Escherichia coli expressing nitrilase activity was severely inhibited by the substrate at high concentrations (>300mM), which resulted in a low yield of the target product (R)-(-)-mandelic acid. To relieve the substrate inhibition and to enhance the (R)-(-)-mandelic acid productivity, eight water-organic solvent biphasic systems were attempted in this work. Toluene was found to be the most suitable solvent as the organic phase among the solvents tested. Various parameters were systematically examined and optimized in shake flasks. The phase volume ratio, buffer pH and reaction temperature were shown to be sensitive parameters affecting both the yield and the enantiopurity of product in the biphasic system. Under the optimized conditions, significant enhancement of substrate tolerance from 200mM to 500mM and average productivity from 179.6gl(-1)d(-1) to 352.6gl(-1)d(-1) were achieved. Subsequently, the biocatalytic hydrolysis of mandelonitrile was successfully carried out in a stirred reactor (2-l scale) by repeated use of the calcium alginate entrapped cells for 5 batches, affording 110.7g (R)-(-)-mandelic acid in 98.0% ee (enantiomeric excess) and a specific production of 13.8g (mandelic acid) g(-1) (cell), respectively. Copyright © 2011 Elsevier B.V. All rights reserved.

  13. In vitro exposure to the herbicide atrazine inhibits T cell activation, proliferation, and cytokine production and significantly increases the frequency of Foxp3+ regulatory T cells.

    Science.gov (United States)

    Thueson, Lindsay E; Emmons, Tiffany R; Browning, Dianna L; Kreitinger, Joanna M; Shepherd, David M; Wetzel, Scott A

    2015-02-01

    The herbicide atrazine (2-chloro-4-[ethylamino]-6-[isopropylamino]-s-triazine) is the most common water contaminant in the United States. Atrazine is a phosphodiesterase inhibitor and is classified as an estrogen disrupting compound because it elevates estrogen levels via induction of the enzyme aromatase. Previous studies have shown that atrazine exposure alters the function of innate immune cells such as NK cells, DC, mast cells, and macrophages. In this study we have examined the impact of in vitro atrazine exposure on the activation, proliferation, and effector cytokine production by primary murine CD4(+) T lymphocytes. We found that atrazine exposure significantly inhibited CD4(+) T cell proliferation and accumulation as well as the expression of the activation markers CD25 and CD69 in a dose-dependent manner. Interestingly, the effects were more pronounced in cells from male animals. These effects were partially mimicked by pharmacological reagents that elevate intracellular cAMP levels and addition of exogenous rmIL-2 further inhibited proliferation and CD25 expression. Consistent with these findings, atrazine exposure during T cell activation resulted in a 2- to 5-fold increase in the frequency of Foxp3(+) CD4(+) T cells. © The Author 2014. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  14. Inhibition of Plasmepsin V activity demonstrates its essential role in protein export, PfEMP1 display, and survival of malaria parasites

    DEFF Research Database (Denmark)

    Sleebs, Brad E; Lopaticki, Sash; Marapana, Danushka S;

    2014-01-01

    PEXEL cleavage occurs cotranslationaly, similar to signal peptidase. Treatment of P. falciparum-infected erythrocytes with the inhibitor caused dose-dependent inhibition of PEXEL processing as well as protein export, including impaired display of the major virulence adhesin, PfEMP1, on the erythrocyte...

  15. NF-κB inhibition significantly upregulates the norepinephrine transporter system, causes apoptosis in pheochromocytoma cell lines and prevents metastasis in an animal model

    Science.gov (United States)

    Pacak, Karel; Sirova, Marta; Giubellino, Alessio; Lencesova, Lubomira; Csaderova, Lucia; Hudecova, Sona; Krizanova, Olga

    2012-01-01

    Pheochromocytomas (PHEOs) and paragangliomas (PGLs) are specific types of neuroendocrine tumors that originate in the adrenal medulla or sympathetic/parasympathetic paraganglia, respectively. Although these tumors are intensively studied, a very effective treatment for metastatic PHEO or PGL has not yet been established. Preclinical evaluations of novel therapies for these tumors are very much required. Therefore, in the present study we tested the effect of triptolide (TTL), a potent nuclear factor-kappaB (NF-κB) inhibitor, on the cell membrane norepinephrine transporter system (NET), considered to be the gatekeeper for the radiotherapeutic agent 131I-metaiodobenzylguanidine (131I-MIBG). We measured changes in the mRNA and protein levels of NET and correlated them with proapoptotic factors and metastasis inhibition. The study was carried out on three different stable pheochromocytoma cell lines. We found that blocking NF-κB with TTL or capsaicin (KPSC) increased both NET mRNA and protein levels. Involvement of NF-κB in the upregulation of NET was verified by mRNA silencing of this site and also by using NF-κB antipeptide. Moreover, MIBG transport was increased in TTL-treated cells and in vivo treatment with TTL significantly reduced metastatic burden in a metastatic animal model of pheochromocytoma. The present study for the first time shows mechanistically how NF-κB inhibitors can be successfully used in the treatment of metastatic PHEO/PGL by a significant upregulation of NET to increase the efficacy of 131I-MIBG and by the induction of apoptosis. PMID:22407736

  16. In vivo demonstration of H3-histaminergic inhibition of cardiac sympathetic stimulation by R-α-methyl-histamine and its prodrug BP 2.94 in the dog

    OpenAIRE

    Mazenot, Catherine; Ribuot, Christophe; Durand, Andrée; Joulin, Yves; Demenge, Pierre; Godin-Ribuot, Diane

    1999-01-01

    The aim of this study was to investigate whether histamine H3-receptor agonists could inhibit the effects of cardiac sympathetic nerve stimulation in the dog.Catecholamine release by the heart and the associated variation of haemodynamic parameters were measured after electrical stimulation of the right cardiac sympathetic nerves (1–4 Hz, 10 V, 10 ms) in the anaesthetized dog treated with R-α-methyl-histamine (R-HA) and its prodrug BP 2.94 (BP).Cardiac sympathetic stimulation induced a noradr...

  17. Potential triple helix-mediated inhibition of IGF-I gene expression significantly reduces tumorigenicity of glioblastoma in an animal model.

    Science.gov (United States)

    Shevelev, A; Burfeind, P; Schulze, E; Rininsland, F; Johnson, T R; Trojan, J; Chernicky, C L; Hélène, C; Ilan, J; Ilan, J

    1997-01-01

    Oligonucleotide-directed triple helix formation is a powerful approach to block transcription of specific genes. Although the oligonucleotide triplex approach is efficient for inhibiting gene expression in cultured cells, suppression is transient. We developed an approach which inhibits insulin-like growth factor-I (IGF-I) expression following stable transfection of C6 rat glioblastoma cells with a plasmid from which an RNA is transcribed that codes for the third strand of a potential triple helix. We tested the ability of this expression vector to inhibit IGF-I gene expression in vitro as well as tumorigenesis in an animal. A dramatic reduction of IGF-I RNA and protein levels in cultured cells occurred following transfection of rat C6 cells with a eukaryotic expression plasmid encoding the oligopurine variant of the triple helix but not the oligopyrimidine or a control sequence. The cells transfected with the oligopurine variant displayed morphological changes, upregulation of major histocompatibility complex I, and increased expression of protease nexin I. Dramatic inhibition of tumor growth occurred in nude mice following injection of transfected C6 cells. To our knowledge, this is the first example of tumor growth inhibition in an animal model employing a triple helix approach.

  18. Tested Demonstrations.

    Science.gov (United States)

    Sands, Robert; And Others

    1982-01-01

    Procedures for two demonstrations are provided. The solubility of ammonia gas in water is demonstrated by introducing water into a closed can filled with the gas, collapsing the can. The second demonstration relates scale of standard reduction potentials to observed behavior of metals in reactions with hydrogen to produce hydrogen gas. (Author/JN)

  19. Solitary Inhibition of the Breast Cancer Resistance Protein Efflux Transporter Results in a Clinically Significant Drug-Drug Interaction with Rosuvastatin by Causing up to a 2-Fold Increase in Statin Exposure.

    Science.gov (United States)

    Elsby, Robert; Martin, Paul; Surry, Dominic; Sharma, Pradeep; Fenner, Katherine

    2016-03-01

    The intestinal efflux transporter breast cancer resistance protein (BCRP) restricts the absorption of rosuvastatin. Of the transporters important to rosuvastatin disposition, fostamatinib inhibited BCRP (IC50 = 50 nM) and organic anion-transporting polypeptide 1B1 (OATP1B1; IC50 > 10 μM), but not organic anion transporter 3, in vitro, predicting a drug-drug interaction (DDI) in vivo through inhibition of BCRP only. Consequently, a clinical interaction study between fostamatinib and rosuvastatin was performed (and reported elsewhere). This confirmed the critical role BCRP plays in statin absorption, as inhibition by fostamatinib resulted in a significant 1.96-fold and 1.88-fold increase in rosuvastatin area under the plasma concentration-time curve (AUC) and Cmax, respectively. An in vitro BCRP inhibition assay, using polarized Caco-2 cells and rosuvastatin as probe substrate, was subsequently validated with literature inhibitors and used to determine BCRP inhibitory potencies (IC50) of the perpetrator drugs eltrombopag, darunavir, lopinavir, clopidogrel, ezetimibe, fenofibrate, and fluconazole. OATP1B1 inhibition was also determined using human embryonic kidney 293-OATP1B1 cells versus estradiol 17β-glucuronide. Calculated parameters of maximum enterocyte concentration [Igut max], maximum unbound hepatic inlet concentration, transporter fraction excreted value, and determined IC50 value were incorporated into mechanistic static equations to compute theoretical increases in rosuvastatin AUC due to inhibition of BCRP and/or OATP1B1. Calculated theoretical increases in exposure correctly predicted the clinically observed changes in rosuvastatin exposure and suggested intestinal BCRP inhibition (not OATP1B1) to be the mechanism underlying the DDIs with these drugs. In conclusion, solitary inhibition of the intestinal BCRP transporter can result in clinically significant DDIs with rosuvastatin, causing up to a maximum 2-fold increase in exposure, which may warrant

  20. Tested Demonstrations.

    Science.gov (United States)

    Gilbert, George L., Ed.

    1983-01-01

    Free radical chlorination of methane is used in organic chemistry to introduce free radical/chain reactions. In spite of its common occurrence, demonstrations of the reaction are uncommon. Therefore, such a demonstration is provided, including background information, preparation of reactants/reaction vessel, introduction of reactants, irradiation,…

  1. Tested Demonstrations.

    Science.gov (United States)

    Gilbert, George L., Ed.

    1983-01-01

    Discusses a supplement to the "water to rose" demonstration in which a pink color is produced. Also discusses blood buffer demonstrations, including hydrolysis of sodium bicarbonate, simulated blood buffer, metabolic acidosis, natural compensation of metabolic acidosis, metabolic alkalosis, acidosis treatment, and alkalosis treatment. Procedures…

  2. Complete Demonstration.

    Science.gov (United States)

    Yelon, Stephen; Maddocks, Peg

    1986-01-01

    Describes four-step approach to educational demonstration: tell learners they will have to perform; what they should notice; describe each step before doing it; and require memorization of steps. Examples illustrate use of this process to demonstrate a general mental strategy, and industrial design, supervisory, fine motor, and specific…

  3. Tested Demonstrations.

    Science.gov (United States)

    Gilbert, George L., Ed.

    1987-01-01

    Describes two laboratory demonstrations in chemistry. One uses dry ice, freon, and freezer bags to demonstrate volume changes, vapor-liquid equilibrium, a simulation of a rain forest, and vaporization. The other uses the clock reaction technique to illustrate fast reactions and kinetic problems in releasing carbon dioxide during respiration. (TW)

  4. Tested Demonstrations.

    Science.gov (United States)

    Gilbert, George L., Ed.

    1986-01-01

    Outlines a simple, inexpensive way of demonstrating electroplating using the reaction between nickel ions and copper metal. Explains how to conduct a demonstration of the electrolysis of water by using a colored Na2SO4 solution as the electrolyte so that students can observe the pH changes. (TW)

  5. Double labelling of tissue combining tritiated thymidine autoradiography with immunodetection of bromodeoxyuridine: the autoradiographic significance of inhibition of thymidine incorporation into DNA by bromodeoxyuridine given simultaneously

    Energy Technology Data Exchange (ETDEWEB)

    Hume, W.J.; Thompson, J. (Leeds Univ. (UK). School of Dentistry)

    1989-09-01

    The authors describe a method for combining tritiated thymidine (({sup 3}H)TdR) autoradiography with immunoperoxidase detection of bromodeoxyuridine (BrdU) in paraffin-embedded tissues, which was used to examine, in mouse tongue epithelium, the inhibition of incorporation into DNA of ({sup 3}H)TdR by simultaneous injection of BrdU in the doses that both compounds are likely to be used in cell proliferation studies. The inhibition of uptake into DNA of ({sup 3}H)TdR from 0.23 to 1.85 MBq (6.25 to 50 {mu}Ci) per animal, produced by a simultaneous injection of 2.5 mg BrdU shows a linear, dose-dependent relationship. Provided the injected dose (in {mu}Ci per animal) multiplied by the autoradiographic exposure time (in days) is greater than a value of 700, then all cells that are labelled after incorporation of ({sup 3}H)TdR alone are also labelled after simultaneous double labelling, despite the latter producing a lower average grain count. (author).

  6. Tested Demonstrations.

    Science.gov (United States)

    Gilbert, George L.

    1990-01-01

    Included are three demonstrations that include the phase change of ice when under pressure, viscoelasticity and colloid systems, and flame tests for metal ions. The materials, procedures, probable results, and applications to real life situations are included. (KR)

  7. Tested Demonstrations.

    Science.gov (United States)

    Gilbert, George L., Ed.

    1980-01-01

    Presented is a Corridor Demonstration which can be set up in readily accessible areas such as hallways or lobbies. Equipment is listed for a display of three cells (solar cells, fuel cells, and storage cells) which develop electrical energy. (CS)

  8. Tested Demonstrations.

    Science.gov (United States)

    Gilbert, George L., Ed.

    1987-01-01

    Presents three demonstrations suitable for undergraduate chemistry classes. Focuses on experiments with calcium carbide, the induction by iron of the oxidation of iodide by dichromate, and the classical iodine clock reaction. (ML)

  9. Five-year results from a prospective multicentre study of percutaneous pulmonary valve implantation demonstrate sustained removal of significant pulmonary regurgitation, improved right ventricular outflow tract obstruction and improved quality of life.

    Science.gov (United States)

    Hager, Alfred; Schubert, Stephan; Ewert, Peter; Søndergaard, Lars; Witsenburg, Maarten; Guccione, Paolo; Benson, Lee N; Suárez de Lezo, José; Lung, Te-Hsin; Hess, John; Eicken, Andreas; Berger, Felix

    2017-02-20

    Percutaneous pulmonary valve implantation (PPVI) is used to treat patients with dysfunctional pulmonary valve conduits. Short- and longer-term results from multiple trials have outlined haemodynamic improvements. Our aim was to report the long-term results, including quality of life, from a multicentre trial in Europe and Canada. From October 2007 to April 2009, 71 patients (24 female; median age 19.0 [IQR: 14.0 to 25.0] years) were enrolled in a prospective cohort study. PPVI was performed successfully in 63 patients. At five-year follow-up four patients had died. Moderate and severe pulmonary regurgitation were completely resolved in all except one patient, who needed re-PPVI. Outflow tract obstruction improved significantly from a mean pressure gradient of 37.7±12.1 mmHg before PPVI to 17.3±9.7 mmHg at five-year follow-up; however, 11 patients needed treatment for restenosis. The EQ-5D quality of life utility index and visual analogue scale scores were both significantly improved six months post PPVI and remained so at five years. Five-year results following PPVI demonstrate resolved moderate or severe pulmonary regurgitation, improved right ventricular outflow tract obstruction, and improved quality of life.

  10. Tested Demonstrations.

    Science.gov (United States)

    Gilbert, George L., Ed.

    1987-01-01

    Describes two demonstrations to illustrate characteristics of substances. Outlines a method to detect the changes in pH levels during the electrolysis of water. Uses water pistols, one filled with methane gas and the other filled with water, to illustrate the differences in these two substances. (TW)

  11. ICT Demonstration

    DEFF Research Database (Denmark)

    Jensen, Tine Wirenfeldt; Bay, Gina

    In this demonstration we present and discuss two interrelated on-line learning resources aimed at supporting international students at Danish universities in building study skills (the Study Metro) and avoiding plagiarism (Stopplagiarism). We emphasize the necessity of designing online learning r...

  12. The hetero-transplantation of human bone marrow stromal cells carried by hydrogel unexpectedly demonstrates a significant role in the functional recovery in the injured spinal cord of rats.

    Science.gov (United States)

    Raynald; Li, Yanbin; Yu, Hao; Huang, Hua; Guo, Muyao; Hua, Rongrong; Jiang, Fenjun; Zhang, Kaihua; Li, Hailong; Wang, Fei; Li, Lusheng; Cui, FuZhai; An, Yihua

    2016-03-01

    Spinal cord injury (SCI) often causes a disturbance in the microenvironment in the lesion site resulting in sudden loss of sensory and motor function. Transplantation of stem cells provides a promising strategy in the treatment of SCI. But limited growth and immunological incompatibility of the stem cells with the host limits the application of this strategy. In order to get better survival and integration with the host, we employed a hyaluronic acid (HA) based scaffold covalently modified by poly-l-Lysine (PLL) as a vehicle to deliver the human bone marrow stromal cells (BMSCs) to the injured spinal cord of rats. The BMSCs were chosen as an ideal candidate for its advantage of low expression of major histocompatibility complex II. The data unexpectedly showed that the hetero-transplanted cells survived well in the lesion site even at 8 weeks post injury. Both the immunofluorescent and the electrophysiological assay indicated better survival of the transplanted cells and improved axonal growth in SCI rats transplanted with BMSCs in HA-PLL in contrast to the groups without either BMSCs or the HA scaffold transplantation. These promotions may account for the functional recovery assessed by Basso-Beattie-Bresnahan (BBB) locomotor rating scale in the HA-PLL seeded with BMSCs group. These data suggests that hetero-transplantation of human BMSCs delivered by HA scaffold demonstrates a significant role in the functional recovery in the injured spinal cord of rats.

  13. GASIS demonstration

    Energy Technology Data Exchange (ETDEWEB)

    Vidas, E.H. [Energy and Environmental Analysis, Inc., Arlington, VA (United States)

    1995-04-01

    A prototype of the GASIS database and retrieval software has been developed and is the subject of this poster session and computer demonstration. The prototype consists of test or preliminary versions of the GASIS Reservoir Data System and Source Directory datasets and the software for query and retrieval. The prototype reservoir database covers the Rocky Mountain region and contains the full GASIS data matrix (all GASIS data elements) that will eventually be included on the CD-ROM. It is populated for development purposes primarily by the information included in the Rocky Mountain Gas Atlas. The software has been developed specifically for GASIS using Foxpro for Windows. The application is an executable file that does not require Foxpro to run. The reservoir database software includes query and retrieval, screen display, report generation, and data export functions. Basic queries by state, basin, or field name will be assisted by scrolling selection lists. A detailed query screen will allow record selection on the basis of any data field, such as depth, cumulative production, or geological age. Logical operators can be applied to any-numeric data element or combination of elements. Screen display includes a {open_quotes}browse{close_quotes} display with one record per row and a detailed single record display. Datasets can be exported in standard formats for manipulation with other software packages. The Source Directory software will allow record retrieval by database type or subject area.

  14. Choosing Outcomes of Significance.

    Science.gov (United States)

    Spady, William G.

    1994-01-01

    Outcomes are high-quality, culminating demonstrations of significant learning in context. The High Success Network uses the "Demonstration Mountain" to differentiate among three major "learning zones" and six different forms of learning demonstrations that increase in complexity, generalizability, and significance, along with…

  15. Exploration Medical System Demonstration

    Science.gov (United States)

    Rubin, D. A.; Watkins, S. D.

    2014-01-01

    BACKGROUND: Exploration class missions will present significant new challenges and hazards to the health of the astronauts. Regardless of the intended destination, beyond low Earth orbit a greater degree of crew autonomy will be required to diagnose medical conditions, develop treatment plans, and implement procedures due to limited communications with ground-based personnel. SCOPE: The Exploration Medical System Demonstration (EMSD) project will act as a test bed on the International Space Station (ISS) to demonstrate to crew and ground personnel that an end-to-end medical system can assist clinician and non-clinician crew members in optimizing medical care delivery and data management during an exploration mission. Challenges facing exploration mission medical care include limited resources, inability to evacuate to Earth during many mission phases, and potential rendering of medical care by non-clinicians. This system demonstrates the integration of medical devices and informatics tools for managing evidence and decision making and can be designed to assist crewmembers in nominal, non-emergent situations and in emergent situations when they may be suffering from performance decrements due to environmental, physiological or other factors. PROJECT OBJECTIVES: The objectives of the EMSD project are to: a. Reduce or eliminate the time required of an on-orbit crew and ground personnel to access, transfer, and manipulate medical data. b. Demonstrate that the on-orbit crew has the ability to access medical data/information via an intuitive and crew-friendly solution to aid in the treatment of a medical condition. c. Develop a common data management framework that can be ubiquitously used to automate repetitive data collection, management, and communications tasks for all activities pertaining to crew health and life sciences. d. Ensure crew access to medical data during periods of restricted ground communication. e. Develop a common data management framework that

  16. LIMB Demonstration Project Extension and Coolside Demonstration

    Energy Technology Data Exchange (ETDEWEB)

    Goots, T.R.; DePero, M.J.; Nolan, P.S.

    1992-11-10

    This report presents results from the limestone Injection Multistage Burner (LIMB) Demonstration Project Extension. LIMB is a furnace sorbent injection technology designed for the reduction of sulfur dioxide (SO[sub 2]) and nitrogen oxides (NO[sub x]) emissions from coal-fired utility boilers. The testing was conducted on the 105 Mwe, coal-fired, Unit 4 boiler at Ohio Edison's Edgewater Station in Lorain, Ohio. In addition to the LIMB Extension activities, the overall project included demonstration of the Coolside process for S0[sub 2] removal for which a separate report has been issued. The primary purpose of the DOE LIMB Extension testing, was to demonstrate the generic applicability of LIMB technology. The program sought to characterize the S0[sub 2] emissions that result when various calcium-based sorbents are injected into the furnace, while burning coals having sulfur content ranging from 1.6 to 3.8 weight percent. The four sorbents used included calcitic limestone, dolomitic hydrated lime, calcitic hydrated lime, and calcitic hydrated lime with a small amount of added calcium lignosulfonate. The results include those obtained for the various coal/sorbent combinations and the effects of the LIMB process on boiler and plant operations.

  17. Fuel Cell Demonstration Program

    Energy Technology Data Exchange (ETDEWEB)

    Gerald Brun

    2006-09-15

    In an effort to promote clean energy projects and aid in the commercialization of new fuel cell technologies the Long Island Power Authority (LIPA) initiated a Fuel Cell Demonstration Program in 1999 with six month deployments of Proton Exchange Membrane (PEM) non-commercial Beta model systems at partnering sites throughout Long Island. These projects facilitated significant developments in the technology, providing operating experience that allowed the manufacturer to produce fuel cells that were half the size of the Beta units and suitable for outdoor installations. In 2001, LIPA embarked on a large-scale effort to identify and develop measures that could improve the reliability and performance of future fuel cell technologies for electric utility applications and the concept to establish a fuel cell farm (Farm) of 75 units was developed. By the end of October of 2001, 75 Lorax 2.0 fuel cells had been installed at the West Babylon substation on Long Island, making it the first fuel cell demonstration of its kind and size anywhere in the world at the time. Designed to help LIPA study the feasibility of using fuel cells to operate in parallel with LIPA's electric grid system, the Farm operated 120 fuel cells over its lifetime of over 3 years including 3 generations of Plug Power fuel cells (Lorax 2.0, Lorax 3.0, Lorax 4.5). Of these 120 fuel cells, 20 Lorax 3.0 units operated under this Award from June 2002 to September 2004. In parallel with the operation of the Farm, LIPA recruited government and commercial/industrial customers to demonstrate fuel cells as on-site distributed generation. From December 2002 to February 2005, 17 fuel cells were tested and monitored at various customer sites throughout Long Island. The 37 fuel cells operated under this Award produced a total of 712,635 kWh. As fuel cell technology became more mature, performance improvements included a 1% increase in system efficiency. Including equipment, design, fuel, maintenance

  18. Polarized Light Corridor Demonstrations.

    Science.gov (United States)

    Davies, G. R.

    1990-01-01

    Eleven demonstrations of light polarization are presented. Each includes a brief description of the apparatus and the effect demonstrated. Illustrated are strain patterns, reflection, scattering, the Faraday Effect, interference, double refraction, the polarizing microscope, and optical activity. (CW)

  19. The POSEIDON Demonstrator

    NARCIS (Netherlands)

    Laar, P.J.L.J. van de

    2013-01-01

    In this chapter, we discuss the Poseidon demonstrator: a demonstrator that integrates the individual research results of all partners of the Poseidon project. After describing how the Poseidon demonstrator was built, deployed, and operated, we will not only show many results obtained from the demons

  20. Overhead Projector Demonstrations.

    Science.gov (United States)

    Kolb, Doris, Ed.

    1988-01-01

    Details two demonstrations for use with an overhead projector in a chemistry lecture. Includes "A Very Rapidly Growing Silicate Crystal" and "A Colorful Demonstration to Simulate Orbital Hybridization." The materials and directions for each demonstration are included as well as a brief explanation of the essential learning involved. (CW)

  1. Btk inhibition treats TLR7/IFN driven murine lupus.

    Science.gov (United States)

    Bender, Andrew T; Pereira, Albertina; Fu, Kai; Samy, Eileen; Wu, Yin; Liu-Bujalski, Lesley; Caldwell, Richard; Chen, Yi-Ying; Tian, Hui; Morandi, Federica; Head, Jared; Koehler, Ursula; Genest, Melinda; Okitsu, Shinji L; Xu, Daigen; Grenningloh, Roland

    2016-03-01

    Bruton's tyrosine kinase (Btk) is expressed in a variety of immune cells and previous work has demonstrated that blocking Btk is a promising strategy for treating autoimmune diseases. Herein, we utilized a tool Btk inhibitor, M7583, to determine the therapeutic efficacy of Btk inhibition in two mouse lupus models driven by TLR7 activation and type I interferon. In BXSB-Yaa lupus mice, Btk inhibition reduced autoantibodies, nephritis, and mortality. In the pristane-induced DBA/1 lupus model, Btk inhibition suppressed arthritis, but autoantibodies and the IFN gene signature were not significantly affected; suggesting efficacy was mediated through inhibition of Fc receptors. In vitro studies using primary human macrophages revealed that Btk inhibition can block activation by immune complexes and TLR7 which contributes to tissue damage in SLE. Overall, our results provide translational insight into how Btk inhibition may provide benefit to a variety of SLE patients by affecting both BCR and FcR signaling.

  2. Strategy Guideline: Demonstration Home

    Energy Technology Data Exchange (ETDEWEB)

    Savage, C.; Hunt, A.

    2012-12-01

    This guideline will provide a general overview of the different kinds of demonstration home projects, a basic understanding of the different roles and responsibilities involved in the successful completion of a demonstration home, and an introduction into some of the lessons learned from actual demonstration home projects. Also, this guideline will specifically look at the communication methods employed during demonstration home projects. And lastly, we will focus on how to best create a communication plan for including an energy efficient message in a demonstration home project and carry that message to successful completion.

  3. Strategy Guideline. Demonstration Home

    Energy Technology Data Exchange (ETDEWEB)

    Hunt, A.; Savage, C.

    2012-12-01

    This guideline will provide a general overview of the different kinds of demonstration home projects, a basic understanding of the different roles and responsibilities involved in the successful completion of a demonstration home, and an introduction into some of the lessons learned from actual demonstration home projects. Also, this guideline will specifically look at the communication methods employed during demonstration home projects. And lastly, we will focus on how to best create a communication plan for including an energy efficient message in a demonstration home project and carry that message to successful completion.

  4. Tidd PFBC demonstration project

    Energy Technology Data Exchange (ETDEWEB)

    Marrocco, M. [American Electric Power, Columbus, OH (United States)

    1997-12-31

    The Tidd project was one of the first joint government-industry ventures to be approved by the US Department of Energy (DOE) in its Clean Coal Technology Program. In March 1987, DOE signed an agreement with the Ohio Power Company, a subsidiary of American Electric Power, to refurbish the then-idle Tidd plant on the banks of the Ohio River with advanced pressurized fluidized bed technology. Testing ended after 49 months of operation, 100 individual tests, and the generation of more than 500,000 megawatt-hours of electricity. The demonstration plant has met its objectives. The project showed that more than 95 percent of sulfur dioxide pollutants could be removed inside the advanced boiler using the advanced combustion technology, giving future power plants an attractive alternative to expensive, add-on scrubber technology. In addition to its sulfur removal effectiveness, the plant`s sustained periods of steady-state operation boosted its availability significantly above design projections, heightening confidence that pressurized fluidized bed technology will be a reliable, baseload technology for future power plants. The technology also controlled the release of nitrogen oxides to levels well below the allowable limits set by federal air quality standards. It also produced a dry waste product that is much easier to handle than wastes from conventional power plants and will likely have commercial value when produced by future power plants.

  5. miR-155, identified as anti-metastatic by global miRNA profiling of a metastasis model, inhibits cancer cell extravasation and colonization in vivo and causes significant signaling alterations

    DEFF Research Database (Denmark)

    Gravgaard, Karina Hedelund; Terp, Mikkel G; Lund, Rikke R

    2015-01-01

    To gain insight into miRNA regulation in metastasis formation, we used a metastasis cell line model that allows investigation of extravasation and colonization of circulating cancer cells to lungs in mice. Using global miRNA profiling, 28 miRNAs were found to exhibit significantly altered express...

  6. Manufacturing Demonstration Facility (MDF)

    Data.gov (United States)

    Federal Laboratory Consortium — The U.S. Department of Energy Manufacturing Demonstration Facility (MDF) at Oak Ridge National Laboratory (ORNL) provides a collaborative, shared infrastructure to...

  7. Toy Demonstrator's "VISIT" Handbook.

    Science.gov (United States)

    Levenstein, Phyllis

    The role of the toy demonstrator in a home-based, mother-involved intervention effort (Verbal Interaction Project) is presented in this handbook for staff members. It is believed that the prerequisites for functioning in the toy demonstrator's role are a sense of responsibility, patience with the children and their mothers, and willingness to be…

  8. Levitation Kits Demonstrate Superconductivity.

    Science.gov (United States)

    Worthy, Ward

    1987-01-01

    Describes the "Project 1-2-3" levitation kit used to demonstrate superconductivity. Summarizes the materials included in the kit. Discusses the effect demonstrated and gives details on how to obtain kits. Gives an overview of the documentation that is included. (CW)

  9. Kinetics and Catalysis Demonstrations.

    Science.gov (United States)

    Falconer, John L.; Britten, Jerald A.

    1984-01-01

    Eleven videotaped kinetics and catalysis demonstrations are described. Demonstrations include the clock reaction, oscillating reaction, hydrogen oxidation in air, hydrogen-oxygen explosion, acid-base properties of solids, high- and low-temperature zeolite reactivity, copper catalysis of ammonia oxidation and sodium peroxide decomposition, ammonia…

  10. Better Ira Remsen Demonstration

    Science.gov (United States)

    Dalby, David K.; Maynard, James H.; Moore, John W.

    2011-01-01

    Many versions of the classic Ira Remsen experience involving copper and concentrated nitric acid have been used as lecture demonstrations. Remsen's original reminiscence from 150 years ago is included in the Supporting Information, and his biography can be found on the Internet. This article presents a new version that makes the demonstration more…

  11. Levitation Kits Demonstrate Superconductivity.

    Science.gov (United States)

    Worthy, Ward

    1987-01-01

    Describes the "Project 1-2-3" levitation kit used to demonstrate superconductivity. Summarizes the materials included in the kit. Discusses the effect demonstrated and gives details on how to obtain kits. Gives an overview of the documentation that is included. (CW)

  12. Sequence-specific cleavage of BM2 gene transcript of influenza B virus by 10-23 catalytic motif containing DNA enzymes significantly inhibits viral RNA translation and replication.

    Science.gov (United States)

    Kumar, Binod; Kumar, Prashant; Rajput, Roopali; Saxena, Latika; Daga, Mradul K; Khanna, Madhu

    2013-10-01

    One of the hallmarks of progression of influenza virus replication is the step involving the virus uncoating that occurs in the host cytoplasm. The BM2 ion channel protein of influenza B virus is highly conserved and is essentially required during the uncoating processes of virus, thus an attractive target for designing antiviral drugs. We screened several DNA enzymes (Dzs) containing the 10-23 catalytic motif against the influenza B virus BM2 RNA. Dzs directed against the predicted single-stranded bulge regions showed sequence-specific cleavage activities. The Dz209 not only showed significant intracellular reduction of BM2 gene expression in transient-expression system but also provided considerable protection against influenza B virus challenge in MDCK cells. Our findings suggest that the Dz molecule can be used as selective and effective inhibitor of viral RNA replication, and can be explored further for development of a potent therapeutic agent against influenza B virus infection.

  13. Methanol Cannon Demonstrations Revisited.

    Science.gov (United States)

    Dolson, David A.; And Others

    1995-01-01

    Describes two variations on the traditional methanol cannon demonstration. The first variation is a chain reaction using real metal chains. The second example involves using easily available components to produce sequential explosions that can be musical in nature. (AIM)

  14. TENCompetence tool demonstration

    NARCIS (Netherlands)

    Kluijfhout, Eric

    2010-01-01

    Kluijfhout, E. (2009). TENCompetence tool demonstration. Presented at Zorgacademie Parkstad (Health Academy Parkstad), Limburg Leisure Academy, Life Long Learning Limburg and a number of regional educational institutions. May, 18, 2009, Heerlen, The Netherlands: Open University of the Netherlands, T

  15. Land Management Research Demonstration

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — In 2002, Neal Smith National Wildlife Refuge became one of the first Land Management and Research Demonstration (LMRD) sites. These sites are intended to serve as...

  16. Pancreaticopleural fistula : CT demonstration

    Energy Technology Data Exchange (ETDEWEB)

    Hahm, Jin Kyeung [Chuncheon Medical Center, ChunChon (Korea, Republic of)

    1997-03-01

    In patients with chronic pancreatitis, the pancreaticopleural fistula is known to cause recurrent exudative or hemorrhagic pleural effusions. These are often large in volume and require treatment, unlike the effusions in acute pancreatitis. Diagnosis can be made either by the finding of elevated pleural fluid amylase level or, using imaging studies, by the direct demonstration of the fistulous tract. We report two cases of pancreaticopleural fistula demonstrated by computed tomography.

  17. Education Payload Operation - Demonstrations

    Science.gov (United States)

    Keil, Matthew

    2009-01-01

    Education Payload Operation - Demonstrations (EPO-Demos) are recorded video education demonstrations performed on the International Space Station (ISS) by crewmembers using hardware already onboard the ISS. EPO-Demos are videotaped, edited, and used to enhance existing NASA education resources and programs for educators and students in grades K-12. EPO-Demos are designed to support the NASA mission to inspire the next generation of explorers.

  18. Edible Astronomy Demonstrations

    Science.gov (United States)

    Lubowich, Donald A.

    2007-12-01

    Astronomy demonstrations with edible ingredients are an effective way to increase student interest and knowledge of astronomical concepts. This approach has been successful with all age groups from elementary school through college students - and the students remember these demonstrations after they are presented. In this poster I describe edible demonstrations I have created to simulate the expansion of the universe (using big-bang chocolate chip cookies); differentiation during the formation of the Earth and planets (using chocolate or chocolate milk with marshmallows, cereal, candy pieces or nuts); and radioactivity/radioactive dating (using popcorn). Other possible demonstrations include: plate tectonics (crackers with peanut butter and jelly); convection (miso soup or hot chocolate); mud flows on Mars (melted chocolate poured over angel food cake); formation of the Galactic disk (pizza); formation of spiral arms (coffee with cream); the curvature of Space (Pringles); constellations patterns with chocolate chips and chocolate chip cookies; planet shaped cookies; star shaped cookies with different colored frostings; coffee or chocolate milk measurement of solar radiation; Oreo cookie lunar phases. Sometimes the students eat the results of the astronomical demonstrations. These demonstrations are an effective teaching tool and can be adapted for cultural, culinary, and ethnic differences among the students.

  19. Solar renovation demonstration projects

    Energy Technology Data Exchange (ETDEWEB)

    Bruun Joergensen, O. [ed.

    1998-10-01

    In the framework of the IEA SHC Programme, a Task on building renovation was initiated, `Task 20, Solar Energy in Building Renovation`. In a part of the task, Subtask C `Design of Solar Renovation Projects`, different solar renovation demonstration projects were developed. The objective of Subtask C was to demonstrate the application of advanced solar renovation concepts on real buildings. This report documents 16 different solar renovation demonstration projects including the design processes of the projects. The projects include the renovation of houses, schools, laboratories, and factories. Several solar techniques were used: building integrated solar collectors, glazed balconies, ventilated solar walls, transparent insulation, second skin facades, daylight elements and photovoltaic systems. These techniques are used in several simple as well as more complex system designs. (au)

  20. Weed Identification Field Training Demonstrations.

    Science.gov (United States)

    Murdock, Edward C.; And Others

    1986-01-01

    Reviews efforts undertaken in weed identification field training sessions for agriprofessionals in South Carolina. Data over a four year period (1980-1983) revealed that participants showed significant improvement in their ability to identify weeds. Reaffirms the value of the field demonstration technique. (ML)

  1. Weed Identification Field Training Demonstrations.

    Science.gov (United States)

    Murdock, Edward C.; And Others

    1986-01-01

    Reviews efforts undertaken in weed identification field training sessions for agriprofessionals in South Carolina. Data over a four year period (1980-1983) revealed that participants showed significant improvement in their ability to identify weeds. Reaffirms the value of the field demonstration technique. (ML)

  2. Demonstrating marketing accountability.

    Science.gov (United States)

    Gombeski, William R; Britt, Jason; Taylor, Jan; Riggs, Karen; Wray, Tanya; Adkins, Wanda; Springate, Suzanne

    2008-01-01

    Pressure on health care marketers to demonstrate effectiveness of their strategies and show their contribution to organizational goals is growing. A seven-tiered model based on the concepts of structure (having the right people, systems), process (doing the right things in the right way), and outcomes (results) is discussed. Examples of measures for each tier are provided and the benefits of using the model as a tool for measuring, organizing, tracking, and communicating appropriate information are provided. The model also provides a framework for helping management understand marketing's value and can serve as a vehicle for demonstrating marketing accountability.

  3. Demonstrating Supernova Remnant Evolution

    Science.gov (United States)

    Leahy, Denis A.; Williams, Jacqueline

    2017-01-01

    We have created a software tool to calculate at display supernova remnant evolution which includes all stages from early ejecta dominated phase to late-time merging with the interstellar medium. The software was created using Python, and can be distributed as Python code, or as an executable file. The purpose of the software is to demonstrate the different phases and transitions that a supernova remnant undergoes, and will be used in upper level undergraduate astrophysics courses as a teaching tool. The usage of the software and its graphical user interface will be demonstrated.

  4. Gigashot Optical Laser Demonstrator

    Energy Technology Data Exchange (ETDEWEB)

    Deri, R. J. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)

    2015-10-13

    The Gigashot Optical Laser Demonstrator (GOLD) project has demonstrated a novel optical amplifier for high energy pulsed lasers operating at high repetition rates. The amplifier stores enough pump energy to support >10 J of laser output, and employs conduction cooling for thermal management to avoid the need for expensive and bulky high-pressure helium subsystems. A prototype amplifier was fabricated, pumped with diode light at 885 nm, and characterized. Experimental results show that the amplifier provides sufficient small-signal gain and sufficiently low wavefront and birefringence impairments to prove useful in laser systems, at repetition rates up to 60 Hz.

  5. Monty Roberts’ public demonstrations

    NARCIS (Netherlands)

    Loftus, Loni; Marks, Kelly; Jones-McVey, Rosie; Gonzales, Jose L.; Fowler, Veronica L.

    2016-01-01

    Effective training of horses relies on the trainer’s awareness of learning theory and equine ethology, and should be undertaken with skill and time. Some trainers, such as Monty Roberts, share their methods through the medium of public demonstrations. This paper describes the opportunistic analys

  6. Arctic Craft Demonstration Report

    Science.gov (United States)

    2012-11-01

    it received a lot of attention from the local population. Demonstration personnel, both Coast Guard and contractors, were asked to be receptive to...www.uscg.mil/top/missions/ . Counter-Drug Interdiction and Alien Migrant Interdiction operations are currently not included. In the non-Polar regions

  7. Participatory Lecture Demonstrations.

    Science.gov (United States)

    Battino, Rubin

    1979-01-01

    The use of participatory lecture demonstrations in the classroom is described. Examples are given for the following topics: chromatography, chemical kinetics, balancing equations, the gas laws, kinetic molecular theory, Henry's law of gas solubility, electronic energy levels in atoms, and translational, vibrational, and rotational energies of…

  8. Demonstrating the Gas Laws.

    Science.gov (United States)

    Holko, David A.

    1982-01-01

    Presents a complete computer program demonstrating the relationship between volume/pressure for Boyle's Law, volume/temperature for Charles' Law, and volume/moles of gas for Avagadro's Law. The programing reinforces students' application of gas laws and equates a simulated moving piston to theoretical values derived using the ideal gas law.…

  9. Polarized Light: Three Demonstrations.

    Science.gov (United States)

    Goehmann, Ruth; Welty, Scott

    1984-01-01

    Describes three demonstrations used in the Chicago Museum of Science and Industry polarized light show. The procedures employed are suitable for the classroom by using smaller polarizers and an overhead projector. Topic areas include properties of cellophane tape, nondisappearing arrows, and rope through a picket fence. (JN)

  10. Passive damping technology demonstration

    Science.gov (United States)

    Holman, Robert E.; Spencer, Susan M.; Austin, Eric M.; Johnson, Conor D.

    1995-05-01

    A Hughes Space Company study was undertaken to (1) acquire the analytical capability to design effective passive damping treatments and to predict the damped dynamic performance with reasonable accuracy; (2) demonstrate reasonable test and analysis agreement for both baseline and damped baseline hardware; and (3) achieve a 75% reduction in peak transmissibility and 50% reduction in rms random vibration response. Hughes Space Company teamed with CSA Engineering to learn how to apply passive damping technology to their products successfully in a cost-effective manner. Existing hardware was selected for the demonstration because (1) previous designs were lightly damped and had difficulty in vibration test; (2) multiple damping concepts could be investigated; (3) the finite element model, hardware, and test fixture would be available; and (4) damping devices could be easily implemented. Bracket, strut, and sandwich panel damping treatments that met the performance goals were developed by analysis. The baseline, baseline with damped bracket, and baseline with damped strut designs were built and tested. The test results were in reasonable agreement with the analytical predictions and demonstrated that the desired reduction in dynamic response could be achieved. Having successfully demonstrated this approach, it can now be used with confidence for future designs as a means for reducing weight and enhancing reliability.

  11. PHARUS ASAR demonstrator

    NARCIS (Netherlands)

    Smith, A.J.E.; Bree, R.J.P. van; Calkoen, C.J.; Dekker, R.J.; Otten, M.P.G.; Rossum, W.L. van

    2001-01-01

    PHARUS is a polarimetric phased array C-band Synthetic Aperture Radar (SAR), designed and built for airborne use. Advanced SAR (ASAR) data in image and alternating polarization mode have been simulated with PHARUS to demonstrate the use of Envisat for a number of typical SAR applications that are no

  12. Distance Learning Environment Demonstration.

    Science.gov (United States)

    1996-11-01

    The Distance Learning Environment Demonstration (DLED) was a comparative study of distributed multimedia computer-based training using low cost high...measurement. The DLED project provides baseline research in the effective use of distance learning and multimedia communications over a wide area ATM/SONET

  13. Calculus Demonstrations Using MATLAB

    Science.gov (United States)

    Dunn, Peter K.; Harman, Chris

    2002-01-01

    The note discusses ways in which technology can be used in the calculus learning process. In particular, five MATLAB programs are detailed for use by instructors or students that demonstrate important concepts in introductory calculus: Newton's method, differentiation and integration. Two of the programs are animated. The programs and the…

  14. Palpability Support Demonstrated

    DEFF Research Database (Denmark)

    Brønsted, Jeppe; Grönvall, Erik; Fors, David

    2007-01-01

    is based on the Active Surfaces concept in which therapists rehabilitate physically and mentally impaired children by means of an activity that stimulates the children both physically and cognitively. In this paper we demonstrate how palpability can be supported in a prototype of the Active Surfaces...

  15. Polarized Light: Three Demonstrations.

    Science.gov (United States)

    Goehmann, Ruth; Welty, Scott

    1984-01-01

    Describes three demonstrations used in the Chicago Museum of Science and Industry polarized light show. The procedures employed are suitable for the classroom by using smaller polarizers and an overhead projector. Topic areas include properties of cellophane tape, nondisappearing arrows, and rope through a picket fence. (JN)

  16. Nucla CFB Demonstration Project

    Energy Technology Data Exchange (ETDEWEB)

    1990-12-01

    This report documents Colorado-Ute Electric Association's Nucla Circulating Atmospheric Fluidized-Bed Combustion (AFBC) demonstration project. It describes the plant equipment and system design for the first US utility-size circulating AFBC boiler and its support systems. Included are equipment and system descriptions, design/background information and appendices with an equipment list and selected information plus process flow and instrumentation drawings. The purpose of this report is to share the information gathered during the Nucla circulating AFBC demonstration project and present it so that the general public can evaluate the technical feasibility and cost effectiveness of replacing pulverized or stoker-fired boiler units with circulating fluidized-bed boiler units. (VC)

  17. IGCC technology and demonstration

    Energy Technology Data Exchange (ETDEWEB)

    Palonen, J. [A. Ahlstrom Corporation, Karhula (Finland). Hans Ahlstrom Lab.; Lundqvist, R.G. [A. Ahlstrom Corporation, Helsinki (Finland); Staahl, K. [Sydkraft AB, Malmoe (Sweden)

    1996-12-31

    Future energy production will be performed by advanced technologies that are more efficient, more environmentally friendly and less expensive than current technologies. Integrated gasification combined cycle (IGCC) power plants have been proposed as one of these systems. Utilising biofuels in future energy production will also be emphasised since this lowers substantially carbon dioxide emissions into the atmosphere due to the fact that biomass is a renewable form of energy. Combining advanced technology and biomass utilisation is for this reason something that should and will be encouraged. A. Ahlstrom Corporation of Finland and Sydkraft AB of Sweden have as one part of company strategies adopted this approach for the future. The companies have joined their resources in developing a biomass-based IGCC system with the gasification part based on pressurised circulating fluidized-bed technology. With this kind of technology electrical efficiency can be substantially increased compared to conventional power plants. As a first concrete step, a decision has been made to build a demonstration plant. This plant, located in Vaernamo, Sweden, has already been built and is now in commissioning and demonstration stage. The system comprises a fuel drying plant, a pressurised CFB gasifier with gas cooling and cleaning, a gas turbine, a waste heat recovery unit and a steam turbine. The plant is the first in the world where the integration of a pressurised gasifier with a gas turbine will be realised utilising a low calorific gas produced from biomass. The capacity of the Vaernamo plant is 6 MW of electricity and 9 MW of district heating. Technology development is in progress for design of plants of sizes from 20 to 120 MWe. The paper describes the Bioflow IGCC system, the Vaernamo demonstration plant and experiences from the commissioning and demonstration stages. (orig.)

  18. The Majorana Demonstrator

    CERN Document Server

    Aguayo, E; Hoppe, E W; Keillor, M E; Kephart, J D; Kouzes, R T; LaFerriere, B D; Merriman, J; Orrell, J L; Overman, N R; Avignone, F T; Back, H O; Combs, D C; Leviner, L E; Young, A R; Barabash, A S; Konovalov, S I; Vanyushin, I; Yumatov, V; Bergevin, M; Chan, Y-D; Detwiler, J A; Loach, J C; Martin, R D; Poon, A W P; Prior, G; Vetter, K; Bertrand, F E; Cooper, R J; Radford, D C; Varner, R L; Yu, C -H; Boswell, M; Elliott, S R; Gehman, V M; Hime, A; Kidd, M F; LaRoque, B H; Rielage, K; Ronquest, M C; Steele, D; Brudanin, V; Egorov, V; Gusey, K; Kochetov, O; Shirchenko, M; Timkin, V; Yakushev, E; Busch, M; Esterline, J; Tornow, W; Christofferson, C D; Horton, M; Howard, S; Sobolev, V; Collar, J I; Fields, N; Creswick, R J; Doe, P J; Johnson, R A; Knecht, A; Leon, J; Marino, M G; Miller, M L; Robertson, R G H; Schubert, A G; Wolfe, B A; Efremenko, Yu; Ejiri, H; Hazama, R; Nomachi, M; Shima, T; Finnerty, P; Fraenkle, F M; Giovanetti, G K; Green, M P; Henning, R; Howe, M A; MacMullin, S; Phillips, D G; Snavely, K J; Strain, J; Vorren, K; Guiseppe, V E; Keller, C; Mei, D -M; Perumpilly, G; Thomas, K; Zhang, C; Hallin, A L; Keeter, K J; Mizouni, L; Wilkerson, J F

    2011-01-01

    A brief review of the history and neutrino physics of double beta decay is given. A description of the MAJORANA DEMONSTRATOR research and development program including background reduction techniques is presented in some detail. The application of point contact (PC) detectors to the experiment is discussed, including the effectiveness of pulse shape analysis. The predicted sensitivity of a PC detector array enriched to 86% in 76Ge is given.

  19. The Majorana Demonstrator

    Energy Technology Data Exchange (ETDEWEB)

    Aguayo, Estanislao; Fast, James E.; Hoppe, Eric W.; Keillor, Martin E.; Kephart, Jeremy D.; Kouzes, Richard T.; LaFerriere, Brian D.; Merriman, Jason H.; Orrell, John L.; Overman, Nicole R.; Avignone, Frank T.; Back, Henning O.; Combs, Dustin C.; Leviner, L.; Young, A.; Barabash, Alexander S.; Konovalov, S.; Vanyushin, I.; Yumatov, Vladimir; Bergevin, M.; Chan, Yuen-Dat; Detwiler, Jason A.; Loach, J. C.; Martin, R. D.; Poon, Alan; Prior, Gersende; Vetter, Kai; Bertrand, F.; Cooper, R. J.; Radford, D. C.; Varner, R. L.; Yu, Chang-Hong; Boswell, M.; Elliott, S.; Gehman, Victor M.; Hime, Andrew; Kidd, M. F.; LaRoque, B. H.; Rielage, Keith; Ronquest, M. C.; Steele, David; Brudanin, V.; Egorov, Viatcheslav; Gusey, K.; Kochetov, Oleg; Shirchenko, M.; Timkin, V.; Yakushev, E.; Busch, Matthew; Esterline, James H.; Tornow, Werner; Christofferson, Cabot-Ann; Horton, Mark; Howard, S.; Sobolev, V.; Collar, J. I.; Fields, N.; Creswick, R.; Doe, Peter J.; Johnson, R. A.; Knecht, A.; Leon, Jonathan D.; Marino, Michael G.; Miller, M. L.; Robertson, R. G. H.; Schubert, Alexis G.; Wolfe, B. A.; Efremenko, Yuri; Ejiri, H.; Hazama, R.; Nomachi, Masaharu; Shima, T.; Finnerty, P.; Fraenkle, Florian; Giovanetti, G. K.; Green, M.; Henning, Reyco; Howe, M. A.; MacMullin, S.; Phillips, D.; Snavely, Kyle J.; Strain, J.; Vorren, Kris R.; Guiseppe, Vincente; Keller, C.; Mei, Dong-Ming; Perumpilly, Gopakumar; Thomas, K.; Zhang, C.; Hallin, A. L.; Keeter, K.; Mizouni, Leila; Wilkerson, J. F.

    2011-09-03

    A brief review of the history and neutrino physics of double beta decay is given. A description of the MAJORANA DEMONSTRATOR research and development program, including background reduction techniques, is presented in some detail. The application of point contact (PC) detectors to the experiment is discussed, including the effectiveness of pulse shape analysis. The predicted sensitivity of a PC detector array enriched to 86% to 76Ge is given.

  20. Inhibition of de novo Palmitate Synthesis by Fatty Acid Synthase Induces Apoptosis in Tumor Cells by Remodeling Cell Membranes, Inhibiting Signaling Pathways, and Reprogramming Gene Expression

    Directory of Open Access Journals (Sweden)

    Richard Ventura

    2015-08-01

    Research in context: Fatty acid synthase (FASN is a vital enzyme in tumor cell biology; the over-expression of FASN is associated with diminished patient prognosis and resistance to many cancer therapies. Our data demonstrate that selective and potent FASN inhibition with TVB-3166 leads to selective death of tumor cells, without significant effect on normal cells, and inhibits in vivo xenograft tumor growth at well-tolerated doses. Candidate biomarkers for selecting tumors highly sensitive to FASN inhibition are identified. These preclinical data provide mechanistic and pharmacologic evidence that FASN inhibition presents a promising therapeutic strategy for treating a variety of cancers.

  1. Factors significantly increasing or inhibiting early stages of malignant melanoma (M.M.) and non-invasive evaluation of new treatment by ingestion and external application of optimal doses of the most effective anti-M.M. substances: haritaki, cilantro, vitamin D3, nori, EPA with DHA, & application of special (+) solar energy stored paper, which reduced the M.M. active area & asbestos rapidly.

    Science.gov (United States)

    Omura, Yoshiaki; Jones, Marilyn; Duvvi, Harsha; Paluch, Kamila; Shimotsuura, Yasuhiro; Ohki, Motomu

    2013-01-01

    Sterilizing the pre-cancer skin of malignant melanoma (M.M.) with 70% Isopropyl alcohol intensified malignancy & the malignant response extended to surrounding normal looking skin, while sterilizing with 80% (vodka) or 12% (plum wine) ethyl alcohol completely inhibited M.M. in the area (both effects lasted for about 90 minutes initially). Burnt food (bread, vegetables, meat, and fish), a variety of smoked & non-smoked fish-skin, many animal's skin, pepper, Vitamin C over 75 mg, mango, pineapple, coconut, almond, sugars, Saccharine & Aspartame, garlic, onion, etc & Electromagnetic field from cellular phones worsened M.M. & induced abnormal M.M. response of surrounding skin. We found the following factors inhibit early stage of M.M. significantly: 1) Increasing normal cell telomere, by taking 500 mg Haritaki, often reached between 400-1150 ng& gradually diminished, but the M.M. response was completely inhibited until normal cell telomeres are reduced to 150 ng, which takes 6-8 hours. More than 70 mg Vitamin C, Orange Juice, & other high Vitamin C containing substances shouldn't be taken because they completely inhibit the effects of Haritaki. 2) We found Chrysotile asbestos & Tremolite asbestos (% of the Chrysotile amount) coexist. A special Cilantro tablet was used to remove asbestos & some toxic metals. 3) Vitamin D3 400 I.U. has a maximum inhibiting effect on M.M. but 800 I.U. or higher promotes malignancy. 4) Noricontaining Iodine, etc., was used. 5) EPA 180 mm with DHA 120 mg was most effectively used after metastasis to the surrounding skin was eliminated. When we combined 1 Cilantro tablet & Vitamin D3 400 I.U. withsmall Nori pieces & EPA with DHA, the effect of complete inhibition of M.M. lasted 9-11 hours. When these anti-M.M.substances (Haritaki, Vitamin D3, Cilantro, Nori, EPA. with DHA) were taken together, the effect lasted 12-14 hoursand M.M. involvement in surrounding normal-looking skin disappeared rapidly & original dark brown or black are as

  2. Learning From Demonstration?

    DEFF Research Database (Denmark)

    Koch, Christian; Bertelsen, Niels Haldor

    2014-01-01

    . This paper reports on an early demonstration project, the Building of a passive house dormitory in the Central Region of Denmark in 2006-2009. The project was supposed to deliver value, lean design, prefabrication, quality in sustainability, certification according to German standards for passive houses...... of control, driven by such challenges as complying with cost goals, the need to choose a German prefab supplier, and local contractors. Energy calculations, indoor climate, issues related to square meter requirements, and the hydrogen element became problematic. The aim to obtain passive house certification...

  3. Learning From Demonstration?

    DEFF Research Database (Denmark)

    Koch, Christian; Bertelsen, Niels Haldor

    2014-01-01

    , and micro combined heat and power using hydrogen. Using sociological and business economic theories of innovation, the paper discusses how early movers of innovation tend to obtain only partial success when demonstrating their products and often feel obstructed by minor details. The empirical work...... encompasses both an evaluation of the design and Construction process as well as a post-occupancy evaluation. Process experiences include the use of a multidisciplinary competence group and performance measurement. The commencement of the project was enthusiastic, but it was forced into more traditional forms...

  4. Visual Electricity Demonstrator

    Science.gov (United States)

    Lincoln, James

    2017-09-01

    The Visual Electricity Demonstrator (VED) is a linear diode array that serves as a dynamic alternative to an ammeter. A string of 48 red light-emitting diodes (LEDs) blink one after another to create the illusion of a moving current. Having the current represented visually builds an intuitive and qualitative understanding about what is happening in a circuit. In this article, I describe several activities for this device and explain how using this technology in the classroom can enhance the understanding and appreciation of physics.

  5. NAVAJO ELECTRIFICATION DEMONSTRATION PROJECT

    Energy Technology Data Exchange (ETDEWEB)

    Terry W. Battiest

    2008-06-11

    The Navajo Electrification Demonstration Project (NEDP) is a multi-year project which addresses the electricity needs of the unserved and underserved Navajo Nation, the largest American Indian tribe in the United States. The program serves to cumulatively provide off-grid electricty for families living away from the electricty infrastructure, line extensions for unserved families living nearby (less than 1/2 mile away from) the electricity, and, under the current project called NEDP-4, the construction of a substation to increase the capacity and improve the quality of service into the central core region of the Navajo Nation.

  6. Education Demonstration Equipment

    Science.gov (United States)

    Nagy, A.; Lee, R. L.

    2003-10-01

    The General Atomics fusion education program ``Scientist in the Classroom" (SIC) now in its sixth year, uses scientists and engineers to present plasma as a state of matter to students in the classroom. Using hands-on equipment, students see how magnets, gas pressure changes, and different gases are turned into plasmas. A piston, sealed volume, and vacuum chamber illuminate ideal gas laws. Liquid nitrogen is used to explore thermodynamic temperature effects and changes in states of matter. Light bulbs are excited with a Tesla coil to ionize gases, thus becoming an inexpensive plasma devices and a plasma tube shows magnetic interactions with plasma. The demonstration equipment used in this program is built with simple designs and common commercial equipment keeping in mind a teacher's tight budget. The SIC program ( ˜25 school presentations per year) has become very popular and has acquired an enthusiastic group of regular teacher clientele requesting repeat visits. In addition, three very popular and successful ``Build-It" days, sponsored by the General Atomics Fusion Education Outreach Program, enables teachers to build and keep in their classroom some of this equipment. The demonstration devices will be presented along with their ``build-it" details.

  7. Inseparable phone books demonstration

    Science.gov (United States)

    Balta, Nuri; Çetin, Ali

    2017-05-01

    This study is aimed at first introducing a well-known discrepant event; inseparable phone books and second, turning it into an experiment for high school or middle school students. This discrepant event could be used especially to indicate how friction force can be effective in producing an unexpected result. Demonstration, discussion, explanation and experiment steps are presented on how to turn a simple discrepant event into an instructional activity. Results showed the relationships between number of pages and force, as well as between amounts of interleave and force. In addition to these, the mathematical equation for the total force between all interleaved pages is derived. As a conclusion, this study demonstrated that not only can phone books be used, but also ordinary books, to investigate this discrepant event. This experiment can be conducted as an example to show the agreement between theoretical and experimental results along with the confounding variables. This discrepant event can be used to create a cognitive conflict in students’ minds about the concepts of ‘force and motion’ and ‘friction force’.

  8. PFBC Utility Demonstration Project

    Energy Technology Data Exchange (ETDEWEB)

    1992-11-01

    This report provides a summary of activities by American Electric Power Service Corporation during the first budget period of the PFBC Utility Demonstration Project. In April 1990, AEP signed a Cooperative Agreement with the US Department of Energy to repower the Philip Sporn Plant, Units 3 4 in New Haven, West Virginia, with a 330 KW PFBC plant. The purpose of the program was to demonstrate and verify PFBC in a full-scale commercial plant. The technical and cost baselines of the Cooperative Agreement were based on a preliminary engineering and design and a cost estimate developed by AEP subsequent to AEP's proposal submittal in May 1988, and prior to the signing of the Cooperative Agreement. The Statement of Work in the first budget period of the Cooperative Agreement included a task to develop a preliminary design and cost estimate for erecting a Greenfield plant and to conduct a comparison with the repowering option. The comparative assessment of the options concluded that erecting a Greenfield plant rather than repowering the existing Sporn Plant could be the technically and economically superior alternative. The Greenfield plant would have a capacity of 340 MW. The ten additional MW output is due to the ability to better match the steam cycle to the PFBC system with a new balance of plant design. In addition to this study, the conceptual design of the Sporn Repowering led to several items which warranted optimization studies with the goal to develop a more cost effective design.

  9. Smart Grid Demonstration Project

    Energy Technology Data Exchange (ETDEWEB)

    Miller, Craig [National Rural Electric Cooperative Association, Arlington, VA (United States); Carroll, Paul [National Rural Electric Cooperative Association, Arlington, VA (United States); Bell, Abigail [National Rural Electric Cooperative Association, Arlington, VA (United States)

    2015-03-11

    The National Rural Electric Cooperative Association (NRECA) organized the NRECA-U.S. Department of Energy (DOE) Smart Grid Demonstration Project (DE-OE0000222) to install and study a broad range of advanced smart grid technologies in a demonstration that spanned 23 electric cooperatives in 12 states. More than 205,444 pieces of electronic equipment and more than 100,000 minor items (bracket, labels, mounting hardware, fiber optic cable, etc.) were installed to upgrade and enhance the efficiency, reliability, and resiliency of the power networks at the participating co-ops. The objective of this project was to build a path for other electric utilities, and particularly electrical cooperatives, to adopt emerging smart grid technology when it can improve utility operations, thus advancing the co-ops’ familiarity and comfort with such technology. Specifically, the project executed multiple subprojects employing a range of emerging smart grid technologies to test their cost-effectiveness and, where the technology demonstrated value, provided case studies that will enable other electric utilities—particularly electric cooperatives— to use these technologies. NRECA structured the project according to the following three areas: Demonstration of smart grid technology; Advancement of standards to enable the interoperability of components; and Improvement of grid cyber security. We termed these three areas Technology Deployment Study, Interoperability, and Cyber Security. Although the deployment of technology and studying the demonstration projects at coops accounted for the largest portion of the project budget by far, we see our accomplishments in each of the areas as critical to advancing the smart grid. All project deliverables have been published. Technology Deployment Study: The deliverable was a set of 11 single-topic technical reports in areas related to the listed technologies. Each of these reports has already been submitted to DOE, distributed to co-ops, and

  10. Jennings Demonstration PLant

    Energy Technology Data Exchange (ETDEWEB)

    Russ Heissner

    2010-08-31

    Verenium operated a demonstration plant with a capacity to produce 1.4 million gallons of cellulosic ethanol from agricultural resiues for about two years. During this time, the plant was able to evaluate the technical issues in producing ethanol from three different cellulosic feedstocks, sugar cane bagasse, energy cane, and sorghum. The project was intended to develop a better understanding of the operating parameters that would inform a commercial sized operation. Issues related to feedstock variability, use of hydrolytic enzymes, and the viability of fermentative organisms were evaluated. Considerable success was achieved with pretreatment processes and use of enzymes but challenges were encountered with feedstock variability and fermentation systems. Limited amounts of cellulosic ethanol were produced.

  11. NASA Bioreactor Demonstration System

    Science.gov (United States)

    2002-01-01

    Leland W. K. Chung (left), Director, Molecular Urology Therapeutics Program at the Winship Cancer Institute at Emory University, is principal investigator for the NASA bioreactor demonstration system (BDS-05). With him is Dr. Jun Shu, an assistant professor of Orthopedics Surgery from Kuming Medical University China. The NASA Bioreactor provides a low turbulence culture environment which promotes the formation of large, three-dimensional cell clusters. Due to their high level of cellular organization and specialization, samples constructed in the bioreactor more closely resemble the original tumor or tissue found in the body. The Bioreactor is rotated to provide gentle mixing of fresh and spent nutrient without inducing shear forces that would damage the cells. The work is sponsored by NASA's Office of Biological and Physical Research. The bioreactor is managed by the Biotechnology Cell Science Program at NASA's Johnson Space Center (JSC). NASA-sponsored bioreactor research has been instrumental in helping scientists to better understand normal and cancerous tissue development. In cooperation with the medical community, the bioreactor design is being used to prepare better models of human colon, prostate, breast and ovarian tumors. Cartilage, bone marrow, heart muscle, skeletal muscle, pancreatic islet cells, liver and kidney are just a few of the normal tissues being cultured in rotating bioreactors by investigators. Credit: Emory University.

  12. Nuclear power demonstrating

    Energy Technology Data Exchange (ETDEWEB)

    Basmajian, V. V.; Haldeman, C. W.

    1980-08-12

    Apparatus for demonstrating the operation of a closed loop nuclear steam electric generating plant includes a transparent boiler assembly having immersion heating elements, which may be quartz lamps or stainless steel encased resistive immersion heating units with a quartz iodide lamp providing a source of visible radiation when using the encased immersion heating units. A variable voltage autotransformer is geared to a support rod for simulated reactor control rods for controlling the energy delivered to the heating elements and arranged so that when the voltage is high, the rods are withdrawn from the boiler to produce increased heating and illumination proportional to rod position, thereby simulating nuclear reaction. A relief valve, steam outlet pipe and water inlet pipe are connected to the boiler with a small stainless steel resistive heating element in the steam outlet pipe providing superheat. This heater is connected in series with a rheostat mounted on the front panel to provide superheat adjustments and an interlock switch that prevents the superheater from being energized when the steam valve is off with with no flow through the superheater. A heavy blue plastic radiation shield surrounds the boiler inside a bell jar.

  13. A Demonstration of Lusail

    KAUST Repository

    Mansour, Essam

    2017-05-10

    There has been a proliferation of datasets available as interlinked RDF data accessible through SPARQL endpoints. This has led to the emergence of various applications in life science, distributed social networks, and Internet of Things that need to integrate data from multiple endpoints. We will demonstrate Lusail; a system that supports the need of emerging applications to access tens to hundreds of geo-distributed datasets. Lusail is a geo-distributed graph engine for querying linked RDF data. Lusail delivers outstanding performance using (i) a novel locality-aware query decomposition technique that minimizes the intermediate data to be accessed by the subqueries, and (ii) selectivityawareness and parallel query execution to reduce network latency and to increase parallelism. During the demo, the audience will be able to query actually deployed RDF endpoints as well as large synthetic and real benchmarks that we have deployed in the public cloud. The demo will also show that Lusail outperforms state-of-the-art systems by orders of magnitude in terms of scalability and response time.

  14. Solar Thermal Demonstration Project

    Energy Technology Data Exchange (ETDEWEB)

    Biesinger, K; Cuppett, D; Dyer, D

    2012-01-30

    HVAC Retrofit and Energy Efficiency Upgrades at Clark High School, Las Vegas, Nevada The overall objectives of this project are to increase usage of alternative/renewable fuels, create a better and more reliable learning environment for the students, and reduce energy costs. Utilizing the grant resources and local bond revenues, the District proposes to reduce electricity consumption by installing within the existing limited space, one principal energy efficient 100 ton adsorption chiller working in concert with two 500 ton electric chillers. The main heating source will be primarily from low nitrogen oxide (NOX), high efficiency natural gas fired boilers. With the use of this type of chiller, the electric power and cost requirements will be greatly reduced. To provide cooling to the information technology centers and equipment rooms of the school during off-peak hours, the District will install water source heat pumps. In another measure to reduce the cooling requirements at Clark High School, the District will replace single pane glass and metal panels with Kalwall building panels. An added feature of the Kalwall system is that it will allow for natural day lighting in the student center. This system will significantly reduce thermal heat/cooling loss and control solar heat gain, thus delivering significant savings in heating ventilation and air conditioning (HVAC) costs.

  15. Effects of lorazepam on short latency afferent inhibition and short latency intracortical inhibition in humans.

    Science.gov (United States)

    Di Lazzaro, V; Oliviero, A; Saturno, E; Dileone, M; Pilato, F; Nardone, R; Ranieri, F; Musumeci, G; Fiorilla, T; Tonali, P

    2005-04-15

    Experimental studies have demonstrated that the GABAergic system modulates acetylcholine release and, through GABA(A) receptors, tonically inhibits cholinergic activity. Little is known about the effects of GABA on the cholinergic activity in the human central nervous system. In vivo evaluation of some cholinergic circuits of the human brain has recently been introduced using a transcranial magnetic stimulation (TMS) protocol based on coupling peripheral nerve stimulation with TMS of the motor cortex. Peripheral nerve inputs have an inhibitory effect on motor cortex excitability at short intervals (short latency afferent inhibition, SAI). We investigated whether GABA(A) activity enhancement by lorazepam modifies SAI. We also evaluated the effects produced by lorazepam on a different TMS protocol of cortical inhibition, the short interval intracortical inhibition (SICI), which is believed to be directly related to GABA(A) activity. In 10 healthy volunteers, the effects of lorazepam were compared with those produced by quetiapine, a psychotropic drug with sedative effects with no appreciable affinity at cholinergic muscarinic and benzodiazepine receptors, and with those of a placebo using a randomized double-blind study design. Administration of lorazepam produced a significant increase in SICI (F(3,9) = 3.19, P = 0.039). In contrast to SICI, SAI was significantly reduced by lorazepam (F(3,9) = 9.39, P = 0.0002). Our findings demonstrate that GABA(A) activity enhancement determines a suppression of SAI and an increase of SICI.

  16. Significant Scales in Community Structure

    CERN Document Server

    Traag, V A; Van Dooren, P

    2013-01-01

    Many complex networks show signs of modular structure, uncovered by community detection. Although many methods succeed in revealing various partitions, it remains difficult to detect at what scale some partition is significant. This problem shows foremost in multi-resolution methods. We here introduce an efficient method for scanning for resolutions in one such method. Additionally, we introduce the notion of "significance" of a partition, based on subgraph probabilities. Significance is independent of the exact method used, so could also be applied in other methods, and can be interpreted as the gain in encoding a graph by making use of a partition. Using significance, we can determine "good" resolution parameters, which we demonstrate on benchmark networks. Moreover, optimizing significance itself also shows excellent performance. We demonstrate our method on voting data from the European Parliament. Our analysis suggests the European Parliament has become increasingly ideologically divided and that nationa...

  17. Bacterial toxins can inhibit host cell autophagy through cAMP generation.

    Science.gov (United States)

    Shahnazari, Shahab; Namolovan, Anton; Mogridge, Jeremy; Kim, Peter K; Brumell, John H

    2011-09-01

    Autophagy plays a significant role in innate and adaptive immune responses to microbial infection. Some pathogenic bacteria have developed strategies to evade killing by host autophagy. These include the use of 'camouflage' proteins to block targeting to the autophagy pathway and the use of pore-forming toxins to block autophagosome maturation. However, general inhibition of host autophagy by bacterial pathogens has not been observed to date. Here we demonstrate that bacterial cAMP-elevating toxins from B. anthracis and V. cholera can inhibit host anti-microbial autophagy, including autophagic targeting of S. Typhimurium and latex bead phagosomes. Autophagy inhibition required the cAMP effector protein kinase A. Formation of autophagosomes in response to rapamycin and the endogenous turnover of peroxisomes was also inhibited by cAMP-elevating toxins. These findings demonstrate that cAMP-elevating toxins, representing a large group of bacterial virulence factors, can inhibit host autophagy to suppress immune responses and modulate host cell physiology.

  18. Neural correlates of central inhibition during physical fatigue.

    Directory of Open Access Journals (Sweden)

    Masaaki Tanaka

    Full Text Available Central inhibition plays a pivotal role in determining physical performance during physical fatigue. Classical conditioning of central inhibition is believed to be associated with the pathophysiology of chronic fatigue. We tried to determine whether classical conditioning of central inhibition can really occur and to clarify the neural mechanisms of central inhibition related to classical conditioning during physical fatigue using magnetoencephalography (MEG. Eight right-handed volunteers participated in this study. We used metronome sounds as conditioned stimuli and maximum handgrip trials as unconditioned stimuli to cause central inhibition. Participants underwent MEG recording during imagery of maximum grips of the right hand guided by metronome sounds for 10 min. Thereafter, fatigue-inducing maximum handgrip trials were performed for 10 min; the metronome sounds were started 5 min after the beginning of the handgrip trials. The next day, neural activities during imagery of maximum grips of the right hand guided by metronome sounds were measured for 10 min. Levels of fatigue sensation and sympathetic nerve activity on the second day were significantly higher relative to those of the first day. Equivalent current dipoles (ECDs in the posterior cingulated cortex (PCC, with latencies of approximately 460 ms, were observed in all the participants on the second day, although ECDs were not identified in any of the participants on the first day. We demonstrated that classical conditioning of central inhibition can occur and that the PCC is involved in the neural substrates of central inhibition related to classical conditioning during physical fatigue.

  19. Exploration Medical System Demonstration Project

    Science.gov (United States)

    Chin, D. A.; McGrath, T. L.; Reyna, B.; Watkins, S. D.

    2011-01-01

    A near-Earth Asteroid (NEA) mission will present significant new challenges including hazards to crew health created by exploring a beyond low earth orbit destination, traversing the terrain of asteroid surfaces, and the effects of variable gravity environments. Limited communications with ground-based personnel for diagnosis and consultation of medical events require increased crew autonomy when diagnosing conditions, creating treatment plans, and executing procedures. Scope: The Exploration Medical System Demonstration (EMSD) project will be a test bed on the International Space Station (ISS) to show an end-to-end medical system assisting the Crew Medical Officers (CMO) in optimizing medical care delivery and medical data management during a mission. NEA medical care challenges include resource and resupply constraints limiting the extent to which medical conditions can be treated, inability to evacuate to Earth during many mission phases, and rendering of medical care by a non-clinician. The system demonstrates the integration of medical technologies and medical informatics tools for managing evidence and decision making. Project Objectives: The objectives of the EMSD project are to: a) Reduce and possibly eliminate the time required for a crewmember and ground personnel to manage medical data from one application to another. b) Demonstrate crewmember's ability to access medical data/information via a software solution to assist/aid in the treatment of a medical condition. c) Develop a common data management architecture that can be ubiquitously used to automate repetitive data collection, management, and communications tasks for all crew health and life sciences activities. d) Develop a common data management architecture that allows for scalability, extensibility, and interoperability of data sources and data users. e) Lower total cost of ownership for development and sustainment of peripheral hardware and software that use EMSD for data management f) Provide

  20. The Edgewater Coolside process demonstration

    Energy Technology Data Exchange (ETDEWEB)

    McCoy, D.C.; Scandrol, R.O.; Statnick, R.M.; Stouffer, M.R.; Winschel, R.A.; Withum, J.A.; Wu, M.M.; Yoon, H. [CONSOL, Inc., Pittsburgh, PA (United States)

    1992-02-01

    The Edgewater Coolside process demonstration met the program objectives which were to determine Coolside SO{sub 2} removal performance, establish short-term process operability, and evaluate the economics of the process versus a limestone wet scrubber. On a flue gas produced from the combustion of 3% sulfur coal, the Coolside process achieved 70% SO{sub 2} removal using commercially-available hydrated lime as the sorbent. The operating conditions were Ca/S mol ratio 2.0, Na/Ca mol ratio 0.2, and 20{degree}F approach to adiabatic saturation temperature ({del}T). During tests using fresh plus recycle sorbent, the recycle sorbent exhibited significant capacity for additional SO{sub 2} removal. The longest steady state operation was eleven days at nominally Ca/S = 2, Na/Ca = 0.22, {del}T = 20--22{degree}F, and 70% SO{sub 2} removal. The operability results achieved during the demonstration indicate that with the recommended process modifications, which are discussed in the Coolside process economic analysis, the process could be designed as a reliable system for utility application. Based on the demonstration program, the Coolside process capital cost for a hypothetical commercial installation was minimized. The optimization consisted of a single, large humidifier, no spare air compressor, no isolation dampers, and a 15 day on-site hydrated lime storage. The levelized costs of the Coolside and the wet limestone scrubbing processes were compared. The Coolside process is generally economically competitive with wet scrubbing for coals containing up to 2.5% sulfur and plants under 350 MWe. Site-specific factors such as plant capacity factor, SO{sub 2} emission limit, remaining plant life, retrofit difficulty, and delivered sorbent cost affect the scrubber-Coolside process economic comparison.

  1. The Edgewater Coolside process demonstration

    Energy Technology Data Exchange (ETDEWEB)

    McCoy, D.C.; Scandrol, R.O.; Statnick, R.M.; Stouffer, M.R.; Winschel, R.A.; Withum, J.A.; Wu, M.M.; Yoon, H. (CONSOL, Inc., Pittsburgh, PA (United States))

    1992-02-01

    The Edgewater Coolside process demonstration met the program objectives which were to determine Coolside SO[sub 2] removal performance, establish short-term process operability, and evaluate the economics of the process versus a limestone wet scrubber. On a flue gas produced from the combustion of 3% sulfur coal, the Coolside process achieved 70% SO[sub 2] removal using commercially-available hydrated lime as the sorbent. The operating conditions were Ca/S mol ratio 2.0, Na/Ca mol ratio 0.2, and 20[degree]F approach to adiabatic saturation temperature ([del]T). During tests using fresh plus recycle sorbent, the recycle sorbent exhibited significant capacity for additional SO[sub 2] removal. The longest steady state operation was eleven days at nominally Ca/S = 2, Na/Ca = 0.22, [del]T = 20--22[degree]F, and 70% SO[sub 2] removal. The operability results achieved during the demonstration indicate that with the recommended process modifications, which are discussed in the Coolside process economic analysis, the process could be designed as a reliable system for utility application. Based on the demonstration program, the Coolside process capital cost for a hypothetical commercial installation was minimized. The optimization consisted of a single, large humidifier, no spare air compressor, no isolation dampers, and a 15 day on-site hydrated lime storage. The levelized costs of the Coolside and the wet limestone scrubbing processes were compared. The Coolside process is generally economically competitive with wet scrubbing for coals containing up to 2.5% sulfur and plants under 350 MWe. Site-specific factors such as plant capacity factor, SO[sub 2] emission limit, remaining plant life, retrofit difficulty, and delivered sorbent cost affect the scrubber-Coolside process economic comparison.

  2. 酶抑制法测定m-AS T试剂性能评价及其在肝病中的意义%Evaluation on the reagent performance for the determination of m-AST by enzyme inhibition method and ;the clinical significance of m-AST in patients with liver disease

    Institute of Scientific and Technical Information of China (English)

    李君; 谢劲松; 臧桂珍

    2013-01-01

    目的:评价酶抑制法测定天门冬氨酸氨基转移酶(AST)线粒体同工酶(m-AST)活性的性能,并探讨m-AST在肝脏疾病中的临床价值。方法采用酶抑制法检测m-AST活性[即采用蛋白酶完全抑制AST细胞质同工酶(c-AST)的活性,然后用速率法进行检测],并与免疫抑制法比较。采用酶抑制法检测259例肝病患者(包括急性肝炎43例、慢性病毒性肝炎95例、肝衰竭20例、重型肝炎11例、肝硬化代偿期40例、肝硬化失代偿期9例、原发性肝癌41例)及220名健康体检者(正常对照组)m-AST活性,并与AST比较。结果酶抑制法批内变异系数(CV)为0.59%~2.23%,批间 CV为5.24%~6.23%;回收率为101.6%~108.0%,平均为104.97%;线性方程Y=0.997X-1.51,r=0.9999,m-AST活性在450 U/L内线性良好;可完全抑制1500 U/L的c-AST活性;与免疫抑制法结果呈高度正相关(r=0.9998);溶血对m-AST检测结果干扰较大;以95%可信区间(x-±1.96s)初步确定m-AST参考区间男性为3.1~9.5 U/L,女性为2.5~8.7 U/L。肝病患者m-AST活性均高于正常对照组(P<0.05),并与AST呈正相关。正常对照组m-AST/AST比值为0.30±0.07,肝病患者m-AST/AST比值均低于正常对照组(P<0.05),但变化不如m-AST活性明显。结论酶抑制法测定m-AST活性自动化程度高,结果准确可靠,重复性好,线性范围宽。m-AST活性能反映肝细胞损伤的严重程度,对肝脏疾病的临床分类和预后具有重要价值。%Objective To evaluate the performance of mitochondrial aspartate aminotransferase (m-AST)by enzyme inhibition method,and to investigate the clinical significance of m-AST in patients with liver disease.Methods The m-AST activity was determined by enzyme inhibition method,and the activity of cytosolic aspartate aminotransferase (c-AST)was inhibited by protease

  3. Contaminant analysis automation demonstration proposal

    Energy Technology Data Exchange (ETDEWEB)

    Dodson, M.G.; Schur, A.; Heubach, J.G.

    1993-10-01

    The nation-wide and global need for environmental restoration and waste remediation (ER&WR) presents significant challenges to the analytical chemistry laboratory. The expansion of ER&WR programs forces an increase in the volume of samples processed and the demand for analysis data. To handle this expanding volume, productivity must be increased. However. The need for significantly increased productivity, faces contaminant analysis process which is costly in time, labor, equipment, and safety protection. Laboratory automation offers a cost effective approach to meeting current and future contaminant analytical laboratory needs. The proposed demonstration will present a proof-of-concept automated laboratory conducting varied sample preparations. This automated process also highlights a graphical user interface that provides supervisory, control and monitoring of the automated process. The demonstration provides affirming answers to the following questions about laboratory automation: Can preparation of contaminants be successfully automated?; Can a full-scale working proof-of-concept automated laboratory be developed that is capable of preparing contaminant and hazardous chemical samples?; Can the automated processes be seamlessly integrated and controlled?; Can the automated laboratory be customized through readily convertible design? and Can automated sample preparation concepts be extended to the other phases of the sample analysis process? To fully reap the benefits of automation, four human factors areas should be studied and the outputs used to increase the efficiency of laboratory automation. These areas include: (1) laboratory configuration, (2) procedures, (3) receptacles and fixtures, and (4) human-computer interface for the full automated system and complex laboratory information management systems.

  4. Significant NRC Enforcement Actions

    Data.gov (United States)

    Nuclear Regulatory Commission — This dataset provides a list of Nuclear Regulartory Commission (NRC) issued significant enforcement actions. These actions, referred to as "escalated", are issued by...

  5. Haloperidol treatment at pre-exposure phase reduces the disturbance of latent inhibition in rats with neonatal ventral hippocampus lesions.

    Science.gov (United States)

    Ouhaz, Zakaria; Ba-M'hamed, Saadia; Bennis, Mohamed

    2014-10-01

    Animals with neonatal ventral hippocampal lesions develop during or after adolescence abnormal behaviors related to schizophrenia such as anxiety and latent inhibition disruption. The aim of this study was to test whether haloperidol injection prior to pre-exposure session in the latent inhibition test would facilitate latent inhibition. Lesioned animals showed a significant decrease in the number and duration of social interactions, a decrease in the marbles buried, a significant increase in locomotor activity, and a disruption of latent inhibition. In the conditioned taste aversion test, injection of haloperidol produced the recovery of latent inhibition. These findings demonstrate that neonatal lidocaine lesion of the ventral hippocampus can induce behavioral changes related to schizophrenia, and injection of haloperidol, when restricted only to a three-day pre-exposure, is sufficient to facilitate latent inhibition.

  6. Peptide inhibition of human cytomegalovirus infection

    Directory of Open Access Journals (Sweden)

    Morris Cindy A

    2011-02-01

    Full Text Available Abstract Background Human cytomegalovirus (HCMV is the most prevalent congenital viral infection in the United States and Europe causing significant morbidity and mortality to both mother and child. HCMV is also an opportunistic pathogen in immunocompromised individuals, including human immunodeficiency virus (HIV- infected patients with AIDS, and solid organ and allogeneic stem cell transplantation recipients. Current treatments for HCMV-associated diseases are insufficient due to the emergence of drug-induced resistance and cytotoxicity, necessitating novel approaches to limit HCMV infection. The aim of this study was to develop therapeutic peptides targeting glycoprotein B (gB, a major glycoprotein of HCMV that is highly conserved across the Herpesviridae family, that specifically inhibit fusion of the viral envelope with the host cell membrane preventing HCMV entry and infection. Results Using the Wimley-White Interfacial Hydrophobicity Scale (WWIHS, several regions within gB were identified that display a high potential to interact with lipid bilayers of cell membranes and hydrophobic surfaces within proteins. The ability of synthetic peptides analogous to WWIHS-positive sequences of HCMV gB to inhibit viral infectivity was evaluated. Human foreskin fibroblasts (HFF were infected with the Towne-GFP strain of HCMV (0.5 MOI, preincubated with peptides at a range of concentrations (78 nm to 100 μM, and GFP-positive cells were visualized 48 hours post-infection by fluorescence microscopy and analyzed quantitatively by flow cytometry. Peptides that inhibited HCMV infection demonstrated different inhibitory concentration curves indicating that each peptide possesses distinct biophysical properties. Peptide 174-200 showed 80% inhibition of viral infection at a concentration of 100 μM, and 51% and 62% inhibition at concentrations of 5 μM and 2.5 μM, respectively. Peptide 233-263 inhibited infection by 97% and 92% at concentrations of 100

  7. Significance Testing Without Truth

    Science.gov (United States)

    2012-07-27

    ICES REPORT 12-34 August 2012 Significance testing without truth by William Perkins, Mark Tygert, and Rachel Ward The Institute for Computational...testing without truth , ICES REPORT 12-34, The Institute for Computational Engineering and Sciences, The University of Texas at Austin, August 2012...2. REPORT TYPE 3. DATES COVERED 00-00-2012 to 00-00-2012 4. TITLE AND SUBTITLE Significance testing without truth 5a. CONTRACT NUMBER 5b

  8. A thought-provoking demonstration

    Science.gov (United States)

    Cowley, E. Roger; Holton, Brian; Horton, George K.

    1998-01-01

    We present and discuss a physics demonstration, similar to, but distinct from, the ballistic-pendulum demonstration, one that illustrates all three conservation laws of mechanics (for energy, momentum, and angular momentum) simultaneously.

  9. Teleoperation for learning by demonstration

    DEFF Research Database (Denmark)

    Kukliński, Kamil; Fischer, Kerstin; Marhenke, Ilka

    2014-01-01

    Learning by demonstration is a useful technique to augment a robot's behavioral inventory, and teleoperation allows lay users to demonstrate novel behaviors intuitively to the robot. In this paper, we compare two modes of teleoperation of an industrial robot, the demonstration by means of a data...... glove and by means of a control object (peg). Experiments with 16 lay users, performing assembly task on the Cranfield benchmark objects, show that the control peg leads to more success, more efficient demonstration and fewer errors....

  10. Teleoperation for learning by demonstration

    DEFF Research Database (Denmark)

    Kukliński, Kamil; Fischer, Kerstin; Marhenke, Ilka;

    2014-01-01

    Learning by demonstration is a useful technique to augment a robot's behavioral inventory, and teleoperation allows lay users to demonstrate novel behaviors intuitively to the robot. In this paper, we compare two modes of teleoperation of an industrial robot, the demonstration by means of a data...... glove and by means of a control object (peg). Experiments with 16 lay users, performing assembly task on the Cranfield benchmark objects, show that the control peg leads to more success, more efficient demonstration and fewer errors....

  11. A Significant Play

    Institute of Scientific and Technical Information of China (English)

    梁海光; 陈明

    2002-01-01

    Yesterday evening, I went to see a play. It was really significant. It was about Zheng Xiaoyue, a very clever and diligent middle school student. Unfortunately, her mother died when she and her brother were very young. Her father was out of work and,

  12. Point mutations in firefly luciferase C-domain demonstrate its significance in green color of bioluminescence.

    Science.gov (United States)

    Modestova, Yulia; Koksharov, Mikhail I; Ugarova, Natalia N

    2014-09-01

    Firefly luciferase is a two-domain enzyme that catalyzes the bioluminescent reaction of firefly luciferin oxidation. Color of the emitted light depends on the structure of the enzyme, yet the exact color-tuning mechanism remains unknown by now, and the role of the C-domain in it is rarely discussed, because a very few color-shifting mutations in the C-domain were described. Recently we reported a strong red-shifting mutation E457K in the C-domain; the bioluminescence spectra of this enzyme were independent of temperature or pH. In the present study we investigated the role of the residue E457 in the enzyme using the Luciola mingrelica luciferase with a thermostabilized N-domain as a parent enzyme for site-directed mutagenesis. We obtained a set of mutants and studied their catalytic properties, thermal stability and bioluminescence spectra. Experimental spectra were represented as a sum of two components (bioluminescence spectra of putative "red" and "green" emitters); λmax of these components were constant for all the mutants, but the ratio of these emitters was defined by temperature and mutations in the C-domain. We suggest that each emitter is stabilized by a specific conformation of the active site; thus, enzymes with two forms of the active site coexist in the reactive media. The rigid structure of the C-domain is crucial for maintaining the conformation corresponding to the "green" emitter. We presume that the emitters are the keto- and enol forms of oxyluciferin.

  13. ‘‘Cooling by Heating’’- Demonstrating the Significance of the Longitudinal Specific Heat

    DEFF Research Database (Denmark)

    Papini, Jon J.; Dyre, J. C.; Christensen, Tage Emil

    2012-01-01

    is generally considerably larger than in solids. This paper presents analytical solutions of the relevant coupled thermoviscoelastic equations. In general, there is a difference between the isobaric specific heat cp measured at constant isotropic pressure and the longitudinal specific heat cl pertaining...... between these two specific heats. For a typical glass-forming liquid, when the temperature at the surface is increased by 1 K, a lowering of the temperature at the sphere center of the order of 5 mK is expected if the experiment is performed at the glass transition. The cooling-by-heating effect......Heating a solid sphere at its surface induces mechanical stresses inside the sphere. If a finite amount of heat is supplied, the stresses gradually disappear as temperature becomes homogeneous throughout the sphere. We show that before this happens, there is a temporary lowering of pressure...

  14. Significant Tsunami Events

    Science.gov (United States)

    Dunbar, P. K.; Furtney, M.; McLean, S. J.; Sweeney, A. D.

    2014-12-01

    Tsunamis have inflicted death and destruction on the coastlines of the world throughout history. The occurrence of tsunamis and the resulting effects have been collected and studied as far back as the second millennium B.C. The knowledge gained from cataloging and examining these events has led to significant changes in our understanding of tsunamis, tsunami sources, and methods to mitigate the effects of tsunamis. The most significant, not surprisingly, are often the most devastating, such as the 2011 Tohoku, Japan earthquake and tsunami. The goal of this poster is to give a brief overview of the occurrence of tsunamis and then focus specifically on several significant tsunamis. There are various criteria to determine the most significant tsunamis: the number of deaths, amount of damage, maximum runup height, had a major impact on tsunami science or policy, etc. As a result, descriptions will include some of the most costly (2011 Tohoku, Japan), the most deadly (2004 Sumatra, 1883 Krakatau), and the highest runup ever observed (1958 Lituya Bay, Alaska). The discovery of the Cascadia subduction zone as the source of the 1700 Japanese "Orphan" tsunami and a future tsunami threat to the U.S. northwest coast, contributed to the decision to form the U.S. National Tsunami Hazard Mitigation Program. The great Lisbon earthquake of 1755 marked the beginning of the modern era of seismology. Knowledge gained from the 1964 Alaska earthquake and tsunami helped confirm the theory of plate tectonics. The 1946 Alaska, 1952 Kuril Islands, 1960 Chile, 1964 Alaska, and the 2004 Banda Aceh, tsunamis all resulted in warning centers or systems being established.The data descriptions on this poster were extracted from NOAA's National Geophysical Data Center (NGDC) global historical tsunami database. Additional information about these tsunamis, as well as water level data can be found by accessing the NGDC website www.ngdc.noaa.gov/hazard/

  15. Gold Nanoparticles Inhibit Matrix Metalloproteases without Cytotoxicity.

    Science.gov (United States)

    Hashimoto, M; Sasaki, J I; Yamaguchi, S; Kawai, K; Kawakami, H; Iwasaki, Y; Imazato, S

    2015-08-01

    Nanoparticles (NPs) are currently the focus of considerable attention for dental applications; however, their biological effects have not been fully elucidated. The long-term, slow release of matrix metalloproteases (MMPs) digests collagen fibrils within resin-dentin bonds. Therefore, MMP inhibitors can prolong the durability of resin-dentin bonds. However, there have been few reports evaluating the combined effect of MMP inhibition and the cytotoxic effects of NPs for dentin bonding. The aim of this study was to evaluate MMP inhibition and cytotoxic responses to gold (AuNPs) and platinum nanoparticles (PtNPs) stabilized by polyvinylpyrrolidone (PVP) in cultured murine macrophages (RAW264) by using MMP inhibition assays, measuring cell viability and inflammatory responses (quantitative reverse transcription polymerase chain reaction [RT-qPCR]), and conducting a micromorphological analysis by fluorescence and transmission electron microscopy. Cultured RAW264 cells were exposed to metal NPs at various concentrations (1, 10, 100, and 400 µg/mL). AuNPs and PtNPs markedly inhibited MMP-8 and MMP-9 activity. Although PtNPs were cytotoxic at high concentrations (100 and 400 µg/mL), no cytotoxic effects were observed for AuNPs at any concentration. Transmission electron microscopy images showed a significant nonrandom intercellular distribution for AuNPs and PtNPs, which were mostly observed to be localized in lysosomes but not in the nucleus. RT-qPCR analysis demonstrated inflammatory responses were not induced in RAW264 cells by AuNPs or PtNPs. The cytotoxicity of nanoparticles might depend on the core metal composition and arise from a "Trojan horse" effect; thus, MMP inhibition could be attributed to the surface charge of PVP, which forms the outer coating of NPs. The negative charge of the surface coating of PVP binds to Zn(2+) from the active center of MMPs by chelate binding and results in MMP inhibition. In summary, AuNPs are attractive NPs that effectively

  16. Laser Communications Relay Demonstration Project

    Data.gov (United States)

    National Aeronautics and Space Administration — The Laser Communications Relay Demonstration project will advance optical communications technology, expanding industry’s capability to produce competitive,...

  17. Magnetic Launch Assist Demonstration Test

    Science.gov (United States)

    2001-01-01

    This image shows a 1/9 subscale model vehicle clearing the Magnetic Launch Assist System, formerly referred to as the Magnetic Levitation (MagLev), test track during a demonstration test conducted at the Marshall Space Flight Center (MSFC). Engineers at MSFC have developed and tested Magnetic Launch Assist technologies. To launch spacecraft into orbit, a Magnetic Launch Assist System would use magnetic fields to levitate and accelerate a vehicle along a track at very high speeds. Similar to high-speed trains and roller coasters that use high-strength magnets to lift and propel a vehicle a couple of inches above a guideway, a launch-assist system would electromagnetically drive a space vehicle along the track. A full-scale, operational track would be about 1.5-miles long and capable of accelerating a vehicle to 600 mph in 9.5 seconds. This track is an advanced linear induction motor. Induction motors are common in fans, power drills, and sewing machines. Instead of spinning in a circular motion to turn a shaft or gears, a linear induction motor produces thrust in a straight line. Mounted on concrete pedestals, the track is 100-feet long, about 2-feet wide and about 1.5-feet high. The major advantages of launch assist for NASA launch vehicles is that it reduces the weight of the take-off, the landing gear, the wing size, and less propellant resulting in significant cost savings. The US Navy and the British MOD (Ministry of Defense) are planning to use magnetic launch assist for their next generation aircraft carriers as the aircraft launch system. The US Army is considering using this technology for launching target drones for anti-aircraft training.

  18. A Significant Step Forward

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Australia officially ratified the Kyoto Protocol on December 3,the first act of its new government under Prime Minister Kevin Rudd.Rudd signed the instrument of ratification the very day he was sworn in by Australia’s Governor General Michael Jeffery. This is a significant step in Australia’s efforts to fight climate change domestically and with the international community,Rudd said in a statement.The Australian Government will do everything in its power to help Australia meet its Kyoto obligations,he added.

  19. Inhibition of SIRT2 suppresses hepatic fibrosis.

    Science.gov (United States)

    Arteaga, Maribel; Shang, Na; Ding, Xianzhong; Yong, Sherri; Cotler, Scott J; Denning, Mitchell F; Shimamura, Takashi; Breslin, Peter; Lüscher, Bernhard; Qiu, Wei

    2016-06-01

    Liver fibrosis can progress to cirrhosis and result in serious complications of liver disease. The pathogenesis of liver fibrosis involves the activation of hepatic stellate cells (HSCs), the underlying mechanisms of which are not fully known. Emerging evidence suggests that the classic histone deacetylases play a role in liver fibrosis, but the role of another subfamily of histone deacetylases, the sirtuins, in the development of hepatic fibrosis remains unknown. In this study, we found that blocking the activity of sirtuin 2 (SIRT2) by using inhibitors or shRNAs significantly suppressed fibrogenic gene expression in HSCs. We further demonstrated that inhibition of SIRT2 results in the degradation of c-MYC, which is important for HSC activation. In addition, we discovered that inhibition of SIRT2 suppresses the phosphorylation of ERK, which is critical for the stabilization of c-MYC. Moreover, we found that Sirt2 deficiency attenuates the hepatic fibrosis induced by carbon tetrachloride (CCl4) and thioacetamide (TAA). Furthermore, we showed that SIRT2, p-ERK, and c-MYC proteins are all overexpressed in human hepatic fibrotic tissues. These data suggest a critical role for the SIRT2/ERK/c-MYC axis in promoting hepatic fibrogenesis. Inhibition of the SIRT2/ERK/c-MYC axis represents a novel strategy to prevent and to potentially treat liver fibrosis and cirrhosis.

  20. Trace element inhibition of phytase activity.

    Science.gov (United States)

    Santos, T; Connolly, C; Murphy, R

    2015-02-01

    Nowadays, 70 % of global monogastric feeds contains an exogenous phytase. Phytase supplementation has enabled a more efficient utilisation of phytate phosphorous (P) and reduction of P pollution. Trace minerals, such as iron (Fe), zinc (Zn), copper (Cu) and manganese (Mn) are essential for maintaining health and immunity as well as being involved in animal growth, production and reproduction. Exogenous sources of phytase and trace elements are regularly supplemented to monogastric diets and usually combined in a premix. However, the possibility for negative interaction between individual components within the premix is high and is often overlooked. Therefore, this initial study focused on assessing the potential in vitro interaction between inorganic and organic chelated sources of Fe, Zn, Cu and Mn with three commercially available phytase preparations. Additionally, this study has investigated if the degree of enzyme inhibition was dependent of the type of chelated sources. A highly significant relationship between phytase inhibition, trace mineral type as well as mineral source and concentration, p phytases for Fe and Zn, as well as for Cu with E. coli and Aspergillus niger phytases. Different chelate trace mineral sources demonstrated diversifying abilities to inhibit exogenous phytase activity.

  1. A Comprehensive General Chemistry Demonstration

    Science.gov (United States)

    Sweeder, Ryan D.; Jeffery, Kathleen A.

    2013-01-01

    This article describes the use of a comprehensive demonstration suitable for a high school or first-year undergraduate introductory chemistry class. The demonstration involves placing a burning candle in a container adjacent to a beaker containing a basic solution with indicator. After adding a lid, the candle will extinguish and the produced…

  2. Teaching and Demonstrating Classical Conditioning.

    Science.gov (United States)

    Sparrow, John; Fernald, Peter

    1989-01-01

    Discusses classroom demonstrations of classical conditioning and notes tendencies to misrepresent Pavlov's procedures. Describes the design and construction of the conditioner that is used for demonstrating classical conditioning. Relates how students experience conditioning, generalization, extinction, discrimination, and spontaneous recovery.…

  3. A Comprehensive General Chemistry Demonstration

    Science.gov (United States)

    Sweeder, Ryan D.; Jeffery, Kathleen A.

    2013-01-01

    This article describes the use of a comprehensive demonstration suitable for a high school or first-year undergraduate introductory chemistry class. The demonstration involves placing a burning candle in a container adjacent to a beaker containing a basic solution with indicator. After adding a lid, the candle will extinguish and the produced…

  4. Optics Demonstrations Using Cylindrical Lenses

    Science.gov (United States)

    Ivanov, Dragia; Nikolov, Stefan

    2015-01-01

    In this paper we consider the main properties of cylindrical lenses and propose several demonstrational experiments that can be performed with them. Specifically we use simple glasses full of water to demonstrate some basic geometrical optics principles and phenomena. We also present some less standard experiments that can be performed with such…

  5. Demonstrative and non-demonstrative reasoning by analogy

    OpenAIRE

    Ippoliti, Emiliano

    2008-01-01

    The paper analizes a set of issues related to analogy and analogical reasoning, namely: 1) The problem of analogy and its duplicity; 2) The role of analogy in demonstrative reasoning; 3) The role of analogy in non-demonstrative reasoning; 4) The limits of analogy; 5) The convergence, particularly in multiple analogical reasoning, of these two apparently distinct aspects and its methodological and philosophical consequences. The paper, using example from number theory, argues for an heuristc c...

  6. Predicting significant torso trauma.

    Science.gov (United States)

    Nirula, Ram; Talmor, Daniel; Brasel, Karen

    2005-07-01

    Identification of motor vehicle crash (MVC) characteristics associated with thoracoabdominal injury would advance the development of automatic crash notification systems (ACNS) by improving triage and response times. Our objective was to determine the relationships between MVC characteristics and thoracoabdominal trauma to develop a torso injury probability model. Drivers involved in crashes from 1993 to 2001 within the National Automotive Sampling System were reviewed. Relationships between torso injury and MVC characteristics were assessed using multivariate logistic regression. Receiver operating characteristic curves were used to compare the model to current ACNS models. There were a total of 56,466 drivers. Age, ejection, braking, avoidance, velocity, restraints, passenger-side impact, rollover, and vehicle weight and type were associated with injury (p < 0.05). The area under the receiver operating characteristic curve (83.9) was significantly greater than current ACNS models. We have developed a thoracoabdominal injury probability model that may improve patient triage when used with ACNS.

  7. Anthropological significance of phenylketonuria.

    Science.gov (United States)

    Saugstad, L F

    1975-01-01

    The highest incidence rates of phenylketonuria (PKU) have been observed in Ireland and Scotlant. Parents heterozygous for PKU in Norway differ significantly from the general population in the Rhesus, Kell and PGM systems. The parents investigated showed an excess of Rh negative, Kell plus and PGM type 1 individuals, which makes them similar to the present populations in Ireland and Scotlant. It is postulated that the heterozygotes for PKU in Norway are descended from a completely assimilated sub-population of Celtic origin, who came or were brought here, 1ooo years ago. Bronze objects of Western European (Scottish, Irish) origin, found in Viking graves widely distributed in Norway, have been taken as evidence of Vikings returning with loot (including a number of Celts) from Western Viking settlements. The continuity of residence since the Viking age in most habitable parts of Norway, and what seems to be a nearly complete regional relationship between the sites where Viking graves contain western imported objects and the birthplaces of grandparents of PKUs identified in Norway, lend further support to the hypothesis that the heterozygotes for PKU in Norway are descended from a completely assimilated subpopulation. The remarkable resemblance between Iceland and Ireland, in respect of several genetic markers (including the Rhesus, PGM and Kell systems), is considered to be an expression of a similar proportion of people of Celtic origin in each of the two countries. Their identical, high incidence rates of PKU are regarded as further evidence of this. The significant decline in the incidence of PKU when one passes from Ireland, Scotland and Iceland, to Denmark and on to Norway and Sweden, is therefore explained as being related to a reduction in the proportion of inhabitants of Celtic extraction in the respective populations.

  8. Bovine Muc1 inhibits binding of enteric bacteria to Caco-2 cells.

    Science.gov (United States)

    Parker, Phillip; Sando, Lillian; Pearson, Roger; Kongsuwan, Kritaya; Tellam, Ross L; Smith, Stuart

    2010-01-01

    Inhibition of bacterial adhesion to intestinal epithelial receptors by the consumption of natural food components is an attractive strategy for the prevention of microbial related gastrointestinal illness. We hypothesised that Muc1, a highly glycosylated mucin present in cows' milk, may be one such food component. Purified bovine Muc1 was tested for its ability to inhibit binding of common enteric bacterial pathogens to Caco-2 cells grown in vitro. Muc1 caused dose-dependent binding inhibition of Escherichia coli, Salmonella enterica serovar Typhimurium (S. Typhimurium), Staphylococcus aureus and Bacillus subtilis. This inhibition was more pronounced for the Gram negative compared with Gram positive bacteria. It was also demonstrated that Muc1, immobilised on a membrane, bound all these bacterial species in a dose-dependent manner, although there was greater interaction with the Gram negative bacteria. A range of monosaccharides, representative of the Muc1 oligosaccharide composition, were tested for their ability to prevent binding of E. coli and S. Typhimurium to Caco-2 cells. Inhibition was structure dependent with sialic acid, L(-) fucose and D(+) mannose significantly inhibiting binding of both Gram negative species. N-acetylglucosamine and N-acetylgalactosamine significantly inhibited binding of E. coli whilst galactose, one of the most abundant Muc1 monosaccharides, showed the strongest inhibition against S. Typhimurium. Treatment with sialidase significantly decreased the inhibitory properties of Muc1, demonstrating the importance of sialic acid in adhesion inhibition. It is concluded that bovine Muc1 prevents binding of bacteria to human intestinal cells and may have a role in preventing the binding of common enteropathogenic bacteria to human intestinal epithelial surfaces.

  9. Inhibition of Advanced Glycation End-Product Formation and Antioxidant Activity by Extracts and Polyphenols from Scutellaria alpina L. and S. altissima L.

    OpenAIRE

    Izabela Grzegorczyk-Karolak; Krzysztof Gołąb; Jakub Gburek; Halina Wysokińska; Adam Matkowski

    2016-01-01

    Methanolic extracts from the aerial parts and roots of two Scutellaria species, S. alpina and S. altissima, and five polyphenols from these plants demonstrated a significant ability to inhibit the formation of advanced glycation end-products (AGE) in vitro. S. alpina, which is richer in polyphenolic compounds, had strong antiglycation properties. These extracts demonstrated also high activity in the FRAP (ferric-reducing antioxidant power), antiradical (DPPH) and lipid peroxidation inhibition...

  10. Offsite demonstrations for MWLID technologies

    Energy Technology Data Exchange (ETDEWEB)

    Williams, C. [Sandia National Labs., Albuquerque, NM (United States); Gruebel, R. [Tech. Reps., Inc., Albuquerque, NM (United States)

    1995-04-01

    The goal of the Offsite Demonstration Project for Mixed Waste Landfill Integrated Demonstration (MWLID)-developed environmental site characterization and remediation technologies is to facilitate the transfer, use, and commercialization of these technologies to the public and private sector. The meet this goal, the project identified environmental restoration needs of mixed waste and/or hazardous waste landfill owners (Native American, municipal, DOE, and DoD); documenting potential demonstration sites and the contaminants present at each site; assessing the environmental regulations that would effect demonstration activities; and evaluating site suitability for demonstrating MWLID technologies at the tribal and municipal sites identified. Eighteen landfill sites within a 40.2-km radius of Sandia National Laboratories are listed on the CERCLIS Site/Event Listing for the state of New Mexico. Seventeen are not located within DOE or DoD facilities and are potential offsite MWLID technology demonstration sites. Two of the seventeen CERCLIS sites, one on Native American land and one on municipal land, were evaluated and identified as potential candidates for off-site demonstrations of MWLID-developed technologies. Contaminants potentially present on site include chromium waste, household/commercial hazardous waste, volatile organic compounds, and petroleum products. MWLID characterization technologies applicable to these sites include Magnetometer Towed Array, Cross-borehole Electromagnetic Imaging, SitePlanner {trademark}/PLUME, Hybrid Directional Drilling, Seamist{trademark}/Vadose Zone Monitoring, Stripping Analyses, and x-ray Fluorescence Spectroscopy for Heavy Metals.

  11. Efficacy of ALK5 inhibition in myelofibrosis

    Science.gov (United States)

    Zhao, Wanke; Ho, Wanting Tina; Han, Ying; Murdun, Cem; Mailloux, Adam W.; Zhang, Ling; Wang, Xuefeng; Budhathoki, Anjali; Pradhan, Kith; Rapaport, Franck; Wang, Huaquan; Shao, Zonghong; Ren, Xiubao; Steidl, Ulrich; Levine, Ross L.; Zhao, Zhizhuang Joe; Verma, Amit; Epling-Burnette, Pearlie K.

    2017-01-01

    Myelofibrosis (MF) is a bone marrow disorder characterized by clonal myeloproliferation, aberrant cytokine production, extramedullary hematopoiesis, and bone marrow fibrosis. Although somatic mutations in JAK2, MPL, and CALR have been identified in the pathogenesis of these diseases, inhibitors of the Jak2 pathway have not demonstrated efficacy in ameliorating MF in patients. TGF-β family members are profibrotic cytokines and we observed significant TGF-β1 isoform overexpression in a large cohort of primary MF patient samples. Significant overexpression of TGF-β1 was also observed in murine clonal MPLW515L megakaryocytic cells. TGF-β1 stimulated the deposition of excessive collagen by mesenchymal stromal cells (MSCs) by activating the TGF-β receptor I kinase (ALK5)/Smad3 pathway. MSCs derived from MPLW515L mice demonstrated sustained overproduction of both collagen I and collagen III, effects that were abrogated by ALK5 inhibition in vitro and in vivo. Importantly, use of galunisertib, a clinically active ALK5 inhibitor, significantly improved MF in both MPLW515L and JAK2V617F mouse models. These data demonstrate the role of malignant hematopoietic stem cell (HSC)/TGF-β/MSC axis in the pathogenesis of MF, and provide a preclinical rationale for ALK5 blockade as a therapeutic strategy in MF.

  12. Crafting a Gauss Gun Demonstration

    Science.gov (United States)

    Blodgett, Matthew E.; Blodgett, E. D.

    2006-12-01

    A Gauss Gun launches a ferromagnetic projectile using a pulsed electromagnet. This demonstration provides a nice counterpoint to the popular Thompson's jumping ring demonstration, which launches a nonferromagnetic ring via repulsion of an induced current. The pulsed current must be short enough in duration so that the projectile is not retarded by lingering current in the launch solenoid, but also large enough to provide a suitably impressive velocity. This project involved an iterative design process, as we worked through balancing all the different design criteria. We recommend it as a very nice electronics design project which will produce a very portable and enjoyable demonstration. AAPT sponsor Earl Blodgett.

  13. Consumption of lycopene inhibits the growth and progression of colon cancer in a mouse xenograft model

    Science.gov (United States)

    A previous study indicated that lycopene could significantly inhibit the proliferation of human colon cancer cells in vitro. However, the in vivo anticancer effects of lycopene against colon cancer have not been demonstrated yet. Therefore, this study investigated whether consumption of lycopene cou...

  14. Chloroquine targets pancreatic cancer stem cells via inhibition of CXCR4 and hedgehog signaling

    DEFF Research Database (Denmark)

    Balic, Anamaria; Sørensen, Morten Dræby; Trabulo, Sara Maria

    2014-01-01

    inhibition of hedgehog signaling by decreasing the production of Smoothened, translating into a significant reduction in sonic hedgehog-induced chemotaxis and downregulation of downstream targets in CSCs and the surrounding stroma. Our study demonstrates that via to date unreported effects, chloroquine...

  15. Meaning and significance of

    Directory of Open Access Journals (Sweden)

    Ph D Student Roman Mihaela

    2011-05-01

    Full Text Available The concept of "public accountability" is a challenge for political science as a new concept in this area in full debate and developement ,both in theory and practice. This paper is a theoretical approach of displaying some definitions, relevant meanings and significance odf the concept in political science. The importance of this concept is that although originally it was used as a tool to improve effectiveness and eficiency of public governance, it has gradually become a purpose it itself. "Accountability" has become an image of good governance first in the United States of America then in the European Union.Nevertheless,the concept is vaguely defined and provides ambiguous images of good governance.This paper begins with the presentation of some general meanings of the concept as they emerge from specialized dictionaries and ancyclopaedies and continues with the meanings developed in political science. The concept of "public accontability" is rooted in economics and management literature,becoming increasingly relevant in today's political science both in theory and discourse as well as in practice in formulating and evaluating public policies. A first conclusin that emerges from, the analysis of the evolution of this term is that it requires a conceptual clarification in political science. A clear definition will then enable an appropriate model of proving the system of public accountability in formulating and assessing public policies, in order to implement a system of assessment and monitoring thereof.

  16. Significance evaluation in factor graphs

    DEFF Research Database (Denmark)

    Madsen, Tobias; Hobolth, Asger; Jensen, Jens Ledet

    2017-01-01

    Background Factor graphs provide a flexible and general framework for specifying probability distributions. They can capture a range of popular and recent models for analysis of both genomics data as well as data from other scientific fields. Owing to the ever larger data sets encountered...... in genomics and the multiple-testing issues accompanying them, accurate significance evaluation is of great importance. We here address the problem of evaluating statistical significance of observations from factor graph models. Results Two novel numerical approximations for evaluation of statistical....... Conclusions The applicability of saddlepoint approximation and importance sampling is demonstrated on known models in the factor graph framework. Using the two methods we can substantially improve computational cost without compromising accuracy. This contribution allows analyses of large datasets...

  17. Homo economicus belief inhibits trust.

    Directory of Open Access Journals (Sweden)

    Ziqiang Xin

    Full Text Available As a foundational concept in economics, the homo economicus assumption regards humans as rational and self-interested actors. In contrast, trust requires individuals to believe partners' benevolence and unselfishness. Thus, the homo economicus belief may inhibit trust. The present three experiments demonstrated that the direct exposure to homo economicus belief can weaken trust. And economic situations like profit calculation can also activate individuals' homo economicus belief and inhibit their trust. It seems that people's increasing homo economicus belief may serve as one cause of the worldwide decline of trust.

  18. Homo economicus belief inhibits trust.

    Science.gov (United States)

    Xin, Ziqiang; Liu, Guofang

    2013-01-01

    As a foundational concept in economics, the homo economicus assumption regards humans as rational and self-interested actors. In contrast, trust requires individuals to believe partners' benevolence and unselfishness. Thus, the homo economicus belief may inhibit trust. The present three experiments demonstrated that the direct exposure to homo economicus belief can weaken trust. And economic situations like profit calculation can also activate individuals' homo economicus belief and inhibit their trust. It seems that people's increasing homo economicus belief may serve as one cause of the worldwide decline of trust.

  19. CT Demonstration of Caput Medusae

    Science.gov (United States)

    Weber, Edward C.; Vilensky, Joel A.

    2009-01-01

    Maximum intensity and volume rendered CT displays of caput medusae are provided to demonstrate both the anatomy and physiology of this portosystemic shunt associated with portal hypertension. (Contains 2 figures.)

  20. Status of the MAJORANA Demonstrator

    CERN Document Server

    Cuesta, C; Arnquist, I J; Avignone, F T; Barabash, A S; Bertrand, F E; Brudanin, V; Busch, M; Buuck, M; Byram, D; Caldwell, A S; Chan, Y-D; Christofferson, C D; Detwiler, J A; Efremenko, Yu; Ejiri, H; Elliott, S R; Galindo-Uribarri, A; Giovanetti, G K; Goett, J; Greenn, M P; Gruszko, J; Guinn, I S; Guiseppe, V E; Henning, R; Hoppe, E W; Howard, S; Howe, M A; Jasinski, B R; Keeter, K J; Kidd, M F; Konovalov, S I; Kouzes, R T; LaFerriere, B D; Leon, J; MacMullin, J; Martin, R D; Meijer, S J; Mertens, S; Orrell, J L; O'Shaughnessy, C; Overman, N R; Poon, A W P; Radford, D C; Rager, J; Rielage, K; Robertson, R G H; Romero-Romero, E; Schmitt, C; Shanks, B; Shirchenko, M; Snyder, N; Suriano, A M; Tedeschi, D; Timkin, V; Trimble, J E; Varner, R L; Vasilyev, S; Vetter, K; Vorren, K; White, B R; Wilkerson, J F; Wiseman, C; Xu, W; Yakushev, E; Yu, C -H; Yumatov, V

    2014-01-01

    The MAJORANA Collaboration is constructing the MAJORANA Demonstrator, an ultra-low background, 40-kg modular high purity Ge detector array to search for neutrinoless double-beta decay in Ge. In view of the next generation of tonne-scale Ge-based neutrinoless double-beta decay searches that will probe the neutrino mass scale in the inverted-hierarchy region, a major goal of the Demonstrator is to demonstrate a path forward to achieving a background rate at or below 1 count/tonne/year in the 4 keV region of interest around the Q-value at 2039 keV. The current status of the Demonstrator is discussed, as are plans for its completion.

  1. Demonstration of Cauchy: Understanding Algebraic

    Directory of Open Access Journals (Sweden)

    T.L. Costa

    2012-11-01

    Full Text Available ABSTRACT: In this study we present some considerations about the End of Course Work undergraduate Full Degree in Mathematics / UFMT, drafted in 2011, and by taking title "A story about Cauchy and Euler's theorem on polyhedra" that gave birth to our research project Master of Education, begun in 2012, on the approaches of Euler's theorem on polyhedra in mathematics textbooks. At work in 2011 presented some considerations about the history of Euler's theorem for polyhedra which focus the demonstration presented by Cauchy (1789-1857, who tries to generalize it, relying on assumptions not observable in Euclidean geometry. Therefore, we seek the accessible literature on the history of mathematics; relate some aspects of the demonstration Cauchy with historical events on the development of mathematics in the nineteenth century, which allowed the acceptance of such a demonstration by mathematicians of his time.Keywords: History of Mathematics. Euler's Theorem on Polyhedra. Demonstration of Cauchy.

  2. Status of the Majorana Demonstrator

    Energy Technology Data Exchange (ETDEWEB)

    Cuesta, C.; Abgrall, N.; Arnquist, Isaac J.; Avignone, Frank T.; Barabash, Alexander S.; Bertrand, F.; Brudanin, V.; Busch, Matthew; Buuck, M.; Byram, D.; Caldwell, A. S.; Chan, Yuen-Dat; Christofferson, Cabot-Ann; Detwiler, Jason A.; Efremenko, Yuri; Ejiri, H.; Elliott, S. R.; Galindo-Uribarri, A.; Giovanetti, G. K.; Goett, J.; Green, M. P.; Gruszko, J.; Guinn, I.; Guiseppe, V. E.; Henning, R.; Hoppe, Eric W.; Howard, Stanley; Howe, M. A.; Jasinski, B. R.; Keeter, K.; Kidd, M. F.; Konovalov, S.; Kouzes, Richard T.; Laferriere, Brian D.; Leon, Jonathan D.; MacMullin, J.; Martin, R. D.; Meijer, S. J.; Mertens, S.; Orrell, John L.; O' Shaughnessy, C.; Overman, Nicole R.; Poon, Alan; Radford, D. C.; Rager, J.; Rielage, Keith; Robertson, R. G. H.; Romero-Romero, E.; Schmitt, C.; Shanks, B.; Shirchenko, M.; Snyder, N.; Suriano, Anne-Marie; Tedeschi, D.; Timkin, V.; Trimble, J. E.; Varner, R. L.; Vasilyev, Sergey; Vetter, Kai; Vorren, Kris R.; White, Brandon R.; Wilkerson, J. F.; Wiseman, C.; Xu, W.; Yakushev, E.; Yu, Chang-Hong; Yumatov, Vladimir

    2015-06-09

    The Majorana Collaboration is constructing the Majorana Demonstrator, an ultra-low background, 40-kg modular high purity Ge detector array to search for neutrinoless double-beta decay in 76Ge. In view of the next generation of tonne-scale Ge-based neutrinoless double-beta decay searches that will probe the neutrino mass scale in the inverted hierarchy region, a major goal of the Demonstrator is to demonstrate a path forward to achieving a background rate at or below 1 count/tonne/year in the 4 keV region of interest around the Q-value at 2039 keV. The current status of the Demonstrator is discussed, as are plans for its completion.

  3. Teacher Training: The Demonstration Lesson

    Science.gov (United States)

    Moore, Alan C.

    1977-01-01

    A teacher training technique is discussed involving a demonstration class given by a local teacher and observed by prospective teachers. After the class a discussion is held analyzing lesson content and teaching techniques. (CHK)

  4. Fuel Gas Demonstration Plant Program. Volume I. Demonstration plant

    Energy Technology Data Exchange (ETDEWEB)

    1979-01-01

    The objective of this project is for Babcock Contractors Inc. (BCI) to provide process designs, and gasifier retort design for a fuel gas demonstration plant for Erie Mining Company at Hoyt Lake, Minnesota. The fuel gas produced will be used to supplement natural gas and fuel oil for iron ore pellet induration. The fuel gas demonstration plant will consist of five stirred, two-stage fixed-bed gasifier retorts capable of handling caking and non-caking coals, and provisions for the installation of a sixth retort. The process and unit design has been based on operation with caking coals; however, the retorts have been designed for easy conversion to handle non-caking coals. The demonstration unit has been designed to provide for expansion to a commercial plant (described in Commercial Plant Package) in an economical manner.

  5. Slant Borehole Demonstration Summary Report

    Energy Technology Data Exchange (ETDEWEB)

    GARDNER, M.G.

    2000-07-19

    This report provides a summary of the demonstration project for development of a slant borehole to retrieve soil samples from beneath the SX-108 single-shell tank. It provides a summary of the findings from the demonstration activities and recommendations for tool selection and methods to deploy into the SX Tank Farm. Daily work activities were recorded on Drilling and Sampling Daily Work Record Reports. The work described in this document was performed during March and April 2000.

  6. Orcc's Compa-Backend demonstration

    OpenAIRE

    Oliva, Yaset; Casseau, Emmanuel; Martin, Kevin; Bomel, Pierre; Diguet, Jean-Philippe; Yviquel, Hervé; Raulet, Mickael; Raffin, Erwan; Morin, Laurent

    2014-01-01

    International audience; This paper presents the implementation of a video decoding application starting from its dataflow and CAL representations. Our objective is to demonstrate the ability of the Open RVC-CAL Compiler (Orcc) to generate code for embedded systems. For the demonstration, the video application will be an MPEG-4 Part2 decoder. The targeted architecture is a multi-core heterogeneous system deployed onto the Zynq platform from Xilinx.

  7. Remote control of an impact demonstration vehicle

    Science.gov (United States)

    Harney, P. F.; Craft, J. B., Jr.; Johnson, R. G.

    1985-01-01

    Uplink and downlink telemetry systems were installed in a Boeing 720 aircraft that was remotely flown from Rogers Dry Lake at Edwards Air Force Base and impacted into a designated crash site on the lake bed. The controlled impact demonstration (CID) program was a joint venture by the National Aeronautics and Space Administration (NASA) and the Federal Aviation Administration (FAA) to test passenger survivability using antimisting kerosene (AMK) to inhibit postcrash fires, improve passenger seats and restraints, and improve fire-retardent materials. The uplink telemetry system was used to remotely control the aircraft and activate onboard systems from takeoff until after impact. Aircraft systems for remote control, aircraft structural response, passenger seat and restraint systems, and anthropomorphic dummy responses were recorded and displayed by the downlink stems. The instrumentation uplink and downlink systems are described.

  8. Inhibition of existing denitrification enzyme activity by chloramphenicol

    Science.gov (United States)

    Brooks, M.H.; Smith, R.L.; Macalady, D.L.

    1992-01-01

    Chloramphenicol completely inhibited the activity of existing denitrification enzymes in acetylene-block incubations with (i) sediments from a nitrate-contaminated aquifer and (ii) a continuous culture of denitrifying groundwater bacteria. Control flasks with no antibiotic produced significant amounts of nitrous oxide in the same time period. Amendment with chloramphenicol after nitrous oxide production had begun resulted in a significant decrease in the rate of nitrous oxide production. Chloramphenicol also decreased (>50%) the activity of existing denitrification enzymes in pure cultures of Pseudomonas denitrificans that were harvested during log- phase growth and maintained for 2 weeks in a starvation medium lacking electron donor. Short-term time courses of nitrate consumption and nitrous oxide production in the presence of acetylene with P. denitrificans undergoing carbon starvation were performed under optimal conditions designed to mimic denitrification enzyme activity assays used with soils. Time courses were linear for both chloramphenicol and control flasks, and rate estimates for the two treatments were significantly different at the 95% confidence level. Complete or partial inhibition of existing enzyme activity is not consistent with the current understanding of the mode of action of chloramphenicol or current practice, in which the compound is frequently employed to inhibit de novo protein synthesis during the course of microbial activity assays. The results of this study demonstrate that chloramphenicol amendment can inhibit the activity of existing denitrification enzymes and suggest that caution is needed in the design and interpretation of denitrification activity assays in which chloramphenicol is used to prevent new protein synthesis.

  9. Evidence of dopaminergic processing of executive inhibition.

    Directory of Open Access Journals (Sweden)

    Rajendra D Badgaiyan

    Full Text Available Inhibition of unwanted response is an important function of the executive system. Since the inhibitory system is impaired in patients with dysregulated dopamine system, we examined dopamine neurotransmission in the human brain during processing of a task of executive inhibition. The experiment used a recently developed dynamic molecular imaging technique to detect and map dopamine released during performance of a modified Eriksen's flanker task. In this study, young healthy volunteers received an intravenous injection of a dopamine receptor ligand ((11C-raclopride after they were positioned in the PET camera. After the injection, volunteers performed the flanker task under Congruent and Incongruent conditions in a single scan session. They were required to inhibit competing options to select an appropriate response in the Incongruent but not in the Congruent condition. The PET data were dynamically acquired during the experiment and analyzed using two variants of the simplified reference region model. The analysis included estimation of a number of receptor kinetic parameters before and after initiation of the Incongruent condition. We found increase in the rate of ligand displacement (from receptor sites and decrease in the ligand binding potential in the Incongruent condition, suggesting dopamine release during task performance. These changes were observed in small areas of the putamen and caudate bilaterally but were most significant on the dorsal aspect of the body of left caudate. The results provide evidence of dopaminergic processing of executive inhibition and demonstrate that neurochemical changes associated with cognitive processing can be detected and mapped in a single scan session using dynamic molecular imaging.

  10. Reduced surround inhibition in musicians.

    Science.gov (United States)

    Shin, Hae-Won; Kang, Suk Y; Hallett, Mark; Sohn, Young H

    2012-06-01

    To investigate whether surround inhibition (SI) in the motor system is altered in professional musicians, we performed a transcranial magnetic stimulation (TMS) study in 10 professional musicians and 15 age-matched healthy non-musicians. TMS was set to be triggered by self-initiated flexion of the index finger at different intervals ranging from 3 to 1,000 ms. Average motor evoked potential (MEP) amplitudes obtained from self-triggered TMS were normalized to average MEPs of the control TMS at rest and expressed as a percentage. Normalized MEP amplitudes of the abductor digiti minimi (ADM) muscles were compared between the musicians and non-musicians with the primary analysis being the intervals between 3 and 80 ms (during the movement). A mixed-design ANOVA revealed a significant difference in normalized ADM MEPs during the index finger flexion between groups, with less SI in the musicians. This study demonstrated that the functional operation of SI is less strong in musicians than non-musicians, perhaps due to practice of movement synergies involving both muscles. Reduced SI, however, could lead susceptible musicians to be prone to develop task-specific dystonia.

  11. Inhibition of the dorsal premotor cortex does not repair surround inhibition in writer's cramp patients.

    Science.gov (United States)

    Veugen, Lidwien C; Hoffland, Britt S; Stegeman, Dick F; van de Warrenburg, Bart P

    2013-03-01

    Writer's cramp is a task-specific form of focal dystonia, characterized by abnormal movements and postures of the hand and arm during writing. Two consistent abnormalities in its pathophysiology are a loss of surround inhibition and overactivity of the dorsal premotor cortex (PMd). This study aimed to assess a possible link between these two phenomena by investigating whether PMd inhibition leads to an improvement of surround inhibition, in parallel with previously demonstrated writing improvement. Fifteen writer's cramp patients and ten controls performed a simple motor hand task during which surround inhibition was measured using transcranial magnetic stimulation. Motor cortical excitability was measured of the active and surround muscles at three phases of the task. Surround inhibition and writing performance were assessed before and after PMd inhibitory continuous theta burst stimulation. In contrast to healthy controls, patients did not show inhibition of the abductor digiti minimi muscle during movement initiation of the first dorsal interosseus muscle, confirming the loss of surround inhibition. PMd inhibition led to an improvement of writing speed in writer's cramp patients. However, in both groups, no changes in surround inhibition were observed. The results confirm a role for the PMd in the pathophysiology of writer's cramp. We show that PMd inhibition does not lead to restoration of the surround inhibition defect in writer's cramp, despite the improvement in writing. This questions the involvement of the PMd in the loss of surround inhibition, and perhaps also the direct link between surround inhibition and dystonia.

  12. Doxycycline inhibits leukemic cell migration via inhibition of matrix metalloproteinases and phosphorylation of focal adhesion kinase.

    Science.gov (United States)

    Wang, Chunhuai; Xiang, Ru; Zhang, Xiangzhong; Chen, Yunxian

    2015-09-01

    Doxycycline, a tetracycline-based antibiotic, has been reported to attenuate melanoma cell migration through inhibiting the focal adhesion kinase (FAK) signaling pathway. However, it remains to be elucidated whether doxycycline exerts this effect on leukemia cell migration. The present study aimed to examine the role of doxycycline in leukemia cell migration. The invasion capacities of the human leukemia cell lines KG1a (acute myelogenous leukemia) and K562 (chronic myelogenous leukemia) were evaluated using Matrigel® matrix‑coated Transwell® chamber assays; leukemic cell lines treated with doxycycline (1 µg/ml) or anti‑β1‑integrin antibodies were added to the upper chamber, while untreated cells were included as controls. Reverse transcription quantitative polymerase chain reaction was performed in order to further understand the influence of doxycycline treatment on the expression of FAK and gelatinases in the KG1a and K562 leukemic cell lines. In addition, FAK protein expression and phosphorylation were determined using western blot analysis in order to investigate the mechanism by which doxycycline inhibited leukemic cell migration. The results revealed that doxycycline treatment significantly attenuated the migration of KG1a and K562 cells, which was demonstrated to be associated with inhibition of the expression and phosphorylation of FAK. In addition, doxycycline treatment inhibited matrix metalloproteinase (MMP)‑2 and MMP‑9 expression. Furthermore, incubation with blocking anti‑β1‑integrin antibodies had an analogous inhibitory effect on leukemic cell migration to that of doxycycline. In conclusion, the results of the present study suggested that doxycycline attenuated leukemic cell migration through inhibiting the FAK signaling pathway. Therefore, doxycycline may have potential for use as a novel strategy for the treatment of leukemia.

  13. Cantharidin biosynthesis in a blister beetle: inhibition by 6-fluoromevalonate causes chemical disarmament.

    Science.gov (United States)

    Carrel, J E; Doom, J P; McCormick, J P

    1986-07-15

    Biosynthesis of cantharidin in a blister beetle, Lytta polita, is effectively inhibited by 6-fluoromevalonate. Inhibition is attributed specifically to the fluorine substituent. Biochemical inhibition has not been demonstrated previously for an arthropod's defensive substance.

  14. GAD65 is essential for synthesis of GABA destined for tonic inhibition regulating epileptiform activity

    DEFF Research Database (Denmark)

    Walls, Anne B; Nilsen, Linn Hege; Eyjolfsson, Elvar M;

    2010-01-01

    ABSTRACT: GABA is synthesized from glutamate by glutamate decarboxylase (GAD), which exists in two isoforms, that is, GAD65 and GAD67. In line with GAD65 being located in the GABAergic synapse, several studies have demonstrated that this isoform is important during sustained synaptic transmission....... In contrast, the functional significance of GAD65 in the maintenance of GABA destined for extrasynaptic tonic inhibition is less well studied. Using GAD65-/- and wild type GAD65+/+ mice, this was examined employing the cortical wedge preparation, a model suitable for investigating extrasynaptic GABA......(A) receptor activity. An impaired tonic inhibition in GAD65-/- mice was revealed demonstrating a significant role of GAD65 in the synthesis of GABA acting extrasynaptically. The correlation between an altered tonic inhibition and metabolic events as well as the functional and metabolic role of GABA...

  15. Inhibition of mouse peritoneal macrophage DNA synthesis by infection with the Arenavirus Pichinde. Interim report

    Energy Technology Data Exchange (ETDEWEB)

    Friedlander, A.M.; Jahrling, P.B.; Merrill, P.; Tobery, S.

    1983-01-19

    Macrophage DNA synthesis and proliferation occur during the development of cell-mediated immunity and in the early non-specific reaction to infection. Arenaviruses have a predilection for infection of cells of the reticuloendothelial system and in this study we have examined the effect of the arenavirus Pichinde on macrophage DNA synthesis. We have found that infection of mouse peritoneal macrophages with Pichinde caused a profound dose dependent inhibition of the DNA synthesis induced by macrophage growth factor/colony stimulating factor. At a multiplicity of inoculum of five there is a 75-95% inhibition of DNA synthesis. Viable virus is necessary for inhibition since Pichinde inactivated by heat or cobalt irradiation had no effect. Similarly, virus pre-treated with an antiserum to Pichinde was without inhibitory effect. Inhibition was demonstrated by measuring DNA synthesis spectrofluorometrically as well as by 3H-thymidine incorporation. The inhibition of DNA synthesis was not associated with any cytopathology. There was no evidence that the inhibition was due to soluble factors, such as prostaglandins or interferon, released by infected cells. These studies demonstrate, for the first time in vitro, a significant alteration in macrophage function caused by infection with an arenavirus. It is possible that inhibition of macrophage proliferation represents a mechanism by which some microorganisms interfere with host resistance.

  16. Status of the Majorana Demonstrator

    Energy Technology Data Exchange (ETDEWEB)

    Cuesta, C.; Buuck, M.; Detwiler, J. A.; Gruszko, J.; Guinn, I. S.; Leon, J.; Robertson, R. G. H. [Center for Experimental Nuclear Physics and Astrophysics, and Department of Physics, University of Washington, Seattle, WA (United States); Abgrall, N.; Bradley, A. W.; Chan, Y.-D.; Mertens, S.; Poon, A. W. P. [Nuclear Science Division, Lawrence Berkeley National Laboratory, Berkeley, CA (United States); Arnquist, I. J.; Hoppe, E. W.; Kouzes, R. T.; LaFerriere, B. D.; Orrell, J. L. [Pacific Northwest National Laboratory, Richland, WA (United States); Avignone, F. T. [Department of Physics and Astronomy, University of South Carolina, Columbia, SC (United States); Oak Ridge National Laboratory, Oak Ridge, TN (United States); Baldenegro-Barrera, C. X.; Bertrand, F. E. [Oak Ridge National Laboratory, Oak Ridge, TN (United States); and others

    2015-10-28

    The MAJORANA Collaboration is constructing the MAJORANA DEMONSTRATOR, an ultra-low background, modular, HPGe detector array with a mass of 44-kg (29 kg {sup 76}Ge and 15 kg {sup nat}Ge) to search for neutrinoless double beta decay in {sup 76}Ge. The next generation of tonne-scale Ge-based neutrinoless double beta decay searches will probe the neutrino mass scale in the inverted-hierarchy region. The MAJORANA DEMONSTRATOR is envisioned to demonstrate a path forward to achieve a background rate at or below 1 count/tonne/year in the 4 keV region of interest around the Q-value of 2039 keV. The MAJORANA DEMONSTRATOR follows a modular implementation to be easily scalable to the next generation experiment. First, the prototype module was assembled; it has been continuously taking data from July 2014 to June 2015. Second, Module 1 with more than half of the total enriched detectors and some natural detectors has been assembled and it is being commissioned. Finally, the assembly of Module 2, which will complete MAJORANA DEMONSTRATOR, is already in progress.

  17. Status of the MAJORANA DEMONSTRATOR

    CERN Document Server

    Cuesta, C; Arnquist, I J; Avignone, F T; Baldenegro-Barrera, C X; Barabash, A S; Bertrand, F E; Bradley, A W; Brudanin, V; Busch, M; Buuck, M; Byram, D; Caldwell, A S; Chan, Y-D; Christofferson, C D; Chu, P -H; Detwiler, J A; Efremenko, Yu; Ejiri, H; Elliott, S R; Galindo-Uribarri, A; Gilliss, T; Giovanetti, G K; Goett, J; Green, M P; Gruszko, J; Guinn, I S; Guiseppe, V E; Henning, R; Hoppe, E W; Howard, S; Howe, M A; Jasinski, B R; Keeter, K J; Kidd, M F; Konovalov, S I; Kouzes, R T; LaFerriere, B D; Leon, J; MacMullin, J; Martin, R D; Massarczyk, R; Meijer, S J; Mertens, S; Orrell, J L; O'Shaughnessy, C; Poon, A W P; Radford, D C; Rager, J; Rielage, K; Robertson, R G H; Romero-Romero, E; Shanks, B; Shirchenko, M; Snyder, N; Suriano, A M; Tedeschi, D; Trimble, J E; Varner, R L; Vasilyev, S; Vetter, K; Vorren, K; White, B R; Wilkerson, J F; Wiseman, C; Xu, W; Yakushev, E; Yu, C -H; Yumatov, V; Zhitnikov, I

    2015-01-01

    The MAJORANA Collaboration is constructing the MAJORANA DEMONSTRATOR, an ultra-low background, modular, HPGe detector array with a mass of 44-kg (29 kg 76Ge and 15 kg natGe) to search for neutrinoless double beta decay in Ge-76. The next generation of tonne-scale Ge-based neutrinoless double beta decay searches will probe the neutrino mass scale in the inverted-hierarchy region. The MAJORANA DEMONSTRATOR is envisioned to demonstrate a path forward to achieve a background rate at or below 1 count/tonne/year in the 4 keV region of interest around the Q-value of 2039 keV. The MAJORANA DEMONSTRATOR follows a modular implementation to be easily scalable to the next generation experiment. First, the prototype module was assembled; it has been continuously taking data from July 2014 to June 2015. Second, Module 1 with more than half of the total enriched detectors and some natural detectors has been assembled and it is being commissioned. Finally, the assembly of Module 2, which will complete MAJORANA DEMONSTRATOR, ...

  18. Demonstration of Active Combustion Control

    Science.gov (United States)

    Lovett, Jeffrey A.; Teerlinck, Karen A.; Cohen, Jeffrey M.

    2008-01-01

    The primary objective of this effort was to demonstrate active control of combustion instabilities in a direct-injection gas turbine combustor that accurately simulates engine operating conditions and reproduces an engine-type instability. This report documents the second phase of a two-phase effort. The first phase involved the analysis of an instability observed in a developmental aeroengine and the design of a single-nozzle test rig to replicate that phenomenon. This was successfully completed in 2001 and is documented in the Phase I report. This second phase was directed toward demonstration of active control strategies to mitigate this instability and thereby demonstrate the viability of active control for aircraft engine combustors. This involved development of high-speed actuator technology, testing and analysis of how the actuation system was integrated with the combustion system, control algorithm development, and demonstration testing in the single-nozzle test rig. A 30 percent reduction in the amplitude of the high-frequency (570 Hz) instability was achieved using actuation systems and control algorithms developed within this effort. Even larger reductions were shown with a low-frequency (270 Hz) instability. This represents a unique achievement in the development and practical demonstration of active combustion control systems for gas turbine applications.

  19. Buried Waste Integrated Demonstration Plan

    Energy Technology Data Exchange (ETDEWEB)

    Kostelnik, K.M.

    1991-12-01

    This document presents the plan of activities for the Buried Waste Integrated Demonstration (BWID) program which supports the environmental restoration (ER) objectives of the Department of Energy (DOE) Complex. Discussed in this plan are the objectives, organization, roles and responsibilities, and the process for implementing and managing BWID. BWID is hosted at the Idaho National Engineering Laboratory (INEL), but involves participants from throughout the DOE Complex, private industry, universities, and the international community. These participants will support, demonstrate, and evaluate a suite of advanced technologies representing a comprehensive remediation system for the effective and efficient remediation of buried waste. The processes for identifying technological needs, screening candidate technologies for applicability and maturity, selecting appropriate technologies for demonstration, field demonstrating, evaluation of results and transferring technologies to environmental restoration programs are also presented. This document further describes the elements of project planning and control that apply to BWID. It addresses the management processes, operating procedures, programmatic and technical objectives, and schedules. Key functions in support of each demonstration such as regulatory coordination, safety analyses, risk evaluations, facility requirements, and data management are presented.

  20. Madecassoside Inhibits Melanin Synthesis by Blocking Ultraviolet-Induced Inflammation

    Directory of Open Access Journals (Sweden)

    Eunsun Jung

    2013-12-01

    Full Text Available Madecassoside (MA, a pentacyclic triterpene isolated from Centella asitica (L., is used as a therapeutic agent in wound healing and also as an anti-inflammatory and anti-aging agent. However, the involvement of MA in skin-pigmentation has not been reported. This study was conducted to investigate the effects of MA on ultraviolet (UV-induced melanogenesis and mechanisms in a co-culture system of keratinocytes and melanocytes. MA significantly inhibited UVR-induced melanin synthesis and melanosome transfer in the co-culture system. These effects were further demonstrated by the MA-induced inhibition of protease-activated receptor-2 expression and its signaling pathway, cyclooxygenase-2, prostaglandin E2 and prostaglandin F2 alpha in keratinocytes. The clinical efficacy of MA was confirmed on artificially tanned human skin. MA significantly reduced UV-induced melanin index at 8 weeks after topical application. Overall, the study demonstrated significant benefits of MA use in the inhibition of hyperpigmentation caused by UV irradiation.

  1. Demonstration of blind quantum computing.

    Science.gov (United States)

    Barz, Stefanie; Kashefi, Elham; Broadbent, Anne; Fitzsimons, Joseph F; Zeilinger, Anton; Walther, Philip

    2012-01-20

    Quantum computers, besides offering substantial computational speedups, are also expected to preserve the privacy of a computation. We present an experimental demonstration of blind quantum computing in which the input, computation, and output all remain unknown to the computer. We exploit the conceptual framework of measurement-based quantum computation that enables a client to delegate a computation to a quantum server. Various blind delegated computations, including one- and two-qubit gates and the Deutsch and Grover quantum algorithms, are demonstrated. The client only needs to be able to prepare and transmit individual photonic qubits. Our demonstration is crucial for unconditionally secure quantum cloud computing and might become a key ingredient for real-life applications, especially when considering the challenges of making powerful quantum computers widely available.

  2. SECURES: Austin, Texas demonstration results

    Science.gov (United States)

    Lewis, Glynn; Shaw, Scott; Scharf, Peter; Stellingworth, Bob

    2003-09-01

    The Law Enforcement technology development community has a growing interest in the technologies associated with gunshot detection and localization. These interests revolve around community-oriented policing. Technologies of interest include those associated with muzzle blast and bullet shockwave detection and the inter-netting of these acoustic sensors with electro-optic sensors. To date, no one sensor technology has proven totally effective for a complete solution. PSI has a muzzle blast detection and localization product which is wireless, highly mobile and reconfigurable, with a user-friendly laptop processor and display unit, which completed a one-year demonstration in Austin, Texas on July 6, 2002. This demonstration was conducted under a Cooperative Agreement with the National Institute of Justice and in cooperation with the Austin Police Department. This paper will discuss the details of the demonstrations, provide a summarized evaluation, elucidate the lessons learned, make recommendations for future deployments and discuss the developmental directions indicated for the future.

  3. Propane Vehicle Demonstration Grant Program

    Energy Technology Data Exchange (ETDEWEB)

    Jack Mallinger

    2004-08-27

    Project Description: Propane Vehicle Demonstration Grants The Propane Vehicle Demonstration Grants was established to demonstrate the benefits of new propane equipment. The US Department of Energy, the Propane Education & Research Council (PERC) and the Propane Vehicle Council (PVC) partnered in this program. The project impacted ten different states, 179 vehicles, and 15 new propane fueling facilities. Based on estimates provided, this project generated a minimum of 1,441,000 new gallons of propane sold for the vehicle market annually. Additionally, two new off-road engines were brought to the market. Projects originally funded under this project were the City of Portland, Colorado, Kansas City, Impco Technologies, Jasper Engines, Maricopa County, New Jersey State, Port of Houston, Salt Lake City Newspaper, Suburban Propane, Mutual Liquid Propane and Ted Johnson.

  4. Probability of Detection Demonstration Transferability

    Science.gov (United States)

    Parker, Bradford H.

    2008-01-01

    The ongoing Mars Science Laboratory (MSL) Propellant Tank Penetrant Nondestructive Evaluation (NDE) Probability of Detection (POD) Assessment (NESC activity) has surfaced several issues associated with liquid penetrant POD demonstration testing. This presentation lists factors that may influence the transferability of POD demonstration tests. Initial testing will address the liquid penetrant inspection technique. Some of the factors to be considered in this task are crack aspect ratio, the extent of the crack opening, the material and the distance between the inspection surface and the inspector's eye.

  5. Evaluation of antioxidant activity of Ruta graveolens L. extract on inhibition of lipid peroxidation and DPPH radicals and the effects of some external factors on plant extract's potency.

    Directory of Open Access Journals (Sweden)

    S. Mohammadi- Motamed

    2014-01-01

    Full Text Available The antioxidant properties of Ruta graveolens L. were evaluated by two different methods; free radical scavenging using DPPH and inhibition of lipid peroxidation by the ferric thiocyanate method. The IC50 value of the methanol extract in DPPH inhibition was 200.5 μg/mL which was acceptable in comparison with BHT (41.8 μg/mL. In thiocyanate method, the plant extract demonstrated activity as much as BHT in prevention of lipid peroxidation. Increasing the temperature during extraction, significantly decreased the extract power in inhibition of DPPH radicals. The storage time and temperature had no effect on lipid peroxidation inhibition.

  6. LIMB Demonstration Project Extension and Coolside Demonstration. [Final report

    Energy Technology Data Exchange (ETDEWEB)

    Goots, T.R.; DePero, M.J.; Nolan, P.S.

    1992-11-10

    This report presents results from the limestone Injection Multistage Burner (LIMB) Demonstration Project Extension. LIMB is a furnace sorbent injection technology designed for the reduction of sulfur dioxide (SO{sub 2}) and nitrogen oxides (NO{sub x}) emissions from coal-fired utility boilers. The testing was conducted on the 105 Mwe, coal-fired, Unit 4 boiler at Ohio Edison`s Edgewater Station in Lorain, Ohio. In addition to the LIMB Extension activities, the overall project included demonstration of the Coolside process for S0{sub 2} removal for which a separate report has been issued. The primary purpose of the DOE LIMB Extension testing, was to demonstrate the generic applicability of LIMB technology. The program sought to characterize the S0{sub 2} emissions that result when various calcium-based sorbents are injected into the furnace, while burning coals having sulfur content ranging from 1.6 to 3.8 weight percent. The four sorbents used included calcitic limestone, dolomitic hydrated lime, calcitic hydrated lime, and calcitic hydrated lime with a small amount of added calcium lignosulfonate. The results include those obtained for the various coal/sorbent combinations and the effects of the LIMB process on boiler and plant operations.

  7. Latent inhibition in human adults without masking.

    Science.gov (United States)

    Escobar, Martha; Arcediano, Francisco; Miller, Ralph R

    2003-09-01

    Latent inhibition refers to attenuated responding to Cue X observed when the X-outcome pairings are preceded by X-alone presentations. It has proven difficult to obtain in human adults unless the preexposure (X-alone) presentations are embedded within a masking (i.e., distracting) task. The authors hypothesized that the difficulty in obtaining latent inhibition with unmasked tasks is related to the usual training procedures, in which the preexposure and conditioning experiences are separated by a set of instructions. Experiment 1 reports latent inhibition without masking in a task in which preexposure and conditioning occur without interruption. Experiments 2 and 3 demonstrate that this attenuation in responding to target Cue X does not pass a summation test for conditioned inhibition and is context specific, thereby confirming that it is latent inhibition. Experiments 3 and 4 confirm that introducing instructions between preexposure and conditioning disrupts latent inhibition.

  8. Safrole oxide inhibits angiogenesis by inducing apoptosis.

    Science.gov (United States)

    Zhao, Jing; Miao, Junying; Zhao, Baoxiang; Zhang, Shangli; Yin, Deling

    2005-06-01

    Our previous studies indicate that 3, 4-(methylenedioxy)-1-(2', 3'-epoxypropyl)-benzene (safrole oxide), a newly synthesized compound, induces apoptosis in vascular endothelial cells (VECs) and A549 lung cancer cells. To our knowledge, the inhibition of angiogenesis by safrole oxide has not been reported yet. We report here that cultured rat aorta treated with safrole oxide exhibited a significant microvessel reduction as determined by counting the number of microvessels in a phase contrast microscope. There were more microvessels formed in the presence of A549 lung cancer cells in rat aorta model, while a dramatic inhibition of angiogenesis was obtained by adding 220-450 micromol l(-1) of safrole oxide to the growth medium (Psafrole oxide produced only some abortive endothelial cells but not microvessels. Furthermore, safrole oxide induced antiangiogenic effect in the chorioallantoic membranes (CAM) as a dose dependent manner. Eggs treated with 2-11 micromol 100 microl(-1) per egg of the safrole oxide for 48 h exhibited a significant reduction in blood vessel area of the CAM, a process likely mediated by apoptosis as demonstrated by DNA fragmentation. Our results suggest that safrole oxide has antiangiogenic activity and this effect might occur by induction of cellular apoptosis.

  9. Inhibition of Midkine Augments Osteoporotic Fracture Healing.

    Directory of Open Access Journals (Sweden)

    Melanie Haffner-Luntzer

    Full Text Available The heparin-binding growth and differentiation factor midkine (Mdk is proposed to negatively regulate osteoblast activity and bone formation in the adult skeleton. As Mdk-deficient mice were protected from ovariectomy (OVX-induced bone loss, this factor may also play a role in the pathogenesis of postmenopausal osteoporosis. We have previously demonstrated that Mdk negatively influences bone regeneration during fracture healing. Here, we investigated whether the inhibition of Mdk using an Mdk-antibody (Mdk-Ab improves compromised bone healing in osteoporotic OVX-mice. Using a standardized femur osteotomy model, we demonstrated that Mdk serum levels were significantly enhanced after fracture in both non-OVX and OVX-mice, however, the increase was considerably greater in osteoporotic mice. Systemic treatment with the Mdk-Ab significantly improved bone healing in osteoporotic mice by increasing bone formation in the fracture callus. On the molecular level, we demonstrated that the OVX-induced reduction of the osteoanabolic beta-catenin signaling in the bony callus was abolished by Mdk-Ab treatment. Furthermore, the injection of the Mdk-Ab increased trabecular bone mass in the skeleton of the osteoporotic mice. These results implicate that antagonizing Mdk may be useful for the therapy of osteoporosis and osteoporotic fracture-healing complications.

  10. Phenolphthalein-Pink Tornado Demonstration

    Science.gov (United States)

    Prall, Bruce R.

    2008-01-01

    The titration of HCl with NaOH has traditionally been used to introduce beginning chemistry students to the concepts of acid-base chemistry and stoichiometry. The demonstration described in this article utilizes this reaction as a means of providing students an opportunity to observe the dynamic motion associated with a swirling vortex and its…

  11. Demonstrating Fermat's Principle in Optics

    Science.gov (United States)

    Paleiov, Orr; Pupko, Ofir; Lipson, S. G.

    2011-01-01

    We demonstrate Fermat's principle in optics by a simple experiment using reflection from an arbitrarily shaped one-dimensional reflector. We investigated a range of possible light paths from a lamp to a fixed slit by reflection in a curved reflector and showed by direct measurement that the paths along which light is concentrated have either…

  12. SunJammer Technology Demonstration

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The Sunjammer Project is a NASA funded contract to L?Garde Inc. to fly a solar sail demonstration for a period of approximately one year. L?Garde is also partnered...

  13. Launch Vehicle Dynamics Demonstrator Model

    Science.gov (United States)

    1963-01-01

    Launch Vehicle Dynamics Demonstrator Model. The effect of vibration on launch vehicle dynamics was studied. Conditions included three modes of instability. The film includes close up views of the simulator fuel tank with and without stability control. [Entire movie available on DVD from CASI as Doc ID 20070030984. Contact help@sti.nasa.gov

  14. Phenolphthalein-Pink Tornado Demonstration

    Science.gov (United States)

    Prall, Bruce R.

    2008-01-01

    The titration of HCl with NaOH has traditionally been used to introduce beginning chemistry students to the concepts of acid-base chemistry and stoichiometry. The demonstration described in this article utilizes this reaction as a means of providing students an opportunity to observe the dynamic motion associated with a swirling vortex and its…

  15. Demonstration of melatonin in amphibia

    NARCIS (Netherlands)

    Veerdonk, F.C.G. van de

    1967-01-01

    The presence of melatonin in the amphibian epiphysis has been ascertained earlier by several indirect methods, demonstrating the synthesizing enzyme or precursors of the compound. This communication describes the presence of melatonin in amphibian brain in a direct way, using dextran gel chromatogra

  16. Latent inhibition in schizophrenia.

    Science.gov (United States)

    Swerdlow, N R; Braff, D L; Hartston, H; Perry, W; Geyer, M A

    1996-05-01

    Latent inhibition (LI) refers to the retarded acquisition of a conditioned response that occurs if the subject being tested is first preexposed to the to-be-conditioned stimulus (CS) without the paired unconditioned stimulus (UCS). Because the 'irrelevance' of the to-be-conditioned stimulus is established during non-contingent preexposure, the slowed acquisition of the CS-UCS association is thought to reflect the process of overcoming this learned irrelevance. Latent inhibition has been reported to be diminished in acutely hospitalized schizophrenia patients. If acutely hospitalized schizophrenia patients are preexposed to the CS, they learn the association as fast as, and perhaps faster than, patients who are not preexposed to the CS. This finding has been interpreted as reflecting the inability of acute schizophrenia patients to ignore irrelevant stimuli. In this study, the LI paradigm was identical to the one used in previous reports of LI deficits in schizophrenia patients (Baruch et al., 1988). Latent inhibition was observed in normal control subjects (n = 73), including individuals identified as 'psychosis-prone' based on established screening criteria, and in anxiety (n = 19) and mood disorder (n = 13) patients. Learning scores (trials to criterion) in "acutely' hospitalized as well as "chronic' hospitalized schizophrenia patients (n = 45) were significantly elevated in both preexposed and non-preexposed subjects, compared to controls. Acute schizophrenia patients exhibited intact LI. Separate cohorts of acute and chronic schizophrenia patients (n = 23) and normal controls (n = 34) exhibited intact LI when tested in a new, easier-to-acquire computerized LI paradigm. These results fail to identify specific LI deficits in schizophrenia patients, and raise the possibility that previously observed LI deficits in schizophrenia patients may reflect, at least in part, performance deficits related to learning acquisition.

  17. Natural Hazard Demonstrations for Teaching

    Science.gov (United States)

    Malamud, B. D.

    2005-12-01

    This paper presents several demonstrations that have been developed or gathered from other sources in the general area of natural hazards (e.g. landslides, earthquakes, volcanoes, wildfires, tsunamis, mass movements, asteroid impacts, etc.). There are many methods of teaching, but as university lecturers, particularly for large class sizes, we find ourselves too often presenting material to students by direct speaking, or some combination of blackboard/whiteboard/slide projector/digital projector. There are certainly a number of techniques to more actively involve students, so that teaching is not just `receiving of information', including breaking up students into small group discussions, encouraging students to actively participate in class through comments and questions, and/or some combination of hands-on activities and demonstrations. It is this latter which is concentrated on here. As a teaching tool, the students themselves became much more excited about what they are learning if use is made of 5--10 minute demonstrations, even if only peripherally related to the subject at hand. The resultant discussion with questions and comments by students keeps both the students and the lecturer (in this case the author) motivated and intrigued about the subjects being discussed. Days, weeks, and months later, the students remember these `demonstrations', but to set these up takes time, effort, and resources of equipment, although not necessarily a large amount of the latter. Several natural hazards demonstrations are presented here, most inexpensive, that have been used in front of large university classes and smaller `break-out groups', and which can also be adapted for secondary-school students.

  18. Lateral inhibition during nociceptive processing.

    Science.gov (United States)

    Quevedo, Alexandre S; Mørch, Carsten Dahl; Andersen, Ole K; Coghill, Robert C

    2017-06-01

    Spatial summation of pain (SSP) is the increase of perceived intensity that occurs as the stimulated area increases. Spatial summation of pain is subadditive in that increasing the stimulus area produces a disproportionately small increase in the perceived intensity of pain. A possible explanation for subadditive summation may be that convergent excitatory information is modulated by lateral inhibition. To test the hypothesis that lateral inhibition may limit SSP, we delivered different patterns of noxious thermal stimuli to the abdomens of 15 subjects using a computer-controlled CO2 laser. Lines (5 mm wide) of variable lengths (4, 8 cm) were compared with 2-point stimuli delivered at the same position/separation as the length of lines. When compared with one-point control stimuli, 2-point stimulus patterns produced statistically significant SSP, while no such summation was detected during line stimulus patterns. Direct comparison of pain intensity evoked by 2-point pattern stimuli with line pattern stimuli revealed that 2-point patterns were perceived as significantly more painful, despite the fact that the 2-point pattern stimulated far smaller areas of skin. Thus, the stimulation of the skin region between the endpoints of the lines appears to produce inhibition. These findings indicate that lateral inhibition limits SSP and is an intrinsic component of nociceptive information processing. Disruption of such lateral inhibition may contribute substantially to the radiation of some types of chronic pain.

  19. Irvine Smart Grid Demonstration, a Regional Smart Grid Demonstration Project

    Energy Technology Data Exchange (ETDEWEB)

    Yinger, Robert [Southern California Edison Company, Rosemead, CA (United States); Irwin, Mark [Southern California Edison Company, Rosemead, CA (United States)

    2015-12-29

    ISGD was a comprehensive demonstration that spanned the electricity delivery system and extended into customer homes. The project used phasor measurement technology to enable substation-level situational awareness, and demonstrated SCE’s next-generation substation automation system. It extended beyond the substation to evaluate the latest generation of distribution automation technologies, including looped 12-kV distribution circuit topology using URCIs. The project team used DVVC capabilities to demonstrate CVR. In customer homes, the project evaluated HAN devices such as smart appliances, programmable communicating thermostats, and home energy management components. The homes were also equipped with energy storage, solar PV systems, and a number of energy efficiency measures (EEMs). The team used one block of homes to evaluate strategies and technologies for achieving ZNE. A home achieves ZNE when it produces at least as much renewable energy as the amount of energy it consumes annually. The project also assessed the impact of device-specific demand response (DR), as well as load management capabilities involving energy storage devices and plug-in electric vehicle charging equipment. In addition, the ISGD project sought to better understand the impact of ZNE homes on the electric grid. ISGD’s SENet enabled end-to-end interoperability between multiple vendors’ systems and devices, while also providing a level of cybersecurity that is essential to smart grid development and adoption across the nation. The ISGD project includes a series of sub-projects grouped into four logical technology domains: Smart Energy Customer Solutions, Next-Generation Distribution System, Interoperability and Cybersecurity, and Workforce of the Future. Section 2.3 provides a more detailed overview of these domains.

  20. Suppression of autophagy augments the radiosensitizing effects of STAT3 inhibition on human glioma cells

    Energy Technology Data Exchange (ETDEWEB)

    Yuan, Xiaopeng; Du, Jie; Hua, Song; Zhang, Haowen; Gu, Cheng; Wang, Jie; Yang, Lei; Huang, Jianfeng; Yu, Jiahua, E-mail: yujiahua@suda.edu.cn; Liu, Fenju, E-mail: fangsh@suda.edu.cn

    2015-01-15

    Radiotherapy is an essential component of the standard therapy for newly diagnosed glioblastoma. To increase the radiosensitivity of glioma cells is a feasible solution to improve the therapeutic effects. It has been suggested that inhibition of signal transducer and activator of transcription 3 (STAT3) can radiosensitize glioma cells, probably via the activation of mitochondrial apoptotic pathway. In this study, human malignant glioma cells, U251 and A172, were treated with an STAT3 inhibitor, WP1066, or a short hairpin RNA plasmid targeting STAT3 to suppress the activation of STAT3 signaling. The radiosensitizing effects of STAT3 inhibition were confirmed in glioma cells. Intriguingly, combination of ionizing radiation exposure and STAT3 inhibition triggered a pronounced increase of autophagy flux. To explore the role of autophagy, glioma cells were treated with 3-methyladenine or siRNA for autophagy-related gene 5, and it was demonstrated that inhibition of autophagy further strengthened the radiosensitizing effects of STAT3 inhibition. Accordingly, more apoptotic cells were induced by the dual inhibition of autophagy and STAT3 signaling. In conclusion, our data revealed a protective role of autophagy in the radiosensitizing effects of STAT3 inhibition, and inhibition of both autophagy and STAT3 might be a potential therapeutic strategy to increase the radiosensitivity of glioma cells. - Highlights: • Inactivation of STAT3 signaling radiosensitizes malignant glioma cells. • STAT3 inhibition triggers a significant increase of autophagy flux induced by ionizing radiation in glioma cells. • Suppression of autophagy further strengthens the radiosensitizing effects of STAT3 inhibition in glioma cells. • Dual inhibition of autophagy and STAT3 induce massive apoptotic cells upon exposure to ionizing radiation.

  1. Resveratrol inhibits mucus overproduction and MUC5AC expression in a murine model of asthma.

    Science.gov (United States)

    Ni, Zhen-Hua; Tang, Ji-Hong; Chen, Guo; Lai, Yi-Min; Chen, Qing-Ge; Li, Zao; Yang, Wei; Luo, Xu-Min; Wang, Xiong-Biao

    2016-01-01

    Previous in vitro studies have demonstrated that resveratrol is able to significantly inhibit the upregulation of mucin 5AC (MUC5AC), a major component of mucus; thus indicating that resveratrol may have potential in regulating mucus overproduction. However, there have been few studies regarding the resveratrol‑mediated prevention of MUC5AC overproduction in vivo, and the mechanisms by which resveratrol regulates MUC5AC expression have yet to be elucidated. In the present study, an ovalbumin (OVA)‑challenged murine model of asthma was used to assess the effects of resveratrol treatment on mucus production in vivo. The results demonstrated that resveratrol significantly inhibited OVA‑induced airway inflammation and mucus production. In addition, the mRNA and protein expression levels of MUC5AC were increased in the OVA‑challenged mice, whereas treatment with resveratrol significantly inhibited this effect. The expression levels of murine calcium‑activated chloride channel (mCLCA)3, an important key mediator of MUC5AC production, were also reduced following resveratrol treatment. Furthermore, in vitro studies demonstrated that resveratrol significantly inhibited human (h)CLCA1 and MUC5AC expression in a dose‑dependent manner. These results indicated that resveratrol was effective in preventing mucus overproduction and MUC5AC expression in vivo, and its underlying mechanism may be associated with regulation of the mCLCA3/hCLCA1 signaling pathway.

  2. The MAJORANA Demonstrator Radioassay Program

    Energy Technology Data Exchange (ETDEWEB)

    Abgrall, N.; Arnquist, Isaac J.; Avignone, F. T.; Back, Henning O.; Barabash, Alexander S.; Bertrand, F.; Boswell, M.; Bradley, A. W.; Brudanin, V.; Busch, Matthew; Buuck, M.; Byram, D.; Caldwell, A. S.; Chan, Yuen-Dat; Christofferson, C. D.; Chu, P. H.; Cuesta, C.; Detwiler, Jason A.; Dunmore, J. A.; Efremenko, Yuri; Ejiri, H.; Elliott, S.; Finnerty, P.; Galindo-Uribarri, A.; Gehman, Victor M.; Gilliss, T.; Giovanetti, G. K.; Goett, J.; Green, M. P.; Gruszko, J.; Guinn, I.; Guiseppe, V. E.; Henning, R.; Hoppe, Eric W.; Howard, S.; Howe, M. A.; Jasinski, B. R.; Johnson, R. A.; Keeter, K.; Kidd, M. F.; Kochetov, Oleg; Konovalov, S.; Kouzes, Richard T.; Laferriere, Brian D.; Leon, Jonathan D.; Loach, J. C.; MacMullin, J.; MacMullin, S.; Martin, R. D.; Massarcyk, R.; Meijer, S. J.; Mertens, S.; Miller, M. L.; Orrell, John L.; O' Shaughnessy, C.; Overman, Nicole R.; Poon, Alan W.; Pushkin, K.; Radford, D. C.; Rager, J.; Rielage, Keith; Robertson, R. G. H.; Romero-Romero, E.; Ronquest, M. C.; Schubert, Alexis G.; Shanks, B.; Shirchenko, M.; Snavely, Kyle J.; Snyder, N.; Steele, David; Suriano, Anne-Marie; Tedeschi, D.; Trimble, J. E.; Varner, R. L.; Vasilyev, Sergey; Vetter, K.; Vorren, Kris R.; White, B. R.; Wilkerson, J. F.; Wiseman, C.; Xu, W.; Yakushev, E.; Yu, Chang-Hong; Yumatov, Vladimir; Zhitnikov, I.

    2016-05-03

    The Majorana collaboration is constructing the Majorana Demonstrator at the Sanford Underground Research Facility at the Homestake gold mine, in Lead, SD. The apparatus will use Ge detectors, enriched in isotope 76Ge, to demonstrate the feasibility of a large-scale Ge detector experiment to search for neutrinoless double beta decay. The long half-life of this postulated process requires that the apparatus be extremely low in radioactive isotopes whose decays may produce backgrounds to the search. The radioassay program conducted by the collaboration to ensure that the materials comprising the apparatus are suffciently pure is described. The resulting measurements of the radioactiveisotope contamination for a number of materials studied for use in the detector are reported.

  3. The MAJORANA DEMONSTRATOR radioassay program

    Energy Technology Data Exchange (ETDEWEB)

    Abgrall, N. [Nuclear Science Division, Lawrence Berkeley National Laboratory, Berkeley, CA (United States); Shanghai Jiao Tong University, Shanghai (China); Arnquist, I.J. [Pacific Northwest National Laboratory, Richland, WA (United States); Avignone, F.T. [Department of Physics and Astronomy, University of South Carolina, Columbia, SC (United States); Oak Ridge National Laboratory, Oak Ridge, TN (United States); Back, H.O. [Department of Physics, North Carolina State University, Raleigh, NC (United States); Triangle Universities Nuclear Laboratory, Durham, NC (United States); Barabash, A.S. [National Research Center, “Kurchatov Institute” Institute for Theoretical and Experimental Physics, Moscow (Russian Federation); Bertrand, F.E. [Oak Ridge National Laboratory, Oak Ridge, TN (United States); Boswell, M. [Los Alamos National Laboratory, Los Alamos, NM (United States); Bradley, A.W. [Nuclear Science Division, Lawrence Berkeley National Laboratory, Berkeley, CA (United States); Brudanin, V. [Joint Institute for Nuclear Research, Dubna (Russian Federation); Busch, M. [Department of Physics, Duke University, Durham, NC (United States); Triangle Universities Nuclear Laboratory, Durham, NC (United States); Buuck, M. [Center for Experimental Nuclear Physics and Astrophysics, and Department of Physics, University of Washington, Seattle, WA (United States); Byram, D. [Department of Physics, University of South Dakota, Vermillion, SD (United States); Caldwell, A.S. [South Dakota School of Mines and Technology, Rapid City, SD (United States); Chan, Y.-D. [Nuclear Science Division, Lawrence Berkeley National Laboratory, Berkeley, CA (United States); Christofferson, C.D. [South Dakota School of Mines and Technology, Rapid City, SD (United States); Chu, P.-H. [Los Alamos National Laboratory, Los Alamos, NM (United States); and others

    2016-08-21

    The MAJORANA collaboration is constructing the MAJORANA DEMONSTRATOR at the Sanford Underground Research Facility at the Homestake gold mine, in Lead, SD. The apparatus will use Ge detectors, enriched in isotope {sup 76}Ge, to demonstrate the feasibility of a large-scale Ge detector experiment to search for neutrinoless double beta decay. The long half-life of this postulated process requires that the apparatus be extremely low in radioactive isotopes whose decays may produce backgrounds to the search. The radioassay program conducted by the collaboration to ensure that the materials comprising the apparatus are sufficiently pure is described. The resulting measurements from gamma-ray counting, neutron activation and mass spectroscopy of the radioactive-isotope contamination for the materials studied for use in the detector are reported. We interpret these numbers in the context of the expected background for the experiment.

  4. The MAJORANA DEMONSTRATOR radioassay program

    Science.gov (United States)

    Abgrall, N.; Arnquist, I. J.; Avignone, F. T.; Back, H. O.; Barabash, A. S.; Bertrand, F. E.; Boswell, M.; Bradley, A. W.; Brudanin, V.; Busch, M.; Buuck, M.; Byram, D.; Caldwell, A. S.; Chan, Y.-D.; Christofferson, C. D.; Chu, P.-H.; Cuesta, C.; Detwiler, J. A.; Dunmore, J. A.; Efremenko, Yu.; Ejiri, H.; Elliott, S. R.; Finnerty, P.; Galindo-Uribarri, A.; Gehman, V. M.; Gilliss, T.; Giovanetti, G. K.; Goett, J.; Green, M. P.; Gruszko, J.; Guinn, I. S.; Guiseppe, V. E.; Henning, R.; Hoppe, E. W.; Howard, S.; Howe, M. A.; Jasinski, B. R.; Johnson, R. A.; Keeter, K. J.; Kidd, M. F.; Kochetov, O.; Konovalov, S. I.; Kouzes, R. T.; LaFerriere, B. D.; Leon, J.; Loach, J. C.; MacMullin, J.; MacMullin, S.; Martin, R. D.; Massarczyk, R.; Meijer, S.; Mertens, S.; Miller, M. L.; Orrell, J. L.; O'Shaughnessy, C.; Overman, N. R.; Poon, A. W. P.; Pushkin, K.; Radford, D. C.; Rager, J.; Rielage, K.; Robertson, R. G. H.; Romero-Romero, E.; Ronquest, M. C.; Schubert, A. G.; Shanks, B.; Shirchenko, M.; Snavely, K. J.; Snyder, N.; Steele, D.; Suriano, A. M.; Tedeschi, D.; Trimble, J. E.; Varner, R. L.; Vasilyev, S.; Vetter, K.; Vorren, K.; White, B. R.; Wilkerson, J. F.; Wiseman, C.; Xu, W.; Yakushev, E.; Yu, C.-H.; Yumatov, V.; Zhitnikov, I.

    2016-08-01

    The MAJORANA collaboration is constructing the MAJORANA DEMONSTRATOR at the Sanford Underground Research Facility at the Homestake gold mine, in Lead, SD. The apparatus will use Ge detectors, enriched in isotope 76Ge, to demonstrate the feasibility of a large-scale Ge detector experiment to search for neutrinoless double beta decay. The long half-life of this postulated process requires that the apparatus be extremely low in radioactive isotopes whose decays may produce backgrounds to the search. The radioassay program conducted by the collaboration to ensure that the materials comprising the apparatus are sufficiently pure is described. The resulting measurements from gamma-ray counting, neutron activation and mass spectroscopy of the radioactive-isotope contamination for the materials studied for use in the detector are reported. We interpret these numbers in the context of the expected background for the experiment.

  5. Performance demonstration by ROC method

    Science.gov (United States)

    Wessel, Hannelore; Nockemann, Christina; Tillack, Gerd-Rüdiger; Mattis, Arne

    1994-12-01

    The question of the efficiency of a material testing system is important, when a competing or advanced system appears at the market. The comparison of the different systems can be done partly by the comparison of the technical specification of the systems, but not all parameters can be expressed by measured values, especially not the influence of human inspectors. A testing system in the field of NDT - for example weld inspection - often consists of several different devices and components (radiographic film, its irradiation and development, conventional inspection with a light box, human inspector). The demonstration of the performance of such a system with similar or advanced methods can be done by a statistical method, the ROC method. This quantitative measure for testing performance allows the comparison of complex NDT systems which will be demonstrated in detail by the comparison of conventional weld inspection with inspection of welds using the digitised image of the radiographs.

  6. Structural Assembly Demonstration Experiment (SADE)

    Science.gov (United States)

    Akin, David L.; Mills, Raymond A.; Bowden, Mary L.

    1987-01-01

    The purpose of the Structural Assembly Demonstration Experiment (SADE) was to create a near-term Shuttle flight experiment focusing on the deployment and erection of structural truss elements. The activities of the MIT Space Systems Laboratory consist of three major areas: preparing and conducting neutral buoyancy simulation test series; producing a formal SADE Experiment plan; and studying the structural dynamics issues of the truss structure. Each of these areas is summarized.

  7. Solar heating demonstration. Final report

    Energy Technology Data Exchange (ETDEWEB)

    Bonicatto, L.; Kozak, C.

    1980-01-01

    The demonstration involved a 4-panel solar collector mounted on the industrial arts building. A 120 gallon storage tank supplements a 66 gallon electric hot water heater which supplies hot water for 5 shop wash basins, girl's and boy's lavatories, and a pressure washer in the auto shop. The installation and educational uses of the system are described. (MHR)

  8. Electric thermal storage demonstration program

    Energy Technology Data Exchange (ETDEWEB)

    1992-02-01

    In early 1989, MMWEC, a joint action agency comprised of 30 municipal light departments in Massachusetts and on affiliate in Rhode Island, responded to a DOE request to proposal for the Least Cost Utility Planning program. The MMWEC submission was for the development of a program, focused on small rural electric utilities, to promote the use of electric thermal storage heating systems in residential applications. This report discusses the demonstration of ETS equipment at four member light departments.

  9. Electric thermal storage demonstration program

    Energy Technology Data Exchange (ETDEWEB)

    1992-01-01

    In early 1989, MMWEC, a joint action agency comprised of 30 municipal light departments in Massachusetts and on affiliate in Rhode Island, responded to a DOE request to proposal for the Least Cost Utility Planning program. The MMWEC submission was for the development of a program, focused on small rural electric utilities, to promote the use of electric thermal storage heating systems in residential applications. This report discusses the demonstration of ETS equipment at four member light departments.

  10. Aerospace Communications Security Technologies Demonstrated

    Science.gov (United States)

    Griner, James H.; Martzaklis, Konstantinos S.

    2003-01-01

    In light of the events of September 11, 2001, NASA senior management requested an investigation of technologies and concepts to enhance aviation security. The investigation was to focus on near-term technologies that could be demonstrated within 90 days and implemented in less than 2 years. In response to this request, an internal NASA Glenn Research Center Communications, Navigation, and Surveillance Aviation Security Tiger Team was assembled. The 2-year plan developed by the team included an investigation of multiple aviation security concepts, multiple aircraft platforms, and extensively leveraged datalink communications technologies. It incorporated industry partners from NASA's Graphical Weather-in-the-Cockpit research, which is within NASA's Aviation Safety Program. Two concepts from the plan were selected for demonstration: remote "black box," and cockpit/cabin surveillance. The remote "black box" concept involves real-time downlinking of aircraft parameters for remote monitoring and archiving of aircraft data, which would assure access to the data following the loss or inaccessibility of an aircraft. The cockpit/cabin surveillance concept involves remote audio and/or visual surveillance of cockpit and cabin activity, which would allow immediate response to any security breach and would serve as a possible deterrent to such breaches. The datalink selected for the demonstrations was VDL Mode 2 (VHF digital link), the first digital datalink for air-ground communications designed for aircraft use. VDL Mode 2 is beginning to be implemented through the deployment of ground stations and aircraft avionics installations, with the goal of being operational in 2 years. The first demonstration was performed December 3, 2001, onboard the LearJet 25 at Glenn. NASA worked with Honeywell, Inc., for the broadcast VDL Mode 2 datalink capability and with actual Boeing 757 aircraft data. This demonstration used a cockpitmounted camera for video surveillance and a coupling to

  11. Demonstration projects : learning by experience : the Seabird Island demonstration project

    Energy Technology Data Exchange (ETDEWEB)

    Anon.

    2009-10-15

    This article described the Seabird Island sustainable community housing demonstration project near Agassiz, British Columbia. The project provides a sustainable, affordable place for 7 families and demonstrates a new way to build and design communities using renewable energy technologies to provide residents with better quality, energy efficient housing while reducing costs and minimizing environmental impacts. The design integrates renewable energy sources such as wind, solar and geothermal energy to save on heating and lighting costs. This article noted some of the dubious design features that could have been screened out at the design stage if careful analysis had been carried out. It described features such as the solar orientation; climatic factors that influenced the form and details of the building; the high-efficiency, condensing, natural gas water heater for space heating combined with a forced-air and radiant-floor heating system; solariums that provided solar preheating of domestic hot water; ventilation air preheating; the solar roof; an earth-tube ventilation system; and 3 wind turbines to generate electricity to offset conventional electricity sources. Canada Mortgage and Housing Corporation has monitored several of the systems in order to evaluate the extent to which these features have influenced the performance of the dwelling units. The energy use in all 7 units was documented along with indoor air quality. An energy performance rating of EnerGuide 80 was achieved, which is comparable to R-2000. The monitoring study revealed that wind energy at this location was not sufficient to justify the installation of the wind turbines. The solar steel roof/solarium energy system did not perform as expected. In addition, the earth-tube ventilation system provided little heat and its overall contribution to ventilation was uncertain. Other deficiencies were also noted, such as leaky ductwork, non-operational dampers and poorly integrated control systems. The

  12. Zinc ions bind to and inhibit activated protein C

    DEFF Research Database (Denmark)

    Zhu, Tianqing; Ubhayasekera, Wimal; Nickolaus, Noëlle

    2010-01-01

    Zn2+ ions were found to efficiently inhibit activated protein C (APC), suggesting a potential regulatory function for such inhibition. APC activity assays employing a chromogenic peptide substrate demonstrated that the inhibition was reversible and the apparent K I was 13 +/- 2 microM. k cat was ...

  13. Growth Arrest on Inhibition of Nonsense-Mediated Decay Is Mediated by Noncoding RNA GAS5

    Directory of Open Access Journals (Sweden)

    Mirna Mourtada-Maarabouni

    2013-01-01

    Full Text Available Nonsense-mediated decay is a key RNA surveillance mechanism responsible for the rapid degradation of mRNAs containing premature termination codons and hence prevents the synthesis of truncated proteins. More recently, it has been shown that nonsense-mediated decay also has broader significance in controlling the expression of a significant proportion of the transcriptome. The importance of this mechanism to the mammalian cell is demonstrated by the observation that its inhibition causes growth arrest. The noncoding RNA growth arrest specific transcript 5 (GAS5 has recently been shown to play a key role in growth arrest induced by several mechanisms, including serum withdrawal and treatment with the mTOR inhibitor rapamycin. Here we show that inhibition of nonsense-mediated decay in several human lymphocyte cell lines causes growth arrest, and siRNA-mediated downregulation of GAS5 in these cells significantly alleviates the inhibitory effects observed. These observations hold true for inhibition of nonsense-mediated decay both through RNA interference and through pharmacological inhibition by aminoglycoside antibiotics gentamycin and G418. These studies have important implications for ototoxicity and nephrotoxicity caused by gentamycin and for the proposed use of NMD inhibition in treating genetic disease. This report further demonstrates the critical role played by GAS5 in the growth arrest of mammalian cells.

  14. The inhibition of Wnt/β-catenin signaling pathway in human colon cancer cells by sulindac.

    Science.gov (United States)

    Tai, Wei-Ping; Hu, Pin-Jin; Wu, Jing; Lin, Xiang-Chun

    2014-01-01

    The aberrant activation of Wnt/β-catenin signaling plays important roles in the initial development of colon cancer. Sulindac is a commonly used non-steroidal anti-inflammatory drug. We demonstrated the effects of sulindac on growth inhibition, apoptosis induction, and Wnt/β-catenin signaling suppression in human colon cancer cells. Sulindac significantly inhibited proliferation of HT-29 colon cancer cells in a dose- and time-dependent manner. Sulindac was found to induce the apoptosis of HT-29 cells and inhibit the Wnt/β-catenin pathway. The inhibition was further confirmed by the decreased protein levels of β-catenin. The results indicate that sulindac may play a beneficial role in the comprehensive treatment of colon cancer.

  15. Charge sniffer for electrostatics demonstrations

    Science.gov (United States)

    Dinca, Mihai P.

    2011-02-01

    An electronic electroscope with a special design for demonstrations and experiments on static electricity is described. It operates as an electric charge sniffer by detecting slightly charged objects when they are brought to the front of its sensing electrode. The sniffer has the advantage of combining high directional sensitivity with a logarithmic bar display. It allows for the identification of electric charge polarity during charge separation by friction, peeling, electrostatic induction, batteries, or secondary coils of power transformers. Other experiments in electrostatics, such as observing the electric field of an oscillating dipole and the distance dependence of the electric field generated by simple charge configurations, are also described.

  16. Background Model for the Majorana Demonstrator

    CERN Document Server

    Cuesta, C; Aguayo, E; Avignone, F T; Barabash, A S; Bertrand, F E; Boswell, M; Brudanin, V; Busch, M; Byram, D; Caldwell, A S; Chan, Y-D; Christofferson, C D; Combs, D C; Cuesta, C; Detwiler, J A; Doe, P J; Efremenko, Yu; Egorov, V; Ejiri, H; Elliott, S R; Fast, J E; Finnerty, P; Fraenkle, F M; Galindo-Uribarri, A; Giovanetti, G K; Goett, J; Green, M P; Gruszko, J; Guiseppe, V E; Gusev, K; Hallin, A L; Hazama, R; Hegai, A; Henning, R; Hoppe, E W; Howard, S; Howe, M A; Keeter, K J; Kidd, M F; Kochetov, O; Konovalov, S I; Kouzes, R T; LaFerriere, B D; Leon, J; Leviner, L E; Loach, J C; MacMullin, J; MacMullin, S; Martin, R D; Meijer, S; Mertens, S; Nomachi, M; Orrell, J L; O'Shaughnessy, C; Overman, N R; Phillips, D G; Poon, A W P; Pushkin, K; Radford, D C; Rager, J; Rielage, K; Robertson, R G H; Romero-Romero, E; Ronquest, M C; Schubert, A G; Shanks, B; Shima, T; Shirchenko, M; Snavely, K J; Snyder, N; Suriano, A M; Thompson, J; Timkin, V; Tornow, W; Trimble, J E; Varner, R L; Vasilyev, S; Vetter, K; Vorren, K; White, B R; Wilkerson, J F; Wiseman, C; Xu, W; Yakushev, E; Young, A R; Yu, C H; Yumatov, V

    2014-01-01

    The Majorana Collaboration is constructing a system containing 40 kg of HPGe detectors to demonstrate the feasibility and potential of a future tonne-scale experiment capable of probing the neutrino mass scale in the inverted-hierarchy region. To realize this, a major goal of the Majorana Demonstrator is to demonstrate a path forward to achieving a background rate at or below 1 cnt/(ROI-t-y) in the 4 keV region of interest around the Q-value at 2039 keV. This goal is pursued through a combination of a significant reduction of radioactive impurities in construction materials with analytical methods for background rejection, for example using powerful pulse shape analysis techniques profiting from the p-type point contact HPGe detectors technology. The effectiveness of these methods is assessed using simulations of the different background components whose purity levels are constrained from radioassay measurements.

  17. Demonstration Telescopes Using "Dollar Optics"

    Science.gov (United States)

    Ross, Paul

    2008-05-01

    I propose a poster that illustrates the use of "dollar optics” for experimentation and for the creation of demonstration telescopes. Handling a variety of lenses and mirrors provides an opportunity for discovering practical optics. Some part of this path of exploration must have been traveled by Galileo as he experimented with spectacle lenses. "Dollar optics” include reading glasses (positive meniscus lenses), convex and concave mirrors, Fresnel sheets, magnifying lenses, and eye loupes. Unwanted distance spectacles (negative meniscus lenses) are available at second-hand stores. Galileo telescopes, "long” 17th century telescopes, and useful demonstration models of Newtonian reflectors can be made with "dollar” optics. The poster will illustrate practical information about "dollar optics” and telescopes: magnification, focal length, and "diopters” disassembling spectacles; creating cheap mounts for spectacle lenses; the importance of optical axes and alignment; eyepieces; and focusing. (A table would be useful with the poster to set out a hands-on display of "dollar optic” telescopes.) Educators, experimenters, and those concerned with astronomy outreach might be interested in this poster. Working with "dollar optics” requires facility with simple tools, interest in planning projects, patience, imagination, and the willingness to invest some time and effort. "Dollar optics” may help to foster creativity and hands-on enthusiasm - as did Galileo's work with simple lenses 400 years ago. "Oh! When will there be an end put to the new observations and discoveries of this admirable instrument?” - Galileo Galilei as quoted by Henry C. King, The History of the Telescope.

  18. Parker Hybrid Hydraulic Drivetrain Demonstration

    Energy Technology Data Exchange (ETDEWEB)

    Collett, Raymond [Parker-Hannifin Corporation, Cleveland, OH (United States); Howland, James [Parker-Hannifin Corporation, Cleveland, OH (United States); Venkiteswaran, Prasad [National Energy Technology Lab. (NETL), Morgantown, WV (United States)

    2014-03-31

    This report examines the benefits of Parker Hannifin hydraulic hybrid brake energy recovery systems used in commercial applications for vocational purposes. A detailed background on the problem statement being addressed as well as the solution set specific for parcel delivery will be provided. Objectives of the demonstration performed in high start & stop applications included opportunities in fuel usage reduction, emissions reduction, vehicle productivity, and vehicle maintenance. Completed findings during the demonstration period and parallel investigations with NREL, CALSTART, along with a literature review will be provided herein on this research area. Lastly, results identified in the study by third parties validated the savings potential in fuel reduction of on average of 19% to 52% over the baseline in terms of mpg (Lammert, 2014, p11), Parker data for parcel delivery vehicles in the field parallels this at a range of 35% - 50%, emissions reduction of 17.4% lower CO2 per mile and 30.4% lower NOx per mile (Gallo, 2014, p15), with maintenance improvement in the areas of brake and starter replacement, while leaving room for further study in the area of productivity in terms of specific metrics that can be applied and studied.

  19. Bentonite mat demonstration. Final report

    Energy Technology Data Exchange (ETDEWEB)

    Serrato, M.G.

    1994-12-30

    The Bentonite Mat Demonstration was developed to provide the Environmental Restoration Department with field performance characteristics and engineering data for an alternative closure cover system configuration. The demonstration was initiated in response to regulatory concerns regarding the use of an alternative cover system for future design configurations. These design considerations are in lieu of the US Environmental Protection Agency (EPA) Recommended Design for Closure Cover Systems and specifically a single compacted kaolin clay layer with a hydraulic conductivity of 1 {times} 10{sup {minus}7} cm/sec. This alternative configuration is a composite geosynthetic material hydraulic barrier consisting from bottom to top: 2 ft compacted sandy clay layer (typical local Savannah River Site soil type) that is covered by a bentonite mat--geosynthetic clay liner (GCL) and is overlaid by a 40 mil High Density Polyethylene (HDPE) geomembrane--flexible membrane liner. This effort was undertaken to obtain and document the necessary field performance/engineering data for future designs and meet regulatory technical requirements for an alternative cover system configuration. The composite geosynthetic materials hydraulic barrier is the recommended alternative cover system configuration for containment of hazardous and low level radiological waste layers that have a high potential of subsidence to be used at the Savannah River Site (SRS). This alternative configuration mitigates subsidence effects in providing a flexible, lightweight cover system to maintain the integrity of the closure. The composite geosynthetic materials hydraulic barrier is recommended for the Sanitary Landfill and Low Level Radiological Waste Disposal Facility (LLRWDF) Closures.

  20. Inhibited and Uninhibited Types of Children.

    Science.gov (United States)

    Kagan, Jerome; And Others

    1989-01-01

    Investigates the preservation of inhibited and uninhibited behaviors in 100 children of 14, 20, 32, and 48 months. Children who had been extremely inhibited or uninhibited at 14 and 20 months differed significantly at 4 years of age in behavior and cardiac acceleration. (RJC)

  1. Biological significance of glucocorticoid receptor beta

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Alternative splicing of the human glucocorticoid receptor (hGR) primary transcript produces two receptor isoforms, termed hGRα and hGRβ. hGRα is a ligand-activated transcription factor which, in the hormone-bound state, modulates the expression of glucocorticoid-responsive genes by binding to specific glucocorticoid response element (GRE) DNA sequences. In contrast, hGRβ dose not bind glucocorticoids and is transcriptionally inactive. We demonstrate here that hGRβ inhibits the hormone-induced, hGRα-mediated stimulations of gene expression, including glucocorticoid-responsive reporter gene (cat) and endogenous p21 gene. We also demonstrate that hGRβ can inhibit hGRα-mediated regulation of proliferation and differentiation of a human osteosarcoma cell line (HOS-8603). Our studies on the expression of hGR mRNA in nephrotic syndrome patients indicate that the hGRα/hGRβ mRNA ratio in peripheral white blood cell of hormone-resistant patients is lower than that of hormone-sensitive patients and health volunteers. These results indicate that hGRβ may be a physiologically and pathophysiologically relevant endogenous inhibitor of hGRα

  2. A first demonstration of CIB delensing

    CERN Document Server

    Larsen, Patricia; Sherwin, Blake D; Mak, Daisy

    2016-01-01

    Delensing is an increasingly important technique to reverse the gravitational lensing of the cosmic microwave background (CMB) and thus reveal primordial signals the lensing may obscure. We present a first demonstration of delensing on Planck temperature maps using the cosmic infrared background (CIB). Reversing the lensing deflections in Planck CMB temperature maps using a linear combination of the 545 and 857GHz maps as a lensing tracer, we find that the lensing effects in the temperature power spectrum are reduced in a manner consistent with theoretical expectations. In particular, the characteristic sharpening of the acoustic peaks of the temperature power spectrum resulting from successful delensing is detected at a significance of 16$\\rm{\\sigma}$, with an amplitude of $A_{\\rm{delens}} = 1.12 \\pm 0.07$ relative to the expected value of unity. This first demonstration on data of CIB delensing, and of delensing techniques in general, is significant because lensing removal will soon be essential for achievi...

  3. Salvinorin A Inhibits Airway Hyperreactivity Induced by Ovalbumin Sensitization

    Science.gov (United States)

    Rossi, Antonietta; Caiazzo, Elisabetta; Bilancia, Rossella; Riemma, Maria A.; Pagano, Ester; Cicala, Carla; Ialenti, Armando; Zjawiony, Jordan K.; Izzo, Angelo A.; Capasso, Raffaele; Roviezzo, Fiorentina

    2017-01-01

    Salvinorin A, a neoclerodane diterpene isolated from Salvia divinorum, exerts a number of pharmacological actions which are not solely limited to the central nervous system. Recently it has been demonstrated that Salvinorin A inhibits acute inflammatory response affecting leukotriene (LT) production. Since LTs are potent lipid mediators implicated in allergic diseases, we evaluated the effect of Salvinorin A on allergic inflammation and on airways following sensitization in the mouse. Mice were sensitized with s.c. injection of ovalbumin (OVA) on days 1 and 8. Sensitized mice received on days 9 and 12 on the shaved dorsal surface air administration to induce the development of the air-pouches. On day 15 animals were challenged by injection of OVA into the air-pouch. Salvinorin A, administered (10 mg/kg) before each allergen exposure, significantly reduced OVA-induced LT increase in the air pouch. This effect was coupled to a reduction in cell recruitment and Th2 cytokine production. In another set of experiments, mice were sensitized with OVA and both bronchial reactivity and pulmonary inflammation were assessed. Salvinorin A abrogated bronchial hyperreactivity and interleukin (IL)-13 production, without effect on pulmonary inflammation. Indeed cell infiltration and peribronchial edema were still present following diterpenoid treatment. Similarly, pulmonary IL-4 and plasmatic IgE levels were not modulated. Conversely, Salvinorin A significantly reduced LTC4 production in the lung of sensitized mice. Finally mast cell activity was evaluated by means of toluidine blue staining. Data obtained evidenced that Salvinorin A significantly inhibited mast cell degranulation in the lung. Our study demonstrates that Salvinorin A inhibits airway hyperreactivity induced by sensitization by inhibition of LT production and mast cell degranulation. In conclusion Salvinorin A could represent a promising candidate for drug development in allergic diseases such as asthma. PMID

  4. Salvinorin A Inhibits Airway Hyperreactivity Induced by Ovalbumin Sensitization.

    Science.gov (United States)

    Rossi, Antonietta; Caiazzo, Elisabetta; Bilancia, Rossella; Riemma, Maria A; Pagano, Ester; Cicala, Carla; Ialenti, Armando; Zjawiony, Jordan K; Izzo, Angelo A; Capasso, Raffaele; Roviezzo, Fiorentina

    2016-01-01

    Salvinorin A, a neoclerodane diterpene isolated from Salvia divinorum, exerts a number of pharmacological actions which are not solely limited to the central nervous system. Recently it has been demonstrated that Salvinorin A inhibits acute inflammatory response affecting leukotriene (LT) production. Since LTs are potent lipid mediators implicated in allergic diseases, we evaluated the effect of Salvinorin A on allergic inflammation and on airways following sensitization in the mouse. Mice were sensitized with s.c. injection of ovalbumin (OVA) on days 1 and 8. Sensitized mice received on days 9 and 12 on the shaved dorsal surface air administration to induce the development of the air-pouches. On day 15 animals were challenged by injection of OVA into the air-pouch. Salvinorin A, administered (10 mg/kg) before each allergen exposure, significantly reduced OVA-induced LT increase in the air pouch. This effect was coupled to a reduction in cell recruitment and Th2 cytokine production. In another set of experiments, mice were sensitized with OVA and both bronchial reactivity and pulmonary inflammation were assessed. Salvinorin A abrogated bronchial hyperreactivity and interleukin (IL)-13 production, without effect on pulmonary inflammation. Indeed cell infiltration and peribronchial edema were still present following diterpenoid treatment. Similarly, pulmonary IL-4 and plasmatic IgE levels were not modulated. Conversely, Salvinorin A significantly reduced LTC4 production in the lung of sensitized mice. Finally mast cell activity was evaluated by means of toluidine blue staining. Data obtained evidenced that Salvinorin A significantly inhibited mast cell degranulation in the lung. Our study demonstrates that Salvinorin A inhibits airway hyperreactivity induced by sensitization by inhibition of LT production and mast cell degranulation. In conclusion Salvinorin A could represent a promising candidate for drug development in allergic diseases such as asthma.

  5. Energy 2007. Research, development, demonstration; Energi 07. Forskning, udvikling, demonstration

    Energy Technology Data Exchange (ETDEWEB)

    Byriel, I.P.; Justesen, Helle; Beck, A.; Borup Jensen, J.; Rosenfeldt Jakobsen, Kl; Jacobsen, Steen Hartvig (eds.)

    2007-08-10

    Danish energy research is in an exciting and challenging situation. Rising oil prices, unstable energy supply, climate policy responsibilities and globalization have brought development of new environmentally friendly and more efficient energy technologies into focus. Promising international markets for newly developed energy technologies are emerging, and at the same time well established Danish positions of strength are challenged by new strong actors on the global market. The Danish government has set to work on its vision of an appreciable strengthening of public energy research funding through the recent law on the energy technological development and demonstration programme EUDP and the realization of globalization funds. The interaction between basic and applied research must be kept intact. In this report the various Danish energy research programmes administered by Energinet.dk, Danish Energy Authority, Danish Energy Association, Danish Council for Strategic Research's Programme Commission on Energy and Environment and Danish National Advanced Technology Foundation, coordinate their annual reports for the first time. The aim of Energy 2007 is to give the reader an idea of how the energy research programmes collaborate on solving the major energy technology challenges - also in an international context. (BA)

  6. Inhibition of nonenzymatic protein glycation by pomegranate and other fruit juices.

    Science.gov (United States)

    Dorsey, Pamela Garner; Greenspan, Phillip

    2014-04-01

    The nonenzymatic glycation of proteins and the formation of advanced glycation endproducts in diabetes leads to the crosslinking of proteins and disease complications. Our study sought to demonstrate the effect of commonly consumed juices (pomegranate, cranberry, black cherry, pineapple, apple, and Concord grape) on the fructose-mediated glycation of albumin. Albumin glycation decreased by 98% in the presence of 10 μL of pomegranate juice/mL; other juices inhibited glycation by only 20%. Pomegranate juice produced the greatest inhibition on protein glycation when incubated at both the same phenolic concentration and the same antioxidant potential. Both punicalagin and ellagic acid significantly inhibited the glycation of albumin by ~90% at 5 μg/mL. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed that pomegranate, but not apple juice, protected albumin from modification. These results demonstrate that pomegranate juice and two of its major constituents are potent inhibitors of fructose-mediated protein glycation.

  7. Sleeve Muscle Actuator: Concept and Prototype Demonstration

    Institute of Scientific and Technical Information of China (English)

    Tad Driver; Xiangrong Shen

    2013-01-01

    This paper presents the concept and prototype demonstration results of a new sleeve muscle actuator,which provides a significantly improved performance through a fundamental structural change to the traditional pneumatic muscle.Specifically,the sleeve muscle incorporates a cylindrical insert to the center of the pneumatic muscle,and thus eliminates the central portion of the intemal volume.Through the analysis of the actuation mechanism,it is shown that the sleeve muscle is able to provide a consistent increase of force capacity over the entire range of motion.Furthermore,the sleeve muscle provides a significant energy saving effect,as a result of the reduced internal volume as well as the enhance force capacity.To demonstrate this new concept,a sleeve muscle prototype was designed and fabricated.Experiments conducted on the prototype verified the improvement in the force capacity and demonstrated a significant energy saving effect (20%-37%).Finally,as the future work on this new concept,the paper presents a new robotic elbow design actuated with the proposed sleeve muscle.This unique design is expected to provide a highly compact and powerful actuation approach for robotic systems.

  8. A demonstrator for bolometric interferometry

    CERN Document Server

    Ghribi, Adnan; Galli, Silvia; Piat, Michel; Breelle, Eric; Hamilton, Jean-Christophe; Spinelli, Sebastiano; Gervasi, Massimo; Zannoni, Mario

    2009-01-01

    Bolometric Interferometry (BI) is one of the most promising techniques for precise measurements of the Cosmic Microwave Background polarization. In this paper, we present the results of DIBO (Demonstrateur d'Interferometrie Bolometrique), a single-baseline demonstrator operating at 90 GHz, built to proof the validity of the BI concept applied to a millimeter-wave interferometer. This instrument has been characterized in the laboratory with a detector at room temperature and with a 4 K bolometer. This allowed us to measure interference patterns in a clean way, both (1) rotating the source and (2) varying with time the phase shift among the two interferometer's arms. Detailed modelisation has also been performed and validated with measurements.

  9. Pilot Scale Advanced Fogging Demonstration

    Energy Technology Data Exchange (ETDEWEB)

    Demmer, Rick L. [Idaho National Lab. (INL), Idaho Falls, ID (United States); Fox, Don T. [Idaho National Lab. (INL), Idaho Falls, ID (United States); Archiblad, Kip E. [Idaho National Lab. (INL), Idaho Falls, ID (United States)

    2015-01-01

    Experiments in 2006 developed a useful fog solution using three different chemical constituents. Optimization of the fog recipe and use of commercially available equipment were identified as needs that had not been addressed. During 2012 development work it was noted that low concentrations of the components hampered coverage and drying in the United Kingdom’s National Nuclear Laboratory’s testing much more so than was evident in the 2006 tests. In fiscal year 2014 the Idaho National Laboratory undertook a systematic optimization of the fogging formulation and conducted a non-radioactive, pilot scale demonstration using commercially available fogging equipment. While not as sophisticated as the equipment used in earlier testing, the new approach is much less expensive and readily available for smaller scale operations. Pilot scale testing was important to validate new equipment of an appropriate scale, optimize the chemistry of the fogging solution, and to realize the conceptual approach.

  10. Clean Coal Diesel Demonstration Project

    Energy Technology Data Exchange (ETDEWEB)

    Robert Wilson

    2006-10-31

    A Clean Coal Diesel project was undertaken to demonstrate a new Clean Coal Technology that offers technical, economic and environmental advantages over conventional power generating methods. This innovative technology (developed to the prototype stage in an earlier DOE project completed in 1992) enables utilization of pre-processed clean coal fuel in large-bore, medium-speed, diesel engines. The diesel engines are conventional modern engines in many respects, except they are specially fitted with hardened parts to be compatible with the traces of abrasive ash in the coal-slurry fuel. Industrial and Municipal power generating applications in the 10 to 100 megawatt size range are the target applications. There are hundreds of such reciprocating engine power-plants operating throughout the world today on natural gas and/or heavy fuel oil.

  11. The Liquid Argon Purity Demonstrator

    CERN Document Server

    Adamowski, M; Dvorak, E; Hahn, A; Jaskierny, W; Johnson, C; Jostlein, H; Kendziora, C; Lockwitz, S; Pahlka, B; Plunkett, R; Pordes, S; Rebel, B; Schmitt, R; Stancari, M; Tope, T; Voirin, E; Yang, T

    2014-01-01

    The Liquid Argon Purity Demonstrator was an R&D test stand designed to determine if electron drift lifetimes adequate for large neutrino detectors could be achieved without first evacuating the cryostat. We describe here the cryogenic system, its operations, and the apparatus used to determine the contaminant levels in the argon and to measure the electron drift lifetime. The liquid purity obtained by this system was facilitated by a gaseous argon purge. Additionally, gaseous impurities from the ullage were prevented from entering the liquid at the gas-liquid interface by condensing the gas and filtering the resulting liquid before returning to the cryostat. The measured electron drift lifetime in this test was greater than 6 ms, sustained over several periods of many weeks. Measurements of the temperature profile in the argon, to assess convective flow and boiling, were also made and are compared to simulation.

  12. The Liquid Argon Purity Demonstrator

    Energy Technology Data Exchange (ETDEWEB)

    Adamowski, M.; Carls, B.; Dvorak, E.; Hahn, A.; Jaskierny, W.; Johnson, C.; Jostlein, H.; Kendziora, C.; Lockwitz, S.; Pahlka, B.; Plunkett, R.; Pordes, S.; Rebel, B.; Schmitt, R.; Stancari, M.; Tope, T.; Voirin, E.; Yang, T.

    2014-07-01

    The Liquid Argon Purity Demonstrator was an R&D test stand designed to determine if electron drift lifetimes adequate for large neutrino detectors could be achieved without first evacuating the cryostat. We describe here the cryogenic system, its operations, and the apparatus used to determine the contaminant levels in the argon and to measure the electron drift lifetime. The liquid purity obtained by this system was facilitated by a gaseous argon purge. Additionally, gaseous impurities from the ullage were prevented from entering the liquid at the gas-liquid interface by condensing the gas and filtering the resulting liquid before returning to the cryostat. The measured electron drift lifetime in this test was greater than 6 ms, sustained over several periods of many weeks. Measurements of the temperature profile in the argon, to assess convective flow and boiling, were also made and are compared to simulation.

  13. Acute Effects of Whole Body Vibration on Inhibition in Healthy Children.

    Directory of Open Access Journals (Sweden)

    Anne E den Heijer

    Full Text Available Whole Body Vibration (WBV is a passive exercise method known to have beneficial effects on various physical measures. Studies on adults furthermore demonstrated beneficial effects of WBV treatment on cognition (e.g. inhibition. The present study replicated these findings in healthy children and examined acute effects of WBV treatment on inhibition.Fifty-five healthy children (aged 8-13 participated in this within-subject design study. WBV treatment was applied by having the children sit on a chair mounted to a vibrating platform. After each condition (vibration vs. non-vibration, inhibition was measured by using the Stroop Color-Word Interference Test. Repeated measures analyses were applied in order to explore the effects of WBV treatment on inhibition, and correlations were computed between the treatment effect and participant characteristics in order to explore individual differences in treatment sensitivity.Three-minute WBV treatments had significant beneficial effects on inhibition in this sample of healthy children. Especially the repeated application (three times of WBV treatment appeared beneficial for cognition. Stronger WBV treatment effects were correlated with higher intelligence and younger age, but not with symptoms of Attention Deficit Hyperactivity Disorder (ADHD.This study demonstrates that especially repeated WBV treatment improves inhibition in healthy children. As this cognitive function is often impaired in children with developmental disorders (e.g. ADHD, future studies should further explore the effects, working mechanism and potential applicability of WBV treatment for this target group.

  14. Platelets Inhibit Migration of Canine Osteosarcoma Cells.

    Science.gov (United States)

    Bulla, S C; Badial, P R; Silva, R C; Lunsford, K; Bulla, C

    2017-01-01

    The interaction between platelets and tumour cells is important for tumour growth and metastasis. Thrombocytopenia or antiplatelet treatment negatively impact on cancer metastasis, demonstrating potentially important roles for platelets in tumour progression. To our knowledge, there is no information regarding the role of platelets in cancer progression in dogs. This study was designed to test whether canine platelets affected the migratory behaviour of three canine osteosarcoma cell lines and to give insights of molecular mechanisms. Intact platelets, platelet lysate and platelet releasate inhibited the migration of canine osteosarcoma cell lines. Addition of blood leucocytes to the platelet samples did not alter the inhibitory effect on migration. Platelet treatment also significantly downregulated the transcriptional levels of SNAI2 and TWIST1 genes. The interaction between canine platelets or molecules released during platelet activation and these tumour cell lines inhibits their migration, which suggests that canine platelets might antagonize metastasis of canine osteosarcoma. This effect is probably due to, at least in part, downregulation of genes related to epithelial-mesenchymal transition. Copyright © 2016. Published by Elsevier Ltd.

  15. Kaempferol inhibits thrombosis and platelet activation.

    Science.gov (United States)

    Choi, Jun-Hui; Park, Se-Eun; Kim, Sung-Jun; Kim, Seung

    2015-08-01

    The objectives of the present study were to investigate whether kaempferol affects pro-coagulant proteinase activity, fibrin clot formation, blood clot and thrombin (or collagen/epinephrine)-stimulated platelet activation, thrombosis, and coagulation in ICR (Imprinting Control Region) mice and SD (Sprague-Dawley) rats. Kaempferol significantly inhibited the enzymatic activities of thrombin and FXa by 68 ± 1.6% and 52 ± 2.4%, respectively. Kaempferol also inhibited fibrin polymer formation in turbidity. Microscopic analysis was performed using a fluorescent conjugate. Kaempferol completely attenuated phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, p38, c-Jun N-terminal kinase (JNK) 1/2, and phosphoinositide 3-kinase (PI3K)/PKB (AKT) in thrombin-stimulated platelets and delayed aggregation time (clotting) by 34.6% in an assay of collagen/epinephrine-stimulated platelet activation. Moreover, kaempferol protected against thrombosis development in 3 animal models, including collagen/epinephrine- and thrombin-induced acute thromboembolism models and an FeCl3-induced carotid arterial thrombus model. The ex vivo anticoagulant effect of kaempferol was further confirmed in ICR mice. This study demonstrated that kaempferol may be clinically useful due to its ability to reduce or prevent thrombotic challenge.

  16. Inhibition of carcinogenesis by tea.

    Science.gov (United States)

    Yang, Chung S; Maliakal, Pius; Meng, Xiaofeng

    2002-01-01

    Tea has received a great deal of attention because tea polyphenols are strong antioxidants, and tea preparations have inhibitory activity against tumorigenesis. The bioavailability and biotransformation of tea polyphenols, however, are key factors limiting these activities in vivo. The inhibition of tumorigenesis by green or black tea preparations has been demonstrated in animal models on different organ sites such as skin, lung, oral cavity, esophagus, forestomach, stomach, small intestine, colon, pancreas, and mammary gland. Epidemiological studies, however, have not yielded clear conclusions concerning the protective effects of tea consumption against cancer formation in humans. The discrepancy between the results from humans and animal models could be due to 1) the much higher doses of tea used in animals in comparison to human consumption, 2) the differences in causative factors between the cancers in humans and animals, and 3) confounding factors limiting the power of epidemiological studies to detect an effect. It is possible that tea may be only effective against specific types of cancer caused by certain etiological factors. Many mechanisms have been proposed for the inhibition of carcinogenesis by tea, including the modulation of signal transduction pathways that leads to the inhibition of cell proliferation and transformation, induction of apoptosis of preneoplastic and neoplastic cells, as well as inhibition of tumor invasion and angiogenesis. These mechanisms need to be evaluated and verified in animal models or humans in order to gain more understanding on the effect of tea consumption on human cancer.

  17. Demonstration of an instrumented patch

    Science.gov (United States)

    Martinez, M.; Renaud, G.; Backman, D.; Genest, M.; Delannoy, M.

    2007-04-01

    The primary objective of this study was to demonstrate the effectiveness of various strain measurement techniques at detecting the disbonding of a composite repair patch and then using this information to validate a new capacitance based disbond detection technique. The instrumented repair patch was parametrically designed with the help of Finite Element Analysis (FEA) software to have a stress concentration at its tip. This stress concentration was designed to produce a disbond during fatigue testing, without the need for the introduction of any foreign material to create an artificial disbond condition. The aluminum substrate was grit blasted and the instrumented patch was bonded using FM ®73 adhesive, and was cured following the recommendations of the manufacturer. The geometric characteristics of the patch followed standard repair guidelines for such variables as material selection, taper angles and loading conditions, with the exception of the area designed for premature disbond. All test specimens were inspected using non-destructive testing technique (ultrasound pulse echo) to guarantee that no disbonding had occurred during curing of the specimen. The specimens were placed under fatigue loading to induce a disbond condition between the aluminum substrate and the patch. The specimens were cyclically loaded and strain gauges bonded to strategic locations on the aluminum and composite patch surface to be able to measure changes in surface strains as the disbond progressed. A Digital Image Correlation (DIC) system was also used to measure full field strains over the gauge length of the coupon. The DIC results were compared with the strain gauge data and were used to provide a qualitative measure of the load transfer in the bonded specimen, which clearly demonstrated the change in surface strain that occurred as the composite patch disbonded from the aluminum substrate. Thermoelastic Stress Analysis (TSA) was also used to measure surface strains on the

  18. The ideal hydrogen demonstration platform

    Energy Technology Data Exchange (ETDEWEB)

    Alt, J. [Village Technology, Annapolis, MD (United States)

    2007-07-01

    This paper suggested that the best platform to demonstrate hydrogen's capability as an emission-free fuel regime is an urban pedestrian system. The on-grade bi-directional downtown people-mover was designed to fit in existing street-scapes without eliminating traffic lanes. The system is comprised of rubber-tired tram-buses that are synchronized to arrive at stop-boarding areas at the same time in order to provide a seamless headway along a single, dedicated guide-lane. The system was designed to operate along strategic urban corridors in order to reduce traffic congestion and air pollution. The vehicles are inductively charged with fixed fuel cell generators at stop-boarding areas. A single people-mover has the capacity to replace several thousand car trips and parking movements per day, or 8000 tonnes of carbon dioxide (CO{sub 2}). It was concluded that the system was designed to dovetail with fuel cell generator stations planned for private vehicles as they begin to be converted in the future. 8 figs.

  19. Demonstration of superconducting micromachined cavities

    Energy Technology Data Exchange (ETDEWEB)

    Brecht, T., E-mail: teresa.brecht@yale.edu; Reagor, M.; Chu, Y.; Pfaff, W.; Wang, C.; Frunzio, L.; Devoret, M. H.; Schoelkopf, R. J. [Department of Applied Physics, Yale University, New Haven, Connecticut 06511 (United States)

    2015-11-09

    Superconducting enclosures will be key components of scalable quantum computing devices based on circuit quantum electrodynamics. Within a densely integrated device, they can protect qubits from noise and serve as quantum memory units. Whether constructed by machining bulk pieces of metal or microfabricating wafers, 3D enclosures are typically assembled from two or more parts. The resulting seams potentially dissipate crossing currents and limit performance. In this letter, we present measured quality factors of superconducting cavity resonators of several materials, dimensions, and seam locations. We observe that superconducting indium can be a low-loss RF conductor and form low-loss seams. Leveraging this, we create a superconducting micromachined resonator with indium that has a quality factor of two million, despite a greatly reduced mode volume. Inter-layer coupling to this type of resonator is achieved by an aperture located under a planar transmission line. The described techniques demonstrate a proof-of-principle for multilayer microwave integrated quantum circuits for scalable quantum computing.

  20. Executive functioning in boys with ADHD: primarily an inhibition deficit?

    NARCIS (Netherlands)

    Scheres, A.P.J.; Oosterlaan, J.; Geurts, H.M.; Morein-Zamir, S.; Meiran, N.; Vlasveld, L.; Sergeant, J.A.

    2004-01-01

    This study was aimed at: (1) testing whether boys with Attention Deficit/Hyperactivity Disorder (ADHD) demonstrate a deficit in response inhibition and deficits in other executive functions (EF), or alternatively, demonstrate a deficit in only response inhibition; (2) investigating which role associ

  1. ET-04MEBENDAZOLE IS EFFICACIOUS IN DIVERSE MEDULLOBLASTOMA TUMOR MODELS AND INHIBITS TUMOR ANGIOGENESIS

    Science.gov (United States)

    Bai, Renyuan; Staedtke, Verena; Rudin, Charles; Bunz, Fred; Riggins, Gregory

    2014-01-01

    Medulloblastoma is the leading cause of cancer death in children. Surgery, radiotherapy and chemotherapy regimens are the current standard for treatment. While effective in most patients, those have long-term neurological sequelae in survivors, and a significant fraction of patients still succumb to the disease. In this study, we found that mebendazole (MBZ), an FDA-approved antiparasitic, demonstrated significant anti-tumor efficacy in etiologically distinct medulloblastoma mouse models. MBZ significantly improved the survival of mice with orthotopic xenograft tumors derived from the SHH group and group 3 medulloblastomas and was also highly efficacious against a PTCH1-mutant medulloblastoma with acquired resistance to the SMO inhibitor vismodgib. Analysis of the vasculature in rodent tumors revealed that MBZ selectively inhibited tumor angiogenesis but not the normal brain vasculature, and inhibited the kinase activity of VEGFR2 in vitro and in vivo. This study demonstrates that MBZ could be a highly promising therapeutic for medulloblastoma with anti- angiogenesis activity.

  2. Syk Inhibition with Fostamatinib Leads to Transitional B Lymphocyte Depletion

    Science.gov (United States)

    Barr, Paul M.; Wei, Chungwen; Roger, James; Schaefer-Cutillo, Julia; Kelly, Jennifer L.; Rosenberg, Alexander F.; Jung, John; Sanz, Iñaki; Friedberg, Jonathan W.

    2012-01-01

    Cell signaling initiated by the B cell receptor is critical to normal development of B lymphocytes, most notably at the transitional B cell stage. Inhibition of this signaling pathway with the syk inhibitor, fostamatinib, has produced significant efficacy in lymphoid malignancies and autoimmune conditions. Here, we demonstrate that short-term use of fostamatinib impairs B lymphocyte development at the transitional stage without affecting mature B cell populations. Additionally, IL-10 producing B cells remained relatively constant throughout the treatment period. These findings provide insight into the mechanism of action of B cell receptor inhibition in autoimmune disease. As the development of agents targeting B cell receptor signaling proceeds, monitoring for long-term consequences as well as functional evaluation of B cell subsets may further improve our understanding of this rapidly growing class of novel agents. PMID:22284392

  3. Curcumin significantly enhances dual PI3K/Akt and mTOR inhibitor NVP-BEZ235-induced apoptosis in human renal carcinoma Caki cells through down-regulation of p53-dependent Bcl-2 expression and inhibition of Mcl-1 protein stability.

    Directory of Open Access Journals (Sweden)

    Bo Ram Seo

    Full Text Available The PI3K/Akt and mTOR signaling pathways are important for cell survival and growth, and they are highly activated in cancer cells compared with normal cells. Therefore, these signaling pathways are targets for inducing cancer cell death. The dual PI3K/Akt and mTOR inhibitor NVP-BEZ235 completely inhibited both signaling pathways. However, NVP-BEZ235 had no effect on cell death in human renal carcinoma Caki cells. We tested whether combined treatment with natural compounds and NVP-BEZ235 could induce cell death. Among several chemopreventive agents, curcumin, a natural biologically active compound that is extracted from the rhizomes of Curcuma species, markedly induced apoptosis in NVP-BEZ235-treated cells. Co-treatment with curcumin and NVP-BEZ235 led to the down-regulation of Mcl-1 protein expression but not mRNA expression. Ectopic expression of Mcl-1 completely inhibited curcumin plus NVP-NEZ235-induced apoptosis. Furthermore, the down-regulation of Bcl-2 was involved in curcumin plus NVP-BEZ235-induced apoptosis. Curcumin or NVP-BEZ235 alone did not change Bcl-2 mRNA or protein expression, but co-treatment reduced Bcl-2 mRNA and protein expression. Combined treatment with NVP-BEZ235 and curcumin reduced Bcl-2 expression in wild-type p53 HCT116 human colon carcinoma cells but not p53-null HCT116 cells. Moreover, Bcl-2 expression was completely reversed by treatment with pifithrin-α, a p53-specific inhibitor. Ectopic expression of Bcl-2 also inhibited apoptosis in NVP-BE235 plus curcumin-treated cells. In contrast, NVP-BEZ235 combined with curcumin did not have a synergistic effect on normal human skin fibroblasts and normal human mesangial cells. Taken together, combined treatment with NVP-BEZ235 and curcumin induces apoptosis through p53-dependent Bcl-2 mRNA down-regulation at the transcriptional level and Mcl-1 protein down-regulation at the post-transcriptional level.

  4. T-705 (favipiravir) inhibition of arenavirus replication in cell culture.

    Science.gov (United States)

    Mendenhall, Michelle; Russell, Andrew; Juelich, Terry; Messina, Emily L; Smee, Donald F; Freiberg, Alexander N; Holbrook, Michael R; Furuta, Yousuke; de la Torre, Juan-Carlos; Nunberg, Jack H; Gowen, Brian B

    2011-02-01

    A number of New World arenaviruses (Junín [JUNV], Machupo [MACV], and Guanarito [GTOV] viruses) can cause human disease ranging from mild febrile illness to a severe and often fatal hemorrhagic fever syndrome. These highly pathogenic viruses and the Old World Lassa fever virus pose a significant threat to public health and national security. The only licensed antiviral agent with activity against these viruses, ribavirin, has had mixed success in treating severe arenaviral disease and is associated with significant toxicities. A novel pyrazine derivative currently in clinical trials for the treatment of influenza virus infections, T-705 (favipiravir), has demonstrated broad-spectrum activity against a number of RNA viruses, including arenaviruses. T-705 has also been shown to be effective against Pichinde arenavirus infection in a hamster model. Here, we demonstrate the robust antiviral activity of T-705 against authentic highly pathogenic arenaviruses in cell culture. We show that T-705 disrupts an early or intermediate stage in viral replication, distinct from absorption or release, and that its antiviral activity in cell culture is reversed by the addition of purine bases and nucleosides, but not with pyrimidines. Specific inhibition of viral replication/transcription by T-705 was demonstrated using a lymphocytic choriomeningitis arenavirus replicon system. Our findings indicate that T-705 acts to inhibit arenavirus replication/transcription and may directly target the viral RNA-dependent RNA polymerase.

  5. Background model for the MAJORANA DEMONSTRATOR

    CERN Document Server

    Cuesta, C; Arnquist, I J; Avignone, F T; Barabash, A S; Bertrand, F E; Bradley, A W; Brudanin, V; Busch, M; Buuck, M; Caldwell, T S; Chan, Y-D; Christofferson, C D; Chu, P -H; Detwiler, J A; Dunagan, C; Efremenko, Yu; Ejiri, H; Elliott, S R; Fullmer, A; Galindo-Uribarri, A; Gilliss, T; Giovanetti, G K; Green, M P; Gruszko, J; Guinn, I S; Guiseppe, V E; Henning, R; Hoppe, E W; Howe, M A; Jasinski, B R; Keeter, K J; Kidd, M F; Konovalov, S I; Kouzes, R T; Leon, J; Lopez, A M; MacMullin, J; Martin, R D; Massarczyk, R; Meijer, S J; Mertens, S; Orrell, J L; O'Shaughnessy, C; Poon, A W P; Radford, D C; Rager, J; Rielage, K; Robertson, R G H; Romero-Romero, E; Shanks, B; Shirchenko, M; Suriano, A M; Tedeschi, D; Trimble, J E; Varner, R L; Vasilyev, S; Vetter, K; Vorren, K; White, B R; Wilkerson, J F; Wiseman, C; Xu, W; Yakushev, E; Yu, C -H; Yumatov, V; Zhitnikov, I

    2016-01-01

    The MAJORANA Collaboration is constructing a system containing 44 kg of high-purity Ge (HPGe) detectors to demonstrate the feasibility and potential of a future tonne-scale experiment capable of probing the neutrino mass scale to ~15 meV. To realize this, a major goal of the MAJORANA DEMONSTRATOR is to demonstrate a path forward to achieving a background rate at or below 1 count/(ROI-t-y) in the 4 keV region of interest (ROI) around the Q-value at 2039 keV. This goal is pursued through a combination of a significant reduction of radioactive impurities in construction materials and analytical methods for background rejection, for example using powerful pulse shape analysis techniques profiting from the p-type point contact HPGe detectors technology. The effectiveness of these methods is assessed using simulations of the different background components whose purity levels are constrained from radioassay measurements. Preliminary background results obtained during the engineering runs of the Demonstrator are pre...

  6. Homocysteine inhibits hepatocyte proliferation via endoplasmic reticulum stress.

    Directory of Open Access Journals (Sweden)

    Xue Yu

    Full Text Available Homocysteine is an independent risk factor for coronary, cerebral, and peripheral vascular diseases. Recent studies have shown that levels of homocysteine are elevated in patients with impaired hepatic function, but the precise role of homocysteine in the development of hepatic dysfunction is unclear. In this study, we examined the effect of homocysteine on hepatocyte proliferation in vitro. Our results demonstrated that homocysteine inhibited hepatocyte proliferation by up-regulating protein levels of p53 as well as mRNA and protein levels of p21(Cip1 in primary cultured hepatocytes. Homocysteine induced cell growth arrest in p53-positive hepatocarcinoma cell line HepG2, but not in p53-null hepatocarcinoma cell line Hep3B. A p53 inhibitor pifithrin-α inhibited the expression of p21(Cip1 and attenuated homocysteine-induced cell growth arrest. Homocysteine induced TRB3 expression via endoplasmic reticulum stress pathway, resulting in Akt dephosphorylation. Knock-down of endogenous TRB3 significantly suppressed the inhibitory effect of homocysteine on cell proliferation and the phosphorylation of Akt. LiCl reversed homocysteine-mediated cell growth arrest by inhibiting TRB3-mediated Akt dephosphorylation. These results demonstrate that both TRB3 and p21(Cip1 are critical molecules in the homocysteine signaling cascade and provide a mechanistic explanation for impairment of liver regeneration in hyperhomocysteinemia.

  7. A Novel SERCA Inhibitor Demonstrates Synergy with Classic SERCA Inhibitors and Targets Multidrug-Resistant AML

    Science.gov (United States)

    Bleeker, Nicholas P.; Cornea, Razvan L.; Thomas, David D.; Xing, Chengguo

    2013-01-01

    Drug resistance exists as a major obstacle in the treatment of cancer and drug molecules that retain effectiveness against resistant cancers are a high clinical priority. Ethyl 2-amino-6-(3,5-dimethoxyphenyl)-4-(2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate (CXL017) was recently identified as a promising lead for the treatment of multidrug-resistant leukemia, which elicits its cytotoxic effect, in part, through inhibition of the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA). Herein initial experiments with SERCA1a, CXL017 demonstrated no significant effect on calcium affinity, competed with ATP, and induced a dose-dependent decrease in ATPase activity. Among all CXLs tested, (−)-CXL017 exhibited the greatest SERCA inhibition with an IC50 = 13.5 ± 0.5 μM. Inhibitor combination studies were used to assess potential interactions between (−)-CXL017 and well-known SERCA inhibitors: thapsigargin, cyclopiazonic acid, and 2, 5-di-tert-butylhydroquinone. Surprisingly, (−)-CXL017 exhibited marked synergy with each of the known SERCA inhibitors whereas all combinations of the known inhibitors yielded additive effects, indicating that (−)-CXL017 may bind at a unique allosteric site. Treatment of parental (HL60) and multidrug-resistant (HL60/MX2) acute myeloid leukemia cells with the known SERCA inhibitors revealed that all of these inhibitors demonstrate selective cytotoxicity (7.7 to 400 fold) for the resistant cell line. Within the CXL series, a positive correlation exists between SERCA inhibition and cytotoxicity in HL60/MX2 but not HL60. (−)-CXL017 was also shown to enhance the cytotoxicity of thapsigargin in HL60/MX2 cells. Given the elevated SERCA levels and ER calcium content in HL60/MX2, SERCA likely plays a significant role in the collateral sensitivity of this multidrug-resistance cell line to CXL molecules as well as known SERCA inhibitors. PMID:24079514

  8. Experimental demonstration of topological error correction.

    Science.gov (United States)

    Yao, Xing-Can; Wang, Tian-Xiong; Chen, Hao-Ze; Gao, Wei-Bo; Fowler, Austin G; Raussendorf, Robert; Chen, Zeng-Bing; Liu, Nai-Le; Lu, Chao-Yang; Deng, You-Jin; Chen, Yu-Ao; Pan, Jian-Wei

    2012-02-22

    Scalable quantum computing can be achieved only if quantum bits are manipulated in a fault-tolerant fashion. Topological error correction--a method that combines topological quantum computation with quantum error correction--has the highest known tolerable error rate for a local architecture. The technique makes use of cluster states with topological properties and requires only nearest-neighbour interactions. Here we report the experimental demonstration of topological error correction with an eight-photon cluster state. We show that a correlation can be protected against a single error on any quantum bit. Also, when all quantum bits are simultaneously subjected to errors with equal probability, the effective error rate can be significantly reduced. Our work demonstrates the viability of topological error correction for fault-tolerant quantum information processing.

  9. Explosive and pyrotechnic aging demonstration

    Science.gov (United States)

    Rouch, L. L., Jr.; Maycock, J. N.

    1976-01-01

    The survivability was experimentally verified of fine selected explosive and pyrotechnic propellant materials when subjected to sterilization, and prolonged exposure to space environments. This verification included thermal characterization, sterilization heat cycling, sublimation measurements, isothermal decomposition measurements, and accelerated aging at a preselected elevated temperature. Temperatures chosen for sublimation and isothermal decomposition measurements were those in which the decomposition processess occurring would be the same as those taking place in real-time aging. The elevated temperature selected (84 C) for accelerated aging was based upon the parameters calculated from the kinetic data obtained in the isothermal measurement tests and was such that one month of accelerated aging in the laboratory approximated one year of real-time aging at 66 C. Results indicate that HNS-IIA, pure PbN6, KDNBF, and Zr/KC10 are capable of withstanding sterilization. The accelerated aging tests indicated that unsterilized HNS-IIA and Zr/KC104 can withstand the 10 year, elevated temperature exposure, pure PbN6 and KDNBF exhibit small weight losses (less than 2 percent) and B/KC104 exhibits significant changes in its thermal characteristics. Accelerated aging tests after sterilization indicated that only HNS-IIA exhibited high stability.

  10. Mitochondrial thiol modification by a targeted electrophile inhibits metabolism in breast adenocarcinoma cells by inhibiting enzyme activity and protein levels.

    Science.gov (United States)

    Smith, M Ryan; Vayalil, Praveen K; Zhou, Fen; Benavides, Gloria A; Beggs, Reena R; Golzarian, Hafez; Nijampatnam, Bhavitavya; Oliver, Patsy G; Smith, Robin A J; Murphy, Michael P; Velu, Sadanandan E; Landar, Aimee

    2016-08-01

    Many cancer cells follow an aberrant metabolic program to maintain energy for rapid cell proliferation. Metabolic reprogramming often involves the upregulation of glutaminolysis to generate reducing equivalents for the electron transport chain and amino acids for protein synthesis. Critical enzymes involved in metabolism possess a reactive thiolate group, which can be modified by certain oxidants. In the current study, we show that modification of mitochondrial protein thiols by a model compound, iodobutyl triphenylphosphonium (IBTP), decreased mitochondrial metabolism and ATP in MDA-MB 231 (MB231) breast adenocarcinoma cells up to 6 days after an initial 24h treatment. Mitochondrial thiol modification also depressed oxygen consumption rates (OCR) in a dose-dependent manner to a greater extent than a non-thiol modifying analog, suggesting that thiol reactivity is an important factor in the inhibition of cancer cell metabolism. In non-tumorigenic MCF-10A cells, IBTP also decreased OCR; however the extracellular acidification rate was significantly increased at all but the highest concentration (10µM) of IBTP indicating that thiol modification can have significantly different effects on bioenergetics in tumorigenic versus non-tumorigenic cells. ATP and other adenonucleotide levels were also decreased by thiol modification up to 6 days post-treatment, indicating a decreased overall energetic state in MB231 cells. Cellular proliferation of MB231 cells was also inhibited up to 6 days post-treatment with little change to cell viability. Targeted metabolomic analyses revealed that thiol modification caused depletion of both Krebs cycle and glutaminolysis intermediates. Further experiments revealed that the activity of the Krebs cycle enzyme, aconitase, was attenuated in response to thiol modification. Additionally, the inhibition of glutaminolysis corresponded to decreased glutaminase C (GAC) protein levels, although other protein levels were unaffected. This study

  11. Mitochondrial thiol modification by a targeted electrophile inhibits metabolism in breast adenocarcinoma cells by inhibiting enzyme activity and protein levels

    Directory of Open Access Journals (Sweden)

    M. Ryan Smith

    2016-08-01

    Full Text Available Many cancer cells follow an aberrant metabolic program to maintain energy for rapid cell proliferation. Metabolic reprogramming often involves the upregulation of glutaminolysis to generate reducing equivalents for the electron transport chain and amino acids for protein synthesis. Critical enzymes involved in metabolism possess a reactive thiolate group, which can be modified by certain oxidants. In the current study, we show that modification of mitochondrial protein thiols by a model compound, iodobutyl triphenylphosphonium (IBTP, decreased mitochondrial metabolism and ATP in MDA-MB 231 (MB231 breast adenocarcinoma cells up to 6 days after an initial 24 h treatment. Mitochondrial thiol modification also depressed oxygen consumption rates (OCR in a dose-dependent manner to a greater extent than a non-thiol modifying analog, suggesting that thiol reactivity is an important factor in the inhibition of cancer cell metabolism. In non-tumorigenic MCF-10A cells, IBTP also decreased OCR; however the extracellular acidification rate was significantly increased at all but the highest concentration (10 µM of IBTP indicating that thiol modification can have significantly different effects on bioenergetics in tumorigenic versus non-tumorigenic cells. ATP and other adenonucleotide levels were also decreased by thiol modification up to 6 days post-treatment, indicating a decreased overall energetic state in MB231 cells. Cellular proliferation of MB231 cells was also inhibited up to 6 days post-treatment with little change to cell viability. Targeted metabolomic analyses revealed that thiol modification caused depletion of both Krebs cycle and glutaminolysis intermediates. Further experiments revealed that the activity of the Krebs cycle enzyme, aconitase, was attenuated in response to thiol modification. Additionally, the inhibition of glutaminolysis corresponded to decreased glutaminase C (GAC protein levels, although other protein levels were

  12. Monoclonal gammopathy of undetermined significance

    National Research Council Canada - National Science Library

    Kyle, Robert A; Vincent Rajkumar, S

    2006-01-01

    Summary Significant advances have been made in our understanding of the natural history, pathogenesis, mechanisms of progression and prognosis of monoclonal gammopathy of undetermined significance (MGUS...

  13. Newberry Volcano EGS Demonstration - Phase I Results

    Energy Technology Data Exchange (ETDEWEB)

    Osborn, William L. [AltaRock Energy, Inc., Seattle, WA (United States); Petty, Susan [AltaRock Energy, Inc., Seattle, WA (United States); Cladouhos, Trenton T. [AltaRock Energy, Inc., Seattle, WA (United States); Iovenitti, Joe [AltaRock Energy, Inc., Seattle, WA (United States); Nofziger, Laura [AltaRock Energy, Inc., Seattle, WA (United States); Callahan, Owen [AltaRock Energy, Inc., Seattle, WA (United States); Perry, Douglas S. [Davenport Newberry Holdings LLC, Stamford, CT (United States); Stern, Paul L. [PLS Environmental, LLC, Boulder, CO (United States)

    2011-10-23

    Phase I of the Newberry Volcano Enhanced Geothermal System (EGS) Demonstration included permitting, community outreach, seismic hazards analysis, initial microseismic array deployment and calibration, final MSA design, site characterization, and stimulation planning. The multi-disciplinary Phase I site characterization supports stimulation planning and regulatory permitting, as well as addressing public concerns including water usage and induced seismicity. A review of the project's water usage plan by an independent hydrology consultant found no expected impacts to local stakeholders, and recommended additional monitoring procedures. The IEA Protocol for Induced Seismicity Associated with Enhanced Geothermal Systems was applied to assess site conditions, properly inform stakeholders, and develop a comprehensive mitigation plan. Analysis of precision LiDAR elevation maps has concluded that there is no evidence of recent faulting near the target well. A borehole televiewer image log of the well bore revealed over three hundred fractures and predicted stress orientations. No natural, background seismicity has been identified in a review of historic data, or in more than seven months of seismic data recorded on an array of seven seismometers operating around the target well. A seismic hazards and induced seismicity risk assessment by an independent consultant concluded that the Demonstration would contribute no additional risk to residents of the nearest town of La Pine, Oregon. In Phase II of the demonstration, an existing deep hot well, NWG 55-29, will be stimulated using hydroshearing techniques to create an EGS reservoir. The Newberry Volcano EGS Demonstration is allowing geothermal industry and academic experts to develop, validate and enhance geoscience and engineering techniques, and other procedures essential to the expansion of EGS throughout the country. Successful development will demonstrate to the American public that EGS can play a significant role

  14. Ligand-independent and tissue-selective androgen receptor inhibition by pyrvinium.

    Science.gov (United States)

    Lim, Minyoung; Otto-Duessel, Maya; He, Miaoling; Su, Leila; Nguyen, Dan; Chin, Emily; Alliston, Tamara; Jones, Jeremy O

    2014-03-21

    Pyrvinium pamoate (PP) is a potent noncompetitive inhibitor of the androgen receptor (AR). Using a novel method of target identification, we demonstrate that AR is a direct target of PP in prostate cancer cells. We demonstrate that PP inhibits AR activity via the highly conserved DNA binding domain (DBD), the only AR inhibitor that functions via this domain. Furthermore, computational modeling predicts that pyrvinium binds at the interface of the DBD dimer and the minor groove of the AR response element. Because PP acts through the DBD, PP is able to inhibit the constitutive activity of AR splice variants, which are thought to contribute to the growth of castration resistant prostate cancer (CRPC). PP also inhibits androgen-independent AR activation by HER2 kinase. The antiandrogen activity of pyrvinium manifests in the ability to inhibit the in vivo growth of CRPC xenografts that express AR splice variants. Interestingly, PP was most potent in cells with endogenous AR expression derived from prostate or bone. PP was able to inhibit several other hormone nuclear receptors (NRs) but not structurally unrelated transcription factors. PP inhibition of other NRs was similarly cell-type selective. Using dual-energy X-ray absorptiometry, we demonstrate that the cell-type specificity of PP manifests in tissue-selective inhibition of AR activity in mice, as PP decreases prostate weight and bone mineral density but does not affect lean body mass. Our results suggest that the noncompetitive AR inhibitor pyrvinium has significant potential to treat CRPC, including cancers driven by ligand-independent AR signaling.

  15. Thrombin-inhibiting nanoparticles rapidly constitute versatile and detectable anticlotting surfaces

    Science.gov (United States)

    Wheatley Myerson, Jacob; He, Li; Allen, John Stacy; Williams, Todd; Lanza, Gregory; Tollefsen, Douglas; Caruthers, Shelton; Wickline, Samuel

    2014-09-01

    Restoring an antithrombotic surface to suppress ongoing thrombosis is an appealing strategy for treatment of acute cardiovascular disorders such as erosion of atherosclerotic plaque. An antithrombotic surface would present an alternative to systemic anticoagulation with attendant risks of bleeding. We have designed thrombin-targeted nanoparticles (NPs) that bind to sites of active clotting to extinguish local thrombin activity and inhibit platelet deposition while exhibiting only transient systemic anticoagulant effects. Perfluorocarbon nanoparticles (PFC NP) were functionalized with thrombin inhibitors (either D-phenylalanyl-L-prolyl-L-arginyl-chloromethyl ketone or bivalirudin) by covalent attachment of more than 15 000 inhibitors to each PFC NP. Fibrinopeptide A (FPA) ELISA demonstrated that thrombin-inhibiting NPs prevented cleavage of fibrinogen by both free and clot-bound thrombin. Magnetic resonance imaging (MRI) confirmed that a layer of thrombin-inhibiting NPs prevented growth of clots in vitro. Thrombin-inhibiting NPs were administered in vivo to C57BL6 mice subjected to laser injury of the carotid artery. NPs significantly delayed thrombotic occlusion of the artery, whereas an equivalent bolus of free inhibitor was ineffective. For thrombin-inhibiting NPs, only a short-lived (˜10 min) systemic effect on bleeding time was observed, despite prolonged clot inhibition. Imaging and quantification of in vivo antithrombotic NP layers was demonstrated by MRI of the PFC NP. 19F MRI confirmed colocalization of particles with arterial thrombi, and quantitative 19F spectroscopy demonstrated specific binding and retention of thrombin-inhibiting NPs in injured arteries. The ability to rapidly form and image a new antithrombotic surface in acute vascular syndromes while minimizing risks of bleeding would permit a safer method of passivating active lesions than current systemic anticoagulant regimes.

  16. Quercetin-induced downregulation of phospholipase D1 inhibits proliferation and invasion in U87 glioma cells

    Energy Technology Data Exchange (ETDEWEB)

    Park, Mi Hee [Department of Molecular Biology, College of Natural Science, Pusan National University, 30 Jangjeon dong, Geumjeong gu, Busan 609-735 (Korea, Republic of); Min, Do Sik, E-mail: minds@pusan.ac.kr [Department of Molecular Biology, College of Natural Science, Pusan National University, 30 Jangjeon dong, Geumjeong gu, Busan 609-735 (Korea, Republic of)

    2011-09-09

    Highlights: {yields} Quercetin, a bioactive flavonoid, suppresses expression and enzymatic activity of phospholipase D1. {yields} Quercetin abolishes NFkB-induced phospholipase D1 expression via inhibition of NFkB transactivation. {yields} Quercetin-induced suppression of phospholipase D1 inhibits invasion and proliferation of human glioma cells. -- Abstract: Phospholipase D (PLD) has been recognized as a regulator of cell proliferation and tumorigenesis, but little is known about the molecules regulating PLD expression. Thus, the identification of small molecules inhibiting PLD expression would be an important advance in PLD-mediated physiology. Quercetin, a ubiquitous bioactive flavonoid, is known to inhibit proliferation and induce apoptosis in a variety of cancer cells. In the present study, we examined the effect of quercetin on the expression of PLD in U87 glioma cells. Quercetin significantly suppressed the expression of PLD1 at the transcriptional level. Moreover, quercetin abolished the protein expression of PLD1 in a time and dose-dependent manner, as well as inhibited PLD activity. Quercetin suppressed NF{kappa}B-induced PLD1 expression via inhibition of NFkB transactivation. Furthermore, quercetin inhibited activation and invasion of metalloproteinase-2 (MMP-2), a key modulator of glioma cell invasion, induced by phosphatidic acid (PA), a product of PLD activity. Taken together these data demonstrate that quercetin abolishes PLD1 expression and subsequently inhibits invasion and proliferation of glioma cells.

  17. Background Model for the Majorana Demonstrator

    Energy Technology Data Exchange (ETDEWEB)

    Cuesta, C.; Abgrall, N.; Aguayo, Estanislao; Avignone, Frank T.; Barabash, Alexander S.; Bertrand, F.; Boswell, M.; Brudanin, V.; Busch, Matthew; Byram, D.; Caldwell, A. S.; Chan, Yuen-Dat; Christofferson, Cabot-Ann; Combs, Dustin C.; Detwiler, Jason A.; Doe, Peter J.; Efremenko, Yuri; Egorov, Viatcheslav; Ejiri, H.; Elliott, S. R.; Fast, James E.; Finnerty, P.; Fraenkle, Florian; Galindo-Uribarri, A.; Giovanetti, G. K.; Goett, J.; Green, M. P.; Gruszko, J.; Guiseppe, Vincente; Gusev, K.; Hallin, A. L.; Hazama, R.; Hegai, A.; Henning, Reyco; Hoppe, Eric W.; Howard, Stanley; Howe, M. A.; Keeter, K.; Kidd, M. F.; Kochetov, Oleg; Konovalov, S.; Kouzes, Richard T.; Laferriere, Brian D.; Leon, Jonathan D.; Leviner, L.; Loach, J. C.; MacMullin, J.; MacMullin, S.; Martin, R. D.; Meijer, S. J.; Mertens, S.; Nomachi, Masaharu; Orrell, John L.; O' Shaughnessy, C.; Overman, Nicole R.; Phillips, D.; Poon, Alan; Pushkin, K.; Radford, D. C.; Rager, J.; Rielage, Keith; Robertson, R. G. H.; Romero-Romero, E.; Ronquest, M. C.; Schubert, Alexis G.; Shanks, B.; Shima, T.; Shirchenko, M.; Snavely, Kyle J.; Snyder, N.; Suriano, Anne-Marie; Thompson, J.; Timkin, V.; Tornow, Werner; Trimble, J. E.; Varner, R. L.; Vasilyev, Sergey; Vetter, Kai; Vorren, Kris R.; White, Brandon R.; Wilkerson, J. F.; Wiseman, C.; Xu, W.; Yakushev, E.; Young, A.; Yu, Chang-Hong; Yumatov, Vladimir

    2015-06-01

    The Majorana Collaboration is constructing a prototype system containing 40 kg of HPGe detectors to demonstrate the feasibility and potential of a future tonne-scale experiment to search for neutrinoless double-beta (0v BB) decay in 76Ge. In view of the requirement that the next generation of tonne-scale Ge-based 0vBB-decay experiment be capable of probing the neutrino mass scale in the inverted-hierarchy region, a major goal of theMajorana Demonstrator is to demonstrate a path forward to achieving a background rate at or below 1 cnt/(ROI-t-y) in the 4 keV region of interest around the Q-value at 2039 keV. This goal is pursued through a combination of a significant reduction of radioactive impurities in construction materials with analytical methods for background rejection, for example using powerful pulse shape analysis techniques profiting from the p-type point contact HPGe detectors technology. The effectiveness of these methods is assessed using Geant4 simulations of the different background components whose purity levels are constrained from radioassay measurements.

  18. Ground test for vibration control demonstrator

    Science.gov (United States)

    Meyer, C.; Prodigue, J.; Broux, G.; Cantinaud, O.; Poussot-Vassal, C.

    2016-09-01

    In the objective of maximizing comfort in Falcon jets, Dassault Aviation is developing an innovative vibration control technology. Vibrations of the structure are measured at several locations and sent to a dedicated high performance vibration control computer. Control laws are implemented in this computer to analyse the vibrations in real time, and then elaborate orders sent to the existing control surfaces to counteract vibrations. After detailing the technology principles, this paper focuses on the vibration control ground demonstration that was performed by Dassault Aviation in May 2015 on Falcon 7X business jet. The goal of this test was to attenuate vibrations resulting from fixed forced excitation delivered by shakers. The ground test demonstrated the capability to implement an efficient closed-loop vibration control with a significant vibration level reduction and validated the vibration control law design methodology. This successful ground test was a prerequisite before the flight test demonstration that is now being prepared. This study has been partly supported by the JTI CleanSky SFWA-ITD.

  19. Controlled Hydrogen Fleet and Infrastructure Demonstration Project

    Energy Technology Data Exchange (ETDEWEB)

    Dr. Scott Staley

    2010-03-31

    the fuel provider, while viability of the vehicle requires an expected level of cost, comfort, safety and operation, especially driving range, that consumers require. This presents a classic 'chicken and egg' problem, which Ford believes can be solved with thoughtful implementation plans. The eighteen Ford Focus FCV vehicles that were operated for this demonstration project provided the desired real world experience. Some things worked better than expected. Most notable was the robustness and life of the fuel cell. This is thought to be the result of the full hybrid configuration of the drive system where the battery helps to overcome the performance reduction associated with time related fuel cell degradation. In addition, customer satisfaction surveys indicated that people like the cars and the concept and operated them with little hesitation. Although the demonstrated range of the cars was near 200 miles, operators felt constrained because of the lack of a number of conveniently located fueling stations. Overcoming this major concern requires overcoming a key roadblock, fuel storage, in a manner that permits sufficient quantity of fuel without sacrificing passenger or cargo capability. Fueling infrastructure, on the other hand, has been problematic. Only three of a planned seven stations were opened. The difficulty in obtaining public approval and local government support for hydrogen fuel, based largely on the fear of hydrogen that grew from past disasters and atomic weaponry, has inhibited progress and presents a major roadblock to implementation. In addition the cost of hydrogen production, in any of the methodologies used in this program, does not show a rapid reduction to commercially viable rates. On the positive side of this issue was the demonstrated safety of the fueling station, equipment and process. In the Ford program, there were no reported safety incidents.

  20. PROBA-3: Precise formation flying demonstration mission

    Science.gov (United States)

    Llorente, J. S.; Agenjo, A.; Carrascosa, C.; de Negueruela, C.; Mestreau-Garreau, A.; Cropp, A.; Santovincenzo, A.

    2013-01-01

    Formation Flying (FF) has generated a strong interest in many space applications, most of them involving a significant complexity for building for example on-board large "virtual structures or distributed observatories". The implementation of these complex formation flying missions with critical dependency on this new, advanced and critical formation technology requires a thorough verification of the system behaviour in order to provide enough guarantees for the target mission success. A significant number of conceptual or preliminary designs, analyses, simulations, and HW on-ground testing have been performed during the last years, but still the limitations of the ground verification determine that enough confidence of the behaviour of the formation flying mission will only be possible by demonstration in flight of the concept and the associated technologies. PROBA-3 is the mission under development at ESA for in-flight formation flying demonstration, dedicated to obtain that confidence and the necessary flight maturity level in the formation flying technologies for those future target missions. PROBA-3 will demonstrate technologies such as formation metrology sensors (from very coarse to highest accuracy), formation control and GNC, system operability, safety, etc. During the last years, PROBA-3 has evolved from the initial CDF study at ESA, to two parallel phase A studies, followed by a change in the industrial configuration for the Bridging step between A and B phases. Currently the SRR consolidation has been completed, and the project is in the middle of the phase B. After the phase A study SENER and GMV were responsible for the Formation Flying System, within a mission core team completed by OHB-Sweden, QinetiQ Space and CASA Espacio. In this paper an overview of the PROBA-3 mission is provided, with a more detailed description of the formation flying preliminary design and results.

  1. Porphyromonas gingivalis Lipids Inhibit Osteoblastic Differentiation and Function▿

    Science.gov (United States)

    Wang, Yu-Hsiung; Jiang, Jin; Zhu, Qiang; AlAnezi, Amer Z.; Clark, Robert B.; Jiang, Xi; Rowe, David W.; Nichols, Frank C.

    2010-01-01

    Porphyromonas gingivalis produces unusual sphingolipids that are known to promote inflammatory reactions in gingival fibroblasts and Toll-like receptor 2 (TLR2)-dependent secretion of interleukin-6 from dendritic cells. The aim of the present study was to examine whether P. gingivalis lipids inhibit osteoblastic function. Total lipids from P. gingivalis and two fractions, phosphoglycerol dihydroceramides and phosphoethanolamine dihydroceramides, were prepared free of lipid A. Primary calvarial osteoblast cultures derived from 5- to 7-day-old CD-1 mice were used to examine the effects of P. gingivalis lipids on mineralized nodule formation, cell viability, apoptosis, cell proliferation, and gene expression. P. gingivalis lipids inhibited osteoblast differentiation and fluorescence expression of pOBCol2.3GFP in a concentration-dependent manner. However, P. gingivalis lipids did not significantly alter osteoblast proliferation, viability, or apoptosis. When administered during specific intervals of osteoblast growth, P. gingivalis total lipids demonstrated inhibitory effects on osteoblast differentiation only after the proliferation stage of culture. Reverse transcription-PCR confirmed the downregulation of osteoblast marker genes, including Runx2, ALP, OC, BSP, OPG, and DMP-1, with concurrent upregulation of RANKL, tumor necrosis factor alpha, and MMP-3 genes. P. gingivalis total lipids and lipid fractions inhibited calvarial osteoblast gene expression and function in vivo, as determined by the loss of expression of another osteoblast differentiation reporter, pOBCol3.6GFPcyan, and reduced uptake of Alizarin complexone stain. Finally, lipid inhibition of mineral nodule formation in vitro was dependent on TLR2 expression. Our results indicate that inhibition of osteoblast function and gene expression by P. gingivalis lipids represents a novel mechanism for altering alveolar bone homeostasis at periodontal disease sites. PMID:20584977

  2. Chondroitin sulfate proteoglycans inhibit oligodendrocyte myelination through PTPσ.

    Science.gov (United States)

    Pendleton, James C; Shamblott, Michael J; Gary, Devin S; Belegu, Visar; Hurtado, Andres; Malone, Misti L; McDonald, John W

    2013-09-01

    CNS damage often results in demyelination of spared axons due to oligodendroglial cell death and dysfunction near the injury site. Although new oligodendroglia are generated following CNS injury and disease, the process of remyelination is typically incomplete resulting in long-term functional deficits. Chondroitin sulfate proteoglycans (CSPGs) are upregulated in CNS grey and white matter following injury and disease and are a major component of the inhibitory scar that suppresses axon regeneration. CSPG inhibition of axonal regeneration is mediated, at least in part, by the protein tyrosine phosphatase sigma (PTPσ) receptor. Recent evidence demonstrates that CSPGs inhibit OL process outgrowth, however, the means by which their effects are mediated remains unclear. Here we investigate the role of PTPσ in CSPG inhibition of OL function. We found that the CSPGs, aggrecan, neurocan and NG2 all imposed an inhibitory effect on OL process outgrowth and myelination. These inhibitory effects were reversed by degradation of CSPGs with Chondroitinase ABC prior to OL exposure. RNAi-mediated down-regulation of PTPσ reversed the inhibitory effect of CSPGs on OL process outgrowth and myelination. Likewise, CSPG inhibition of process outgrowth and myelination was significantly reduced in cultures containing PTPσ(-/-) OLs. Finally, inhibition of Rho-associated kinase (ROCK) increased OL process outgrowth and myelination during exposure to CSPGs. These results suggest that in addition to their inhibitory effects on axon regeneration, CSPGs have multiple inhibitory actions on OLs that result in incomplete remyelination following CNS injury. The identification of PTPσ as a receptor for CSPGs, and the participation of ROCK downstream of CSPG exposure, reveal potential therapeutic targets to enhance white matter repair in the damaged CNS.

  3. Genetic ablation and short-duration inhibition of lipoxygenase results in increased macroautophagy

    Energy Technology Data Exchange (ETDEWEB)

    Jang, Insook; Park, Sujin; Cho, Jin Won [Department of Integrated OMICS for Biomedical Science, WCU Program of Graduate School, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-749 (Korea, Republic of); Yigitkanli, Kazim; Leyen, Klaus van [Neuroprotection Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129 (United States); Roth, Jürgen, E-mail: jurgen.roth@bluewin.ch [Department of Integrated OMICS for Biomedical Science, WCU Program of Graduate School, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-749 (Korea, Republic of)

    2014-02-15

    12/15-lipoxygenase (12/15-LOX) is involved in organelle homeostasis by degrading mitochondria in maturing red blood cells and by eliminating excess peroxisomes in liver. Furthermore, 12/15-LOX contributes to diseases by exacerbating oxidative stress-related injury, notably in stroke. Nonetheless, it is unclear what the consequences are of abolishing 12/15-LOX activity. Mice in which the alox15 gene has been ablated do not show an obvious phenotype, and LOX enzyme inhibition is not overtly detrimental. We show here that liver histology is also unremarkable. However, electron microscopy demonstrated that 12/15-LOX knockout surprisingly leads to increased macroautophagy in the liver. Not only macroautophagy but also mitophagy and pexophagy were increased in hepatocytes, which otherwise showed unaltered fine structure and organelle morphology. These findings were substantiated by immunofluorescence showing significantly increased number of LC3 puncta and by Western blotting demonstrating a significant increase for LC3-II protein in both liver and brain homogenates of 12/15-LOX knockout mice. Inhibition of 12/15-LOX activity by treatment with four structurally different inhibitors had similar effects in cultured HepG2 hepatoma cells and SH-SY5Y neuroblastoma cells with significantly increased autophagy discernable already after 2 hours. Hence, our study reveals a link between ablation or inhibition of 12/15-LOX and stimulation of macroautophagy. The enhanced macroautophagy may be related to the known tissue-protective effects of LOX ablation or inhibition under various diseased conditions caused by oxidative stress and ischemia. This could provide an important cleaning mechanism of cells and tissues to prevent accumulation of damaged mitochondria and other cellular components. - Highlights: • A relationship between lipoxygenases and autophagy is disclosed. • 12/15-lipoxygenase knockout increases autophagy in mice liver and brain. • Lipoxygenase inhibition boosts

  4. Mycobacterium tuberculosis nuoG is a virulence gene that inhibits apoptosis of infected host cells.

    Directory of Open Access Journals (Sweden)

    Kamalakannan Velmurugan

    2007-07-01

    Full Text Available The survival and persistence of Mycobacterium tuberculosis depends on its capacity to manipulate multiple host defense pathways, including the ability to actively inhibit the death by apoptosis of infected host cells. The genetic basis for this anti-apoptotic activity and its implication for mycobacterial virulence have not been demonstrated or elucidated. Using a novel gain-of-function genetic screen, we demonstrated that inhibition of infection-induced apoptosis of macrophages is controlled by multiple genetic loci in M. tuberculosis. Characterization of one of these loci in detail revealed that the anti-apoptosis activity was attributable to the type I NADH-dehydrogenase of M. tuberculosis, and was mainly due to the subunit of this multicomponent complex encoded by the nuoG gene. Expression of M. tuberculosis nuoG in nonpathogenic mycobacteria endowed them with the ability to inhibit apoptosis of infected human or mouse macrophages, and increased their virulence in a SCID mouse model. Conversely, deletion of nuoG in M. tuberculosis ablated its ability to inhibit macrophage apoptosis and significantly reduced its virulence in mice. These results identify a key component of the genetic basis for an important virulence trait of M. tuberculosis and support a direct causal relationship between virulence of pathogenic mycobacteria and their ability to inhibit macrophage apoptosis.

  5. BST2/Tetherin Inhibition of Alphavirus Exit

    Directory of Open Access Journals (Sweden)

    Yaw Shin Ooi

    2015-04-01

    Full Text Available Alphaviruses such as chikungunya virus (CHIKV and Semliki Forest virus (SFV are small enveloped RNA viruses that bud from the plasma membrane. Tetherin/BST2 is an interferon-induced host membrane protein that inhibits the release of many enveloped viruses via direct tethering of budded particles to the cell surface. Alphaviruses have highly organized structures and exclude host membrane proteins from the site of budding, suggesting that their release might be insensitive to tetherin inhibition. Here, we demonstrated that exogenously-expressed tetherin efficiently inhibited the release of SFV and CHIKV particles from host cells without affecting virus entry and infection. Alphavirus release was also inhibited by the endogenous levels of tetherin in HeLa cells. While rubella virus (RuV and dengue virus (DENV have structural similarities to alphaviruses, tetherin inhibited the release of RuV but not DENV. We found that two recently identified tetherin isoforms differing in length at the N-terminus exhibited distinct capabilities in restricting alphavirus release. SFV exit was efficiently inhibited by the long isoform but not the short isoform of tetherin, while both isoforms inhibited vesicular stomatitis virus exit. Thus, in spite of the organized structure of the virus particle, tetherin specifically blocks alphavirus release and shows an interesting isoform requirement.

  6. Inhibition of urinary calculi -- a spectroscopic study

    Science.gov (United States)

    Manciu, Felicia; Govani, Jayesh; Durrer, William; Reza, Layra; Pinales, Luis

    2008-10-01

    Although a considerable number of investigations have already been undertaken and many causes such as life habits, metabolic disorders, and genetic factors have been noted as sources that accelerate calculi depositions and aggregations, there are still plenty of unanswered questions regarding efficient inhibition and treatment mechanisms. Thus, in an attempt to acquire more insights, we propose here a detailed scientific study of kidney stone formation and growth inhibition based on a traditional medicine approach with Rotula Aquatica Lour (RAL) herbal extracts. A simplified single diffusion gel growth technique was used for synthesizing the samples for the present study. The unexpected Zn presence in the sample with RAL inhibitor, as revealed by XPS measurements, explains the inhibition process and the dramatic reflectance of the incident light observed in the infrared transmission studies. Raman data demonstrate potential binding of the inhibitor with the oxygen of the kidney stone. Photoluminescence results corroborate to provide additional evidence of Zn-related inhibition.

  7. Reciprocal inhibition in man.

    Science.gov (United States)

    Crone, C

    1993-11-01

    Reciprocal inhibition is the automatic antagonist alpha motor neurone inhibition which is evoked by contraction of the agonist muscle. This so-called natural reciprocal inhibition is a ubiquitous and pronounced phenomenon in man and must be suspected of playing a major role in the control of voluntary movements. The spinal pathways underlying this inhibitory phenomenon were studied. The disynaptic reciprocal Ia inhibitory pathway between the tibial anterior muscle and the soleus alpha motor neurones was identified and described in man. It was shown that the inhibition can be evoked in most healthy subjects at rest, but the degree of inhibition varies considerably from one subject to another. It was concluded that it corresponds to the disynaptic reciprocal Ia inhibitory pathway which has been extensively described in animal experiments. The disynaptic reciprocal inhibition was shown to increase during the dynamic phase of a dorsiflexion movement of the foot, but not during the tonic phase. However, when the peripheral afferent feedback from the contracting muscle was blocked by ischaemia, an increase of the inhibition was revealed also during the tonic phase of the dorsiflexion. The concealment of this increase during unrestrained peripheral feedback from the muscle was thought to be due to the post-activation depression mechanism; a mechanism which was described further and which probably involves reduced transmitter release at Ia afferent terminals as a result of previous activation of these afferent fibers. Hence the hypothesis was supported that alpha motor neurones and the corresponding inhibitory interneurones, which project reciprocal inhibition to the antagonist motor neurones, are activated in parallel during voluntary contraction of agonist muscles. An additional reciprocal inhibitory mechanism, the long latency reciprocal inhibition, was described between the tibial anterior muscle and the soleus alpha motor neurones. It was shown to be evoked by group I

  8. Polyamines Inhibit Porin-Mediated Fluoroquinolone Uptake in Mycobacteria

    Science.gov (United States)

    Sarathy, Jansy Passiflora; Lee, Edmund; Dartois, Véronique

    2013-01-01

    Polyamines decrease the permeability of the outer membrane of Escherichia coli to fluoroquinolones and β-lactams. In this study, we tested the effect of four polyamines (spermidine, spermine, cadaverine and putrescine) on fluoroquinolone uptake in Mycobacterium bovis BCG. Our results show that polyamines are also capable of reducing the permeability of the mycobacterial outer membrane to fluoroquinolones. Spermidine was most effective and demonstrated reversible dose- and pH-dependent inhibition of ciprofloxacin accumulation. The extent of this inhibition was demonstrated across the fluoroquinolone compound class to varying degrees. Furthermore, we have shown that the addition of spermidine increases the survival of M. bovis BCG after a 5-day exposure to ciprofloxacin by up to 25 times. The treatment of actively-replicating Mycobacterium tuberculosis with spermidine reduced ciprofloxacin accumulation by half while non-replicating nutrient-starved M. tuberculosis cultures lacked similar sensitivity to polyamines. Gene expression studies showed that several outer membrane proteins are significantly down–regulated during the shift to non–replication. Collectively, these characteristics of fluoroquinolone uptake in M. bovis BCG are consistent with facilitated transport by porin-like proteins and suggest that a reduction in intracellular uptake contributes to the phenotypic drug resistance demonstrated by M. tuberculosis in the non-replicating state. PMID:23755283

  9. Inhibition of catalase by tea catechins in free and cellular state: a biophysical approach.

    Science.gov (United States)

    Pal, Sandip; Dey, Subrata Kumar; Saha, Chabita

    2014-01-01

    Tea flavonoids bind to variety of enzymes and inhibit their activities. In the present study, binding and inhibition of catalase activity by catechins with respect to their structure-affinity relationship has been elucidated. Fluorimetrically determined binding constants for (-)-epigallocatechin gallate (EGCG) and (-)-epicatechin gallate (ECG) with catalase were observed to be 2.27×106 M(-1) and 1.66×106 M(-1), respectively. Thermodynamic parameters evidence exothermic and spontaneous interaction between catechins and catalase. Major forces of interaction are suggested to be through hydrogen bonding along with electrostatic contributions and conformational changes. Distinct loss of α-helical structure of catalase by interaction with EGCG was captured in circular dichroism (CD) spectra. Gallated catechins demonstrated higher binding constants and inhibition efficacy than non-gallated catechins. EGCG exhibited maximum inhibition of pure catalase. It also inhibited cellular catalase in K562 cancer cells with significant increase in cellular ROS and suppression of cell viability (IC50 54.5 µM). These results decipher the molecular mechanism by which tea catechins interact with catalase and highlight the potential of gallated catechin like EGCG as an anticancer drug. EGCG may have other non-specific targets in the cell, but its anticancer property is mainly defined by ROS accumulation due to catalase inhibition.

  10. Inhibition of catalase by tea catechins in free and cellular state: a biophysical approach.

    Directory of Open Access Journals (Sweden)

    Sandip Pal

    Full Text Available Tea flavonoids bind to variety of enzymes and inhibit their activities. In the present study, binding and inhibition of catalase activity by catechins with respect to their structure-affinity relationship has been elucidated. Fluorimetrically determined binding constants for (--epigallocatechin gallate (EGCG and (--epicatechin gallate (ECG with catalase were observed to be 2.27×106 M(-1 and 1.66×106 M(-1, respectively. Thermodynamic parameters evidence exothermic and spontaneous interaction between catechins and catalase. Major forces of interaction are suggested to be through hydrogen bonding along with electrostatic contributions and conformational changes. Distinct loss of α-helical structure of catalase by interaction with EGCG was captured in circular dichroism (CD spectra. Gallated catechins demonstrated higher binding constants and inhibition efficacy than non-gallated catechins. EGCG exhibited maximum inhibition of pure catalase. It also inhibited cellular catalase in K562 cancer cells with significant increase in cellular ROS and suppression of cell viability (IC50 54.5 µM. These results decipher the molecular mechanism by which tea catechins interact with catalase and highlight the potential of gallated catechin like EGCG as an anticancer drug. EGCG may have other non-specific targets in the cell, but its anticancer property is mainly defined by ROS accumulation due to catalase inhibition.

  11. Inhibition of total oxygen uptake by silica nanoparticles in activated sludge

    Energy Technology Data Exchange (ETDEWEB)

    Sibag, Mark [Department of Environment and Energy, Sejong University, 98 Gunja-Dong, Gwangjin-Gu, Seoul 143-747 (Korea, Republic of); Choi, Byeong-Gyu [School of Civil, Environmental and Architectural Engineering, Korea University, 145, Anam-ro, Sungbuk-ku, Seoul 136-701 (Korea, Republic of); Suh, Changwon [Energy Lab, Environment Group, Samsung Advanced Institute of Technology, 130 Samsung-ro, Yeongtong-gu, Suwon-si, Gyeonggi-do 443-803 (Korea, Republic of); Lee, Kwan Hyung; Lee, Jae Woo [Department of Environmental Engineering and Program in Environmental Technology and Policy, Korea University, Sejong 339-700 (Korea, Republic of); Maeng, Sung Kyu [Department of Civil and Environmental Engineering, Sejong University, 98 Gunja-Dong, Gwangjin-Gu, Seoul 143-747 (Korea, Republic of); Cho, Jinwoo, E-mail: jinwoocho@sejong.edu [Department of Environment and Energy, Sejong University, 98 Gunja-Dong, Gwangjin-Gu, Seoul 143-747 (Korea, Republic of)

    2015-02-11

    Highlights: • Silica nanoparticles (SNP) inhibit total oxygen uptake in activated sludge. • Relatively smaller SNP are inhibitorier than larger SNP. • SNP alters C15:0, C16:0 and C18:0 in activated sludge fatty acid methyl ester profile. - Abstract: Nanoparticle toxicity to biological activities in activated sludge is largely unknown. Among the widely used nanoparticles, silica nanoparticles (SNP) have a limited number of studies associated with inhibition to the activated sludge process (ASP). We demonstrated SNP inhibition of activated sludge respiration through oxygen uptake rate (OUR) measurement. Based on the percentage inhibition of total oxygen consumption (I{sub T}), we observed that smaller SNPs (12 nm, I{sub T} = 33 ± 3%; 151 nm, I{sub T} = 23 ± 2%) were stronger inhibitors than larger SNPs (442 and 683 nm, I{sub T} = 5 ± 1%). Transmission electron micrographs showed that some of the SNPs were adsorbed on and/or apparently embedded somewhere in the microbial cell membrane. Whether SNPs are directly associated with the inhibition of total oxygen uptake warrants further studies. However, it is clear that SNPs statistically significantly altered the composition of microbial membrane lipids, which was more clearly described by principal component analysis and weighted Euclidian distance (PCA-ED) of the fatty acid methyl ester (FAME) data. This study suggests that SNPs potentially affect the biological activity in activated sludge through the inhibition of total oxygen uptake.

  12. Demonstration Of A Nanomaterial-Modified Primer For Use In Corrosion-Inhibiting Coating Systems

    Science.gov (United States)

    2011-11-01

    QA Toolkit database. (User feedback was being ob- ERDC/CERL TR-11-42 11 tained for the Navy as part of a separate task). A certified National...C6 .TJON VIEW V p~w-1- Me,t..uel -f-o fo e_ efl -~le--Geo-rftl f Pt s I’""’ " " . 7 ui<’J ~~~WING IS FOR PROPOSED ONLY. ’OilS ORA SCAFFOLD USED

  13. Quassinoids and Their Chemotaxonomic Significance

    Directory of Open Access Journals (Sweden)

    Anakshi Khare

    2013-06-01

    Full Text Available The quassinoids are a group of complex, highly oxygenated, degraded triterpene mostly found in Simaroubaceae family. Two quassinoids (degraded triterpenes, 1 and 2 were isolated first time from the stem bark of Ailanthus excelsa. Compound 1 is C19 quassinoid. C19 quassinoid derived biogenetically from a C20 quassinoid, via a 1,2 –dioxo derivative. The structural elucidation is based on the analysis of spectroscopic data. Interest in these quassinoids has increased enormously in recent years due in part to the finding of the American National Cancer Institute that these compounds display marked antileukamic activity. The ways in which plants interact with other organisms in an environment are complex. Ailanthus also produces toxins in its root, bark and leaves. These toxins inhibit the growth of other plants. The isolated quassinoids are currently being studied as a possible source of a natural herbicide. Extracts of this plant have anti-insect activity and anti-tuberculosis activity.

  14. Osteoclast inhibitory peptide-1 (OIP-1) inhibits measles virus nucleocapsid protein stimulated osteoclast formation/activity.

    Science.gov (United States)

    Shanmugarajan, Srinivasan; Youssef, Rimon F; Pati, Parmita; Ries, William L; Rao, D Sudhaker; Reddy, Sakamuri V

    2008-07-01

    Paget's disease (PD) of bone is characterized by increased activity of large abnormal osteoclasts (OCLs) which contain paramyxoviral nuclear and cytoplasmic inclusions. MVNP gene expression has been shown to induce pagetic phenotype in OCLs. We previously characterized the osteoclast inhibitory peptide-1 (OIP-1/hSca) which inhibits OCL formation/bone resorption. OIP-1 is a glycophosphatidylinositol (GPI)-linked membrane protein containing a 79 amino acid extra cellular peptide and a 32 amino acid carboxy terminal GPI-linked peptide (c-peptide) which is critical for OCL inhibition. In this study, we demonstrate that OIP-1 c-peptide significantly decreased (43%) osteoclast differentiation of peripheral blood mononuclear cells from patients with PD. Also, OIP-1 treatment to normal human bone marrow mononuclear cells transduced with the MVNP inhibited (41%) osteoclast precursor (CFU-GM) growth in methyl-cellulose cultures. We further tested if OIP-1 overexpression in the OCL lineage in transgenic mice inhibits MVNP stimulated OCL formation. MVNP transduction and RANKL stimulation of OIP-1 mouse bone marrow cells showed a significant decrease (43%) in OCL formation and inhibition (38%) of bone resorption area compared to wild-type mice. Western blot analysis identified that OIP-1 decreased (3.5-fold) MVNP induced TRAF2 expression during OCL differentiation. MVNP or OIP-1 expression did not affect TRAF6 levels. Furthermore, OIP-1 expression resulted in a significant inhibition of MVNP stimulated ASK1, Rac1, c-Fos, p-JNK, and NFATc1 expression during OCL differentiation. These results suggest that OIP-1 inhibits MVNP induced pagetic OCL formation/activity through suppression of RANK signaling. Thus, OIP-1 may have therapeutic utility against excess bone resorption in patients with PD.

  15. The Significance of Adolescents' Relationships with Significant Others and School Failure

    Science.gov (United States)

    Domagala-Zysk, Ewa

    2006-01-01

    This article demonstrates the importance of social support from students' significant others (parents, peers and teachers) in the process of doing well at school. The main focus of the research project was to find correlations between the quality of adolescents' relationships with significant others and their school success or school failure, as…

  16. Multi-targeted inhibition of tumor growth and lung metastasis by redox-sensitive shell crosslinked micelles loading disulfiram

    Science.gov (United States)

    Duan, Xiaopin; Xiao, Jisheng; Yin, Qi; Zhang, Zhiwen; Yu, Haijun; Mao, Shirui; Li, Yaping

    2014-03-01

    Metastasis, the main cause of cancer related deaths, remains the greatest challenge in cancer treatment. Disulfiram (DSF), which has multi-targeted anti-tumor activity, was encapsulated into redox-sensitive shell crosslinked micelles to achieve intracellular targeted delivery and finally inhibit tumor growth and metastasis. The crosslinked micelles demonstrated good stability in circulation and specifically released DSF under a reductive environment that mimicked the intracellular conditions of tumor cells. As a result, the DSF-loaded redox-sensitive shell crosslinked micelles (DCMs) dramatically inhibited cell proliferation, induced cell apoptosis and suppressed cell invasion, as well as impairing tube formation of HMEC-1 cells. In addition, the DCMs could accumulate in tumor tissue and stay there for a long time, thereby causing significant inhibition of 4T1 tumor growth and marked prevention in lung metastasis of 4T1 tumors. These results suggested that DCMs could be a promising delivery system in inhibiting the growth and metastasis of breast cancer.

  17. Inhibition of the multidrug efflux pump LmrS from Staphylococcus aureus by cumin spice Cuminum cyminum.

    Science.gov (United States)

    Kakarla, Prathusha; Floyd, Jared; Mukherjee, MunMun; Devireddy, Amith R; Inupakutika, Madhuri A; Ranweera, Indrika; Kc, Ranjana; 'Shrestha, Ugina; Cheeti, Upender Rao; Willmon, Thomas Mark; Adams, Jaclyn; Bruns, Merissa; Gunda, Shravan Kumar; Varela, Manuel F

    2017-04-01

    Staphylococcus aureus is a serious causative agent of infectious disease. Multidrug-resistant strains like methicillin-resistant S. aureus compromise treatment efficacy, causing significant morbidity and mortality. Active efflux represents a major antimicrobial resistance mechanism. The proton-driven multidrug efflux pump, LmrS, actively exports structurally distinct antimicrobials. To circumvent resistance and restore clinical efficacy of antibiotics, efflux pump inhibitors are necessary, and natural edible spices like cumin are potential candidates. The mode of cumin antibacterial action and underlying mechanisms behind drug resistance inhibition, however, are unclear. We tested the hypothesis that cumin inhibits LmrS drug transport. We found that cumin inhibited bacterial growth and LmrS ethidium transport in a dosage-dependent manner. We demonstrate that cumin is antibacterial toward a multidrug-resistant host and that resistance modulation involves multidrug efflux inhibition.

  18. Analysis of occludin trafficking, demonstrating continuous endocytosis, degradation, recycling and biosynthetic secretory trafficking.

    Directory of Open Access Journals (Sweden)

    Sarah J Fletcher

    Full Text Available Tight junctions (TJs link adjacent cells and are critical for maintenance of apical-basolateral polarity in epithelial monolayers. The TJ protein occludin functions in disparate processes, including wound healing and Hepatitis C Virus infection. Little is known about steady-state occludin trafficking into and out of the plasma membrane. Therefore, we determined the mechanisms responsible for occludin turnover in confluent Madin-Darby canine kidney (MDCK epithelial monolayers. Using various biotin-based trafficking assays we observed continuous and rapid endocytosis of plasma membrane localised occludin (the majority internalised within 30 minutes. By 120 minutes a significant reduction in internalised occludin was observed. Inhibition of lysosomal function attenuated the reduction in occludin signal post-endocytosis and promoted co-localisation with the late endocytic system. Using a similar method we demonstrated that ∼20% of internalised occludin was transported back to the cell surface. Consistent with these findings, significant co-localisation between internalised occludin and recycling endosomal compartments was observed. We then quantified the extent to which occludin synthesis and transport to the plasma membrane contributes to plasma membrane occludin homeostasis, identifying inhibition of protein synthesis led to decreased plasma membrane localised occludin. Significant co-localisation between occludin and the biosynthetic secretory pathway was demonstrated. Thus, under steady-state conditions occludin undergoes turnover via a continuous cycle of endocytosis, recycling and degradation, with degradation compensated for by biosynthetic exocytic trafficking. We developed a mathematical model to describe the endocytosis, recycling and degradation of occludin, utilising experimental data to provide quantitative estimates for the rates of these processes.

  19. Significance Tests for Periodogram Peaks

    CERN Document Server

    Frescura, F A M; Frank, B S

    2007-01-01

    We discuss methods currently in use for determining the significance of peaks in the periodograms of time series. We discuss some general methods for constructing significance tests, false alarm probability functions, and the role played in these by independent random variables and by empirical and theoretical cumulative distribution functions. We also discuss the concept of "independent frequencies" in periodogram analysis. We propose a practical method for estimating the significance of periodogram peaks, applicable to all time series irrespective of the spacing of the data. This method, based on Monte Carlo simulations, produces significance tests that are tailor-made for any given astronomical time series.

  20. Fatty acyl-CoA esters inhibit glucose-6-phosphatase in rat liver microsomes.

    Science.gov (United States)

    Fulceri, R; Gamberucci, A; Scott, H M; Giunti, R; Burchell, A; Benedetti, A

    1995-01-01

    In native rat liver microsomes glucose 6-phosphatase activity is dependent not only on the activity of the glucose-6-phosphatase enzyme (which is lumenal) but also on the transport of glucose-6-phosphate, phosphate and glucose through the respective translocases T1, T2 and T3. By using enzymic assay techniques, palmitoyl-CoA or CoA was found to inhibit glucose-6-phosphatase activity in intact microsomes. The effect of CoA required ATP and fatty acids to form fatty acyl esters. Increasing concentrations (2-50 microM) of CoA (plus ATP and 20 microM added palmitic acid) or of palmitoyl-CoA progressively decreased glucose-6-phosphatase activity to 50% of the control value. The inhibition lowered the Vmax without significantly changing the Km. A non-hydrolysable analogue of palmitoyl-CoA also inhibited, demonstrating that binding of palmitoyl-CoA rather than hydrolysis produces the inhibition. Light-scattering measurements of osmotically induced changes in the size of rat liver microsomal vesicles pre-equilibrated in a low-osmolality buffer demonstrated that palmitoyl-CoA alone or CoA plus ATP and palmitic acid altered the microsomal permeability to glucose 6-phosphate, but not to glucose or phosphate, indicating that T1 is the site of palmitoyl-CoA binding and inhibition of glucose-6-phosphatase activity in native microsomes. The type of inhibition found suggests that liver microsomes may comprise vesicles heterogeneous with respect to glucose-6-phosphate translocase(s), i.e. sensitive or insensitive to fatty acid ester inhibition. PMID:7733874

  1. The evolution of contact-dependent inhibition in non-growing populations of Escherichia coli.

    Science.gov (United States)

    Lemonnier, Marc; Levin, Bruce R; Romeo, Tony; Garner, Kim; Baquero, María-Rosario; Mercante, Jeff; Lemichez, Emmanuel; Baquero, Fernando; Blázquez, Jesús

    2008-01-01

    In the course of liquid culture, serial passage experiments with Escherichia coli K-12 bearing a mutator gene deletion (DeltamutS) we observed the evolution of strains that appeared to kill or inhibit the growth of the bacteria from where they were derived, their ancestors. We demonstrate that this inhibition occurs after the cells stop growing and requires physical contact between the evolved and ancestral bacteria. Thereby, it is referred to as stationary phase contact-dependent inhibition (SCDI). The evolution of this antagonistic relationship is not anticipated from existing theory and experiments of competition in mass (liquid) culture. Nevertheless, it occurred in the same way (parallel evolution) in the eight independent serial transfer cultures, through different single base substitutions in a gene in the glycogen synthesis pathway, glgC. We demonstrate that the observed mutations in glgC, which codes for ADP-glucose pyrophosphorylase, are responsible for both the ability of the evolved bacteria to inhibit or kill their ancestors and their immunity to that inhibition or killing. We present evidence that without additional evolution, mutator genes, or known mutations in glgC, other strains of E. coli K-12 are also capable of SCDI or sensitive to this inhibition. We interpret this, in part, as support for the generality of SCDI and also as suggesting that the glgC mutations responsible for the SCDI, which evolved in our experiments, may suppress the action of one or more genes responsible for the sensitivity of E. coli to SCDI. Using numerical solutions to a mathematical model and in vitro experiments, we explore the population dynamics of SCDI and postulate the conditions responsible for its evolution in mass culture. We conclude with a brief discussion of the potential ecological significance of SCDI and its possible utility for the development of antimicrobial agents, which unlike existing antibiotics, can kill or inhibit the growth of bacteria that are

  2. Salmonella infection inhibits intestinal biotin transport: cellular and molecular mechanisms.

    Science.gov (United States)

    Ghosal, Abhisek; Jellbauer, Stefan; Kapadia, Rubina; Raffatellu, Manuela; Said, Hamid M

    2015-07-15

    Infection with the nontyphoidal Salmonella is a common cause of food-borne disease that leads to acute gastroenteritis/diarrhea. Severe/prolonged cases of Salmonella infection could also impact host nutritional status, but little is known about its effect on intestinal absorption of vitamins, including biotin. We examined the effect of Salmonella enterica serovar Typhimurium (S. typhimurium) infection on intestinal biotin uptake using in vivo (streptomycin-pretreated mice) and in vitro [mouse (YAMC) and human (NCM460) colonic epithelial cells, and human intestinal epithelial Caco-2 cells] models. The results showed that infecting mice with wild-type S. typhimurium, but not with its nonpathogenic isogenic invA spiB mutant, leads to a significant inhibition in jejunal/colonic biotin uptake and in level of expression of the biotin transporter, sodium-dependent multivitamin transporter. In contrast, infecting YAMC, NCM460, and Caco-2 cells with S. typhimurium did not affect biotin uptake. These findings suggest that the effect of S. typhimurium infection is indirect and is likely mediated by proinflammatory cytokines, the levels of which were markedly induced in the intestine of S. typhimurium-infected mice. Consistent with this hypothesis, exposure of NCM460 cells to the proinflammatory cytokines TNF-α and IFN-γ led to a significant inhibition of biotin uptake, sodium-dependent multivitamin transporter expression, and activity of the SLC5A6 promoter. The latter effects appear to be mediated, at least in part, via the NF-κB signaling pathway. These results demonstrate that S. typhimurium infection inhibits intestinal biotin uptake, and that the inhibition is mediated via the action of proinflammatory cytokines.

  3. Interleukin 2 inhibits in vitro growth of human T cell lines carrying retrovirus.

    Science.gov (United States)

    Sugamura, K; Nakai, S; Fujii, M; Hinuma, Y

    1985-05-01

    Four human T cell lines, TL-Mor, TL-Su, TL-TerI, and TL-OmI, carrying human T cell leukemia virus (HTLV), were established previously. TL-Mor, TL-Su, and TL-TerI were derived from interleukin 2 (IL-2)-dependent parental cell lines cloned from peripheral blood leukocytes (PBL) of three healthy HTLV carriers, while TL-OmI was directly established from PBL of a patient with adult T cell leukemia. These four TL cell lines grow autonomously without IL-2. When they were cultured in the presence of IL-2, their growth was inhibited after a few days. This growth inhibition depended on the dose of IL-2, and the effective dose significantly promoted growth of their parental IL-2-dependent cell lines. The growth inhibition is demonstrated to be due to specific binding of IL-2 to receptors on the TL cells.

  4. Demethoxycurcumin modulates human P-glycoprotein function via uncompetitive inhibition of ATPase hydrolysis activity.

    Science.gov (United States)

    Teng, Yu-Ning; Hsieh, Yow-Wen; Hung, Chin-Chuan; Lin, Hui-Yi

    2015-01-28

    Curcuminoids are major components of Curcuma longa L., which is widely used as spice in food. This study aimed at identifying whether curcumin, demethoxycurcumin, and bisdemethoxycurcumin could modulate efflux function of human P-glycoprotein and be used as chemosensitizers in cancer treatments. Without altering P-glycoprotein expression levels and conformation, the purified curcuminoids significantly inhibited P-glycoprotein efflux function. In rhodamine 123 efflux and calcein-AM accumulation assays, demethoxycurcumin demonstrated the highest inhibition potency (inhibitory IC50 = 1.56 ± 0.13 μM) among the purified curcuminoids, as well as in the fold of reversal assays. Demethoxycurcumin inhibited P-glycoprotein-mediated ATP hydrolysis under concentrations of P-glycoprotein. These results suggested that demethoxycurcumin may be a potential additive natural product in combination with chemotherapeutic agents in drug-resistant cancers.

  5. Somatostatin receptor-1 induces cell cycle arrest and inhibits tumor growth in pancreatic cancer.

    Science.gov (United States)

    Li, Min; Wang, Xiaochi; Li, Wei; Li, Fei; Yang, Hui; Wang, Hao; Brunicardi, F Charles; Chen, Changyi; Yao, Qizhi; Fisher, William E

    2008-11-01

    Functional somatostatin receptors (SSTR) are lost in human pancreatic cancer. Transfection of SSTR-1 inhibited pancreatic cancer cell proliferation in vitro. We hypothesize that stable transfection of SSTR-1 may inhibit pancreatic cancer growth in vivo possibly through cell cycle arrest. In this study, we examined the expression of SSTR-1 mRNA in human pancreatic cancer tissue specimens, and investigated the effect of SSTR-1 overexpression on cell proliferation, cell cycle, and tumor growth in a subcutaneous nude mouse model. We found that SSTR-1 mRNA was downregulated in the majority of pancreatic cancer tissue specimens. Transfection of SSTR-1 caused cell cycle arrest at the G(0)/G(1) growth phase, with a corresponding decline of cells in the S (mitotic) phase. The overexpression of SSTR-1 significantly inhibited subcutaneous tumor size by 71% and 43% (n = 5, P < 0.05, Student's t-test), and inhibited tumor weight by 69% and 47% (n = 5, P < 0.05, Student's t-test), in Panc-SSTR-1 and MIA-SSTR-1 groups, respectively, indicating the potent inhibitory effect of SSTR-1 on pancreatic cancer growth. Our data demonstrate that overexpression of SSTR-1 significantly inhibits pancreatic cancer growth possibly through cell cycle arrest. This study suggests that gene therapy with SSTR-1 may be a potential adjuvant treatment for pancreatic cancer.

  6. Neutral pH hydrogen-enriched electrolyzed water achieves tumor-preferential clonal growth inhibition over normal cells and tumor invasion inhibition concurrently with intracellular oxidant repression.

    Science.gov (United States)

    Saitoh, Yasukazu; Okayasu, Hajime; Xiao, Li; Harata, Yoshikazu; Miwa, Nobuhiko

    2008-01-01

    The properties and effects of neutral pH hydrogen-enriched electrolyzed water (NHE water) on tumor cells were examined. NHE water diminished hydroxyl radicals as demonstrated by ESR in a cell-free system. Human tongue carcinoma cells HSC-4 were inhibited for either colony formation efficiencies or colony sizes by NHE water without significant inhibition to normal human tongue epithelial-like cells DOK. Furthermore, NHE water caused growth inhibition, cell degeneration, and inhibition of invasion through the reconstituted basement membrane to human fibrosarcoma cells HT-1080. Intracellular oxidants such as hydroperoxides and hydrogen peroxides were scavenged in HSC-4 or HT-1080 cells by NHE water. In the human oral cavity, a dissolved hydrogen concentrations (DH) of NHE water was drastically declined from 1.1 to 0.5 ppm, but settled to 0.3-0.4 ppm until 180 s, upon static holding without gargling. Thus, NHE water was shown to achieve tumor-preferential growth inhibition and tumor invasion together with scavenging of intracellular oxidants, and is expected as a preventive material against tumor progression and invasion.

  7. Demonstrating Value for Biosimilars: A Conceptual Framework

    Science.gov (United States)

    Rompas, Sotiris; Goss, Thomas; Amanuel, Sally; Coutinho, Victoria; Lai, Zhihong; Antonini, Paola; Murphy, Michael F.

    2015-01-01

    Background The value proposition for biosimilars can be characterized as a concept that moves beyond the argument of cost reduction relative to the innovator biologic drug and into a framework that incorporates the diverse needs of key healthcare stakeholders during the transition from clinical development to commercialization in the marketplace. Objectives To identify factors that facilitate and inhibit the development, commercialization, and adoption of biosimilars, and to recommend modifications in program design that are likely to support the demonstration of the value of biosimilars for payers, providers, and patients. Methods The primary data sources for this article include surveys conducted by Boston Healthcare Associates with payers and clinicians in the United States and the European Union 5 markets and blinded international protocol feasibility assessments completed by Worldwide Clinical Trials. Survey methodology used either convenience or purposeful sampling as appropriate, with participants extracted from diverse audiences, representative of those who generate or evaluate clinical data shaping the economic exchange and preferential status influencing physician adoption and patient access to biosimilars. Patient characteristics and psychosocial issues influencing patients' perception of small-molecule generics were extracted from the available literature to inform exploratory hypotheses, given the relative absence of such information for biosimilars. Discussion This article reviews the current evidence and summarizes results of surveys conducted with payers, providers, and drug investigation sites in the United States. Based on a review of published literature, as well as these survey results, conflicting and convergent demands exist for gathering data related to biosimilars. The motivations and data needs for these new agents are diverse, requiring adjudication of regulatory, economic, and clinical incentives beginning at program inception and

  8. Demonstration of quantum advantage in machine learning

    Science.gov (United States)

    Ristè, Diego; da Silva, Marcus P.; Ryan, Colm A.; Cross, Andrew W.; Córcoles, Antonio D.; Smolin, John A.; Gambetta, Jay M.; Chow, Jerry M.; Johnson, Blake R.

    2017-04-01

    The main promise of quantum computing is to efficiently solve certain problems that are prohibitively expensive for a classical computer. Most problems with a proven quantum advantage involve the repeated use of a black box, or oracle, whose structure encodes the solution. One measure of the algorithmic performance is the query complexity, i.e., the scaling of the number of oracle calls needed to find the solution with a given probability. Few-qubit demonstrations of quantum algorithms, such as Deutsch-Jozsa and Grover, have been implemented across diverse physical systems such as nuclear magnetic resonance, trapped ions, optical systems, and superconducting circuits. However, at the small scale, these problems can already be solved classically with a few oracle queries, limiting the obtained advantage. Here we solve an oracle-based problem, known as learning parity with noise, on a five-qubit superconducting processor. Executing classical and quantum algorithms using the same oracle, we observe a large gap in query count in favor of quantum processing. We find that this gap grows by orders of magnitude as a function of the error rates and the problem size. This result demonstrates that, while complex fault-tolerant architectures will be required for universal quantum computing, a significant quantum advantage already emerges in existing noisy systems.

  9. The Kwajalein bioremediation demonstration: Final technical report

    Energy Technology Data Exchange (ETDEWEB)

    Walker, J.R. Jr.; Walker, A.B.

    1994-12-01

    The US Army Kwajalein Atoll (USAKA) Base, located in the Republic of the Marshall Islands (RMI) in the east-central Pacific Ocean, has significant petroleum hydrocarbon contamination resulting from years of military activities. Because of its remoteness, the lack of on-site sophisticated remediation or waste disposal facilities, the amenability of petroleum hydrocarbons to biodegradation, and the year-round temperature favorable for microbial activity, USAKA requested, through the Hazardous Waste Remedial Actions Program (HAZWRAP), that a project be conducted to evaluate the feasibility of using bioremediation for environmental restoration of contaminated sites within the atoll. The project was conducted in four distinct phases: (1) initial site characterization and on-site biotreatability studies, (2) selection of the demonstration area and collection of soil columns, (3) laboratory column biotreatability studies, and (4) an on-site bioremediation demonstration. The results of phases (1) and (3) have been detailed in previous reports. This report summarizes the results of phases (1) and (3) and presents phases (2) and (4) in detail.

  10. Inhibition of morphine metabolism by ketamine.

    Science.gov (United States)

    Qi, Xiaoxin; Evans, Allan M; Wang, Jiping; Miners, John O; Upton, Richard N; Milne, Robert W

    2010-05-01

    Clinical observation of a synergistic effect of ketamine on morphine analgesia remains controversial. Although a pharmacodynamic basis for an interaction has been explored in animal and clinical studies, the possibility of a pharmacokinetic mechanism has not been investigated. Whereas both morphine and morphine-6-glucuronide are effective analgesics, morphine-3-glucuronide (M3G) lacks activity. Thus, changes in the metabolism and disposition of morphine may result in an altered response. First, we investigated the interaction between morphine and ketamine in the isolated perfused rat liver preparation. The clearance of morphine was decreased from 16.8 +/- 4.6 ml/min in the control period to 7.7 +/- 2.8 ml/min in the ketamine-treatment period, with the formation clearance of M3G decreasing from 8.0 +/- 4.1 ml/min to 2.1 +/- 1.1 ml/min. Fractional conversion of morphine to M3G was significantly decreased from 0.46 +/- 0.17 in the control period to 0.28 +/- 0.14 upon the addition of ketamine. The possible mechanism of the interaction was further investigated in vitro with rat liver microsomes as the enzyme source. The formation of M3G followed single-enzyme Michaelis-Menten kinetics, with a mean apparent K(m) of 2.18 +/- 0.45 mM and V(max) of 8.67 +/- 0.59 nmol/min/mg. Ketamine inhibited morphine 3-glucuronidation noncompetitively, with a mean K(i) value of 33.3 +/- 7.9 microM. The results demonstrate that ketamine inhibits the glucuronidation of morphine in a rat model.

  11. Enoxacin Directly Inhibits Osteoclastogenesis without Inducing Apoptosis*

    Science.gov (United States)

    Toro, Edgardo J.; Zuo, Jian; Ostrov, David A.; Catalfamo, Dana; Bradaschia-Correa, Vivian; Arana-Chavez, Victor; Caridad, Aliana R.; Neubert, John K.; Wronski, Thomas J.; Wallet, Shannon M.; Holliday, L. Shannon

    2012-01-01

    Enoxacin has been identified as a small molecule inhibitor of binding between the B2-subunit of vacuolar H+-ATPase (V-ATPase) and microfilaments. It inhibits bone resorption by calcitriol-stimulated mouse marrow cultures. We hypothesized that enoxacin acts directly and specifically on osteoclasts by disrupting the interaction between plasma membrane-directed V-ATPases, which contain the osteoclast-selective a3-subunit of V-ATPase, and microfilaments. Consistent with this hypothesis, enoxacin dose-dependently reduced the number of multinuclear cells expressing tartrate-resistant acid phosphatase (TRAP) activity produced by RANK-L-stimulated osteoclast precursors. Enoxacin (50 μm) did not induce apoptosis as measured by TUNEL and caspase-3 assays. V-ATPases containing the a3-subunit, but not the “housekeeping” a1-subunit, were isolated bound to actin. Treatment with enoxacin reduced the association of V-ATPase subunits with the detergent-insoluble cytoskeleton. Quantitative PCR revealed that enoxacin triggered significant reductions in several osteoclast-selective mRNAs, but levels of various osteoclast proteins were not reduced, as determined by quantitative immunoblots, even when their mRNA levels were reduced. Immunoblots demonstrated that proteolytic processing of TRAP5b and the cytoskeletal protein l-plastin was altered in cells treated with 50 μm enoxacin. Flow cytometry revealed that enoxacin treatment favored the expression of high levels of DC-STAMP on the surface of osteoclasts. Our data show that enoxacin directly inhibits osteoclast formation without affecting cell viability by a novel mechanism that involves changes in posttranslational processing and trafficking of several proteins with known roles in osteoclast function. We propose that these effects are downstream to blocking the binding interaction between a3-containing V-ATPases and microfilaments. PMID:22474295

  12. Enoxacin directly inhibits osteoclastogenesis without inducing apoptosis.

    Science.gov (United States)

    Toro, Edgardo J; Zuo, Jian; Ostrov, David A; Catalfamo, Dana; Bradaschia-Correa, Vivian; Arana-Chavez, Victor; Caridad, Aliana R; Neubert, John K; Wronski, Thomas J; Wallet, Shannon M; Holliday, L Shannon

    2012-05-18

    Enoxacin has been identified as a small molecule inhibitor of binding between the B2-subunit of vacuolar H+-ATPase (V-ATPase) and microfilaments. It inhibits bone resorption by calcitriol-stimulated mouse marrow cultures. We hypothesized that enoxacin acts directly and specifically on osteoclasts by disrupting the interaction between plasma membrane-directed V-ATPases, which contain the osteoclast-selective a3-subunit of V-ATPase, and microfilaments. Consistent with this hypothesis, enoxacin dose-dependently reduced the number of multinuclear cells expressing tartrate-resistant acid phosphatase (TRAP) activity produced by RANK-L-stimulated osteoclast precursors. Enoxacin (50 μM) did not induce apoptosis as measured by TUNEL and caspase-3 assays. V-ATPases containing the a3-subunit, but not the "housekeeping" a1-subunit, were isolated bound to actin. Treatment with enoxacin reduced the association of V-ATPase subunits with the detergent-insoluble cytoskeleton. Quantitative PCR revealed that enoxacin triggered significant reductions in several osteoclast-selective mRNAs, but levels of various osteoclast proteins were not reduced, as determined by quantitative immunoblots, even when their mRNA levels were reduced. Immunoblots demonstrated that proteolytic processing of TRAP5b and the cytoskeletal protein L-plastin was altered in cells treated with 50 μM enoxacin. Flow cytometry revealed that enoxacin treatment favored the expression of high levels of DC-STAMP on the surface of osteoclasts. Our data show that enoxacin directly inhibits osteoclast formation without affecting cell viability by a novel mechanism that involves changes in posttranslational processing and trafficking of several proteins with known roles in osteoclast function. We propose that these effects are downstream to blocking the binding interaction between a3-containing V-ATPases and microfilaments.

  13. Education & Collection Facility GSHP Demonstration Project

    Energy Technology Data Exchange (ETDEWEB)

    Joplin, Jeff [Denver Museum of Nature and Science, Denver, CO (United States)

    2015-03-28

    The Denver Museum of Nature & Science (DMNS) designed and implemented an innovative ground source heat pump (GSHP) system for heating and cooling its new Education and Collection Facility (ECF) building addition. The project goal was to successfully design and install an open-loop GSHP system that utilized water circulating within an underground municipal recycled (non-potable) water system as the heat sink/source as a demonstration project. The expected results were to significantly reduce traditional GSHP installation costs while increasing system efficiency, reduce building energy consumption, require significantly less area and capital to install, and be economically implemented wherever access to a recycled water system is available. The project added to the understanding of GSHP technology by implementing the first GSHP system in the United States utilizing a municipal recycled water system as a heat sink/source. The use of this fluid through a GSHP system has not been previously documented. This use application presents a new opportunity for local municipalities to develop and expand the use of underground municipal recycled (non-potable) water systems. The installation costs for this type of technology in the building structure would be a cost savings over traditional GSHP costs, provided the local municipal infrastructure was developed. Additionally, the GSHP system functions as a viable method of heat sink/source as the thermal characteristics of the fluid are generally consistent throughout the year and are efficiently exchanged through the GSHP system and its components. The use of the recycled water system reduces the area required for bore or loop fields; therefore, presenting an application for building structures that have little to no available land use or access. This GSHP application demonstrates the viability of underground municipal recycled (non-potable) water systems as technically achievable, environmentally supportive, and an efficient

  14. SIRT1 controls cell proliferation by regulating contact inhibition.

    Science.gov (United States)

    Cho, Elizabeth H; Dai, Yan

    2016-09-16

    Contact inhibition keeps cell proliferation in check and serves as a built-in protection against cancer development by arresting cell division upon cell-cell contact. Yet the complete mechanism behind this anti-cancer process remains largely unclear. Here we present SIRT1 as a novel regulator of contact inhibition. SIRT1 performs a wide variety of functions in biological processes, but its involvement in contact inhibition has not been explored to date. We used NIH3T3 cells, which are sensitive to contact inhibition, and H460 and DU145 cancer cells, which lack contact inhibition, to investigate the relationship between SIRT1 and contact inhibition. We show that SIRT1 overexpression in NIH3T3 cells overcomes contact inhibition while SIRT1 knockdown in cancer cells restores their lost contact inhibition. Moreover, we demonstrate that p27 protein expression is controlled by SIRT1 in contact inhibition. Overall, our findings underline the critical role of SIRT1 in contact inhibition and suggest SIRT1 inhibition as a potential strategy to suppress cancer cell growth by restoring contact inhibition. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. Significance of the technique of simultaneous demonstration of neurons and nerve fibres in central nervous system of rat in the research on its nature determination, semi-quantitation and localization%同时显示大鼠中枢神经系统神经元和神经纤维技术对其定性、半定量、定位研究的意义

    Institute of Scientific and Technical Information of China (English)

    李喆; 陈德英

    2004-01-01

    背景:在神经损伤与修复的研究工作中,常常会涉及损伤后以及修复过程中神经元和神经纤维的定性、定位和半定量的问题.目前神经生物学常规实验技术还很难解决这样的问题.目的:探索一种简便易行并能同时显示大鼠中枢神经系统(central nervous system,CNS)神经元和神经纤维的全程连续切片的块染方法.设计:非随机非对照的实验研究.地点和材料:第三军医大学组胚教研室(组织学常规技术实验室),实验动物中心.动物:健康成年Wistar无菌级大鼠2只(第三军医大学实验动物中心提供),体质量200~300 g,雌雄不拘.干预:取大鼠嗅脑至脊髓骶段的完整CNS组织,将CNS按顺序以冠状切面切成厚2 em的块待切,氨乙醇固定组织吸干后直接入30 g/L硝酸银水溶液,于22℃恒温箱中浸银染色1周.常规脱水、透明、石蜡包埋,全程连续切片的制作.一个大鼠的CNS全程标本可做成3套相近的连续切片.主要观察指标:神经元及突起和神经纤维的形态结构.结果:大鼠全程CNS连续切片各断面上神经元呈深棕黄色,核膜及核仁呈黑色;神经纤维呈黑色;背景淡黄色.结论:运用灌流冲洗后固定、Cajal氏镀银块染、连续石蜡切片的方法,可制作同时显示CNS神经元和神经纤维的全程连续切片.将此技术方法运用到神经损伤与修复的实验研究中,对于神经元和神经纤维的定性、半定量和定位的研究都具有较高的实用价值.%BACKGROUND: In the research of the neural injury and rehabilitation, the problems as nature determination, localization and semi-quantitation of nerve fibres and neurons after injury and during rehabilitation were often involved. However, recent routine laboratory techniques in neurobiology had difficulties in solving such problems.OBJECTIVE: To explore an easy and practical way of mass staining in,which was able to demonstrate the serial sectioning process in neurons

  16. Optogenetic and chemogenetic strategies for sustained inhibition of pain

    Science.gov (United States)

    Iyer, Shrivats M.; Vesuna, Sam; Ramakrishnan, Charu; Huynh, Karen; Young, Stephanie; Berndt, Andre; Lee, Soo Yeun; Gorini, Christopher J.; Deisseroth, Karl; Delp, Scott L.

    2016-01-01

    Spatially targeted, genetically-specific strategies for sustained inhibition of nociceptors may help transform pain science and clinical management. Previous optogenetic strategies to inhibit pain have required constant illumination, and chemogenetic approaches in the periphery have not been shown to inhibit pain. Here, we show that the step-function inhibitory channelrhodopsin, SwiChR, can be used to persistently inhibit pain for long periods of time through infrequent transdermally delivered light pulses, reducing required light exposure by >98% and resolving a long-standing limitation in optogenetic inhibition. We demonstrate that the viral expression of the hM4D receptor in small-diameter primary afferent nociceptor enables chemogenetic inhibition of mechanical and thermal nociception thresholds. Finally, we develop optoPAIN, an optogenetic platform to non-invasively assess changes in pain sensitivity, and use this technique to examine pharmacological and chemogenetic inhibition of pain. PMID:27484850

  17. Inhibition of matrix metalloproteinase-2 by PARP inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Nicolescu, Adrian C.; Holt, Andrew; Kandasamy, Arulmozhi D. [Departments of Pharmacology and Pediatrics, Cardiovascular Research Centre, University of Alberta, Edmonton, Alta., Canada T6G 2S2 (Canada); Pacher, Pal [National Institutes of Health, NIAAA, Laboratory of Physiologic Studies, Bethesda, MD (United States); Schulz, Richard, E-mail: richard.schulz@ualberta.ca [Departments of Pharmacology and Pediatrics, Cardiovascular Research Centre, University of Alberta, Edmonton, Alta., Canada T6G 2S2 (Canada)

    2009-10-02

    Matrix metalloproteinase-2 (MMP-2), a ubiquitously expressed zinc-dependent endopeptidase, and poly(ADP-ribosyl) polymerase (PARP), a nuclear enzyme regulating DNA repair, are activated by nitroxidative stress associated with various pathologies. As MMP-2 plays a detrimental role in heart injuries resulting from enhanced nitroxidative stress, where PARP and MMP inhibitors are beneficial, we hypothesized that PARP inhibitors may affect MMP-2 activity. Using substrate degradation assays to determine MMP-2 activity we found that four PARP inhibitors (3-AB, PJ-34, 5-AIQ, and EB-47) inhibited 64 kDa MMP-2 in a concentration-dependent manner. The IC{sub 50} values of PJ-34 and 5-AIQ were in the high micromolar range and comparable to those of known MMP-2 inhibitors doxycycline, minocycline or o-phenanthroline, whereas those for 3-AB and EB-47 were in the millimolar range. Co-incubation of PARP inhibitors with doxycycline showed an additive inhibition of MMP-2 that was significant for 3-AB alone. These data demonstrate that the protective effects of some PARP inhibitors may include inhibition of MMP-2 activity.

  18. Prolyl hydroxylase 3 inhibited the tumorigenecity of gastric cancer cells.

    Science.gov (United States)

    Cui, Lei; Qu, Jianguo; Dang, Shengchun; Mao, Zhengfa; Wang, Xuqing; Fan, Xin; Sun, Kang; Zhang, Jianxin

    2014-09-01

    Gastric cancer is one of the most common malignancies and the second leading cause of cancer-related death in the world, and it is very urgent to develop novel therapeutic strategies. Although HIF-1α is the most highly characterized target of prolyl hydroxylase 3 (PHD3), PHD3 has been shown to regulate several signal pathways independent of HIF-1α. Here, we found that the expression of PHD3 was decreased in the clinical gastric cancer samples and reversely correlated with tumor size and tumor stage. Over-expression of PHD3 in the gastric cancer cells significantly inhibited cell growth in vitro and in vivo, while knockdown the expression of PHD3 promoted the tumorigenecity of gastric cancer cells. Mechanistically, it showed that PHD3 downregulated the expression of beta-catenin and inhibited beta-catenin/T-cell factor (TCF) signaling. Taken together, our findings demonstrate that PHD3 inhibits gastric cancer by suppressing the beta-catenin/TCF signaling and PHD3 might be an important therapeutic target in gastric cancer.

  19. Optogenetic inhibition of neurons by internal light production

    Directory of Open Access Journals (Sweden)

    Benjamin eLand

    2014-04-01

    Full Text Available Optogenetics is an extremely powerful tool for selective neuronal activation/inhibition and dissection of neural circuits. However, a limitation of in vivo optogenetics is that an animal must be tethered to an optical fiber for delivery of light. Here, we describe a new method for in vivo, optogenetic inhibition of neural activity using an internal, animal-generated light source based on firefly luciferase. Two adeno-associated viruses encoding luciferase were tested and both produced concentration-dependent light after administration of the substrate, luciferin. Mice were co-infected with halorhodopsin- and luciferase-expressing viruses in the striatum, and luciferin administration significantly reduced Fos activity compared to control animals infected with halorhodopsin only. Recordings of neuronal activity in behaving animals confirmed that firing was greatly reduced after luciferin administration. Finally, amphetamine-induced locomotor activity was reduced in halorhodopsin/luciferase mice pre-injected with luciferin compared to controls. This demonstrates that virally encoded luciferase is able to generate sufficient light to activate halorhodopsin and suppress neural activity and change behavior. This approach could be used to generate inhibition in response to activation of specific molecular pathways.

  20. Antioxidant Activity and Acetylcholinesterase Inhibition of Grape Skin Anthocyanin (GSA

    Directory of Open Access Journals (Sweden)

    Mehnaz Pervin

    2014-07-01

    Full Text Available We aimed to investigate the antioxidant and acetylcholinesterase inhibitory activities of the anthocyanin rich extract of grape skin. Grape skin anthocyanin (GSA neutralized free radicals in different test systems, such as 2,-2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid (ABTS and 2,2-diphenyl-1-picrylhydrazyl (DPPH assays, to form complexes with Fe2+ preventing 2,2'-azobis(2-amidinopropane dihydrochloride (AAPH-induced erythrocyte hemolysis and oxidative DNA damage. Moreover, GSA decreased reactive oxygen species (ROS generation in isolated mitochondria thus inhibiting 2',-7'-dichlorofluorescin (DCFH oxidation. In an in vivo study, female BALB/c mice were administered GSA, at 12.5, 25, and 50 mg per kg per day orally for 30 consecutive days. Herein, we demonstrate that GSA administration significantly elevated the level of antioxidant enzymes in mice sera, livers, and brains. Furthermore, GSA inhibited acetylcholinesterase (AChE in the in vitro assay with an IC50 value of 363.61 µg/mL. Therefore, GSA could be an excellent source of antioxidants and its inhibition of cholinesterase is of interest with regard to neurodegenerative disorders such as Alzheimer’s disease.

  1. Mercury and zinc differentially inhibit shark and human CFTR orthologues: involvement of shark cysteine 102.

    Science.gov (United States)

    Weber, Gerhard J; Mehr, Ali Poyan; Sirota, Jeffrey C; Aller, Stephen G; Decker, Sarah E; Dawson, David C; Forrest, John N

    2006-03-01

    The apical membrane is an important site of mercury toxicity in shark rectal gland tubular cells. We compared the effects of mercury and other thiol-reacting agents on shark CFTR (sCFTR) and human CFTR (hCFTR) chloride channels using two-electrode voltage clamping of cRNA microinjected Xenopus laevis oocytes. Chloride conductance was stimulated by perfusing with 10 microM forskolin (FOR) and 1 mM IBMX, and then thio-reactive species were added. In oocytes expressing sCFTR, FOR + IBMX mean stimulated Cl(-) conductance was inhibited 69% by 1 microM mercuric chloride and 78% by 5 microM mercuric chloride (IC(50) of 0.8 microM). Despite comparable stimulation of conductance, hCFTR was insensitive to 1 microM HgCl(2) and maximum inhibition was 15% at the highest concentration used (5 microM). Subsequent exposure to glutathione (GSH) did not reverse the inhibition of sCFTR by mercury, but dithiothreitol (DTT) completely reversed this inhibition. Zinc (50-200 microM) also reversibly inhibited sCFTR (40-75%) but did not significantly inhibit hCFTR. Similar inhibition of sCFTR but not hCFTR was observed with an organic mercurial, p-chloromercuriphenylsulfonic acid (pCMBS). The first membrane spanning domain (MSD1) of sCFTR contains two unique cysteines, C102 and C303. A chimeric construct replacing MSD1 of hCFTR with the corresponding sequence of sCFTR was highly sensitive to mercury. Site-specific mutations introducing the first but not the second shark unique cysteine in hCFTR MSD1 resulted in full sensitivity to mercury. These experiments demonstrate a profound difference in the sensitivity of shark vs. human CFTR to inhibition by three thiol-reactive substances, an effect that involves C102 in the shark orthologue.

  2. Inhibition of proliferation and migration of stricture fibroblasts by epithelial cell-conditioned media

    Directory of Open Access Journals (Sweden)

    Nilima Nath

    2015-01-01

    Conclusion: These results demonstrate the ability of ECCM to inhibit the proliferation and migration of stricture fibroblasts and present it as an effective adjunct in urethroplasty, which may influence stricture wound healing and inhibit the recurrence of stricture.

  3. Copper depletion inhibits CoCl2-induced aggressive phenotype of MCF-7 cells via downregulation of HIF-1 and inhibition of Snail/Twist-mediated epithelial-mesenchymal transition.

    Science.gov (United States)

    Li, Shun; Zhang, Jing; Yang, Hong; Wu, Chunhui; Dang, Xitong; Liu, Yiyao

    2015-07-15

    Copper, a strictly regulated trace element, is essential for many physiological processes including angiogenesis. Dysregulated angiogenesis has been associated with increased copper in tumors, and thus copper chelators have been used to inhibit tumor angiogenesis. However, it remains unclear whether copper has any effect on epithelial-mesenchymal transition (EMT). Using CoCl2-induced EMT of human breast carcinoma MCF-7 cells, we found that TEPA, a copper chelator, inhibited EMT-like cell morphology and cytoskeleton arrangement triggered by CoCl2; decreased the expression of vimentin and fibronectin, markers typical of EMT; inhibited HIF-1 activation and HIF1-α accumulation in nuclear; and down-regulated the expression of hypoxia-associated transcription factors, Snail and Twist1. Moreover, knockdown copper transport protein, Ctr1, also inhibited CoCl2-induced EMT and reversed the mesenchymal phenotype. In EMT6 xenograft mouse models, TEPA administration inhibited the tumor growth and increased mice survival. Immunohistochemical analysis of the xenograft further demonstrated that TEPA administration significantly inhibited tumor angiogenesis, down-regulated hypoxia-induced transcription factors, Snail and Twist1, leading to decreased transactivation of EMT-associated marker genes, vimentin and fibronectin. These results indicate that TEPA inhibits CoCl2-induced EMT most likely via HIF1-α-Snail/Twist signaling pathway, and copper depletion may be exploited as a therapeutic for breast cancer.

  4. ATF3 represses PPARγ expression and inhibits adipocyte differentiation

    Energy Technology Data Exchange (ETDEWEB)

    Jang, Min-Kyung; Jung, Myeong Ho, E-mail: jung0603@pusan.ac.kr

    2014-11-07

    Highlights: • ATF3 decrease the expression of PPARγ and its target gene in 3T3-L1 adipocytes. • ATF3 represses the promoter activity of PPARγ2 gene. • ATF/CRE (−1537/−1530) is critical for ATF3-mediated downregulation of PPARγ. • ATF3 binds to the promoter region containing the ATF/CRE. • ER stress inhibits adipocyte differentiation through downregulation of PPARγ by ATF3. - Abstract: Activating transcription factor 3 (ATF3) is a stress-adaptive transcription factor that mediates cellular stress response signaling. We previously reported that ATF3 represses CCAAT/enhancer binding protein α (C/EBPα) expression and inhibits 3T3-L1 adipocyte differentiation. In this study, we explored potential role of ATF3 in negatively regulating peroxisome proliferator activated receptor-γ (PPARγ). ATF3 decreased the expression of PPARγ and its target gene in 3T3-L1 adipocytes. ATF3 also repressed the activity of −2.6 Kb promoter of mouse PPARγ2. Overexpression of PPARγ significantly prevented the ATF3-mediated inhibition of 3T3-L1 differentiation. Transfection studies with 5′ deleted-reporters showed that ATF3 repressed the activity of −2037 bp promoter, whereas it did not affect the activity of −1458 bp promoter, suggesting that ATF3 responsive element is located between the −2037 and −1458. An electrophoretic mobility shift assay and chromatin immunoprecipitation assay demonstrated that ATF3 binds to ATF/CRE site (5′-TGACGTTT-3′) between −1537 and −1530. Mutation of the ATF/CRE site abrogated ATF3-mediated transrepression of the PPARγ2 promoter. Treatment with thapsigargin, endoplasmic reticulum (ER) stress inducer, increased ATF3 expression, whereas it decreased PPARγ expression. ATF3 knockdown significantly blocked the thapsigargin-mediated downregulation of PPARγ expression. Furthermore, overexpression of PPARγ prevented inhibition of 3T3-L1 differentiation by thapsigargin. Collectively, these results suggest that ATF3-mediated

  5. Astronomical Significance of Ancient Monuments

    Science.gov (United States)

    Simonia, I.

    2011-06-01

    Astronomical significance of Gokhnari megalithic monument (eastern Georgia) is considered. Possible connection of Amirani ancient legend with Gokhnari monument is discussed. Concepts of starry practicality and solar stations are proposed.

  6. Historical Significant Volcanic Eruption Locations

    Data.gov (United States)

    Department of Homeland Security — A significant eruption is classified as one that meets at least one of the following criteriacaused fatalities, caused moderate damage (approximately $1 million or...

  7. Inhibition of Heme Peroxidases by Melamine

    Directory of Open Access Journals (Sweden)

    Pattaraporn Vanachayangkul

    2012-01-01

    Full Text Available In 2008 melamine-contaminated infant formula and dairy products in China led to over 50,000 hospitalizations of children due to renal injuries. In North America during 2007 and in Asia during 2004, melamine-contaminated pet food products resulted in numerous pet deaths due to renal failure. Animal studies have confirmed the potent renal toxicity of melamine combined with cyanuric acid. We showed previously that the solubility of melamine cyanurate is low at physiologic pH and ionic strength, provoking us to speculate how toxic levels of these compounds could be transported through the circulation without crystallizing until passing into the renal filtrate. We hypothesized that melamine might be sequestered by heme proteins, which could interfere with heme enzyme activity. Four heme peroxidase enzymes were selected for study: horseradish peroxidase (HRP, lactoperoxidase (LPO, and cyclooxygenase-1 and -2 (COX-1 and -2. Melamine exhibited noncompetitive inhibition of HRP (9.5±0.7mM, and LPO showed a mixed model of inhibition (14.5±4.7mM. The inhibition of HRP and LPO was confirmed using a chemiluminescent peroxidase assay. Melamine also exhibited COX-1 inhibition, but inhibition of COX-2 was not detected. Thus, our results demonstrate that melamine inhibits the activity of three heme peroxidases.

  8. UCP2 inhibition triggers ROS-dependent nuclear translocation of GAPDH and autophagic cell death in pancreatic adenocarcinoma cells.

    Science.gov (United States)

    Dando, Ilaria; Fiorini, Claudia; Pozza, Elisa Dalla; Padroni, Chiara; Costanzo, Chiara; Palmieri, Marta; Donadelli, Massimo

    2013-03-01

    Mitochondrial uncoupling protein 2 (UCP2) can moderate oxidative stress by favoring the influx of protons into the mitochondrial matrix, thus reducing electron leakage from respiratory chain and mitochondrial superoxide production. Here, we demonstrate that UCP2 inhibition by genipin or UCP2 siRNA strongly increases reactive oxygen species (ROS) production inhibiting pancreatic adenocarcinoma cell growth. We also show that UCP2 inhibition triggers ROS-dependent nuclear translocation of the glycolytic enzyme glyceraldehyde 3-phosphate dehydrogenase (GAPDH), formation of autophagosomes, and the expression of the autophagy marker LC3-II. Consistently, UCP2 over-expression significantly reduces basal autophagy confirming the anti-autophagic role of UCP2. Furthermore, we demonstrate that autophagy induced by UCP2 inhibition determines a ROS-dependent cell death, as indicated by the apoptosis decrease in the presence of the autophagy inhibitors chloroquine (CQ) or 3-methyladenine (3-MA), or the radical scavenger NAC. Intriguingly, the autophagy induced by genipin is able to potentiate the autophagic cell death triggered by gemcitabine, the standard chemotherapeutic drug for pancreatic adenocarcinoma, supporting the development of an anti-cancer therapy based on UCP2 inhibition associated to standard chemotherapy. Our results demonstrate for the first time that UCP2 plays a role in autophagy regulation bringing new insights into mitochondrial uncoupling protein field.

  9. 1-o-acetylbritannilactone (ABL) inhibits angiogenesis and lung cancer cell growth through regulating VEGF-Src-FAK signaling

    Energy Technology Data Exchange (ETDEWEB)

    Zhengfu, He; Hu, Zhang; Huiwen, Miao; Zhijun, Li [Department of Thoracic Surgery, Sir Run Run Shaw Hospital of Zhejiang University School of Medicine, Hangzhou (China); Jiaojie, Zhou [Zhejiang University School of Medicine, Hangzhou (China); Xiaoyi, Yan, E-mail: xiaoyiyan163@163.com [Zhejiang University School of Medicine, Hangzhou (China); Xiujun, Cai, E-mail: xiujuncaomaj@163.com [Sir Run Run Shaw Hospital of Zhejiang University School of Medicine, Hangzhou (China)

    2015-08-21

    The search for safe, effective and affordable therapeutics against non-small cell lung cancer (NSCLC) and other lung cancers is important. Here we explored the potential effect of 1-o-acetylbritannilactone (ABL), a novel extract from Inula britannica-F, on angiogenesis and lung cancer cell growth. We demonstrated that ABL dose-dependently inhibited vascular endothelial growth factor (VEGF)-induced proliferation, migration, and capillary structure formation of cultured human umbilical vascular endothelial cells (HUVECs). In vivo, ABL administration suppressed VEGF-induced new vasculature formation in Matrigel plugs. For the mechanism investigations, we found that ABL largely inhibited VEGF-mediated activation of Src kinase and focal adhesion kinase (FAK) in HUVECs. Furthermore, treatment of A549 NSCLC cells with ABL resulted in cell growth inhibition and Src-FAK in-activation. Significantly, administration of a single dose of ABL (12 mg/kg/day) remarkably suppressed growth of A549 xenografts in nude mice. In vivo microvessels formation and Src activation were also significantly inhibited in ABL-treated xenograft tumors. Taken together, our findings suggest that ABL suppresses angiogenesis and lung cancer cell growth possibly via regulating the VEGFR-Src-FAK signaling. - Highlights: • 1-o-acetylbritannilactone (ABL) inhibits VEGF-induced angiogenesis in vivo. • ABL inhibits VEGF-induced HUVEC migration, proliferation, capillary tube formation. • ABL inhibits VEGF-mediated activation of Src and FAK in HUVECs. • ABL inhibits growth and Src-FAK activation in A549 cells. • ABL administration inhibits A549 tumor angiogenesis and growth in nude mice.

  10. Effective inhibition of viral reproduction by hydrophobised antiviral antibodies.

    Science.gov (United States)

    Kabanov, A V; Ovcharenko, A V; Melik-Nubarov, N S; Bannikov, A I; Lisok, T P; Klyushnenkova, E V; Cherchenko, N G; Alakhov VYu; Levashov, A V; Kiselev, V I

    1990-01-01

    A method is proposed for the inhibition of viral reproduction in cells by means of fatty-acylated antiviral antibodies which, in contrast to the unmodified antibodies, have the ability to enter the cells. The potential of this technique is demonstrated in experiments involving inhibition of the reproduction of various strains of influenza virus and respiratory syncytial virus.

  11. Corrosion Inhibition of High Speed Steel by Biopolymer HPMC Derivatives

    OpenAIRE

    Shih-Chen Shi; Chieh-Chang Su

    2016-01-01

    The corrosion inhibition characteristics of the derivatives of biopolymer hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose phthalate (HPMCP), and hydroxypropyl methylcellulose acetate succinate (HPMCAS) film are investigated. Based on electrochemical impedance spectroscopic measurements and potentiodynamic polarization, the corrosion inhibition performance of high speed steel coated with HPMC derivatives is evaluated. The Nyquist plot and Tafel polarization demonstrate prom...

  12. The Root-inhibiting Substance of Allium Cepa

    NARCIS (Netherlands)

    Stolk, Anth.

    1953-01-01

    Whereas scientific research on inhibiting substances has mainly occupied itself with the effect of these substances on the germination process, I was able to demonstrate the presence of a root-inhibiting agent during my studies on root formation in Fuchsia hybrida and Pelargonium zonale (Stolk, 1952

  13. Thrombosis is reduced by inhibition of COX-1, but unaffected by inhibition of COX-2, in an acute model of platelet activation in the mouse.

    Directory of Open Access Journals (Sweden)

    Paul C Armstrong

    Full Text Available BACKGROUND: Clinical use of selective inhibitors of cyclooxygenase (COX-2 appears associated with increased risk of thrombotic events. This is often hypothesised to reflect reduction in anti-thrombotic prostanoids, notably PGI(2, formed by COX-2 present within endothelial cells. However, whether COX-2 is actually expressed to any significant extent within endothelial cells is controversial. Here we have tested the effects of acute inhibition of COX on platelet reactivity using a functional in vivo approach in mice. METHODOLOGY/PRINCIPAL FINDINGS: A non-lethal model of platelet-driven thromboembolism in the mouse was used to assess the effects of aspirin (7 days orally as control diclofenac (1 mg.kg(-1, i.v. and parecoxib (0.5 mg.kg(-1, i.v. on thrombus formation induced by collagen or the thromboxane (TX A(2-mimetic, U46619. The COX inhibitory profiles of the drugs were confirmed in mouse tissues ex vivo. Collagen and U46619 caused in vivo thrombus formation with the former, but not latter, sensitive to oral dosing with aspirin. Diclofenac inhibited COX-1 and COX-2 ex vivo and reduced thrombus formation in response to collagen, but not U46619. Parecoxib inhibited only COX-2 and had no effect upon thrombus formation caused by either agonist. CONCLUSIONS/SIGNIFICANCE: Inhibition of COX-1 by diclofenac or aspirin reduced thrombus formation induced by collagen, which is partly dependent upon platelet-derived TXA(2, but not that induced by U46619, which is independent of platelet TXA(2. These results are consistent with the model demonstrating the effects of COX-1 inhibition in platelets, but provide no support for the hypothesis that acute inhibition of COX-2 in the circulation increases thrombosis.

  14. Significance analysis of prognostic signatures.

    Directory of Open Access Journals (Sweden)

    Andrew H Beck

    Full Text Available A major goal in translational cancer research is to identify biological signatures driving cancer progression and metastasis. A common technique applied in genomics research is to cluster patients using gene expression data from a candidate prognostic gene set, and if the resulting clusters show statistically significant outcome stratification, to associate the gene set with prognosis, suggesting its biological and clinical importance. Recent work has questioned the validity of this approach by showing in several breast cancer data sets that "random" gene sets tend to cluster patients into prognostically variable subgroups. This work suggests that new rigorous statistical methods are needed to identify biologically informative prognostic gene sets. To address this problem, we developed Significance Analysis of Prognostic Signatures (SAPS which integrates standard prognostic tests with a new prognostic significance test based on stratifying patients into prognostic subtypes with random gene sets. SAPS ensures that a significant gene set is not only able to stratify patients into prognostically variable groups, but is also enriched for genes showing strong univariate associations with patient prognosis, and performs significantly better than random gene sets. We use SAPS to perform a large meta-analysis (the largest completed to date of prognostic pathways in breast and ovarian cancer and their molecular subtypes. Our analyses show that only a small subset of the gene sets found statistically significant using standard measures achieve significance by SAPS. We identify new prognostic signatures in breast and ovarian cancer and their corresponding molecular subtypes, and we show that prognostic signatures in ER negative breast cancer are more similar to prognostic signatures in ovarian cancer than to prognostic signatures in ER positive breast cancer. SAPS is a powerful new method for deriving robust prognostic biological signatures from clinically

  15. Infrared neural stimulation (INS) inhibits electrically evoked neural responses in the deaf white cat

    Science.gov (United States)

    Richter, Claus-Peter; Rajguru, Suhrud M.; Robinson, Alan; Young, Hunter K.

    2014-03-01

    Infrared neural stimulation (INS) has been used in the past to evoke neural activity from hearing and partially deaf animals. All the responses were excitatory. In Aplysia californica, Duke and coworkers demonstrated that INS also inhibits neural responses [1], which similar observations were made in the vestibular system [2, 3]. In deaf white cats that have cochleae with largely reduced spiral ganglion neuron counts and a significant degeneration of the organ of Corti, no cochlear compound action potentials could be observed during INS alone. However, the combined electrical and optical stimulation demonstrated inhibitory responses during irradiation with infrared light.

  16. Potentiation of latent inhibition.

    Science.gov (United States)

    Rodriguez, Gabriel; Hall, Geoffrey

    2008-07-01

    Rats were given exposure either to an odor (almond) or a compound of odor plus taste (almond plus saline), prior to training in which the odor served as the conditioned stimulus. It was found, for both appetitive and aversive procedures, that conditioning was retarded by preexposure (a latent inhibition effect), and the extent of the retardation was greater in rats preexposed to the compound (i.e., latent inhibition to the odor was potentiated by the presence of the taste). In contrast, the presence of the taste during conditioning itself overshadowed learning about the odor. We argue that the presence of the salient taste in compound with the odor enhances the rate of associative learning, producing a rapid loss in the associability of the odor. This loss of associability will generate both overshadowing and the potentiation of latent inhibition that is observed after preexposure to the compound.

  17. Inhibition of oxidative stress-elicited AKT activation facilitates PPARγ agonist-mediated inhibition of stem cell character and tumor growth of liver cancer cells.

    Directory of Open Access Journals (Sweden)

    Lanlan Liu

    Full Text Available Emerging evidence suggests that tumor-initiating cells (TICs are the most malignant cell subpopulation in tumors because of their resistance to chemotherapy or radiation treatment. Targeting TICs may be a key innovation for cancer treatment. In this study, we found that PPARγ agonists inhibited the cancer stem cell-like phenotype and attenuated tumor growth of human hepatocellular carcinoma (HCC cells. Reactive oxygen species (ROS initiated by NOX2 upregulation were partially responsible for the inhibitory effects mediated by PPARγ agonists. However, PPARγ agonist-mediated ROS production significantly activated AKT, which in turn promoted TIC survival by limiting ROS generation. Inhibition of AKT, by either pharmacological inhibitors or AKT siRNA, significantly enhanced PPARγ agonist-mediated inhibition of cell proliferation and stem cell-like properties in HCC cells. Importantly, in nude mice inoculated with HCC Huh7 cells, we demonstrated a synergistic inhibitory effect of the PPARγ agonist rosiglitazone and the AKT inhibitor triciribine on tumor growth. In conclusion, we observed a negative feedback loop between oxidative stress and AKT hyperactivation in PPARγ agonist-mediated suppressive effects on HCCs. Combinatory application of an AKT inhibitor and a PPARγ agonist may provide a new strategy for inhibition of stem cell-like properties in HCCs and treatment of liver cancer.

  18. Knockdown of Collagen Triple Helix Repeat Containing-1 Inhibits the Proliferation and Epithelial-to-Mesenchymal Transition in Renal Cell Carcinoma Cells.

    Science.gov (United States)

    Jin, Xue-Fei; Li, Hai; Zong, Shi; Li, Hong-Yan

    2016-10-27

    Collagen triple helix repeat containing-1 (CTHRC1), a secreted glycoprotein, is frequently upregulated in human cancers. However, the functional role of CTHRC1 in renal cell carcinoma (RCC) remains unclear. Thus, the aim of this study was to explore the role of CTHRC1 in RCC. Our results demonstrated that CTHRC1 was upregulated in RCC tissues and cell lines. Knockdown of CTHRC1 significantly inhibits the proliferation in RCCs. Furthermore, knockdown of CTHRC1 significantly inhibited the epithelial-to-mesenchymal transition (EMT) process in RCCs, as well as suppressed RCC cell migration and invasion. Mechanistically, knockdown of CTHRC1 inhibited the expression of β-catenin, c-Myc, and cyclin D1 in RCC cells. In conclusion, the results of the present study indicated that CTHRC1 downregulation inhibited proliferation, migration, EMT, and β-catenin expression in RCC cells. Therefore, CTHRC1 may be a potential therapeutic target for the treatment of RCC.

  19. Leptin reverses corticosterone-induced inhibition of neural stem cell proliferation through activating the NR2B subunits of NMDA receptors

    Energy Technology Data Exchange (ETDEWEB)

    Shi, Wen-Zhu [Anesthesia and Operation Center, Hainan Branch of Chinese PLA General Hospital, Hainan 572013 (China); Anesthesia and Operation Center, Chinese PLA General Hospital, Beijing 100853 (China); Miao, Yu-Liang [Department of Anesthesiology, PLA No. 306 Hospital, Beijing 100101 (China); Guo, Wen-Zhi [Department of Anesthesiology, Beijing Military General Hospital of Chinese People’s Liberation Army, Beijing 100700 (China); Wu, Wei, E-mail: wwzwgk@163.com [Department of Head and Neck Surgery of Otolaryngology, PLA No. 306 Hospital, Beijing 100101 (China); Li, Bao-Wei [Department of Head and Neck Surgery of Otolaryngology, PLA No. 306 Hospital, Beijing 100101 (China); An, Li-Na [Department of Anesthesiology, Armed Police General Hospital, Beijing 100039 (China); Fang, Wei-Wu [Department of Anesthesiology, PLA No. 306 Hospital, Beijing 100101 (China); Mi, Wei-Dong, E-mail: elite2005gg@163.com [Anesthesia and Operation Center, Chinese PLA General Hospital, Beijing 100853 (China)

    2014-04-25

    Highlights: • Leptin promotes the proliferation of neural stem cells isolated from embryonic mouse hippocampus. • Leptin reverses corticosterone-induced inhibition of neural stem cell proliferation. • The effects of leptin are partially mediated by upregulating NR2B subunits. - Abstract: Corticosterone inhibits the proliferation of hippocampal neural stem cells (NSCs). The removal of corticosterone-induced inhibition of NSCs proliferation has been reported to contribute to neural regeneration. Leptin has been shown to regulate brain development, improve angiogenesis, and promote neural regeneration; however, its effects on corticosterone-induced inhibition of NSCs proliferation remain unclear. Here we reported that leptin significantly promoted the proliferation of hippocampal NSCs in a concentration-dependent pattern. Also, leptin efficiently reversed the inhibition of NSCs proliferation induced by corticosterone. Interestingly, pre-treatment with non-specific NMDA antagonist MK-801, specific NR2B antagonist Ro 25-6981, or small interfering RNA (siRNA) targeting NR2B, significantly blocked the effect of leptin on corticosterone-induced inhibition of NSCs proliferation. Furthermore, corticosterone significantly reduced the protein expression of NR2B, whereas pre-treatment with leptin greatly reversed the attenuation of NR2B expression caused by corticosterone in cultured hippocampal NSCs. Our findings demonstrate that leptin reverses the corticosterone-induced inhibition of NSCs proliferation. This process is, at least partially mediated by increased expression of NR2B subunits of NMDA receptors.

  20. Demonstration of Uncued Optical Surveillance of LEO

    Science.gov (United States)

    Zimmer, P.; Ackermann, M.; McGraw, J.

    2014-09-01

    J.T. McGraw and Associates, LLC, in collaboration with the University of New Mexico (UNM), has built and is operating two proof-of-concept wide-field imaging systems to test novel techniques for uncued surveillance of LEO. The imaging systems are built from off-the-shelf optics and detectors resulting in a 350mm aperture and a 6 square degree field of view. For streak detection, field of view is of critical importance because the maximum exposure time on the object is limited by its crossing time and measurements of apparent angular motion are better constrained with longer streaks. The current match of the detector to the optical system is optimized for detection of objects at altitudes above 450km, which for a circular orbit, corresponds to apparent motions of approximately 1 deg./sec. Using our GPU-accelerated detection scheme, the proof-of-concept systems have detected objects fainter than V=12.3, which approximately corresponds to a 24 cm object at 1000 km altitude at better than 6 sigma significance, from sites near and within Albuquerque, NM. This work demonstrates scalable optical systems designed for near real time detection of fast moving objects, which can be then handed off to other instruments capable of tracking and characterizing them. The two proof-of-concept systems, separated by ~30km, work together by taking simultaneous images of the same orbital volume to constrain the orbits of detected objects using parallax measurements. These detections are followed-up by photometric observations taken at UNM to independently assess the objects and the quality of the derived orbits. We believe this demonstrates the potential of small telescope arrays for detecting and cataloguing heretofore unknown LEO objects.

  1. In-Space Recycler Technology Demonstration

    Science.gov (United States)

    Hoyt, Rob; Werkheiser, NIKI; Kim, Tony

    2016-01-01

    In 2014, a 3D printer was installed and used successfully on the International Space Station (ISS), creating the first additively manufactured part in space. While additive manufacturing is a game changing technology for exploration missions, the process still requires raw feedstock material to fabricate parts. Without a recycling capability, a large supply of feedstock would need to be stored onboard, which negates the logistical benefits of these capabilities. Tethers Unlimited, Inc. (TUI), received a Small Business Innovation Research (SBIR) award to design and build the first In-space Recycler for demonstration aboard the ISS in 2017. To fully test this technology in microgravity, parts will be 3D printed, recycled into reusable filament, and then reprinted into new parts. Recycling scrap into printer filament is quite challenging in that a recycler must be able to handle a large variety of possible scrap configurations and densities. New challenges include: dealing with inevitable contamination of the scrap material, minimizing damage to the molecular structure of the plastic during reprocessing, managing a larger volume of hot liquid plastic, and exercising greater control over the cooling/resolidification of the material. TUI has developed an architecture that addresses these challenges by combining standard, proven technologies with novel, patented processes developed through this effort. Results show that the filament diameter achieved is more consistent than commercial filament, with only minimal degradation of material properties over recycling steps. In May 2016, TUI completed fabrication of a flight prototype, which will ultimately progress to the demonstration unit for the ISS as a testbed for future exploration missions. This capability will provide significant cost savings by reducing the launch mass and volume required for printer feedstock as well as reduce waste that must be stored or disposed.

  2. Secure Interoperable Open Smart Grid Demonstration Project

    Energy Technology Data Exchange (ETDEWEB)

    Magee, Thoman

    2014-12-31

    The Consolidated Edison, Inc., of New York (Con Edison) Secure Interoperable Open Smart Grid Demonstration Project (SGDP), sponsored by the United States (US) Department of Energy (DOE), demonstrated that the reliability, efficiency, and flexibility of the grid can be improved through a combination of enhanced monitoring and control capabilities using systems and resources that interoperate within a secure services framework. The project demonstrated the capability to shift, balance, and reduce load where and when needed in response to system contingencies or emergencies by leveraging controllable field assets. The range of field assets includes curtailable customer loads, distributed generation (DG), battery storage, electric vehicle (EV) charging stations, building management systems (BMS), home area networks (HANs), high-voltage monitoring, and advanced metering infrastructure (AMI). The SGDP enables the seamless integration and control of these field assets through a common, cyber-secure, interoperable control platform, which integrates a number of existing legacy control and data systems, as well as new smart grid (SG) systems and applications. By integrating advanced technologies for monitoring and control, the SGDP helps target and reduce peak load growth, improves the reliability and efficiency of Con Edison’s grid, and increases the ability to accommodate the growing use of distributed resources. Con Edison is dedicated to lowering costs, improving reliability and customer service, and reducing its impact on the environment for its customers. These objectives also align with the policy objectives of New York State as a whole. To help meet these objectives, Con Edison’s long-term vision for the distribution grid relies on the successful integration and control of a growing penetration of distributed resources, including demand response (DR) resources, battery storage units, and DG. For example, Con Edison is expecting significant long-term growth of DG

  3. Secure Interoperable Open Smart Grid Demonstration Project

    Energy Technology Data Exchange (ETDEWEB)

    Magee, Thoman [Consolidated Edison Company Of New York, Inc., NY (United States)

    2014-12-28

    The Consolidated Edison, Inc., of New York (Con Edison) Secure Interoperable Open Smart Grid Demonstration Project (SGDP), sponsored by the United States (US) Department of Energy (DOE), demonstrated that the reliability, efficiency, and flexibility of the grid can be improved through a combination of enhanced monitoring and control capabilities using systems and resources that interoperate within a secure services framework. The project demonstrated the capability to shift, balance, and reduce load where and when needed in response to system contingencies or emergencies by leveraging controllable field assets. The range of field assets includes curtailable customer loads, distributed generation (DG), battery storage, electric vehicle (EV) charging stations, building management systems (BMS), home area networks (HANs), high-voltage monitoring, and advanced metering infrastructure (AMI). The SGDP enables the seamless integration and control of these field assets through a common, cyber-secure, interoperable control platform, which integrates a number of existing legacy control and data systems, as well as new smart grid (SG) systems and applications. By integrating advanced technologies for monitoring and control, the SGDP helps target and reduce peak load growth, improves the reliability and efficiency of Con Edison’s grid, and increases the ability to accommodate the growing use of distributed resources. Con Edison is dedicated to lowering costs, improving reliability and customer service, and reducing its impact on the environment for its customers. These objectives also align with the policy objectives of New York State as a whole. To help meet these objectives, Con Edison’s long-term vision for the distribution grid relies on the successful integration and control of a growing penetration of distributed resources, including demand response (DR) resources, battery storage units, and DG. For example, Con Edison is expecting significant long-term growth of DG

  4. Synthetic resveratrol aliphatic acid inhibits TLR2-mediated apoptosis and an involvement of Akt/GSK3beta pathway.

    Science.gov (United States)

    Chen, Lin; Zhang, Yi; Sun, Xiuli; Li, Hui; LeSage, Gene; Javer, Avani; Zhang, Xiumei; Wei, Xinbing; Jiang, Yulin; Yin, Deling

    2009-07-01

    As resveratrol derivatives, resveratrol aliphatic acids were synthesized in our laboratory. Previously, we reported the improved pharmaceutical properties of the compounds compared to resveratrol, including better solubility in water and much tighter binding with human serum albumin. Here, we investigate the role of resveratrol aliphatic acids in Toll-like receptor 2 (TLR2)-mediated apoptosis. We showed that resveratrol aliphatic acid (R6A) significantly inhibits the expression of TLR2. In addition, overexpression of TLR2 in HEK293 cells caused a significant decrease in apoptosis after R6A treatment. Moreover, inhibition of TLR2 by R6A decreases serum deprivation-reduced the levels of phosphorylated Akt and phosphorylated glycogen synthase kinase 3beta (GSK3beta). Our study thus demonstrates that the resveratrol aliphatic acid inhibits cell apoptosis through TLR2 by the involvement of Akt/GSK3beta pathway.

  5. Significant advancement in algebraic geometry

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    @@ Supported by a grant for Distinguished Young Scholars of the National Natural Science Foundation of China,Prof.SUN Xiaotao with the CAS Academy of Mathematics and Systems Science has recently achieved a research breakthrough in revealing the deep relationship between stability of vector bundles and Frobenius morphism.It is considered as significant work with important theoretical value.

  6. Useful Demonstrations for a Medial Biochemistry Course.

    Science.gov (United States)

    Ragatz, Barth H.; Modrak, Gina

    1986-01-01

    Describes six demonstrations used in a medical biochemistry course. These demonstrations focus on: (1) platelet aggregometry; (2) ion-transporting antibiotics; (3) glycosylated hemoglobin; (4) molecular models; (5) serum preparation; and (6) bioluminescence. (JN)

  7. Introduction to Atomic Structure: Demonstrations and Labs.

    Science.gov (United States)

    Ciparick, Joseph D.

    1988-01-01

    Demonstrates a variety of electrical phenomena to help explain atomic structure. Topics include: establishing electrical properties, electrochemistry, and electrostatic charges. Recommends demonstration equipment needed and an explanation of each. (MVL)

  8. Inhibition of FGFR signaling by PD173074 improves antitumor immunity and impairs breast cancer metastasis.

    Science.gov (United States)

    Ye, Tinghong; Wei, Xiawei; Yin, Tao; Xia, Yong; Li, Deliang; Shao, Bin; Song, Xuejiao; He, Sisi; Luo, Min; Gao, Xiang; He, Zhiyao; Luo, Can; Xiong, Ying; Wang, Ningyu; Zeng, Jun; Zhao, Lifeng; Shen, Guobo; Xie, Yongmei; Yu, Luoting; Wei, Yuquan

    2014-02-01

    Aberrant fibroblast growth factor (FGF) and FGF receptor (FGFR) system have been associated with breast cancer. The objectives of our study were to investigate the effects and mechanisms of FGFR inhibition on tumor growth and metastasis on breast cancer. Our studies showed that the FGFR inhibitor PD173074 decreased the viability of several human breast cancer cells, as well as 4T1 murine mammary tumor cells. Therefore, we chose 4T1 cells to study PD173074's antitumor mechanism. Flow cytometry showed that PD173074 induced 4T1 cell apoptosis in a concentration-dependent manner. Western blot demonstrated that PD173074-induced apoptosis was correlated with the inhibition of Mcl-1 and survivin. Moreover, PD173074 also significantly increased the ratio of Bax/Bcl-2. PD173074 could also block 4T1 cell migration and invasion in vitro. In 4T1 tumor-bearing mice, PD173074 significantly inhibited tumor growth without obvious side effects. Meanwhile, PD173074 functionally reduced microvessel density and proliferation index and induced tumor apoptosis. Importantly, we found that FGFR inhibition by PD173074 reduced myeloid-derived suppressor cells (MDSCs) in the blood, spleens and tumors, accompanied by the increased infiltration of CD4(+) and CD8(+) T cells in the spleens and tumors. Furthermore, PD173074 significantly inhibited breast tumor metastasis to the lung of inoculated 4T1 breast cancer cells, which was accompanied by a reduction in MDSCs. Our findings suggested that FGFR inhibition could delay breast tumor progression, impair lung metastasis and break immunosuppression by effecting on tumor microenvironment, which may provide a promising therapeutic approach for breast cancer patient.

  9. Inhibition of HIV-1 replication in human monocyte-derived macrophages by parasite Trypanosoma cruzi.

    Directory of Open Access Journals (Sweden)

    Guadalupe Andreani

    Full Text Available BACKGROUND: Cells of monocyte/macrophage lineage are one of the major targets of HIV-1 infection and serve as reservoirs for viral persistence in vivo. These cells are also the target of the protozoa Trypanosoma cruzi, the causative agent of Chagas disease, being one of the most important endemic protozoonoses in Latin America. It has been demonstrated in vitro that co-infection with other pathogens can modulate HIV replication. However, no studies at cellular level have suggested an interaction between T. cruzi and HIV-1 to date. METHODOLOGY/PRINCIPAL FINDINGS: By using a fully replicative wild-type virus, our study showed that T. cruzi inhibits HIV-1 antigen production by nearly 100% (p99% being stronger than HIV-T. cruzi (approximately 90% for BaL and approximately 85% for VSV-G infection. In MDM with established HIV-1 infection, T. cruzi significantly inhibited luciferate activity (p<0.01. By quantifying R-U5 and U5-gag transcripts by real time PCR, our study showed the expression of both transcripts significantly diminished in the presence of trypomastigotes (p<0.05. Thus, T. cruzi inhibits viral post-integration steps, early post-entry steps and entry into MDM. Trypomastigotes also caused a approximately 60-70% decrease of surface CCR5 expression on MDM. Multiplication of T. cruzi inside the MDM does not seem to be required for inhibiting HIV-1 replication since soluble factors secreted by trypomastigotes have shown similar effects. Moreover, the major parasite antigen cruzipain, which is secreted by the trypomastigote form, was able to inhibit viral production in MDM over 90% (p<0.01. CONCLUSIONS/SIGNIFICANCE: Our study showed that T. cruzi inhibits HIV-1 replication at several replication stages in macrophages, a major cell target for both pathogens.

  10. The Hippo pathway mediates inhibition of vascular smooth muscle cell proliferation by cAMP.

    Science.gov (United States)

    Kimura, Tomomi E; Duggirala, Aparna; Smith, Madeleine C; White, Stephen; Sala-Newby, Graciela B; Newby, Andrew C; Bond, Mark

    2016-01-01

    Inhibition of vascular smooth muscle cell (VSMC) proliferation by intracellular cAMP prevents excessive neointima formation and hence angioplasty restenosis and vein-graft failure. These protective effects are mediated via actin-cytoskeleton remodelling and subsequent regulation of gene expression by mechanisms that are incompletely understood. Here we investigated the role of components of the growth-regulatory Hippo pathway, specifically the transcription factor TEAD and its co-factors YAP and TAZ in VSMC. Elevation of cAMP using forskolin, dibutyryl-cAMP or the physiological agonists, Cicaprost or adenosine, significantly increased phosphorylation and nuclear export YAP and TAZ and inhibited TEAD-luciferase report gene activity. Similar effects were obtained by inhibiting RhoA activity with C3-transferase, its downstream kinase, ROCK, with Y27632, or actin-polymerisation with Latrunculin-B. Conversely, expression of constitutively-active RhoA reversed the inhibitory effects of forskolin on TEAD-luciferase. Forskolin significantly inhibited the mRNA expression of the pro-mitogenic genes, CCN1, CTGF, c-MYC and TGFB2 and this was reversed by expression of constitutively-active YAP or TAZ phospho-mutants. Inhibition of YAP and TAZ function with RNAi or Verteporfin significantly reduced VSMC proliferation. Furthermore, the anti-mitogenic effects of forskolin were reversed by overexpression of constitutively-active YAP or TAZ. Taken together, these data demonstrate that cAMP-induced actin-cytoskeleton remodelling inhibits YAP/TAZ-TEAD dependent expression of pro-mitogenic genes in VSMC. This mechanism contributes novel insight into the anti-mitogenic effects of cAMP in VSMC and suggests a new target for intervention. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  11. Inhibition of Complement Retards Ankylosing Spondylitis Progression

    Science.gov (United States)

    Yang, Chaoqun; Ding, Peipei; Wang, Qingkai; Zhang, Long; Zhang, Xin; Zhao, Jianquan; Xu, Enjie; Wang, Na; Chen, Jianfeng; Yang, Guang; Hu, Weiguo; Zhou, Xuhui

    2016-01-01

    Ankylosing spondylitis (AS) is a chronic axial spondyloarthritis (SpA) resulting in back pain and progressive spinal ankyloses. Currently, there are no effective therapeutics targeting AS largely due to elusive pathogenesis mechanisms, even as potential candidates such as HLA-B27 autoantigen have been identified. Herein, we employed a proteoglycan (PG)-induced AS mouse model together with clinical specimens, and found that the complement system was substantially activated in the spinal bone marrow, accompanied by a remarkable proportion alteration of neutrophils and macrophage in bone marrow and spleen, and by the significant increase of TGF-β1 in serum. The combined treatment with a bacteria-derived complement inhibitor Efb-C (C-terminal of extracellular fibrinogen-binding protein of Staphylococcus aureus) remarkably retarded the progression of mouse AS by reducing osteoblast differentiation. Furthermore, we demonstrated that two important modulators involved in AS disease, TGF-β1 and RANKL, were elevated upon in vitro complement attack in osteoblast and/or osteoclast cells. These findings further unravel that complement activation is closely related with the pathogenesis of AS, and suggest that complement inhibition may hold great potential for AS therapy. PMID:27698377

  12. Quorum sensing inhibition

    DEFF Research Database (Denmark)

    Persson, T.; Givskov, Michael Christian; Nielsen, J.

    2005-01-01

    /receptor transcriptional regulator in some clinically relevant Gram-negative bacteria. The present review contains all reported compound types that are currently known to inhibit the QS transcriptional regulator in Gram-negative bacteria. These compounds are sub-divided into two main groups, one comprising structural...

  13. Enzyme inhibition by iminosugars

    DEFF Research Database (Denmark)

    López, Óscar; Qing, Feng-Ling; Pedersen, Christian Marcus

    2013-01-01

    Imino- and azasugar glycosidase inhibitors display pH dependant inhibition reflecting that both the inhibitor and the enzyme active site have groups that change protonation state with pH. With the enzyme having two acidic groups and the inhibitor one basic group, enzyme-inhibitor complexes...

  14. Inhibition of ethylene production by putrescine alleviates aluminium-induced root inhibition in wheat plants.

    Science.gov (United States)

    Yu, Yan; Jin, Chongwei; Sun, Chengliang; Wang, Jinghong; Ye, Yiquan; Zhou, Weiwei; Lu, Lingli; Lin, Xianyong

    2016-01-08

    Inhibition of root elongation is one of the most distinct symptoms of aluminium (Al) toxicity. Although putrescine (Put) has been identified as an important signaling molecule involved in Al tolerance, it is yet unknown how Put mitigates Al-induced root inhibition. Here, the possible mechanism was investigated by using two wheat genotypes differing in Al resistance: Al-tolerant Xi Aimai-1 and Al-sensitive Yangmai-5. Aluminium caused more root inhibition in Yangmai-5 and increased ethylene production at the root apices compared to Xi Aimai-1, whereas the effects were significantly reversed by ethylene biosynthesis inhibitors. The simultaneous exposure of wheat seedlings to Al and ethylene donor, ethephon, or ethylene biosynthesis precursor, 1-aminocyclopropane-1-carboxylic acid (ACC), increased ethylene production and aggravated root inhibition, which was more pronounced in Xi Aimai-1. In contrast, Put treatment decreased ethylene production and alleviated Al-induced root inhibition in both genotypes, and the effects were more conspicuous in Yangmai-5. Furthermore, our results indicated that Al-induced ethylene production was mediated by ACC synthase (ACS) and ACC oxidase, and that Put decreased ethylene production by inhibiting ACS. Altogether, these findings indicate that ethylene is involved in Al-induced root inhibition and this process could be alleviated by Put through inhibiting ACS activity.

  15. Significance and Progress of Bionics

    Institute of Scientific and Technical Information of China (English)

    Yongxiang Lu

    2004-01-01

    The four topics are described including the driving force and source of the scientific and technological creation, the definition and history of the bionics, the important significance of bionics in the development of the human beings, and the leading edge and progress of bionics. The appetency of human for the creation is the essential motivity of the innovation in science and technology. Nature and society are the objects for us to cognize and serve, meanwhile, the best teachers for us to learn from them. It is only 5 million years for human's development, but evolution of life has over 3.5 billion years history. Although, copying the creation from the human being is important, however, it has much more potential and opportunity in imitating the nature, and more possibility to promote the ability of original innovation. The significance and progress of bionics are summarized, in this paper, and the leading edges of bionics, in the near future, are forecasted.

  16. Leptin Acts via Lateral Hypothalamic Area Neurotensin Neurons to Inhibit Orexin Neurons by Multiple GABA-Independent Mechanisms

    Science.gov (United States)

    Goforth, Paulette B.; Leinninger, Gina M.; Patterson, Christa M.

    2014-01-01

    The adipocyte-derived hormone leptin modulates neural systems appropriately for the status of body energy stores. Leptin inhibits lateral hypothalamic area (LHA) orexin (OX; also known as hypocretin)-producing neurons, which control feeding, activity, and energy expenditure, among other parameters. Our previous results suggest that GABAergic LHA leptin receptor (LepRb)-containing and neurotensin (Nts)-containing (LepRbNts) neurons lie in close apposition with OX neurons and control Ox mRNA expression. Here, we show that, similar to leptin, activation of LHA Nts neurons by the excitatory hM3Dq DREADD (designer receptor exclusively activated by designer drugs) hyperpolarizes membrane potential and suppresses action potential firing in OX neurons in mouse hypothalamic slices. Furthermore, ablation of LepRb from Nts neurons abrogated the leptin-mediated inhibition, demonstrating that LepRbNts neurons mediate the inhibition of OX neurons by leptin. Leptin did not significantly enhance GABAA-mediated inhibitory synaptic transmission, and GABA receptor antagonists did not block leptin-mediated inhibition of OX neuron activity. Rather, leptin diminished the frequency of spontaneous EPSCs onto OX neurons. Furthermore, leptin indirectly activated an ATP-sensitive potassium (KATP) channel in OX neurons, which was required for the hyperpolarization of OX neurons by leptin. Although Nts did not alter OX activity, galanin, which is coexpressed in LepRbNts neurons, inhibited OX neurons, whereas the galanin receptor antagonist M40 (galanin-(1–12)-Pro3-(Ala-Leu)2-Ala amide) prevented the leptin-induced hyperpolarization of OX cells. These findings demonstrate that leptin indirectly inhibits OX neurons by acting on LHA LepRbNts neurons to mediate two distinct GABA-independent mechanisms of inhibition: the presynaptic inhibition of excitatory neurotransmission and the opening of KATP channels. PMID:25143620

  17. MiR-34a inhibits colon cancer proliferation and metastasis by inhibiting platelet-derived growth factor receptor α.

    Science.gov (United States)

    Li, Chunyan; Wang, Yulin; Lu, Shuming; Zhang, Zhuqing; Meng, Hua; Liang, Lina; Zhang, Yan; Song, Bo

    2015-11-01

    The microRNA (miRNA), miR‑34a is significant in colon cancer progression. In the present study, the role of miR‑34a in colon cancer cell proliferation and metastasis was investigated. It was found that the expression of miR‑34a in colon cancer tissues and cell lines was lower when compared with that of normal tissues and cells. Further research demonstrated that miR‑34a inhibited cell proliferation, induced G1 phase arrest, and suppressed metastasis and epithelial mesenchymal transition in colon cancer cells. Bioinformatic prediction indicated that platelet‑derived growth factor receptor α (PDGFRA) was a potential target gene of miR‑34a and a luciferase assay identified that PDGFRA was a novel direct target gene of miR‑34a. In addition, assays of western blot analyses and quantitative reverse‑transcription polymerase chain reaction confirmed that miR‑34a decreased PDGFRA mRNA expression and protein levels in colon cancer cells. Assessment of cellular function indicated that miR‑34a inhibited colon cancer progression via PDGFRA. These findings demonstrate that miR‑34a may act as a negative regulator in colon cancer by targeting PDGFRA.

  18. Which Reconstruction Results are Significant?

    Science.gov (United States)

    1980-05-01

    other significant result is due to Tutte [17]. Tutte’s Theorem: The characteristic polynomial of a graph can be reconstructed. Equivalently, two...hypomorphic graphs must have the same characteristic polynomial . Several points should be noted concerning this theorem: 1. The derivative of the...characteristic polynomial is the sum of the char- acteristic polynomials of the vertex-deleted subgraphs. Thus the characteristic polynomials of hypomorphic

  19. AFRL's Demonstration and Science Experiments (DSX) Mission

    Science.gov (United States)

    Scherbarth, M.; Adler, A.; Smith, D.; Loretti, V.; Stuart, J.

    The Air Force Research Laboratory (AFRL) Space Vehicles Directorate has developed the Demonstration and Science Experiments (DSX) mission to research technologies needed to significantly advance Department of Defense (DoD) capabilities to operate spacecraft in the harsh radiation environment of medium-earth orbits (MEO). The ability to operate effectively in the MEO environment significantly increases the DoDs capability to field space systems that provide persistent global targeting-grade space surveillance and reconnaissance, high-speed satellite-based communication, lower-cost GPS navigation, and protection from space weather and environmental effects on a responsive satellite platform. The three DSX physics-based research/experiment areas are: 1. Wave Particle Interaction Experiment (WPIx): Researching the physics of very-low-frequency (VLF) electro-magnetic wave transmissions through the ionosphere and in the magnetosphere and characterizing the feasibility of natural and man-made VLF waves to reduce and precipitate space radiation; 2. Space Weather Experiment (SWx): Characterizing, mapping, and modeling the space radiation environment in MEO, an orbital regime attractive for future DoD, Civil, and Commercial missions; 3. Space Environmental Effects (SFx): Researching and characterizing the MEO space weather effects on spacecraft electronics and materials. Collectively, thirteen individual payloads are synergized together from these three research areas and integrated onto a single platform (DSX) which provides a low-cost opportunity for AFRL due to their common requirements. All three groups of experiments require a 3-axis stabilized spacecraft bus (but no propulsion), a suite of radiation sensors, and extended duration in a low inclination, elliptical, MEO orbit. DSX will be launch ready in summer 2010 for a likely launch co-manifest with an operational DoD satellite on an EELV (evolved expendable launch vehicle).

  20. Complete corrosion inhibition through graphene defect passivation.

    Science.gov (United States)

    Hsieh, Ya-Ping; Hofmann, Mario; Chang, Kai-Wen; Jhu, Jian Gang; Li, Yuan-Yao; Chen, Kuang Yao; Yang, Chang Chung; Chang, Wen-Sheng; Chen, Li-Chyong

    2014-01-28

    Graphene is expected to enable superior corrosion protection due to its impermeability and chemical inertness. Previous reports, however, demonstrate limited corrosion inhibition and even corrosion enhancement of graphene on metal surfaces. To enable the reliable and complete passivation, the origin of the low inhibition efficiency of graphene was investigated. Combining electrochemical and morphological characterization techniques, nanometer-sized structural defects in chemical vapor deposition grown graphene were found to be the cause for the limited passivation effect. Extremely fast mass transport on the order of meters per second both across and parallel to graphene layers results in an inhibition efficiency of only ∼50% for Cu covered with up to three graphene layers. Through selective passivation of the defects by atomic layer deposition (ALD) an enhanced corrosion protection of more than 99% was achieved, which compares favorably with commercial corrosion protection methods.

  1. Neural inhibition enables selection during language processing.

    Science.gov (United States)

    Snyder, Hannah R; Hutchison, Natalie; Nyhus, Erika; Curran, Tim; Banich, Marie T; O'Reilly, Randall C; Munakata, Yuko

    2010-09-21

    Whether grocery shopping or choosing words to express a thought, selecting between options can be challenging, especially for people with anxiety. We investigate the neural mechanisms supporting selection during language processing and its breakdown in anxiety. Our neural network simulations demonstrate a critical role for competitive, inhibitory dynamics supported by GABAergic interneurons. As predicted by our model, we find that anxiety (associated with reduced neural inhibition) impairs selection among options and associated prefrontal cortical activity, even in a simple, nonaffective verb-generation task, and the GABA agonist midazolam (which increases neural inhibition) improves selection, whereas retrieval from semantic memory is unaffected when selection demands are low. Neural inhibition is key to choosing our words.

  2. Cinnamic acid amides from Tribulus terrestris displaying uncompetitive α-glucosidase inhibition.

    Science.gov (United States)

    Song, Yeong Hun; Kim, Dae Wook; Curtis-Long, Marcus J; Park, Chanin; Son, Minky; Kim, Jeong Yoon; Yuk, Heung Joo; Lee, Keun Woo; Park, Ki Hun

    2016-05-23

    The α-glucosidase inhibitory potential of Tribulus terrestris extracts has been reported but as yet the active ingredients are unknown. This study attempted to isolate the responsible metabolites and elucidate their inhibition mechanism of α-glucosidase. By fractionating T. terristris extracts, three cinnamic acid amide derivatives (1-3) were ascertained to be active components against α-glucosidase. The lead structure, N-trans-coumaroyltyramine 1, showed significant inhibition of α-glucosidase (IC50 = 0.42 μM). Moreover, all active compounds displayed uncompetitive inhibition mechanisms that have rarely been reported for α-glucosidase inhibitors. This kinetic behavior was fully demonstrated by showing a decrease of both Km and Vmax, and Kik/Kiv ratio ranging between 1.029 and 1.053. We progressed to study how chemical modifications to the lead structure 1 may impact inhibition. An α, β-unsaturation carbonyl group and hydroxyl group in A-ring of cinnamic acid amide emerged to be critical functionalities for α-glucosidase inhibition. The molecular modeling study revealed that the inhibitory activities are tightly related to π-π interaction as well as hydrogen bond interaction between enzyme and inhibitors.

  3. In vitro inhibition of the replication of classical swine fever virus by porcine Mx1 protein.

    Science.gov (United States)

    He, Dan-ni; Zhang, Xiao-min; Liu, Ke; Pang, Ran; Zhao, Jin; Zhou, Bin; Chen, Pu-yan

    2014-04-01

    Classical swine fever virus (CSFV) is the causative pathogen of classical swine fever (CSF), a highly contagious disease of swine. Mx proteins are interferon-induced dynamin-like GTPases present in all vertebrates with a wide range of antiviral activities. Although Zhao et al. (2011) have reported that human MxA can inhibit CSFV replication, whether porcine Mx1 (poMx1) has anti-CSFV activity remains unknown. In this study, we generated a cell line designated PK-15/EGFP-poMx1 which expressed porcine Mx1 protein constitutively, and we observed that the proliferation of progeny virus in this cell line was significantly inhibited as measured by virus titration, indirect immune fluorescence assay, Q-PCR and Western blot. Furthermore, when PTD-poMx1 fusion protein expressed in Escherichia coli (Zhang et al., 2013) was used to treat CSFV-infected PK-15 cells, the results showed that PTD-poMx1 inhibited CSFV replication in a dose-dependent manner. Additionally, the proliferation of progeny virus was inhibited as measured by virus titration and Q-PCR. Overall, the results demonstrated that poMx1 effectively inhibited CSFV replication, suggesting that poMx1 may be a valuable therapeutic agent against CSFV infection.

  4. Liver δ-Aminolevulinate Dehydratase Activity is Inhibited by Neonicotinoids and Restored by Antioxidant Agents

    Directory of Open Access Journals (Sweden)

    Elisa Sauer

    2014-11-01

    Full Text Available Neonicotinoids represent the most used class of insecticides worldwide, and their precursor, imidacloprid, is the most widely marketed. The aim of this study was to evaluate the effect of imidacloprid on the activity of hepatic δ-aminolevulinate dehydratase (δ-ALA-D, protective effect of potential antioxidants against this potential effect and presence of chemical elements in the constitution of this pesticide. We observed that δ-ALA-D activity was significantly inhibited by imidacloprid at all concentrations tested in a dose-dependent manner. The IC50 value was obtained and used to evaluate the restoration of the enzymatic activity. δ-ALA-D inhibition was completely restored by addition of dithiotreitol (DTT and partly by ZnCl2, demonstrating that the inhibition occurs by oxidation of thiol groups and by displacement of the Zn (II, which can be explained by the presence of chemical elements found in the constitution of pesticides. Reduced glutathione (GSH had the best antioxidant effect against to δ-ALA-D inhibition caused by imidacloprid, followed by curcumin and resveratrol. It is well known that inhibition of the enzyme δ-ALA-D may result in accumulation of its neurotoxic substrate (δ-ALA, in this line, our results suggest that further studies are needed to investigate the possible neurotoxicity induced by neonicotinoids and the involvement of antioxidants in cases of poisoning by neonicotinoids.

  5. Sex Differences on the Go/No-Go Test of Inhibition.

    Science.gov (United States)

    Sjoberg, Espen A; Cole, Geoff G

    2017-06-12

    Parental investment theory suggests that women, due to greater investment in child rearing, can be more choosy than men when considering a potential mate. A corollary to this is that women should possess greater inhibition abilities compared to men in contexts related to sex and reproduction. This notion has found support from the inhibition literature demonstrating that while women do indeed show greater inhibition on tasks that include a social aspect, no such effect is found on cognitive tasks that do not possess a social component. In the present experiment, participants (N = 66) performed a variant of a classic Go/No-Go task consisting of infrequent No-Go trials in which a response needed to be withheld. Importantly, the stimuli were geometric shapes possessing no social component. Results showed that women outperformed men on the No-Go trials, indicating greater inhibition. No significant difference was found in reaction time on Go trials. Thus, the results cannot be explained in terms of a speed/accuracy trade-off. We discuss the findings in the context of the female-evolved inhibition hypothesis.

  6. Evasion of antiviral innate immunity by Theiler's virus L* protein through direct inhibition of RNase L.

    Directory of Open Access Journals (Sweden)

    Frédéric Sorgeloos

    Full Text Available Theiler's virus is a neurotropic picornavirus responsible for chronic infections of the central nervous system. The establishment of a persistent infection and the subsequent demyelinating disease triggered by the virus depend on the expression of L*, a viral accessory protein encoded by an alternative open reading frame of the virus. We discovered that L* potently inhibits the interferon-inducible OAS/RNase L pathway. The antagonism of RNase L by L* was particularly prominent in macrophages where baseline oligoadenylate synthetase (OAS and RNase L expression levels are elevated, but was detectable in fibroblasts after IFN pretreatment. L* mutations significantly affected Theiler's virus replication in primary macrophages derived from wild-type but not from RNase L-deficient mice. L* counteracted the OAS/RNase L pathway through direct interaction with the ankyrin domain of RNase L, resulting in the inhibition of this enzyme. Interestingly, RNase L inhibition was species-specific as Theiler's virus L* protein blocked murine RNase L but not human RNase L or RNase L of other mammals or birds. Direct RNase L inhibition by L* and species specificity were confirmed in an in vitro assay performed with purified proteins. These results demonstrate a novel viral mechanism to elude the antiviral OAS/RNase L pathway. By targeting the effector enzyme of this antiviral pathway, L* potently inhibits RNase L, underscoring the importance of this enzyme in innate immunity against Theiler's virus.

  7. Targeted inhibition of RAGE in substantia nigra of rats blocks 6-OHDA-induced dopaminergic denervation.

    Science.gov (United States)

    Gasparotto, Juciano; Ribeiro, Camila Tiefensee; Bortolin, Rafael Calixto; Somensi, Nauana; Rabelo, Thallita Kelly; Kunzler, Alice; Souza, Natália Cabral; Pasquali, Matheus Augusto de Bittencourt; Moreira, José Claudio Fonseca; Gelain, Daniel Pens

    2017-08-18

    The receptor for advanced glycation endproducts (RAGE) is a pattern-recognition receptor associated with inflammation in most cell types. RAGE up-regulates the expression of proinflammatory mediators and its own expression via activation of NF-kB. Recent works have proposed a role for RAGE in Parkinson's disease (PD). In this study, we used the multimodal blocker of RAGE FPS-ZM1, which has become available recently, to selectively inhibit RAGE in the substantia nigra (SN) of rats intracranially injected with 6-hydroxydopamine (6-OHDA). FPS-ZM1 (40 μg per rat), injected concomitantly with 6-OHDA (10 μg per rat) into the SN, inhibited the increase in RAGE, activation of ERK1/2, Src and nuclear translocation of NF-kB p65 subunit in the SN. RAGE inhibition blocked glial fibrillary acidic protein and Iba-1 upregulation as well as associated astrocyte and microglia activation. Circulating cytokines in serum and CSF were also decreased by FPS-ZM1 injection. The loss of tyrosine hydroxylase and NeuN-positive neurons was significantly inhibited by RAGE blocking. Finally, FPS-ZM1 attenuated locomotory and exploratory deficits induced by 6-OHDA. Our results demonstrate that RAGE is an essential component in the neuroinflammation and dopaminergic denervation induced by 6-OHDA in the SN. Selective inhibition of RAGE may offer perspectives for therapeutic approaches.

  8. Fusion Power Demonstrations I and II

    Energy Technology Data Exchange (ETDEWEB)

    Doggett, J.N. (ed.)

    1985-01-01

    In this report we present a summary of the first phase of the Fusion Power Demonstration (FPD) design study. During this first phase, we investigated two configurations, performed detailed studies of major components, and identified and examined critical issues. In addition to these design specific studies, we also assembled a mirror-systems computer code to help optimize future device designs. The two configurations that we have studied are based on the MARS magnet configuration and are labeled FPD-I and FPD-II. The FPD-I configuration employs the same magnet set used in the FY83 FPD study, whereas the FPD-II magnets are a new, much smaller set chosen to help reduce the capital cost of the system. As part of the FPD study, we also identified and explored issues critical to the construction of an Engineering Test Reactor (ETR). These issues involve subsystems or components, which because of their cost or state of technology can have a significant impact on our ability to meet FPD's mission requirements on the assumed schedule. General Dynamics and Grumman Aerospace studied two of these systems, the high-field choke coil and the halo pump/direct converter, in great detail and their findings are presented in this report.

  9. A demonstration and evaluation of trajectory mapping

    Energy Technology Data Exchange (ETDEWEB)

    Morris, G.A. [Rice Univ., Houston, TX (United States). Dept. of Space Physics and Astronomy

    1994-09-01

    Problem of creating synoptic maps from asynoptically gathered data has prompted the development of a number schemes, the most notable being the Kalman filter, Salby-Fourier technique, and constituent reconstruction. This thesis presents a new technique, called trajectory mapping, which employs a simple model of air parcel motion to create synoptic maps from asynoptically gathered data. Four sources of trajectory mapping errors were analyzed; results showed that (1) the computational error is negligible; (2) measurement uncertainties can result in errors which grow with time scales of a week; (3) isentropic approximations lead to errors characterized by time scales of a week; and (4) wind field inaccuracies can cause significant errors in individual parcel trajectories in a matter of hours. All the studies, however, indicated that while individual trajectory errors can grow rapidly, constituent distributions, such as on trajectory maps, are much more robust, maintaining a high level of accuracy for periods on the order of several weeks. This technique was successfully applied to a variety of problems:(1) dynamical wave- breaking events; (2) satellite data validation for both instrument accuracy and precision; and (3) accuracy of meteorological wind fields. Such demonstrations imply that trajectory mapping will become an important tool in answering questions of global change, particularly the issue of ozone depletion.

  10. Adams natural gas/diesel demonstration project

    Energy Technology Data Exchange (ETDEWEB)

    1990-06-01

    The results of a ore-year program to demonstrate the viability of fuelling and operating diesel road vehicles on dual fuel natural gas/diesel under commercial operating conditions is presented. During this project a natural gas fuelling station designed to accomodate the specific needs of heavy trucks was constructed, and a Canada Safeway Ltd. tractor was converted to dual fuel natural gas/diesel operation. The truck accumulated more than 64,000 km during the one-year monitoring period, providing useful data in terms of comparative fuel efficiency, natural gas/diesel proportions of fuel use, operating range, and refuelling times, along with assessments of its performance by drivers and fleet management. In the dual fuel mode the truck experienced a 15% loss in thermal efficiency relative to straight diesel fuel during highway operation, and a 20% loss during local operation. Fuel cost savings resulting from the use of natural gas were not large given the increased level of fuel consumption and the purchase of natural gas at higher prices. If the fleet were to have its own natural gas fuelling station fuel cost savings would be substantially increased. Areas in which further development is needed for natural gas to emerge as a significant fuel for heavy trucks are mentioned. 3 figs., 15 tabs.

  11. Demonstrating diamond wire cutting of the TFTR

    Energy Technology Data Exchange (ETDEWEB)

    Rule, K.; Perry, E.; Larson, S.; Viola, M. [and others

    2000-02-24

    The Tokamak Fusion Test Reactor (TFTR) ceased operation in April 1997 and decommissioning commenced in October 1999. The deuterium-tritium fusion experiments resulted in contaminating the vacuum vessel with tritium and activating the materials with 14 Mev neutrons. The total tritium content within the vessel is in excess of 7,000 Curies while dose rates approach 50 mRem/hr. These radiological hazards along with the size of the Tokamak (100 cubic meters) present a unique and challenging task for dismantling. Plasma arc cutting is the current baseline technology for the dismantlement of fission reactors. This technology is typically used because of its faster cutting times. Alternatively, an innovative approach for dismantlement of the TFTR is the use of diamond wire cutting technology. Recent improvements in diamond wire technology have allowed the cutting of carbon steel components such as pipe, plate, and tube bundles in heat exchangers. Some expected benefits of this technology include: significantly reduction in airborne contaminates, reduced personnel exposure, a reduced risk of spread of tritium contamination, and reduced overall costs as compared to using plasma arc cutting. This paper will provide detailed results of the diamond wire cutting demonstration that was completed in September of 1999, on a mock-up of this complex reactor. The results will identify cost, safety, industrial and engineering parameters, and the related performance of each situation.

  12. An Undergraduate Laboratory Activity Demonstrating Bacteriophage Specificity

    Directory of Open Access Journals (Sweden)

    Mary E. Allen

    2013-02-01

    Full Text Available Bacteriophage are among the most diverse and numerous microbes inhabiting our planet. Yet many laboratory activities fail to engage students in meaningful exploration of their diversity, unique characteristics, and abundance. In this curriculum activity students use a standard plaque assay to enumerate bacteriophage particles from a natural sample and use the scientific method to address questions about host specificity and diversity. A raw primary sewage sample is enriched for bacteriophage using hosts in the family Enterobacteriaceae. Students hypothesize about host specificity and use quantitative data (serial dilution and plaque assay to test their hypotheses. Combined class data also help them answer questions about phage diversity. The exercise was field tested with a class of 47 students using pre- and posttests. For all learning outcomes posttest scores were higher than pretest scores at or below p = 0.01. Average individualized learning gain (G was also calculated for each learning outcome. Students’ use of scientific language in reference to bacteriophage and host interaction significantly improved (p = 0.002; G = 0.50. Improved means of expression helped students construct better hypotheses on phage host specificity (G = 0.31, p = 0.01 and to explain the plaque assay method (G = 0.33, p = 0.002. At the end of the exercise students also demonstrated improved knowledge and understanding of phage specificity as related to phage therapy in humans (p < 0.001; G = 51.

  13. Naringenin Inhibits Adipogenesis and Reduces Insulin Sensitivity and Adiponectin Expression in Adipocytes

    Directory of Open Access Journals (Sweden)

    Allison J. Richard

    2013-01-01

    Full Text Available Adipose tissue development and function are widely studied to examine the relationship between obesity and the metabolic syndrome. It is well documented that the inability of adipose tissue to properly increase its lipid storage capacity during the obese state can lead to metabolic dysfunction. In a blind screen of 425 botanicals, we identified naringenin as an inhibitor of adipocyte differentiation. Naringenin is one of the most abundant citrus flavonoids, and recent studies have demonstrated antihyperlipidemic capabilities. These studies have largely focused on the effects of naringenin on the liver. Our biochemical studies clearly demonstrate that naringenin inhibits adipogenesis and impairs mature fat cell function. Naringenin specifically inhibited adipogenesis in a dose-dependent fashion as judged by examining lipid accumulation and induction of adipocyte marker protein expression. In mature 3T3-L1 adipocytes, naringenin reduced the ability of insulin to induce IRS-1 tyrosine phosphorylation and substantially inhibited insulin-stimulated glucose uptake in a dose-dependent manner and over a time frame of 1.5 to 24 hours. Exposure to naringenin also inhibited adiponectin protein expression in mature murine and human adipocytes. Our studies have revealed that naringenin may have a negative impact on adipocyte-related diseases by limiting differentiation of preadipocytes, by significantly inducing insulin resistance, and by decreasing adiponectin expression in mature fat cells.

  14. Inflammasome-IL-1β signaling mediates ethanol inhibition of hippocampal neurogenesis

    Directory of Open Access Journals (Sweden)

    Fulton eCrews

    2012-05-01

    Full Text Available AbstractRegulation of hippocampal neurogenesis is poorly understood, but appears to contribute to mood and cognition. Ethanol and neuroinflammation are known to reduce neurogenesis. We have found that ethanol induces neuroinflammation supporting the hypothesis that ethanol induction of neuroinflammation contributes to ethanol inhibition of neurogenesis. To identify the key proinflammatory molecule that may be responsible for ethanol-impaired neurogenesis we used an ex vivo model of organotypic hippocampal-entorhinal cortex (HEC brain slice cultures. Here, we demonstrated a key role of proinflammatory cytokine IL-1β signaling in mediating ethanol inhibition of neurogenesis. Ethanol inhibition of neurogenesis was reversed by neutralizing antibody to IL-1β or blockade of the IL-1β receptor with antagonist IL-1RIa. Ethanol-impaired neurogenesis is associated with strong induction of IL-1β and inflammasome proteins NALP1 and NALP3 in both neurons and astrocytes. Blockade of IL-1β synthesis with inflammasome inhibitors Parthenolide and Bay11708 significantly reversed ethanol inhibited neurogenesis. Furthermore, we also found that IL-1β and inflammasome proteins NALP1 and NALP3 are increased in hippocampal neurons and astrocytes in postmortem alcoholic human brain. Together, these novel findings demonstrate that targeting inflammasome-IL-1β signaling can normalize ethanol-impaired hippocampal neurogenesis, which may have therapeutic implications for treatment of cognitive impairment associated with hippocampal dysfunction in alcoholics.

  15. Peptide aldehyde inhibitors of cathepsin K inhibit bone resorption both in vitro and in vivo.

    Science.gov (United States)

    Votta, B J; Levy, M A; Badger, A; Bradbeer, J; Dodds, R A; James, I E; Thompson, S; Bossard, M J; Carr, T; Connor, J R; Tomaszek, T A; Szewczuk, L; Drake, F H; Veber, D F; Gowen, M

    1997-09-01

    We have shown previously that cathepsin K, a recently identified member of the papain superfamily of cysteine proteases, is expressed selectively in osteoclasts and is the predominant cysteine protease in these cells. Based upon its abundant cell type-selective expression, potent endoprotease activity at low pH and cellular localization at the bone interface, cathepsin K has been proposed to play a specialized role in osteoclast-mediated bone resorption. In this study, we evaluated a series of peptide aldehydes and demonstrated that they are potent cathepsin K inhibitors. These compounds inhibited osteoclast-mediated bone resorption in fetal rat long bone (FRLB) organ cultures in vitro in a concentration-dependent manner. Selected compounds were also shown to inhibit bone resorption in a human osteoclast-mediated assay in vitro. Chz-Leu-Leu-Leu-H (in vitro enzyme inhibition Ki,app = 1.4 nM) inhibited parathyroid hormone (PTH)-stimulated resorption in the FRLB assay with an IC-50 of 20 nM and inhibited resorption by isolated human osteoclasts cultured on bovine cortical bone slices with an IC-50 of 100 nM. In the adjuvant-arthritic (AA) rat model, in situ hybridization studies demonstrated high levels of cathepsin K expression in osteoclasts at sites of extensive bone loss in the distal tibia. Cbz-Leu-Leu-Leu-H (30 mg/kg, intraperitoneally) significantly reduced this bone loss, as well as the associated hind paw edema. In the thyroparathyriodectomized rat model, Cbz-Leu-Leu-Leu-H inhibited the increase in blood ionized calcium induced by a 6 h infusion of PTH. These data indicate that inhibitors of cathepsin K are effective at reducing osteoclast-mediated bone resorption and may have therapeutic potential in diseases of excessive bone resorption such as rheumatoid arthritis or osteoporosis.

  16. Production of a Purified Marine Neurotoxin and Demonstration of its Binding Affinity to Ion Channel Receptors

    Science.gov (United States)

    1989-06-10

    Saxitoxin Conotoxins 2 Batrachotoxin Persistent activation Veratrum alkaloids Grayanotoxins 3 a- scorpion toxins Inhibit inactivation sea anemone... toxins 4 b- scorpion toxins Shift activation 5 Brevetoxins Shift activation and Ciguatoxin Inhibit J.nactivation Baden 1989 5 The objectives of this study...includes 1) demonstration of dinoflagellate toxin binding to synaptosome ion ch nnels 2) investigation of the effects of maitotoxin on the binding of

  17. Preference toward a polylysine enantiomer in inhibiting prions.

    Science.gov (United States)

    Jackson, Karen S; Yeom, Jihyun; Han, Youngmi; Bae, Younsoo; Ryou, Chongsuk

    2013-03-01

    Differential anti-prion activity of polylysine enantiomers was studied. Based on our recent discovery that poly-L-lysine (PLK) is a potent anti-prion agent, we investigated suppression of prions in cultured cells using poly-D-lysine (PDK). The results showed that PDK was more efficacious than PLK to inhibit prions. Protein misfolding cyclic amplification assay demonstrated improved efficacy of PDK in inhibiting plasminogen-mediated prion propagation, corresponding to the enantio-preference of PDK observed in cultured cells. Furthermore, our study demonstrated that polylysines formed a complex with plasminogen. These results propose to hypothesize a plausible mechanism that elicits prion inhibition by polylysine enantiomers.

  18. Fatty acid synthase inhibitors induce apoptosis in non-tumorigenic melan-a cells associated with inhibition of mitochondrial respiration.

    Directory of Open Access Journals (Sweden)

    Franco A Rossato

    Full Text Available The metabolic enzyme fatty acid synthase (FASN is responsible for the endogenous synthesis of palmitate, a saturated long-chain fatty acid. In contrast to most normal tissues, a variety of human cancers overexpress FASN. One such cancer is cutaneous melanoma, in which the level of FASN expression is associated with tumor invasion and poor prognosis. We previously reported that two FASN inhibitors, cerulenin and orlistat, induce apoptosis in B16-F10 mouse melanoma cells via the intrinsic apoptosis pathway. Here, we investigated the effects of these inhibitors on non-tumorigenic melan-a cells. Cerulenin and orlistat treatments were found to induce apoptosis and decrease cell proliferation, in addition to inducing the release of mitochondrial cytochrome c and activating caspases-9 and -3. Transfection with FASN siRNA did not result in apoptosis. Mass spectrometry analysis demonstrated that treatment with the FASN inhibitors did not alter either the mitochondrial free fatty acid content or composition. This result suggests that cerulenin- and orlistat-induced apoptosis events are independent of FASN inhibition. Analysis of the energy-linked functions of melan-a mitochondria demonstrated the inhibition of respiration, followed by a significant decrease in mitochondrial membrane potential (ΔΨm and the stimulation of superoxide anion generation. The inhibition of NADH-linked substrate oxidation was approximately 40% and 61% for cerulenin and orlistat treatments, respectively, and the inhibition of succinate oxidation was approximately 46% and 52%, respectively. In contrast, no significant inhibition occurred when respiration was supported by the complex IV substrate N,N,N',N'-tetramethyl-p-phenylenediamine (TMPD. The protection conferred by the free radical scavenger N-acetyl-cysteine indicates that the FASN inhibitors induced apoptosis through an oxidative stress-associated mechanism. In combination, the present results demonstrate that cerulenin

  19. Latent inhibition and autonomic responses: a psychophysiological approach.

    Science.gov (United States)

    Vaitl, D; Lipp, O V

    1997-10-01

    Latent inhibition, retarded learning after preexposure to the to-be-conditioned stimulus, has been implied as a tool for the investigation of attentional deficits in schizophrenia and related disorders. The present paper reviews research that used Pavlovian conditioning as indexed by autonomic responses (electrodermal, vasomotor, cardiac) to investigate latent inhibition in adult humans. Latent inhibition has been demonstrated repeatedly in healthy subjects in absence of a masking task that is required in other latent inhibition paradigms. Moreover, latent inhibition of Pavlovian conditioning is stimulus-specific and increases with an increased number of preexposure trials which mirrors results from research in animals. A reduction of latent inhibition has been shown in healthy subjects who score high on questionnaire measures of psychosis proneness and in unmedicated schizophrenic patients. The latter result was obtained in a within-subject paradigm that holds promise for research with patient samples.

  20. Robust Simulations and Significant Separations

    CERN Document Server

    Fortnow, Lance

    2010-01-01

    We define and study a new notion of "robust simulations" between complexity classes which is intermediate between the traditional notions of infinitely-often and almost-everywhere, as well as a corresponding notion of "significant separations". A language L has a robust simulation in a complexity class C if there is a language in C which agrees with L on arbitrarily large polynomial stretches of input lengths. There is a significant separation of L from C if there is no robust simulation of L in C. The new notion of simulation is a cleaner and more natural notion of simulation than the infinitely-often notion. We show that various implications in complexity theory such as the collapse of PH if NP = P and the Karp-Lipton theorem have analogues for robust simulations. We then use these results to prove that most known separations in complexity theory, such as hierarchy theorems, fixed polynomial circuit lower bounds, time-space tradeoffs, and the theorems of Allender and Williams, can be strengthened to signifi...

  1. Significance of biofilms in dentistry.

    Science.gov (United States)

    Wróblewska, Marta; Strużycka, Izabela; Mierzwińska-Nastalska, Elżbieta

    2015-01-01

    In the past decades significant scientific progress has taken place in the knowledge about biofilms. They constitute multilayer conglomerates of bacteria and fungi, surrounded by carbohydrates which they produce, as well as substances derived from saliva and gingival fluid. Modern techniques showed significant diversity of the biofilm environment and a system of microbial communication (quorum sensing), enhancing their survival. At present it is believed that the majority of infections, particularly chronic with exacerbations, are a result of biofilm formation, particularly in the presence of biomaterials. It should be emphasised that penetration of antibiotics and other antimicrobial agents into deeper layers of a biofilm is poor, causing therapeutic problems and necessitating sometimes removal of the implant or prosthesis. Biofilms play an increasing role in dentistry as a result of more and more broad use in dental practice of plastic and implantable materials. Biofilms are produced on the surfaces of teeth as dental plaque, in the para-nasal sinuses, on prostheses, dental implants, as well as in waterlines of a dental unit, constituting a particular risk for severely immunocompromised patients. New methods of therapy and prevention of infections linked to biofilms are under development.

  2. Calpain Inhibition Reduces Axolemmal Leakage in Traumatic Axonal Injury

    Directory of Open Access Journals (Sweden)

    János Sándor

    2009-12-01

    Full Text Available Calcium-induced, calpain-mediated proteolysis (CMSP has recently been implicated to the pathogenesis of diffuse (traumatic axonal injury (TAI. Some studies suggested that subaxolemmal CMSP may contribute to axolemmal permeability (AP alterations observed in TAI. Seeking direct evidence for this premise we investigated whether subaxolemmal CMSP may contribute to axolemmal permeability alterations (APA and pre-injury calpain-inhibition could reduce AP in a rat model of TAI. Horseradish peroxidase (HRP, a tracer that accumulates in axons with APA was administered one hour prior to injury into the lateral ventricle; 30 min preinjury a single tail vein bolus injection of 30 mg/kg MDL-28170 (a calpain inhibitor or its vehicle was applied in Wistar rats exposed to impact acceleration brain injury. Histological detection of traumatically injured axonal segments accumulating HRP and statistical analysis revealed that pre-injury administration of the calpain inhibitor MDL-28170 significantly reduced the average length of HRP-labeled axonal segments. The axono-protective effect of pre-injury calpain inhibition recently demonstrated with classical immunohistochemical markers of TAI was further corroborated in this experiment; significant reduction of the length of labeled axons in the drug-treated rats implicate CMSP in the progression of altered AP in TAI.

  3. Progression of pancreatic adenocarcinoma is significantly impeded with a combination of vaccine and COX-2 inhibition.

    Science.gov (United States)

    Mukherjee, Pinku; Basu, Gargi D; Tinder, Teresa L; Subramani, Durai B; Bradley, Judy M; Arefayene, Million; Skaar, Todd; De Petris, Giovanni

    2009-01-01

    With a 5-year survival rate of <5%, pancreatic cancer is one of the most rapidly fatal malignancies. Current protocols for the treatment of pancreas cancer are not as effective as we desire. In this study, we show that a novel Mucin-1 (MUC1)-based vaccine in combination with a cyclooxygenase-2 inhibitor (celecoxib), and low-dose chemotherapy (gemcitabine) was effective in preventing the progression of preneoplastic intraepithelial lesions to invasive pancreatic ductal adenocarcinomas. The study was conducted in an appropriate triple transgenic model of spontaneous pancreatic cancer induced by the KRAS(G12D) mutation and that expresses human MUC1 as a self molecule. The combination treatment elicited robust antitumor cellular and humoral immune responses and was associated with increased apoptosis in the tumor. The mechanism for the increased immune response was attributed to the down-regulation of circulating prostaglandin E(2) and indoleamine 2, 3,-dioxygenase enzymatic activity, as well as decreased levels of T regulatory and myeloid suppressor cells within the tumor microenvironment. The preclinical data provide the rationale to design clinical trials with a combination of MUC1-based vaccine, celecoxib, and gemcitabine for the treatment of pancreatic cancer.

  4. Genetic or chemical protease inhibition causes significant changes in the Bacillus subtilis exoproteome

    NARCIS (Netherlands)

    Westers, Lidia; Westers, Helga; Zanen, Geeske; Antelmann, Haike; Hecker, Michael; Noone, David; Devine, Kevin M.; van Dijl, Jan Maarten; Quax, Wim J.

    2008-01-01

    Bacillus subtilis is a prolific producer of enzymes and biopharmaceuticals. However, the susceptibility of heterologous proteins to degradation by (extracellular) proteases is a major limitation for use of B. subtilis as a protein cell factory. An increase in protein production levels has previously

  5. The history of Z-VAD-FMK, a tool for understanding the significance of caspase inhibition.

    Science.gov (United States)

    Van Noorden, C J

    2001-07-01

    Dr. Robert Smith is one of the pioneers in histochemistry. One of his most important achievements is the recognition of proteolysis as a major physiological and pathophysiological process. As a consequence, he developed selective fluorogenic and chromogenic substrates and specific inhibitors of proteases that allow the (histochemical) analysis of protease activity. One of the latest successes is the design of Z-VAD-fluoromethylketone (FMK), the specific caspase inhibitor, that is a key compound for studies on apoptosis. Its development was originally meant for therapeutic use but unforeseen cytotoxicity of a metabolic derivative of the FMK compound disabled its potential as a drug. However, as a tool for fundamental research it is a great success. The history of Z-VAD-FMK is an example of the creative brain and the tireless perseverance of Robert Smith for which histochemistry and cytochemistry owes him so much. This history of Z-VAD-FMK is a well-deserved tribute at the occasion of his 70th birthday.

  6. Biochemical Effects of Cadmium Exposure and the Potential Pharmacologic Significance of Cadmium Mediated Hydrolase Inhibition

    Science.gov (United States)

    1997-04-18

    increase Cd absorption from the intestines (Larson and Piscator 1971; Itokawa, Abe et al. 197 4; Pond and Walker 1975). Pyridoxine, vitamin B 6 , is...considerations on uptake and retention of cadmium in human kidney cortex. Cadmium in the Environment. L. Friberg, M. Piscator and G. F. Nordberg. Cleveland...Columbia, Missouri, University of Missouri. Larson, S.-E. and M. Piscator (1971). "Effect of cadmium on skeletal tissue in normal and calcium

  7. Influenza A virus nucleoprotein exploits Hsp40 to inhibit PKR activation.

    Directory of Open Access Journals (Sweden)

    Kulbhushan Sharma

    Full Text Available BACKGROUND: Double-stranded RNA dependent protein kinase (PKR is a key regulator of the anti-viral innate immune response in mammalian cells. PKR activity is regulated by a 58 kilo Dalton cellular inhibitor (P58(IPK, which is present in inactive state as a complex with Hsp40 under normal conditions. In case of influenza A virus (IAV infection, P58(IPK is known to dissociate from Hsp40 and inhibit PKR activation. However the influenza virus component responsible for PKR inhibition through P58(IPK activation was hitherto unknown. PRINCIPAL FINDINGS: Human heat shock 40 protein (Hsp40 was identified as an interacting partner of Influenza A virus nucleoprotein (IAV NP using a yeast two-hybrid screen. This interaction was confirmed by co-immunoprecipitation studies from mammalian cells transfected with IAV NP expressing plasmid. Further, the IAV NP-Hsp40 interaction was validated in mammalian cells infected with various seasonal and pandemic strains of influenza viruses. Cellular localization studies showed that NP and Hsp40 co-localize primarily in the nucleus. During IAV infection in mammalian cells, expression of NP coincided with the dissociation of P58(IPK from Hsp40 and decrease PKR phosphorylation. We observed that, plasmid based expression of NP in mammalian cells leads to decrease in PKR phosphorylation. Furthermore, inhibition of NP expression during influenza virus replication led to PKR activation and concomitant increase in eIF2α phosphorylation. Inhibition of NP expression also led to reduced IRF3 phosphorylation, enhanced IFN β production and concomitant reduction of virus replication. Taken together our data suggest that NP is the viral factor responsible for P58(IPK activation and subsequent inhibition of PKR-mediated host response during IAV infection. SIGNIFICANCE: Our findings demonstrate a novel role of IAV NP in inhibiting PKR-mediated anti-viral host response and help us understand P58(IPK mediated inhibition of PKR activity

  8. Lovastatin inhibits VEGFR and AKT activation: synergistic cytotoxicity in combination with VEGFR inhibitors.

    Directory of Open Access Journals (Sweden)

    Tong T Zhao

    Full Text Available BACKGROUND: In a recent study, we demonstrated the ability of lovastatin, a potent inhibitor of mevalonate synthesis, to inhibit the function of the epidermal growth factor receptor (EGFR. Lovastatin attenuated ligand-induced receptor activation and downstream signaling through the PI3K/AKT pathway. Combining lovastatin with gefitinib, a potent EGFR inhibitor, induced synergistic cytotoxicity in a variety of tumor derived cell lines. The vascular endothelial growth factor receptor (VEGFR and EGFR share similar activation, internalization and downstream signaling characteristics. METHODOLOGY/PRINCIPAL FINDINGS: The VEGFRs, particularly VEGFR-2 (KDR, Flt-1, play important roles in regulating tumor angiogenesis by promoting endothelial cell proliferation, survival and migration. Certain tumors, such as malignant mesothelioma (MM, also express both the VEGF ligand and VEGFRs that act in an autocrine loop to directly stimulate tumor cell growth and survival. In this study, we have shown that lovastatin inhibits ligand-induced VEGFR-2 activation through inhibition of receptor internalization and also inhibits VEGF activation of AKT in human umbilical vein endothelial cells (HUVEC and H28 MM cells employing immunofluorescence and Western blotting. Combinations of lovastatin and a VEGFR-2 inhibitor showed more robust AKT inhibition than either agent alone in the H28 MM cell line. Furthermore, combining 5 µM lovastatin treatment, a therapeutically relevant dose, with two different VEGFR-2 inhibitors in HUVEC and the H28 and H2052 mesothelioma derived cell lines demonstrated synergistic cytotoxicity as demonstrated by MTT cell viability and flow cytometric analyses. CONCLUSIONS/SIGNIFICANCE: These results highlight a novel mechanism by which lovastatin can regulate VEGFR-2 function and a potential therapeutic approach for MM through combining statins with VEGFR-2 inhibitors.

  9. Joint immobilization inhibits spontaneous hyaline cartilage regeneration induced by a novel double-network gel implantation.

    Science.gov (United States)

    Arakaki, Kazunobu; Kitamura, Nobuto; Kurokawa, Takayuki; Onodera, Shin; Kanaya, Fuminori; Gong, Jian-Ping; Yasuda, Kazunori

    2011-02-01

    We have recently discovered that spontaneous hyaline cartilage regeneration can be induced in an osteochondral defect in the rabbit, when we implant a novel double-network (DN) gel plug at the bottom of the defect. To clarify whether joint immobilization inhibits the spontaneous hyaline cartilage regeneration, we conducted this study with 20 rabbits. At 4 or 12 weeks after surgery, the defect in the mobile knees was filled with a sufficient volume of the hyaline cartilage tissue rich in proteoglycan and type-2 collagen, while no cartilage tissues were observed in the defect in the immobilized knees. Type-2 collagen, Aggrecan, and SOX9 mRNAs were expressed only in the mobile knees at each period. This study demonstrated that joint immobilization significantly inhibits the spontaneous hyaline cartilage regeneration induced by the DN gel implantation. This fact suggested that the mechanical environment is one of the significant factors to induce this phenomenon.

  10. Inactivation of Candida albicans by Corona Discharge: The Increase of Inhibition Zones Area After Far Subsequent Exposition

    Directory of Open Access Journals (Sweden)

    Vladyslava Fantova

    2013-01-01

    Full Text Available The cold atmospheric pressure plasma generated by the negative corona discharge has inhibition effect on the microorganism growth. This effect is well-known and it can be demonstrated on the surface of cultivation agar plates by the formation of inhibition zones. We exposed the cultures of Candida albicans to the negative corona discharge plasma in a special arrangement in this study: The equal doses of plasma were applied subsequently twice or four times on the same culture on one Petri dish, while the distance between exposed points was variable. Only small differences were observed in decontaminated zone areas for twice exposed agar at the shortest distance between exposed points (1.5 cm. In case of the four times exposed agars, we observed significant differences in inhibition zone areas, dependent not only on the exposition site distances, but also on the exposition order. The largest inhibition zone size was observed for the first exposition decreasing to the fourth one. To check relevancy of these dependencies, we presume to conduct further set of experiments with lower yeast concentration. In conclusion, significant difference in partial inhibition zone sizes appeared only when four expositions on one Petri dish were carried out, whereas no significant difference was observed for two subsequent expositions. The explanation of this effect may be the subject of subsequent remote exposition(s, when minute amounts of scattered active particles act on the previously exposed areas; the influence of diffused ozone may also take place.

  11. Near-Net Forging Technology Demonstration Program

    Science.gov (United States)

    Hall, I. Keith

    1996-01-01

    Significant advantages in specific mechanical properties, when compared to conventional aluminum (Al) alloys, make aluminum-lithium (Al-Li) alloys attractive candidate materials for use in cryogenic propellant tanks and dry bay structures. However, the cost of Al-Li alloys is typically five times that of 2219 aluminum. If conventional fabrication processes are employed to fabricate launch vehicle structure, the material costs will restrict their utilization. In order to fully exploit the potential cost and performance benefits of Al-Li alloys, it is necessary that near-net manufacturing methods be developed to off-set or reduce raw material costs. Near-net forging is an advanced manufacturing method that uses elevated temperature metal movement (forging) to fabricate a single piece, near-net shape, structure. This process is termed 'near-net' because only a minimal amount of post-forge machining is required. The near-net forging process was developed to reduce the material scrap rate (buy-to-fly ratio) and fabrication costs associated with conventional manufacturing methods. The goal for the near-net forging process, when mature, is to achieve an overall cost reduction of approximately 50 percent compared with conventional manufacturing options for producing structures fabricated from Al-Li alloys. This NASA Marshall Space Flight Center (MSFC) sponsored program has been a part of a unique government / industry partnership, coordinated to develop and demonstrate near-net forging technology. The objective of this program was to demonstrate scale-up of the near-net forging process. This objective was successfully achieved by fabricating four integrally stiffened, 170- inch diameter by 20-inch tall, Al-Li alloy 2195, Y-ring adapters. Initially, two 2195 Al-Li ingots were converted and back extruded to produce four cylindrical blockers. Conventional ring rolling of the blockers was performed to produce ring preforms, which were then contour ring rolled to produce

  12. The significance of constitutional values

    Directory of Open Access Journals (Sweden)

    HN Nisihara

    2001-12-01

    Full Text Available This article addresses the question of the meaning and legal significance of constitutional values in contemporary times. The article attends also to related questions namely, what constitute “constitutional values” and what are the limitations of the meaning afforded to this notion. Attention is paid in the particular, to freedom, equality and democracy as value-neutral criteria of fairness and government neutrality with reference to the South African and German contexts as well as to value-neutrality as a culturally conditioned value. The author concludes with a cosmopolitan view of freedom and the right to peace with reference to the constitutional texts of Japan and the United States.

  13. The significance of small streams

    Science.gov (United States)

    Wohl, Ellen

    2017-09-01

    Headwaters, defined here as first- and secondorder streams, make up 70%‒80% of the total channel length of river networks. These small streams exert a critical influence on downstream portions of the river network by: retaining or transmitting sediment and nutrients; providing habitat and refuge for diverse aquatic and riparian organisms; creating migration corridors; and governing connectivity at the watershed-scale. The upstream-most extent of the channel network and the longitudinal continuity and lateral extent of headwaters can be difficult to delineate, however, and people are less likely to recognize the importance of headwaters relative to other portions of a river network. Consequently, headwaters commonly lack the legal protections accorded to other portions of a river network and are more likely to be significantly altered or completely obliterated by land use.

  14. [Hypertriglyceridemia: concept and clinical significance].

    Science.gov (United States)

    Hirano, Tsutomu

    2013-09-01

    Hypertriglyceridemia is a common lipid disorder as well as hypercholesterolemia. However clinical significance of hypertriglyceridemia is not fully understood because of its heterogeneous lipoprotein phenotypes and complex etiology. Severe hypertriglyceridemia increases the risk for pancreatitis, whereas mild or moderate hypertriglyceridemia may be a risk factor for cardiovascular disease. Patients with hypertriglyceridemia are usually accompanied by other cardiovascular related disorders, such as central obesity, type 2 diabetes, and liver steatosis. Ectopic fat accumulation is often seen in hypertriglyceridemic subjects and various organ injuries are developed by the lipotoxicity. Hypertriglyceridemia is strongly associated with remnant lipoprotein accumulation, increased small dense LDL, and low HDL-cholesterol. All these lipid abnormalities are recognized as cardiovascular risk factors. The pathophysiology of lipoprotein metabolism related to the hypertriglyceridemia is summarized in this brief review.

  15. Sensitization of Pancreatic Cancers to Gemcitabine Chemoradiation by WEE1 Kinase Inhibition Depends on Homologous Recombination Repair

    Directory of Open Access Journals (Sweden)

    Tasneem Kausar

    2015-10-01

    Full Text Available To improve the efficacy of chemoradiation therapy for locally advanced pancreatic cancer and begin to establish patient selection criteria, we investigated the combination of the WEE1 inhibitor AZD1775 with gemcitabine-radiation in homologous recombination (HR repair proficient and deficient pancreatic cancers. Sensitization to gemcitabine-radiation by AZD1775 was assessed in pancreatic cancer cells by clonogenic survival and in patient-derived xenografts by tumor growth. The contributions of HR repair inhibition and G2 checkpoint abrogation to sensitization were assessed by γH2AX, BRCA2 manipulation, and RAD51 focus formation and pHistone H3 flow cytometry, respectively. We found that AZD1775 sensitized to gemcitabine-radiation in BRCA2 wild-type but not BRCA2 mutant pancreatic cancer cells. In all cells, AZD1775 caused inhibition of CDK1 phosphorylation and G2 checkpoint abrogation. However, sensitization by AZD1775 was associated with persistent γH2AX and inhibition of RAD51 focus formation. In HR-proficient (BRCA2 wild-type or -deficient (BRAC2 null isogenic cells, AZD1775 sensitized to gemcitabine-radiation in BRCA2 wild-type, but not in BRCA2 null cells, despite significant G2 checkpoint abrogation. In patient-derived pancreatic tumor xenografts, AZD1775 significantly inhibited tumor growth and impaired RAD51 focus formation in response to gemcitabine-radiation. In conclusion, WEE1 inhibition by AZD1775 is an effective strategy for sensitizing pancreatic cancers to gemcitabine chemoradiation. Although this sensitization is accompanied by inhibition of CDK1 phosphorylation and G2 checkpoint abrogation, this mechanism is not sufficient for sensitization. Our findings demonstrate that sensitization to chemoradiation by WEE1 inhibition results from inhibition of HR repair and suggest that patient tumors without underlying HR defects would benefit most from this therapy.

  16. Plastics for corrosion inhibition

    CERN Document Server

    Goldade, Victor A; Makarevich, Anna V; Kestelman, Vladimir N

    2005-01-01

    The development of polymer composites containing inhibitors of metal corrosion is an important endeavour in modern materials science and technology. Corrosion inhibitors can be located in a polymer matrix in the solid, liquid or gaseous phase. This book details the thermodynamic principles for selecting these components, their compatibility and their effectiveness. The various mechanisms of metal protection – barrier, inhibiting and electromechanical – are considered, as are the conflicting requirements placed on the structure of the combined material. Two main classes of inhibited materials (structural and films/coatings) are described in detail. Examples are given of structural plastics used in friction units subjected to mechano-chemical wear and of polymer films/coatings for protecting metal objects against corrosion.

  17. Ozone inhibits endothelial cell cyclooxygenase activity through formation of hydrogen peroxide

    Energy Technology Data Exchange (ETDEWEB)

    Madden, M.C.; Eling, T.E.; Friedman, M.

    1987-09-01

    We have previously demonstrated that a 2H exposure of cultured pulmonary endothelial cells to ozone (0.0-1.0 ppm) in-vitro resulted in a concentration-dependent reduction of endothelial prostacyclin production (90% decrease at the 1.0 ppm level). Ozone-exposed endothelial cells, incubated with 20 uM arachidonate, also demonstrated a significant inhibition of prostacyclin synthesis. To further examine the mechanisms of the inhibition of prostacyclin synthesis, bovine pulmonary endothelial cells were exposed to 1.0 ppm ozone for 2H. A significant decrease in prostacyclin synthesis was found within 5 min of exposure (77 +/- 36% of air-exposed control values, p less than 0.05). Endothelial prostacyclin synthesis returned to baseline levels by 12H after ozone exposure, a time point which was similar to the recovery time of unexposed endothelium treated with 0.5 uM acetylsalicylic acid. Incubation of endothelial cells, previously exposed to 1.0 ppm ozone for 2 hours, with 4 uM PGH2 resulted in restoration of essentially normal prostacyclin synthesis. When endothelial cells were co-incubated with catalase (5 U/ml) during ozone exposure, no inhibition of prostacyclin synthesis was observed. Co-incubation with either heat-inactivated catalase or superoxide dismutase (10 U/ml) did not affect the ozone-induced inhibition of prostacyclin synthesis. These data suggest that H/sub 2/O/sub 2/ is a major toxic species produced in endothelial cells during ozone exposure and responsible for the inhibition of endothelial cyclooxygenase activity.

  18. Detecting significant changes in protein abundance

    Directory of Open Access Journals (Sweden)

    Kai Kammers

    2015-06-01

    Full Text Available We review and demonstrate how an empirical Bayes method, shrinking a protein's sample variance towards a pooled estimate, leads to far more powerful and stable inference to detect significant changes in protein abundance compared to ordinary t-tests. Using examples from isobaric mass labelled proteomic experiments we show how to analyze data from multiple experiments simultaneously, and discuss the effects of missing data on the inference. We also present easy to use open source software for normalization of mass spectrometry data and inference based on moderated test statistics.

  19. Thermodynamic Significance of Human Basal Metabolism

    Institute of Scientific and Technical Information of China (English)

    WangCuncheng

    1993-01-01

    The human basal state,a non-equilibrium steady state,is analysed in this paper in the light of the First and Second Laws of Thermodynamics whereby the thermodynamic significance of the basal metabolic rate and its distinction to the dissipation function and exergy loss are identified.The analysis demonstrates the correct expression of the effects of the blood flow on the heat balance in a human-body bio-heat model and the relationship between the basal metabolic rate and the blood perfusion.

  20. Inhibition and Brain Work

    OpenAIRE

    Buzsáki, György; Kaila, Kai; Raichle, Marcus

    2007-01-01

    The major part of the brain’s energy budget (~60%–80%) is devoted to its communication activities. While inhibition is critical to brain function, relatively little attention has been paid to its metabolic costs. Understanding how inhibitory interneurons contribute to brain energy consumption (brain work) is not only of interest in understanding a fundamental aspect of brain function but also in understanding functional brain imaging techniques which rely on measurements related to blood flow...

  1. Inhibition of 17β-estradiol activation by CYP1A1: genotype- and regioselective inhibition by St. John's Wort and several natural polyphenols.

    Science.gov (United States)

    Schwarz, Dieter; Kisselev, Pyotr; Schunck, Wolf-Hagen; Roots, Ivar

    2011-01-01

    Several epidemiological studies associate certain CYP1A1 genotypes, alone or in combination, with an increased risk of estrogen-related cancers. Previously we demonstrated that metabolic activation of estrogens by CYP1A1 is a genotype-dependent reaction with the CYP1A1.2 (Ile462Val) variant being the most efficient catalyst (Kisselev et al.). To answer the question whether genotype-dependent inhibition of activation of estrogens by CYP1A1 could also contribute, we studied the inhibition of hydroxylation activity of the most common allelic variants of human CYP1A1 towards 17β-estradiol. We expressed and purified CYP1A1.1 (wild-type), CYP1A1.2 (Ile462Val), and CYP1A1.4 (Thr461Asn) and performed inhibition assays by natural polyphenols of our diet and drugs of NADPH-dependent estradiol hydroxylation in reconstituted CYP1A1 systems. From the polyphenols studied, a St. John's Wort (Hypericum perforatum) extract, some of its main single constituents hypericin, pseudohypericin, and quercetin, as well as the flavonols kaempferol, myricetin and the phytoestrogens resveratrol and tetramethyl-stilbene exhibited strong inhibition. For the St. John's Wort extract and its single constituents hypericin, pseudohypericin, and quercetin, inhibition exhibited a remarkable dependency on the CYP1A1 genotype. Whereas (wild-type) CYP1A1.1 was most inhibited by the whole crude extract, the variant CYP1A1.2 (Ile462Val) was significantly stronger inhibited by the constituents in its pure form: IC₅₀ values for 2-hydroxylation was more than two times lower compared with the wild-type enzyme and the variant CYP1A1.4 (Thr461Asn). Besides this, the inhibition exhibited a remarkable regioselectivity. The data suggest that risk of estrogen-mediated diseases might be not only influenced by CYP1A1 genotype-dependent activation but also its inhibition by natural polyphenols of our diet and drugs.

  2. Fluoxetine prevents oligodendrocyte cell death by inhibiting microglia activation after spinal cord injury.

    Science.gov (United States)

    Lee, Jee Y; Kang, So R; Yune, Tae Y

    2015-05-01

    Oligodendrocyte cell death and axon demyelination after spinal cord injury (SCI) are known to be important secondary injuries contributing to permanent neurological disability. Thus, blocking oligodendrocyte cell death should be considered for therapeutic intervention after SCI. Here, we demonstrated that fluoxetine, an antidepressant drug, alleviates oligodendrocyte cell death by inhibiting microglia activation after SCI. After injury at the T9 level with a Precision Systems and Instrumentation (Lexington, KY) device, fluoxetine (10 mg/kg, intraperitoneal) was administered once a day for the indicated time points. Immunostaining with CD11b (OX-42) antibody and quantification analysis showed that microglia activation was significantly inhibited by fluoxetine at 5 days after injury. Fluoxetine also significantly inhibited activation of p38 mitogen-activated protein kinase (p38-MAPK) and expression of pro-nerve growth factor (pro-NGF), which is known to mediate oligodendrocyte cell death through the p75 neurotrophin receptor after SCI. In addition, fluoxetine attenuated activation of Ras homolog gene family member A and decreased the level of phosphorylated c-Jun and, ultimately, alleviated caspase-3 activation and significantly reduced cell death of oligodendrocytes at 5 days after SCI. Further, the decrease of myelin basic protein, myelin loss, and axon loss in white matter was also significantly blocked by fluoxetine, as compared to vehicle control. These results suggest that fluoxetine inhibits oligodendrocyte cell death by inhibiting microglia activation and p38-MAPK activation, followed by pro-NGF production after SCI, and provide a potential usage of fluoxetine for a therapeutic agent after acute SCI in humans.

  3. Test and Demonstration Assets of New Mexico

    Energy Technology Data Exchange (ETDEWEB)

    None

    2008-03-31

    This document was developed by the Arrowhead Center of New Mexico State University as part of the National Security Preparedness Project (NSPP), funded by a DOE/NNSA grant. The NSPP has three primary components: business incubation, workforce development, and technology demonstration and validation. The document contains a survey of test and demonstration assets in New Mexico available for external users such as small businesses with security technologies under development. Demonstration and validation of national security technologies created by incubator sources, as well as other sources, are critical phases of technology development. The NSPP will support the utilization of an integrated demonstration and validation environment.

  4. Morphine decreases enteric neuron excitability via inhibition of sodium channels.

    Directory of Open Access Journals (Sweden)

    Tricia H Smith

    Full Text Available Gastrointestinal peristalsis is significantly dependent on the enteric nervous system. Constipation due to reduced peristalsis is a major side-effect of morphine, which limits the chronic usefulness of this excellent pain reliever in man. The ionic basis for the inhibition of enteric neuron excitability by morphine is not well characterized as previous studies have mainly utilized microelectrode recordings from whole mount myenteric plexus preparations in guinea pigs. Here we have developed a Swiss-Webster mouse myenteric neuron culture and examined their electrophysiological properties by patch-clamp techniques and determined the mechanism for morphine-induced decrease in neuronal excitability. Isolated neurons in culture were confirmed by immunostaining with pan-neuronal marker, β-III tubulin and two populations were identified by calbindin and calretinin staining. Distinct neuronal populations were further identified based on the presence and absence of an afterhyperpolarization (AHP. Cells with AHP expressed greater density of sodium currents. Morphine (3 µM significantly reduced the amplitude of the action potential, increased the threshold for spike generation but did not alter the resting membrane potential. The decrease in excitability resulted from inhibition of sodium currents. In the presence of morphine, the steady-state voltage dependence of Na channels was shifted to the left with almost 50% of channels unavailable for activation from hyperpolarized potentials. During prolonged exposure to morphine (two hours, action potentials recovered, indicative of the development of tolerance in single enteric neurons. These results demonstrate the feasibility of isolating mouse myenteric neurons and establish sodium channel inhibition as a mechanism for morphine-induced decrease in neuronal excitability.

  5. Theobromine inhibits sensory nerve activation and cough.

    Science.gov (United States)

    Usmani, Omar S; Belvisi, Maria G; Patel, Hema J; Crispino, Natascia; Birrell, Mark A; Korbonits, Márta; Korbonits, Dezso; Barnes, Peter J

    2005-02-01

    Cough is a common and protective reflex, but persistent coughing is debilitating and impairs quality of life. Antitussive treatment using opioids is limited by unacceptable side effects, and there is a great need for more effective remedies. The present study demonstrates that theobromine, a methylxanthine derivative present in cocoa, effectively inhibits citric acid-induced cough in guinea-pigs in vivo. Furthermore, in a randomized, double-blind, placebo-controlled study in man, theobromine suppresses capsaicin-induced cough with no adverse effects. We also demonstrate that theobromine directly inhibits capsaicin-induced sensory nerve depolarization of guinea-pig and human vagus nerve suggestive of an inhibitory effect on afferent nerve activation. These data indicate the actions of theobromine appear to be peripherally mediated. We conclude theobromine is a novel and promising treatment, which may form the basis for a new class of antitussive drugs.

  6. Clinical significance of MET in gastric cancer

    Institute of Scientific and Technical Information of China (English)

    Mikito; Inokuchi; Sho; Otsuki; Yoshitaka; Fujimori; Yuya; Sato; Masatoshi; Nakagawa; Kazuyuki; Kojima

    2015-01-01

    Chemotherapy has become the global standard treatment for patients with metastatic or unresectable gastric cancer(GC),although outcomes remain unfavorable.Many molecular-targeted therapies inhibiting signaling pathways of various tyrosine kinase receptors have been developed,and monoclonal antibodies targeting human epidermal growth factor receptor 2 or vascular endothelial growth factor receptor 2 have become standard therapy for GC.Hepatocyte growth factor and its receptor,c-MET(MET),play key roles in tumor growth through activated signaling pathways from receptor in GC cells.Genomic amplification of MET leads to the aberrant activation found in GC tumors and is related to survival in patients with GC.This review discusses the clinical significance of MET in GC and examines MET as a potential therapeutic target in patients with GC.Preclinical studies in animal models have shown that MET antibodies or smallmolecule MET inhibitors suppress tumor-cell proliferation and tumor progression in MET-amplified GC cells.These drugs are now being evaluated in clinical trials as treatments for metastatic or unresectable GC.

  7. Low levels of graphene and graphene oxide inhibit cellular xenobiotic defense system mediated by efflux transporters.

    Science.gov (United States)

    Liu, Su; Jiang, Wei; Wu, Bing; Yu, Jing; Yu, Haiyan; Zhang, Xu-Xiang; Torres-Duarte, Cristina; Cherr, Gary N

    2016-01-01

    Low levels of graphene and graphene oxide (GO) are considered to be environmentally safe. In this study, we analyzed the potential effects of graphene and GO at relatively low concentrations on cellular xenobiotic defense system mediated by efflux transporters. The results showed that graphene (graphene and GO at the nontoxic concentrations could increase calcein-AM (CAM, an indicator of membrane ATP-binding cassette (ABC) transporter) activity) accumulation, indicating inhibition of ABC transporters' efflux capabilities. This inhibition was observed even at 0.005 μg/mL graphene and 0.05 μg/mL GO, which are 100 times and 400 times lower than their lowest toxic concentration from cytotoxicity experiments, respectively. The inhibition of ABC transporters significantly increased the toxicity of paraquat and arsenic, known substrates of ABC transporters. The inhibition of ABC transporters was found to be based on graphene and GO damaging the plasma membrane structure and fluidity, thus altering functions of transmembrane ABC transporters. This study demonstrates that low levels of graphene and GO are not environmentally safe since they can significantly make cell more susceptible to other xenobiotics, and this chemosensitizing activity should be considered in the risk assessment of graphene and GO.

  8. Rosmarinic acid inhibits poly(I:C)-induced inflammatory reaction of epidermal keratinocytes.

    Science.gov (United States)

    Zhou, Ming-Wei; Jiang, Ri-Hua; Kim, Ki-Duck; Lee, Jin-Hyup; Kim, Chang-Deok; Yin, Wei-Tian; Lee, Jeung-Hoon

    2016-06-15

    Keratinocytes are the predominant cells in the epidermis, exerting their primary role of physical barrier through sophisticated differentiation process. In addition, keratinocytes contribute to the activation of innate immunity, providing the surveillant role against external pathogens. It has been known that chronic skin inflammatory disease such as psoriasis can be provoked by viral pathogens including double-stranded RNA. In this study, we demonstrated that rosmarinic acid (RA) has an inhibitory potential on inflammatory reaction induced by double-stranded RNA mimic poly(I:C) in epidermal keratinocytes. We cultured human epidermal keratinocytes and induced inflammatory reaction by poly(I:C) treatment. The effect of RA on inflammatory reaction of keratinocytes was determined by RT-PCR and Western blot. RA significantly inhibited poly(I:C)-induced expression of inflammatory cytokines including IL-1β, IL-6, IL-8, CCL20, and TNF-α, and downregulated NF-κB signaling pathway in human keratinocytes. In addition, RA significantly inhibited poly(I:C)-induced inflammasome activation, in terms of secretion of active form of IL-1β and caspase-1. Furthermore, RA markedly inhibited poly(I:C)-induced NLRP3 and ASC expression. These results indicate that RA can inhibit poly(I:C)-induced inflammatory reaction of keratinocytes, and suggest that it may be a potential candidate for the treatment of psoriasis. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. 3-Bromopyruvate inhibits cell proliferation and induces apoptosis in CD133+ population in human glioma.

    Science.gov (United States)

    Xu, Dong-Qiang; Tan, Xiao-Yu; Zhang, Bao-Wei; Wu, Tao; Liu, Ping; Sun, Shao-Jun; Cao, Yin-Guang

    2016-03-01

    The study was aimed to investigate the role of 3-bromopyruvate in inhibition of CD133+ U87 human glioma cell population growth. The results demonstrated that 3-bromopyruvate inhibited the viability of both CD133+ and parental cells derived from U87 human glioma cell line. However, the 3-bromopyruvate-induced inhibition in viability was more prominent in CD133+ cells at 10 μM concentration after 48 h. Treatment of CD133+ cells with 3-bromopyruvate caused reduction in cell population and cell size, membrane bubbling, and degradation of cell membranes. Hoechst 33258 staining showed condensation of chromatin material and fragmentation of DNA in treated CD133+ cells after 48 h. 3-Bromopyruvate inhibited the migration rate of CD133+ cells significantly compared to the parental cells. Flow cytometry revealed that exposure of CD133+ cells to 3-bromopyruvate increased the cell population in S phase from 24.5 to 37.9 % with increase in time from 12 to 48 h. In addition, 3-bromopyruvate significantly enhanced the expression of Bax and cleaved caspase 3 in CD133+ cells compared to the parental cells. Therefore, 3-bromopyruvate is a potent chemotherapeutic agent for the treatment of glioma by targeting stem cells selectively.

  10. Nuclear factor-kappa B inhibition can enhance apoptosis of differentiated thyroid cancer cells induced by 131I.

    Directory of Open Access Journals (Sweden)

    Zhaowei Meng

    Full Text Available OBJECTIVE: To evaluate changes of nuclear factor-kappa B (NF-κB during radioiodine 131 ((131I therapy and whether NF-κB inhibition could enhance (131I-induced apoptosis in differentiated thyroid cancer (DTC cells in a synergistic manner. METHODS: Three human DTC cell lines were used. NF-κB inhibition was achieved by using a NF-κB inhibitor (Bay 11-7082 or by p65 siRNA transfection. Methyl-thiazolyl-tetrazolium assay was performed for cell viability assessment. DNA-binding assay, luciferase reporter assay, and Western blot were adopted to determine function and expression changes of NF-κB. Then NF-κB regulated anti-apoptotic factors XIAP, cIAP1, and Bcl-xL were measured. Apoptosis was analyzed by Western blot for caspase 3 and PARP, and by flow cytometry as well. An iodide uptake assay was performed to determine whether NF-κB inhibition could influence radioactive iodide uptake. RESULTS: The methyl-thiazolyl-tetrazolium assay showed significant decrease of viable cells by combination therapy than by mono-therapies. The DNA-binding assay and luciferase reporter assay showed enhanced NF-κB function and reporter gene activities due to (131I, yet significant suppression was achieved by NF-κB inhibition. Western blot proved (131I could increase nuclear NF-κB concentration, while NF-κB inhibition reduced NF-κB concentration. Western blot also demonstrated significant up-regulation of XIAP, cIAP1, and Bcl-xL after (131I therapy. And inhibition of NF-κB could significantly down-regulate these factors. Finally, synergism induced by combined therapy was displayed by significant enhancements of cleaved caspase 3 and PARP from Western blot, and of Annexin V positively staining from flow cytometry. The iodine uptake assay did not show significant changes when NF-κB was inhibited. CONCLUSION: We demonstrated that (131I could induce NF-κB activation, which would attenuate (131I efficacy in DTC cells. NF-κB inhibition by Bay 11-7082 or by p65 si

  11. Magnetic Launch Assist System Demonstration Test

    Science.gov (United States)

    2001-01-01

    Engineers at the Marshall Space Flight Center (MSFC) have been testing Magnetic Launch Assist Systems, formerly known as Magnetic Levitation (MagLev) technologies. To launch spacecraft into orbit, a Magnetic Launch Assist system would use magnetic fields to levitate and accelerate a vehicle along a track at a very high speed. Similar to high-speed trains and roller coasters that use high-strength magnets to lift and propel a vehicle a couple of inches above a guideway, the launch-assist system would electromagnetically drive a space vehicle along the track. A full-scale, operational track would be about 1.5-miles long and capable of accelerating a vehicle to 600 mph in 9.5 seconds. This photograph shows a subscale model of an airplane running on the experimental track at MSFC during the demonstration test. This track is an advanced linear induction motor. Induction motors are common in fans, power drills, and sewing machines. Instead of spinning in a circular motion to turn a shaft or gears, a linear induction motor produces thrust in a straight line. Mounted on concrete pedestals, the track is 100-feet long, about 2-feet wide, and about 1.5- feet high. The major advantages of launch assist for NASA launch vehicles is that it reduces the weight of the take-off, the landing gear, the wing size, and less propellant resulting in significant cost savings. The US Navy and the British MOD (Ministry of Defense) are planning to use magnetic launch assist for their next generation aircraft carriers as the aircraft launch system. The US Army is considering using this technology for launching target drones for anti-aircraft training.

  12. Wave Power Demonstration Project at Reedsport, Oregon

    Energy Technology Data Exchange (ETDEWEB)

    Mekhiche, Mike [Principal Investigator; Downie, Bruce [Project Manager

    2013-10-21

    Ocean wave power can be a significant source of large‐scale, renewable energy for the US electrical grid. The Electrical Power Research Institute (EPRI) conservatively estimated that 20% of all US electricity could be generated by wave energy. Ocean Power Technologies, Inc. (OPT), with funding from private sources and the US Navy, developed the PowerBuoy to generate renewable energy from the readily available power in ocean waves. OPT's PowerBuoy converts the energy in ocean waves to electricity using the rise and fall of waves to move the buoy up and down (mechanical stroking) which drives an electric generator. This electricity is then conditioned and transmitted ashore as high‐voltage power via underwater cable. OPT's wave power generation system includes sophisticated techniques to automatically tune the system for efficient conversion of random wave energy into low cost green electricity, for disconnecting the system in large waves for hardware safety and protection, and for automatically restoring operation when wave conditions normalize. As the first utility scale wave power project in the US, the Wave Power Demonstration Project at Reedsport, OR, will consist of 10 PowerBuoys located 2.5 miles off the coast. This U.S. Department of Energy Grant funding along with funding from PNGC Power, an Oregon‐based electric power cooperative, was utilized for the design completion, fabrication, assembly and factory testing of the first PowerBuoy for the Reedsport project. At this time, the design and fabrication of this first PowerBuoy and factory testing of the power take‐off subsystem are complete; additionally the power take‐off subsystem has been successfully integrated into the spar.

  13. Matrine Inhibits Infiltration of the Inflammatory Gr1hi Monocyte Subset in Injured Mouse Liver through Inhibition of Monocyte Chemoattractant Protein-1

    Directory of Open Access Journals (Sweden)

    Duo Shi

    2013-01-01

    Full Text Available Matrine (Mat is a major alkaloid extracted from Sophora flavescens Ait, an herb which is used in the traditional Chinese medicine for treatment of inflammation, cancer, and other diseases. The present study examined the impact of Mat on the CCl4-induced hepatic infiltration of Gr1hi monocytes to explore the possible mechanisms underlying its anti-inflammatory and antifibrotic effects. The results indicated that Mat protected mice from acute liver injury induced by single intraperitoneal injection of CCl4 and attenuated liver fibrosis induced by repeated CCl4 injection. Meanwhile, the infiltrations of Gr1hi monocytes in both acute and chronic injured livers were all inhibited, and the enhanced hepatic expression of MCP-1 was suppressed. Cellular experiments demonstrated that Mat directly inhibited MCP-1 production in both nonparenchymal cells and hepatic stellate cells derived from CCl4-injured livers. Transwell chemotaxis assays showed that Mat significantly inhibited the chemotactic activity of MCP-1. These results suggest that the anti-inflammatory and antifibrotic effects of Mat could be contributed, at least in part, to its prevention of Gr1hi monocyte infiltration into the injured livers and inhibition of MCP-1 production and activity. These findings extend our understanding of the mechanisms underlying the anti-inflammatory and antifibrotic effects of Mat.

  14. Reflex excitability regulates prepulse inhibition.

    Science.gov (United States)

    Schicatano, E J; Peshori, K R; Gopalaswamy, R; Sahay, E; Evinger, C

    2000-06-01

    Presentation of a weak stimulus, a prepulse, before a reflex-evoking stimulus decreases the amplitude of the reflex response relative to reflex amplitude evoked without a preceding prepulse. For example, presenting a brief tone before a trigeminal blink-eliciting stimulus significantly reduces reflex blink amplitude. A common explanation of such data are that sensory processing of the prepulse modifies reflex circuit behavior. The current study investigates the converse hypothesis that the intrinsic characteristics of the reflex circuit rather than prepulse processing determine prepulse modification of trigeminal and acoustic reflex blinks. Unilateral lesions of substantia nigra pars compacta neurons created rats with hyperexcitable trigeminal reflex blinks but normally excitable acoustic reflex blinks. In control rats, presentation of a prepulse reduced the amplitude of both trigeminal and acoustic reflex blinks. In 6-OHDA-lesioned rats, however, the same acoustic prepulse facilitated trigeminal reflex blinks but inhibited acoustic reflex blinks. The magnitude of prepulse modification correlated with reflex excitability. Humans exhibited the same pattern of prepulse modification. An acoustic prepulse facilitated the trigeminal reflex blinks of subjects with hyperexcitable trigeminal reflex blinks caused by Parkinson's disease. The same prepulse inhibited trigeminal reflex blinks of age-matched control subjects. Prepulse modification also correlated with trigeminal reflex blink excitability. These data show that reflex modification by a prepulse reflects the intrinsic characteristics of the reflex circuit rather than an external adjustment of the reflex circuit by the prepulse.

  15. Statistically significant relational data mining :

    Energy Technology Data Exchange (ETDEWEB)

    Berry, Jonathan W.; Leung, Vitus Joseph; Phillips, Cynthia Ann; Pinar, Ali; Robinson, David Gerald; Berger-Wolf, Tanya; Bhowmick, Sanjukta; Casleton, Emily; Kaiser, Mark; Nordman, Daniel J.; Wilson, Alyson G.

    2014-02-01

    This report summarizes the work performed under the project (3z(BStatitically significant relational data mining.(3y (BThe goal of the project was to add more statistical rigor to the fairly ad hoc area of data mining on graphs. Our goal was to develop better algorithms and better ways to evaluate algorithm quality. We concetrated on algorithms for community detection, approximate pattern matching, and graph similarity measures. Approximate pattern matching involves finding an instance of a relatively small pattern, expressed with tolerance, in a large graph of data observed with uncertainty. This report gathers the abstracts and references for the eight refereed publications that have appeared as part of this work. We then archive three pieces of research that have not yet been published. The first is theoretical and experimental evidence that a popular statistical measure for comparison of community assignments favors over-resolved communities over approximations to a ground truth. The second are statistically motivated methods for measuring the quality of an approximate match of a small pattern in a large graph. The third is a new probabilistic random graph model. Statisticians favor these models for graph analysis. The new local structure graph model overcomes some of the issues with popular models such as exponential random graph models and latent variable models.

  16. Determining Semantically Related Significant Genes.

    Science.gov (United States)

    Taha, Kamal

    2014-01-01

    GO relation embodies some aspects of existence dependency. If GO term xis existence-dependent on GO term y, the presence of y implies the presence of x. Therefore, the genes annotated with the function of the GO term y are usually functionally and semantically related to the genes annotated with the function of the GO term x. A large number of gene set enrichment analysis methods have been developed in recent years for analyzing gene sets enrichment. However, most of these methods overlook the structural dependencies between GO terms in GO graph by not considering the concept of existence dependency. We propose in this paper a biological search engine called RSGSearch that identifies enriched sets of genes annotated with different functions using the concept of existence dependency. We observe that GO term xcannot be existence-dependent on GO term y, if x- and y- have the same specificity (biological characteristics). After encoding into a numeric format the contributions of GO terms annotating target genes to the semantics of their lowest common ancestors (LCAs), RSGSearch uses microarray experiment to identify the most significant LCA that annotates the result genes. We evaluated RSGSearch experimentally and compared it with five gene set enrichment systems. Results showed marked improvement.

  17. Matrix Extracellular Phosphoglycoprotein Inhibits Phosphate Transport

    OpenAIRE

    Marks, J; Churchill, L J; Debnam, E. S.; Unwin, R J

    2008-01-01

    The role of putative humoral factors, known as phosphatonins, in phosphate homeostasis and the relationship between phosphate handling by the kidney and gastrointestinal tract are incompletely understood. Matrix extracellular phosphoglycoprotein (MEPE), one of several candidate phosphatonins, promotes phosphaturia, but whether it also affects intestinal phosphate absorption is unknown. Here, using the in situ intestinal loop technique, we demonstrated that short-term infusion of MEPE inhibits...

  18. Salidroside protects cortical neurons against glutamate-induced cytotoxicity by inhibiting autophagy.

    Science.gov (United States)

    Yin, Wei-Yong; Ye, Qiang; Huang, Huan-Jie; Xia, Nian-Ge; Chen, Yan-Yan; Zhang, Yi; Qu, Qiu-Min

    2016-08-01

    Recent evidence suggests that glutamate-induced cytotoxicity contributes to autophagic neuron death and is partially mediated by increased oxidative stress. Salidroside has been demonstrated to have neuroprotective effects in glutamate-induced neuronal damage. The precise mechanism of its regulatory role in neuronal autophagy is, however, poorly understood. This study aimed to probe the effects and mechanisms of salidroside in glutamate-induced autophagy activation in cultured rat cortical neurons. Cell viability assay, Western blotting, coimmunoprecipitation, and small interfering RNA were performed to analyze autophagy activities during glutamate-evoked oxidative injury. We found that salidroside protected neonatal neurons from glutamate-induced apoptotic cell death. Salidroside significantly attenuated the LC3-II/LC3-I ratio and expression of Beclin-1, but increased (SQSTM1)/p62 expression under glutamate exposure. Pretreatment with 3-methyladenine (3-MA), an autophagy inhibitor, decreased LC3-II/LC3-I ratio, attenuated glutamate-induced cell injury, and mimicked some of the protective effects of salidroside against glutamate-induced cell injury. Molecular analysis demonstrated that salidroside inhibited cortical neuron autophagy in response to glutamate exposure through p53 signaling by increasing the accumulation of cytoplasmic p53. Salidroside inhibited the glutamate-induced dissociation of the Bcl-2-Beclin-1 complex with minor affects on the PI3K/Akt/mTOR signaling pathways. These data demonstrate that the inhibition of autophagy could be responsible for the neuroprotective effects of salidroside on glutamate-induced neuronal injury.

  19. Tidd PFBC Demonstration Project, A DOE Assessment

    Energy Technology Data Exchange (ETDEWEB)

    National Energy Technology Laboratory

    2001-08-31

    The Clean Coal Technology (CCT) Demonstration Program is a government and industry co-funded technology development effort to demonstrate a new generation of innovative coal utilization processes. One goal of the program is to furnish the energy marketplace with a variety of energy efficient, environmentally superior coal-based technologies. Demonstration projects seek to establish the commercial feasibility of the most promising coal technologies that have proceeded beyond the proof-of-concept stage. This report is a post-project assessment of the DOE CCT Demonstration Program, the Tidd PFBC Demonstration Project. A major objective of the CCT Program is to provide the technical data necessary for the private sector to proceed confidently with the commercial replication of the demonstrated technologies. An essential element of meeting this goal is the dissemination of results from the demonstration projects. This post-project assessment (PPA) report is an independent DOE appraisal of the successes that the completed project had in achieving its objectives and aiding in the commercialization of the demonstrated technology. The report also provides an assessment of the expected technical, environmental, and economic performance of the commercial version of the technology, as well as an analysis of the commercial market.

  20. Acrylic Tanks for Stunning Chemical Demonstrations

    Science.gov (United States)

    Mirholm, Alexander; Ellervik, Ulf

    2009-01-01

    We describe the use of acrylic tanks (400 x 450 x 27 mm) for visualization of chemical demonstrations in aqueous solutions. Examples of well-suited demonstrations are oscillating reactions, pH indicators, photochemical reduction of Lauth's violet, and chemoluminiscent reactions. (Contains 1 figure.)

  1. Developing Noticing of Reasoning through Demonstration Lessons

    Science.gov (United States)

    Bragg, Leicha A.; Vale, Colleen

    2014-01-01

    Observation of fellow educators conducting demonstration lessons is one avenue for teachers to develop sensitivity to noticing students' reasoning. We examined teachers' noticing of children's learning behaviours in one demonstration lesson of the "Mathematical Reasoning Professional Learning Research Program" (MRPLRP). The observations…

  2. Experimental Demonstrations in Teaching Chemical Reactions.

    Science.gov (United States)

    Hugerat, Muhamad; Basheer, Sobhi

    2001-01-01

    Presents demonstrations of chemical reactions by employing different features of various compounds that can be altered after a chemical change occurs. Experimental activities include para- and dia-magnetism in chemical reactions, aluminum reaction with base, reaction of acid with carbonates, use of electrochemical cells for demonstrating chemical…

  3. Pyrrolidine dithiocarbamate inhibits enterovirus 71 replication by down-regulating ubiquitin-proteasome system.

    Science.gov (United States)

    Lin, Lexun; Qin, Ying; Wu, Heng; Chen, Yang; Wu, Shuo; Si, Xiaoning; Wang, Hui; Wang, Tianying; Zhong, Xiaoyan; Zhai, Xia; Tong, Lei; Pan, Bo; Zhang, Fengmin; Zhong, Zhaohua; Wang, Yan; Zhao, Wenran

    2015-01-02

    Enterovirus 71 (EV71) is the main causative pathogen of hand, foot, and mouth disease (HFMD). The severe neurological complications caused by EV71 infection and the lack of effective therapeutic medicine underline the importance of searching for antiviral substances. Pyrrolidine dithiocarbamate (PDTC), an antioxidant, has been reported to inhibit the replication of coxsackievirus B (CVB) through dysregulating ubiquitin-proteasome system (UPS). In this study, we demonstrated that PDTC exerted potent antiviral effect on EV71. Viral RNA synthesis, viral protein expression, and the production of viral progeny were significantly reduced by the treatment of PDTC in Vero cells infected with EV71. Similar to the previous report about the inhibitory effect of PDTC on UPS, we found that PDTC treatment led to decreased levels of polyubiquitinated proteins in EV71-infected cells. The inhibitory effect of PDTC on UPS was further confirmed by the increased accumulation of cell cycle regulatory proteins p21 and p53, which are normally degraded through UPS, while the expression levels of both proteins remained unchanged. We also showed that PDTC had no impact on the activity of proteasome. Thus, we demonstrated that the down-regulation of PDTC on UPS was the result of its inhibition on ubiquitination. More importantly, this study provides evidence that the inhibition on UPS was required for the antiviral activity of PDTC, since MG132, a potent proteasome inhibitor, significantly inhibited the cytopathic effect and viral protein synthesis in EV71-infected cells. We also found that the antioxidant property of PDTC did not contribute to its antiviral effect, since N-acetyl-l-cysteine, a potent antioxidant, could not inhibit viral replication. In addition, CPE and viral protein synthesis were not inhibited in the cells pretreated with PDTC 2h before viral infection and then cultured in the media with no PDTC supplement, while the antioxidant effect of PDTC was retained. PDTC also

  4. ORNL fusion power demonstration study: interim report

    Energy Technology Data Exchange (ETDEWEB)

    STeiner, D.; Bettis, E. S.; Huxford, T. J.

    1977-03-01

    The purpose of the ORNL Fusion Power Demonstration Study (Demo study) is to develop a plan for demonstrating, in this century, the commercial feasibility of fusion power based on the tokamak concept. The two-year study was initiated in FY 1976, and this interim report summarizes the results for FY 1976. Major results include: (1) the outline of a three-phase plan for demonstrating the commercial feasibility of tokamak fusion power in this century; (2) a parametric analysis of tokamak costs which provides the economic basis for the demonstration plan; and (3) a critical evaluation of the technological directions, design approaches, and plasma characteristics which serve as the technical basis for the demonstration plan.

  5. Inhibition of Autoimmune Diabetes in NOD Mice by miRNA Therapy.

    Directory of Open Access Journals (Sweden)

    Duncheng Wang

    Full Text Available Autoimmune destruction of the pancreatic islets in Type 1 diabetes is mediated by both increased proinflammatory (Teff and decreased regulatory (Treg T lymphocytes resulting in a significant decrease in the Treg:Teff ratio. The non-obese diabetic (NOD mouse is an excellent in vivo model for testing potential therapeutics for attenuating the decrease in the Treg:Teff ratio and inhibiting disease pathogenesis. Here we show for the first time that a bioreactor manufactured therapeutic consisting of a complex of miRNA species (denoted as TA1 can effectively reset the NOD immune system from a proinflammatory to a tolerogenic state thus preventing or delaying autoimmune diabetes. Treatment of NOD mice with TA1 resulted in a systemic broad-spectrum upregulation of tolerogenic T cell subsets with a parallel downregulation of Teff subsets yielding a dramatic increase in the Treg:Teff ratio. Moreover, the murine-derived TA1 was highly effective in the inhibition of allorecognition of HLA-disparate human PBMC. TA1 demonstrated dose-responsiveness and exhibited equivalent or better inhibition of allorecognition driven proliferation than etanercept (a soluble TNF receptor. These findings demonstrate that miRNA-based therapeutics can effectively attenuate or arrest autoimmune disease processes and may be of significant utility in a broad range of autoimmune diseases including Type 1 diabetes.

  6. The effect of static and dynamic visual gestures on stuttering inhibition.

    Science.gov (United States)

    Guntupalli, Vijaya K; Nanjundeswaran, Chayadevie; Kalinowski, Joseph; Dayalu, Vikram N

    2011-03-29

    The aim of the study was to evaluate the role of steady-state and dynamic visual gestures of vowels in stuttering inhibition. Eight adults who stuttered recited sentences from memory while watching video presentations of the following visual speech gestures: (a) a steady-state /u/, (b) dynamic production of /a-i-u/, (c) steady-state /u/ with an accompanying audible 1 kHz pure tone, and (d) dynamic production of /a-i-u/ with an accompanying audible 1 kHz pure tone. A 1 kHz pure tone and a no-external signal condition served as control conditions. Results revealed a significant main effect of auditory condition on stuttering frequency. Relative to the no-external signal condition, the combined visual plus pure tone conditions resulted in a statistically significant reduction in stuttering frequency. In addition, a significant difference in stuttering frequency was also observed when the visual plus pure tone conditions were compared to the visual only conditions. However, no significant differences were observed between the no-external signal condition and visual only conditions, or the no-external signal condition and pure tone condition. These findings are in contrast to previous findings demonstrated by similar vowel gestures presented via the auditory modality that resulted in high levels of stuttering inhibition. The differential role of sensory modalities in speech perception and production as well as their individual capacities to transfer gestural information for the purposes of stuttering inhibition is discussed.

  7. Astrobiological Significance of Microbial Extremophiles

    Science.gov (United States)

    Pikuta, Elena V.; Hoover, Richard B.

    2007-01-01

    The microflora of the cryosphere of planet Earth provides the best analogs for life forms that might be found in the permafrost or polar ice caps of Mars, near the surface of the cometary nuclei, or in the liquid water beneath and the ice crusts of icy moons of Jupiter and Saturn. The importance of study alkaliphilic microorganisms for astrobiology was enhanced by the findings of abundant carbonates and carbonate globules rimmed with possibly biogenic magnetites in association with the putative microfossils in the ALH84001 meteorite. Although the ALH84001 "nanofossils" were to small and simple to be unambiguously recognized as biogenic, they stimulated Astrobiology research and studies of microbial extremophiles and biomarkers in ancient rocks and meteorites. Recent studies of CI and CM carbonaceous meteorites have resulted in the detection of the well-preserved mineralized remains of coccoidal and filamentous microorganisms in cyanobacterial mats. Energy Dispersive X-ray Analysis has shown anomalous biogenic element ratios clearly indicating they are not recent biological contaminants. This paper reviews microbial extremophiles in context of their significance to Astrobiology. The study of halophilic microorganisms was started from work with saline soils and lakes, and one of the record of good growth for Haloferax mediterranei was shown at 30 percent NaC1. Although alkali-tolerant nitrifying bacteria had previously been reported, the first described alkaliphilic microorganism was the bacterium Streptococcus faecalis. Halophilic and alkaliphilic forms are relevant to conditions that might be found in closed impact basins and craters on Mars filled with evaporite deposits. The first obligately acidophilic bacterium described was Acidithiobacillus ferrooxydans (formally Thiobacillus ferrooxidans). Later thermophilic lithotrophic acidophiles were found, and the hyperacidophilic moderately thermophilic species of the genus Picrophilus were found to grow at negative p

  8. Gastric siderosis: patterns and significance.

    Science.gov (United States)

    Marginean, Esmeralda C; Bennick, Michael; Cyczk, Jan; Robert, Marie E; Jain, Dhanpat

    2006-04-01

    Recently, we encountered 2 cases of diffuse iron deposition in gastric antral and fundic glandular epithelium, which in 1 patient eventually led to the diagnosis of hemochromatosis. Gastric mucosal siderosis (GS) has previously been described in hemochromatosis patients, alcoholics, and in association with iron medications. However, the prevalence of various patterns of iron deposition in the gastric mucosa and their clinical significance have not been studied in detail. The 2 index cases mentioned above and 500 additional consecutive gastric biopsies examined over a period of 8 months at our institution were stained for iron by the Prussian blue method. In addition, all patients with genetic hemochromatosis diagnosed by liver biopsy in our department between 1998 and 2003 who also had gastric biopsies were identified from the surgical pathology files and included in the study (n = 3). The location of iron deposition [stromal cells (endothelium, fibroblasts, macrophages), glandular epithelium, or extracellular] was recorded and subjectively graded as 1+ to 3+ according to the severity of deposition within the mucosa. Relevant histologic changes (inflammation, presence of H. pylori, ulceration) and clinical features were reviewed. Three patterns of GS were identified: A) "nonspecific GS" with predominant iron deposition in the stromal cells including macrophages, and focally in epithelium; B) "iron-pill gastritis" with often mild gastritis and reactive gastropathy type changes, and mostly extracellular deposition with focal stromal cells and epithelial deposition; and C) predominant deposition in antral and fundic glandular epithelium. Of the 500 cases studied, a total of 18 (3.6%) cases were found to have GS. Of these 18 cases, 11 (2.2%) showed pattern A, 4 (0.8%) showed pattern B, and 3 (0.6%) showed pattern C. The GS in patterns A and B was always focal or patchy (1+ to 2+), whereas in pattern C it was generally diffuse and strong (2+ to 3+). A history of oral

  9. Functional significance of brain glycogen in sustaining glutamatergic neurotransmission

    DEFF Research Database (Denmark)

    Sickmann, Helle M; Walls, Anne B; Schousboe, Arne

    2009-01-01

    The involvement of brain glycogen in sustaining neuronal activity has previously been demonstrated. However, to what extent energy derived from glycogen is consumed by astrocytes themselves or is transferred to the neurons in the form of lactate for oxidative metabolism to proceed is at present...... in co-cultures of cerebellar neurons and astrocytes. In the astrocytes it was shown that uptake of the glutamate analogue D-[3H]aspartate was impaired when glycogen degradation was inhibited irrespective of the presence of glucose, signifying that energy derived from glycogen degradation is important...... for the astrocytic compartment. By inhibiting glycogen degradation in co-cultures it was evident that glycogen provides energy to sustain glutamatergic neurotransmission, i.e. release and uptake of glutamate. The relocation of glycogen derived lactate to the neuronal compartment was investigated by employing d...

  10. Inhibition of Quorum Sensing-Controlled Virulence Factor Production in Pseudomonas aeruginosa PAO1 by Ayurveda Spice Clove (Syzygium Aromaticum Bud Extract

    Directory of Open Access Journals (Sweden)

    Kok-Gan Chan

    2012-03-01

    Full Text Available Quorum sensing controls the virulence determinants in most proteobacteria. In this work, the hexane, chloroform and methanol extracts of an Ayurveda spice, namely clove (Syzygium aromaticum, shown anti-quorum sensing activity. Hexane and methanol extracts of clove inhibited the response of C. violaceum CV026 to exogenously supplied N‑hexanoylhomoserine lactone, in turn preventing violacein production. Chloroform and methanol extracts of clove significantly reduced bioluminescence production by E. coli [pSB1075] grown in the presence of N-(3-oxododecanoyl-L-homoserine lactone. We demonstrated that clove extract inhibited quorum sensing-regulated phenotypes in Pseudomonas aeruginosa PA01, including expression of lecA::lux (by hexane extract, swarming (maximum inhibition by methanol extract, pyocyanin (maximum inhibition by hexane extract. This study shows that the presence of natural compounds that exhibit anti-quorum sensing activity in the clove extracts may be useful as the lead of anti-infective drugs.

  11. AEP Ohio gridSMART Demonstration Project Real-Time Pricing Demonstration Analysis

    Energy Technology Data Exchange (ETDEWEB)

    Widergren, Steven E.; Subbarao, Krishnappa; Fuller, Jason C.; Chassin, David P.; Somani, Abhishek; Marinovici, Maria C.; Hammerstrom, Janelle L.

    2014-02-01

    This report contributes initial findings from an analysis of significant aspects of the gridSMART® Real-Time Pricing (RTP) – Double Auction demonstration project. Over the course of four years, Pacific Northwest National Laboratory (PNNL) worked with American Electric Power (AEP), Ohio and Battelle Memorial Institute to design, build, and operate an innovative system to engage residential consumers and their end-use resources in a participatory approach to electric system operations, an incentive-based approach that has the promise of providing greater efficiency under normal operating conditions and greater flexibility to react under situations of system stress. The material contained in this report supplements the findings documented by AEP Ohio in the main body of the gridSMART report. It delves into three main areas: impacts on system operations, impacts on households, and observations about the sensitivity of load to price changes.

  12. Milliken Clean Coal Technology Demonstration Project. Project performance summary, Clean Coal Technology Demonstration Program

    Energy Technology Data Exchange (ETDEWEB)

    None, None

    2002-11-30

    The New York State Electric & Gas Corporation (NYSEG) demonstrated a combination of technologies at its Milliken Station in Lansing, New York, designed to: (1) achieve high sulfur dioxide (SO2) capture efficiency, (2) bring nitrogen oxide (NOx) emissions into compliance with Clean Air Act Amendments of 1990 (CAAA), (3) maintain high station efficiency, and (4) eliminate waste water discharge. This project is part of the U.S. Department of Energy's (DOE) Clean Coal Technology Demonstration Program (CCTDP) established to address energy and environmental concerns related to coal use. DOE sought cost-shared partnerships with industry through five nationally competed solicitations to accelerate commercialization of the most promising advance coal-based power generation and pollution control technologies. The CCTDP, valued at over five billion dollars, has significantly leveraged federal funding by forging effective partnerships founded on sound principles. For every federal dollar invested, CCTDP participants have invested two dollars. These participants include utilities, technology developers, state governments, and research organizations. The project presented here was one of nine selected in January 1991 from 33 proposals submitted in response to the program's fourth solicitation.

  13. Milliken Clean Coal Technology Demonstration Project. Project performance summary, Clean Coal Technology Demonstration Program

    Energy Technology Data Exchange (ETDEWEB)

    None, None

    2002-11-30

    The New York State Electric & Gas Corporation (NYSEG) demonstrated a combination of technologies at its Milliken Station in Lansing, New York, designed to: (1) achieve high sulfur dioxide (SO2) capture efficiency, (2) bring nitrogen oxide (NOx) emissions into compliance with Clean Air Act Amendments of 1990 (CAAA), (3) maintain high station efficiency, and (4) eliminate waste water discharge. This project is part of the U.S. Department of Energy's (DOE) Clean Coal Technology Demonstration Program (CCTDP) established to address energy and environmental concerns related to coal use. DOE sought cost-shared partnerships with industry through five nationally competed solicitations to accelerate commercialization of the most promising advance coal-based power generation and pollution control technologies. The CCTDP, valued at over five billion dollars, has significantly leveraged federal funding by forging effective partnerships founded on sound principles. For every federal dollar invested, CCTDP participants have invested two dollars. These participants include utilities, technology developers, state governments, and research organizations. The project presented here was one of nine selected in January 1991 from 33 proposals submitted in response to the program's fourth solicitation.

  14. Propulsion Technology Demonstrator. [Demonstrating Novel CubeSat Technologies in Low Earth Orbit

    Science.gov (United States)

    Marmie, John; Martinez, Andres; Petro, Andrew

    2015-01-01

    NASA's Pathfinder Technology Demonstrator (PTD) project will test the operation of a variety of novel CubeSat technologies in low- Earth orbit, providing significant enhancements to the performance of these small and effective spacecraft. Each Pathfinder Technology Demonstrator mission consists of a 6-unit (6U) CubeSat weighing approximately 26 pounds (12 kilograms) and measuring 12 inches x 10 inches x 4 inches (30 centimeters x 25 centimeters x 10 centimeters), comparable in size to a common shoebox. CubeSats are a class of nanosatellites that use a standard size and form factor. The standard Cube- Sat size uses a "one unit" or "1U" measuring 4 inches x 4 inches x 4 inches (10x10x10 centimeters) and is extendable to larger sizes by "stacking" a number of the 1U blocks to form a larger spacecraft. Each PTD spacecraft will also be equipped with deployable solar arrays that provide an average of 44 watts of power while in orbit.

  15. Notch signaling and EMT in non-small cell lung cancer: biological significance and therapeutic application.

    Science.gov (United States)

    Yuan, Xun; Wu, Hua; Han, Na; Xu, Hanxiao; Chu, Qian; Yu, Shiying; Chen, Yuan; Wu, Kongming

    2014-12-05

    Through epithelial-mesenchymal transition (EMT), cancer cells acquire enhanced ability of migration and invasion, stem cell like characteristics and therapeutic resistance. Notch signaling regulates cell-cell connection, cell polarity and motility during organ development. Recent studies demonstrate that Notch signaling plays an important role in lung cancer initiation and cross-talks with several transcriptional factors to enhance EMT, contributing to the progression of non-small cell lung cancer (NSCLC). Correspondingly, blocking of Notch signaling inhibits NSCLC migration and tumor growth by reversing EMT. Clinical trials have showed promising effect in some cancer patients received treatment with Notch1 inhibitor. This review attempts to provide an overview of the Notch signal in NSCLC: its biological significance and therapeutic application.

  16. ANTICOMPLEMENTARY ACTIVITY IN HUMAN SERUM OF LUNG CANCER PATIENTS AND ITS POSSIBLE CLINICAL SIGNIFICANCE

    Institute of Scientific and Technical Information of China (English)

    Liu Huirong; Liang Feng; Zhang Weifang; Zheng Zhenqun

    1998-01-01

    Objective: To identify whether the level of anticomplementary activity in serum is different between lung cancer patients and normal subjects. Method: With a sensitive immune haemolytic assay, the anticomplementary activity in the sera of 50 normal subjects and 61lung cancer patients were demonstrated. Results: It was found that all samples contained complement-inhibition activity, although some were of low degree. Increased anticomplementary activity was found to be associated significantly with lung cancer. With the progression of cancer the anticomplementary activity in sera increased in different lung cancer patients. Conclusion: Such a higher anticomplementary activity in sera of lung cancer patients might be one of the immunosuppressive contents induced by the tumor cells.

  17. Inhibition of lung tumorigenesis by tea.

    Science.gov (United States)

    Yang, Chung S; Liao, Jie; Yang, Guang-yu; Lu, Gary

    2005-01-01

    Tea and tea constituents have been shown by different investigators to inhibit lung tumorigenesis in different animal model systems. This includes lung tumorigenesis in A/J mice induced by 4-(methylnitrosamino)-1-(3pyridyl)-1-butanone (NNK), N-nitrosodiethylamine, benzo[a]pyrene, N-nitrosomethylurea, or cisplatin. Inhibition of lung tumorigenesis has also been demonstrated in C3H mice treated with N-nitrosodiethylamine. In most of these experiments, reduction in tumor number and tumor size has been observed in the tea-treated group, and in some experiments, decreased tumor incidence has also been observed. The green tea constituent, epigallocatechin-3-gallate (EGCG), and the black tea constituent, theaflavins, have also been shown to be effective. Black tea preparations have been shown to reduce the incidence and number of spontaneously generated lung adenocarcinomas and rhabdomyosarcoma in A/J mice, as well as inhibit the progression of lung adenoma to adenocarcinoma. The mechanisms for the inhibitory action have not been well elucidated. It may be related to the antiproliferative, proapoptotic, and antiangiogenic activities of tea constituents that have been demonstrated in some experiments. These activities may be a result of the inhibition of key protein kinases involved in signal transduction and cell cycle regulation. Tea catechins, such as EGCG, have been suggested to be the effective components. However, a study suggests that caffeine is the key effective constituent for the inhibitory activity of lung tumorigenesis in Fisher 344 rats by black tea. In many of the experiments, tea consumption resulted in the reduction of body fat and body weight; these factors may also contribute to the inhibition of tumorigenesis.

  18. Demonstrating superconductivity at liquid nitrogen temperatures

    Science.gov (United States)

    Early, E. A.; Seaman, C. L.; Yang, K. N.; Maple, M. B.

    1988-07-01

    This article describes two demonstrations of superconductivity at the boiling temperature of liquid nitrogen (77 K) using the 90 K superconductor YBa2Cu3O7-δ(δ≊0.2). Both demonstrations involve the repulsion of a permanent magnet by a superconductor due to the expulsion of the magnetic field from the interior of the latter. In the first demonstration, the repulsion is manifested in the separation of a permanent magnet and a superconductor that are suspended from separate threads, while in the second it results in the levitation of a permanent magnet above a flat superconducting disk.

  19. Marketing Plan for Demonstration and Validation Assets

    Energy Technology Data Exchange (ETDEWEB)

    None, None

    2008-05-30

    The National Security Preparedness Project (NSPP), is to be sustained by various programs, including technology demonstration and evaluation (DEMVAL). This project assists companies in developing technologies under the National Security Technology Incubator program (NSTI) through demonstration and validation of technologies applicable to national security created by incubators and other sources. The NSPP also will support the creation of an integrated demonstration and validation environment. This report documents the DEMVAL marketing and visibility plan, which will focus on collecting information about, and expanding the visibility of, DEMVAL assets serving businesses with national security technology applications in southern New Mexico.

  20. Significance of targeting polyamine metabolism as an antineoplastic strategy: unique targets for polyamine analogues.

    Science.gov (United States)

    Casero, Robert A; Frydman, Benjamin; Stewart, Tracy Murray; Woster, Patrick M

    2005-01-01

    The polyamines, putrescine, spermidine, and spermine, are naturally occurring polycationic alkylamines that are absolutely required for eukaryotic cell growth. Importantly, the polyamine metabolic pathway, as well as the requirement of polyamines for cell growth, is frequently dysregulated in cancer cells, thus providing a unique set of targets for therapeutic intervention. Ornithine decarboxylase (ODC), a rate-limiting enzyme in polyamine biosynthesis, is frequently up-regulated in preneoplastic cells, and has been implicated as an oncogene in multiple tumor types. Several model systems have demonstrated that inhibition of ODC's enzymatic activity and down-regulation of its expression are rational strategies for both chemotherapy and chemoprevention. Specific inhibitors of ODC, most notably 2-difluoromethylornithine (DFMO), have been used experimentally to validate polyamine metabolism as an antineoplastic strategy. However, multiple biochemical and clinical limitations to these ODC-targeting strategies minimize their value as therapeutic tools. Included among these limitations are poor bioavailability of the inhibitor, and the compensatory up-regulation of polyamine metabolism and transport that allow tumor cells to escape the growth inhibitory effects of blockers specifically targeting ODC. As a strategy to overcome the limitations of direct enzyme inhibition, several groups have pursued the design of polyamine analogues that specifically target the dysregulated polyamine metabolism found in tumors. These analogues have been developed specifically to target the specific polyamine transporter, thus competing with circulating natural polyamines. Additionally, most of the analogues examined thus far maintain the regulatory function of the natural polyamines, but are unable to functionally substitute for them in promoting growth. Specifically, individual analogues have demonstrated the ability to down-regulate each of the biosynthetic enzymes without causing

  1. Sesamin inhibits IL-1β-stimulated inflammatory response in human osteoarthritis chondrocytes by activating Nrf2 signaling pathway.

    Science.gov (United States)

    Kong, Pengyu; Chen, Guanghua; Jiang, Anlong; Wang, Yufu; Song, Chengchao; Zhuang, Jinpeng; Xi, Chunyang; Wang, Guangxi; Ji, Ye; Yan, Jinglong

    2016-12-13

    Sesamin, a bioactive component extracted from sesame, has been reported to exert anti-inflammatory and anti-oxidant effects. In this study, we evaluated the anti-inflammatory effects of sesamin on IL-1β-stimulated human osteoarthritis chondrocytes and investigated the possible mechanism. Results demonstrated that sesamin treatment significantly inhibited PGE2 and NO production induced by IL-1β. Sesamin inhibited MMP1, MMP3, and MMP13 production in IL-1β-stimulated chondrocytes. Sesamin also inhibited IL-1β-induced phosphorylation of NF-κB p65 and IκBα. Meanwhile, sesamin was found to up-regulate the expression of Nrf2 and HO-1. However, Nrf2 siRNA reversed the anti-inflammatory effects of sesamin. In conclusion, our results suggested that sesamin showed anti-inflammatory effects in IL-1β-stimulated chondrocytes by activating Nrf2 signaling pathway.

  2. Wnt/β-catenin pathway regulates MGMT gene expression in cancer and inhibition of Wnt signalling prevents chemoresistance.

    Science.gov (United States)

    Wickström, Malin; Dyberg, Cecilia; Milosevic, Jelena; Einvik, Christer; Calero, Raul; Sveinbjörnsson, Baldur; Sandén, Emma; Darabi, Anna; Siesjö, Peter; Kool, Marcel; Kogner, Per; Baryawno, Ninib; Johnsen, John Inge

    2015-11-25

    The DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) is commonly overexpressed in cancers and is implicated in the development of chemoresistance. The use of drugs inhibiting MGMT has been hindered by their haematologic toxicity and inefficiency. As a different strategy to inhibit MGMT we investigated cellular regulators of MGMT expression in multiple cancers. Here we show a significant correlation between Wnt signalling and MGMT expression in cancers with different origin and confirm the findings by bioinformatic analysis and immunofluorescence. We demonstrate Wnt-dependent MGMT gene expression and cellular co-localization between active β-catenin and MGMT. Pharmacological or genetic inhibition of Wnt activity downregulates MGMT expression and restores chemosensitivity of DNA-alkylating drugs in mouse models. These findings have potential therapeutic implications for chemoresistant cancers, especially of brain tumours where the use of temozolomide is frequently used in treatment.

  3. FtsZ inhibition and redox modulation with one chemical scaffold: Potential use of dihydroquinolines against mycobacteria.

    Science.gov (United States)

    Duggirala, Sridevi; Napoleon, John Victor; Nankar, Rakesh P; Senu Adeeba, V; Manheri, Muraleedharan K; Doble, Mukesh

    2016-11-10

    The dual effect of FtsZ inhibition and oxidative stress by a group of 1,2-dihydroquinolines that culminate in bactericidal effect on mycobacterium strains is demonstrated. They inhibited the non-pathogenic Mycobacterium smegmatis mc(2) 155 with MIC as low as 0.9 μg/mL and induced filamentation. Detailed studies revealed their ability to inhibit polymerization and GTPase activity of MtbFtsZ (Mycobacterial filamentous temperature sensitive Z) with an IC50 value of ∼40 μM. In addition to such target specific effects, these compounds exerted a global cellular effect by causing redox-imbalance that was evident from overproduction of ROS in treated cells. Such multi-targeting effect with one chemical scaffold has considerable significance in this era of emerging drug resistance and could offer promise in the development of new therapeutic agents against tuberculosis.

  4. Disulfiram Is a DNA Demethylating Agent and Inhibits Prostate Cancer Cell Growth

    Science.gov (United States)

    Lin, Jianqing; Haffner, Michael C.; Zhang, Yonggang; Lee, Byron H.; Brennen, W. Nathaniel; Britton, Justin; Kachhap, Sushant K.; Shim, Joong Sup; Liu, Jun O.; Nelson, William G.; Yegnasubramanian, Srinivasan; Carducci, Michael A.

    2011-01-01

    BACKGROUND The clinical success of the nucleoside analogs 5-aza-cytidine (5-azaC) and 5-aza-2′deoxycytidine (5-aza-dC) as DNA methyltransferase (DNMT) inhibitors has spurred interest in the development of non-nucleoside inhibitors with improved pharmacologic and safety profiles. Because DNMT catalysis features attack of cytosine bases by an enzyme thiol group, we tested whether disulfiram (DSF), a thiol-reactive compound with known clinical safety, demonstrated DNMT inhibitory activity. METHODS Inhibition of DNMT1 activity by DSF was assessed using methyltransferase activity assays with recombinant DNMT1. Next, prostate cancer cell lines were exposed to DSF and assessed for: i) reduction of global 5-methyl cytosine (5meC) content using liquid chromatography/tandem mass spectrometry (LC-MS/MS); ii) gene-specific promoter demethylation by methylation-specific PCR (MSP); and iii) gene-reactivation by real-time RT-PCR. DSF was also tested for growth inhibition using prostate cancer cell lines propagated in vitro in cell culture and in vivo as xenografts in nude mice. RESULTS Disulfiram showed a dose-dependent inhibition of DNMT1 activity on a hemimethylated DNA substrate. In prostate cancer cells in culture, DSF exposure led to reduction of global genomic 5meC content, increase in unmethylated APC and RARB gene promoters, and associated re-expression of these genes, but did not significantly alter prostate-specific antigen (PSA) expression. DSF significantly inhibited growth and clonogenic survival of prostate cancer cell lines in culture and showed a trend for reduced growth of prostate cancer xenografts. CONCLUSIONS Disulfiram is a non-nucleoside DNMT1 inhibitor that can reduce global 5meC content, reactivate epigenetically silenced genes, and significantly inhibit growth in prostate cancer cell lines. PMID:20809552

  5. JAZF1 can regulate the expression of lipid metabolic genes and inhibit lipid accumulation in adipocytes

    Energy Technology Data Exchange (ETDEWEB)

    Ming, Guang-feng [Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410078, Hunan (China); Department of Critical Care Medicine, Xiangya Hospital, Central South University, Changsha 410008, Hunan (China); Xiao, Di; Gong, Wei-jing [Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410078, Hunan (China); Liu, Hui-xia; Liu, Jun [Department of Geriatrics, Xiangya Hospital, Central South University, Changsha 410008, Hunan (China); Zhou, Hong-hao [Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410078, Hunan (China); Liu, Zhao-qian, E-mail: liuzhaoqian63@126.com [Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410078, Hunan (China)

    2014-03-14

    Highlights: • JAZF1 was significantly upregulated during the differentiation of 3T3-L1 preadipocytes. • JAZF1 overexpression inhibited lipid accumulation in differentiated mature 3T3-L1 adipocytes. • JAZF1 overexpression inhibited the expression of SREBP1, ACC, and FAS. • JAZF1 overexpression upregulated the expression of HSL and ATGL. • SREBP1 and JAZF1 could regulate each other in adipocytes. - Abstract: JAZF1 is a newly identified gene with unknown functions. A recent genome-wide association study showed that JAZF1 is associated with type 2 diabetes and is highly expressed in liver and adipose tissue. Studies have demonstrated that JAZF1 is the co-repressor for nuclear orphan receptor TAK1, whereas most nuclear orphan receptor family members are involved in the regulation of lipid metabolism. Therefore, JAZF1 could be closely related to glycolipid metabolism. In this study, JAZF1 was significantly upregulated during the induced differentiation process of 3T3-L1 preadipocytes. The overexpression of JAZF1 inhibited lipid accumulation in differentiated mature 3T3-L1 adipocytes and significantly inhibited the expression of SREBPl, ACC, and FAS, which were important in lipid synthesis, while upregulating the expression of key enzyme hormone-sensitive lipase in lipoclasis. Moreover, SREBPl exhibited an inhibitory function on the expression of JAZF1. SREBP1 reversed the inhibitory action on lipid accumulation of JAZF1. SREBP1 and JAZF1 were observed to regulate each other in adipocytes. Therefore, JAZF1 could regulate the expression of particular genes related to lipid metabolism and inhibit lipid accumulation in adipocytes. This result suggests that JAZF1 may be a potential target for the treatment of diseases, such as obesity and lipid metabolism disorders.

  6. Ratite oils promote keratinocyte cell growth and inhibit leukocyte activation.

    Science.gov (United States)

    Bennett, Darin C; Leung, Gigi; Wang, Eddy; Ma, Sam; Lo, Blanche K K; McElwee, Kevin J; Cheng, Kimberly M

    2015-09-01

    Traditionally, native Australian aborigines have used emu oil for the treatment of inflammation and to accelerate wound healing. Studies on mice suggest that topically applied emu oil may have anti-inflammatory properties and may promote wound healing. We investigated the effects of ratite oils (6 emu, 3 ostrich, 1 rhea) on immortalized human keratinocytes (HaCaT cells) in vitro by culturing the cells in media with oil concentrations of 0%, 0.5%, and 1.0%. Peking duck, tea tree, and olive oils were used as comparative controls. The same oils at 0.5% concentration were evaluated for their influence on peripheral blood mononuclear cell (PBMC) survival over 48 hr and their ability to inhibit IFNγ production in PBMCs activated by phytohemagglutinin (PHA) in ELISpot assays. Compared to no oil control, significantly shorter population doubling time durations were observed for HaCaT cells cultured in emu oil (1.51×faster), ostrich oil (1.46×faster), and rhea oil (1.64×faster). Tea tree oil demonstrated significant antiproliferative activity and olive oil significantly prolonged (1.35×slower) cell population doubling time. In contrast, almost all oils, particularly tea tree oil, significantly reduced PBMC viability. Different oils had different levels of inhibitory effect on IFNγ production with individual emu, ostrich, rhea, and duck oil samples conferring full inhibition. This preliminary investigation suggests that emu oil might promote wound healing by accelerating the growth rate of keratinocytes. Combined with anti-inflammatory properties, ratite oil may serve as a useful component in bandages and ointments for the treatment of wounds and inflammatory skin conditions.

  7. Ratite oils promote keratinocyte cell growth and inhibit leukocyte activation

    Science.gov (United States)

    Bennett, Darin C.; Leung, Gigi; Wang, Eddy; Ma, Sam; Lo, Blanche K. K.; McElwee, Kevin J.; Cheng, Kimberly M.

    2015-01-01

    Traditionally, native Australian aborigines have used emu oil for the treatment of inflammation and to accelerate wound healing. Studies on mice suggest that topically applied emu oil may have anti-inflammatory properties and may promote wound healing. We investigated the effects of ratite oils (6 emu, 3 ostrich, 1 rhea) on immortalized human keratinocytes (HaCaT cells) in vitro by culturing the cells in media with oil concentrations of 0%, 0.5%, and 1.0%. Peking duck, tea tree, and olive oils were used as comparative controls. The same oils at 0.5% concentration were evaluated for their influence on peripheral blood mononuclear cell (PBMC) survival over 48 hr and their ability to inhibit IFNγ production in PBMCs activated by phytohemagglutinin (PHA) in ELISpot assays. Compared to no oil control, significantly shorter population doubling time durations were observed for HaCaT cells cultured in emu oil (1.51 × faster), ostrich oil (1.46 × faster), and rhea oil (1.64 × faster). Tea tree oil demonstrated significant antiproliferative activity and olive oil significantly prolonged (1.35 × slower) cell population doubling time. In contrast, almost all oils, particularly tea tree oil, significantly reduced PBMC viability. Different oils had different levels of inhibitory effect on IFNγ production with individual emu, ostrich, rhea, and duck oil samples conferring full inhibition. This preliminary investigation suggests that emu oil might promote wound healing by accelerating the growth rate of keratinocytes. Combined with anti-inflammatory properties, ratite oil may serve as a useful component in bandages and ointments for the treatment of wounds and inflammatory skin conditions. PMID:26217022

  8. Luteolin inhibits human prostate tumor growth by suppressing vascular endothelial growth factor receptor 2-mediated angiogenesis.

    Directory of Open Access Journals (Sweden)

    Poyil Pratheeshkumar

    Full Text Available Angiogenesis, the formation of new blood vessels from pre-existing vascular beds, is essential for tumor growth, invasion, and metastasis. Luteolin is a common dietary flavonoid found in fruits and vegetables. We studied the antiangiogenic activity of luteolin using in vitro, ex vivo, and in vivo models. In vitro studies using rat aortic ring assay showed that luteolin at non-toxic concentrations significantly inhibited microvessel sprouting and proliferation, migration, invasion and tube formation of endothelial cells, which are key events in the process of angiogenesis. Luteolin also inhibited ex vivo angiogenesis as revealed by chicken egg chorioallantoic membrane assay (CAM and matrigel plug assay. Gelatin zymographic analysis demonstrated the inhibitory effect of luteolin on the activation of matrix metalloproteinases MMP-2 and MMP-9. Western blot analysis showed that luteolin suppressed VEGF induced phosphorylation of VEGF receptor 2 and their downstream protein kinases AKT, ERK, mTOR, P70S6K, MMP-2, and MMP-9 in HUVECs. Proinflammatory cytokines such as IL-1β, IL-6, IL-8, and TNF-α level were significantly reduced by the treatment of luteolin in PC-3 cells. Luteolin (10 mg/kg/d significantly reduced the volume and the weight of solid tumors in prostate xenograft mouse model, indicating that luteolin inhibited tumorigenesis by targeting angiogenesis. CD31 and CD34 immunohistochemical staining further revealed that the microvessel density could be remarkably suppressed by luteolin. Moreover, luteolin reduced cell viability and induced apoptosis in prostate cancer cells, which were correlated with the downregulation of AKT, ERK, mTOR, P70S6K, MMP-2, and MMP-9 expressions. Taken together, our findings demonstrate that luteolin inhibits human prostate tumor growth by suppressing vascular endothelial growth factor receptor 2-mediated angiogenesis.

  9. Shoot-supplied ammonium targets the root auxin influx carrier AUX1 and inhibits lateral root emergence in Arabidopsis

    KAUST Repository

    Li, Baohai

    2011-03-24

    Deposition of ammonium (NH4 +) from the atmosphere is a substantial environmental problem. While toxicity resulting from root exposure to NH4 + is well studied, little is known about how shoot-supplied ammonium (SSA) affects root growth. In this study, we show that SSA significantly affects lateral root (LR) development. We show that SSA inhibits lateral root primordium (LRP) emergence, but not LRP initiation, resulting in significantly impaired LR number. We show that the inhibition is independent of abscisic acid (ABA) signalling and sucrose uptake in shoots but relates to the auxin response in roots. Expression analyses of an auxin-responsive reporter, DR5:GUS, and direct assays of auxin transport demonstrated that SSA inhibits root acropetal (rootward) auxin transport while not affecting basipetal (shootward) transport or auxin sensitivity of root cells. Mutant analyses indicated that the auxin influx carrier AUX1, but not the auxin efflux carriers PIN-FORMED (PIN)1 or PIN2, is required for this inhibition of LRP emergence and the observed auxin response. We found that AUX1 expression was modulated by SSA in vascular tissues rather than LR cap cells in roots. Taken together, our results suggest that SSA inhibits LRP emergence in Arabidopsis by interfering with AUX1-dependent auxin transport from shoot to root. © 2011 Blackwell Publishing Ltd.

  10. Highly Conducting Graphite Epoxy Composite Demonstrated

    Science.gov (United States)

    Gaier, James R.

    1999-01-01

    Weight savings as high as 80 percent could be achieved if graphite polymer composites could replace aluminum in structures such as electromagnetic interference shielding covers and grounding planes. This could result in significant cost savings, especially for the mobile electronics found in spacecraft, aircraft, automobiles, and hand-held consumer electronics. However, such composites had not yet been fabricated with conductivity sufficient to enable these applications. To address this lack, a partnership of the NASA Lewis Research Center, Manchester College, and Applied Sciences, Inc., fabricated nonmetallic composites with unprecedented electrical conductivity. For these composites, heat-treated, vapor-grown graphite fibers were selected which have a resistivity of about 80 mW-cm, more than 20 times more conductive than typical carbon fibers. These fibers were then intercalated with iodine bromide (IBr). Intercalation is the insertion of guest atoms or molecules between the carbon planes of the graphite fibers. Since the carbon planes are not highly distorted in the process, intercalation has little effect on mechanical and thermal properties. Intercalation does, however, lower the carbon fiber resistivity to less than 10 mW-cm, which is comparable to that of metal fibers. Scaleup of the reaction was required since the initial intercalation experiments would be carried out on 20-mg quantities of fibers, and tens of grams of intercalated fibers would be needed to fabricate even small demonstration composites. The reaction was first optimized through a time and temperature study that yielded fibers with a resistivity of 8.7 2 mW-cm when exposed to IBr vapor at 114 C for 24 hours. Stability studies indicated that the intercalated fibers rapidly lost their conductivity when exposed to temperatures as low as 40 C in air. They were not, however, susceptible to degradation by water vapor in the manner of most graphite intercalation compounds. The 1000-fold scaleup

  11. Medicare Demonstration Projects and Evaluation Reports

    Data.gov (United States)

    U.S. Department of Health & Human Services — The Centers for Medicare and Medicaid Services (CMS) conducts and sponsors a number of innovative demonstration projects to test and measure the effect of potential...

  12. A simple demonstration of corrosion cells

    Science.gov (United States)

    Guichelaar, Philip J.; Williams, Molly W.

    1990-01-01

    The objective is to reinforce and enhance the understanding of galvanic cells, anode cathode reactions and polarization phenomena. Complete instructions are given for laboratory demonstration to be performed by students.

  13. Integrated Ground Operations Demonstration Units Project

    Data.gov (United States)

    National Aeronautics and Space Administration — The overall goal of the project is to demonstrate cost efficient cryogenic operations on a relevant scale that can be projected onto future Spaceport architectures...

  14. Status of the MAJORANA DEMONSTRATOR experiment

    Energy Technology Data Exchange (ETDEWEB)

    Martin, R. D.; Abgrall, N.; Aguayo, Estanislao; Avignone, F. T.; Barabash, Alexander S.; Bertrand, F.; Boswell, M.; Brudanin, V.; Busch, Matthew; Caldwell, A. S.; Chan, Yuen-Dat; Christofferson, Cabot-Ann; Combs, Dustin C.; Detwiler, Jason A.; Doe, P. J.; Efremenko, Yuri; Egorov, Viatcheslav; Ejiri, H.; Elliott, S.; Esterline, James H.; Fast, James E.; Finnerty, P.; Fraenkle, Florian; Galindo-Uribarri, A.; Giovanetti, G. K.; Goett, J.; Green, M.; Gruszko, J.; Guiseppe, Vincente; Gusev, K.; Hallin, A. L.; Hazama, R.; Hegai, A.; Henning, R.; Hoppe, Eric W.; Howard, Stanley; Howe, M. A.; Keeter, K.; Kidd, M. F.; Kochetov, Oleg; Konovalov, S.; Kouzes, Richard T.; LaFerriere, Brian D.; Leon, Jonathan D.; Leviner, L.; Loach, J. C.; MacMullin, J.; MacMullin, S.; Mertens, S.; Mizouni, Leila; Nomachi, Masaharu; Orrell, John L.; O' Shaughnessy, Mark D.; Overman, Nicole R.; Phillips, David; Poon, Alan; Pushkin, K.; Radford, D. C.; Rielage, Keith; Robertson, R. G. H.; Romero-Romero, E.; Ronquest, M. C.; Schubert, Alexis G.; Shanks, B.; Shima, T.; Shirchenko, M.; Snavely, Kyle J.; Snyder, N.; Soin, Aleksandr; Suriano, Anne-Marie; Thompson, J.; Timkin, V.; Tornow, W.; Varner, R. L.; Vasilyev, Sergey; Vetter, Kai; Vorren, Kris R.; White, Brandon R.; Wilkerson, J. F.; Xu, W.; Yakushev, E.; Young, A.; Yu, Chang-Hong; Yumatov, Vladimir

    2014-07-08

    The MAJORANA DEMONSTRATOR neutrinoless double beta-decay experiment is currently under construction at the Sanford Underground Research Facility in South Dakota, USA. An overview and status of the experiment are given.

  15. Medicare Demonstration Projects and Evaluation Reports

    Data.gov (United States)

    U.S. Department of Health & Human Services — The Centers for Medicare and Medicaid Services (CMS) conducts and sponsors a number of innovative demonstration projects to test and measure the effect of potential...

  16. Demonstration Advanced Avionics System (DAAS), Phase 1

    Science.gov (United States)

    Bailey, A. J.; Bailey, D. G.; Gaabo, R. J.; Lahn, T. G.; Larson, J. C.; Peterson, E. M.; Schuck, J. W.; Rodgers, D. L.; Wroblewski, K. A.

    1981-01-01

    Demonstration advanced anionics system (DAAS) function description, hardware description, operational evaluation, and failure mode and effects analysis (FMEA) are provided. Projected advanced avionics system (PAAS) description, reliability analysis, cost analysis, maintainability analysis, and modularity analysis are discussed.

  17. Codes & standards research, development & demonstration Roadmap

    Energy Technology Data Exchange (ETDEWEB)

    None, None

    2008-07-22

    This Roadmap is a guide to the Research, Development & Demonstration activities that will provide data required for SDOs to develop performance-based codes and standards for a commercial hydrogen fueled transportation sector in the U.S.

  18. Keys to Successful EPIQ Business Demonstrator Implementation

    NARCIS (Netherlands)

    Shoikova, Elena; Denishev, Vladislav

    2009-01-01

    Shoikova, E., & Denishev, V. (2009). Keys to Successful EPIQ Business Demonstrator Implementation. Paper presented at the 'Open workshop of TENCompetence - Rethinking Learning and Employment at a Time of Economic Uncertainty-event'. November, 19, 2009, Manchester, United Kingdom: TENCompetence. [unp

  19. Keys to Successful EPIQ Business Demonstrator Implementation

    NARCIS (Netherlands)

    Shoikova, Elena; Denishev, Vladislav

    2009-01-01

    Shoikova, E., & Denishev, V. (2009). Keys to Successful EPIQ Business Demonstrator Implementation. Paper presented at the 'Open workshop of TENCompetence - Rethinking Learning and Employment at a Time of Economic Uncertainty-event'. November, 19, 2009, Manchester, United Kingdom: TENCompetence. [unp

  20. Rubbertown NGEM Demonstration Project - Update to Industry

    Science.gov (United States)

    Follow-up communication to Rubbertown industry group as part of the planning process for the Rubbertown NGEM demonstration study. These slides are for discussion purposes and will not be presented publically beyond the project team and industry group.

  1. A Demonstration of Automatically Switched Optical Network

    Institute of Scientific and Technical Information of China (English)

    2003-01-01

    We build an automatically switched optical network (ASON) testbed with four optical cross-connect nodes. Many fundamental ASON features are demonstrated, which is implemented by control protocols based on generalized multi-protocol label switching (GMPLS) framework.

  2. Status of the MAJORANA DEMONSTRATOR experiment

    CERN Document Server

    Martin, R D; Aguayo, E; Avignone, F T; Barabash, A S; Bertrand, F E; Boswell, M; Brudanin, V; Busch, M; Caldwell, A S; Chan, Y-D; Christofferson, C D; Combs, D C; Detwiler, J A; Doe, P J; Efremenko, Yu; Egorov, V; Ejiri, H; Elliott, S R; Esterline, J; Fast, J E; Finnerty, P; Fraenkle, F M; Galindo-Uribarri, A; Giovanetti, G K; Goett, J; Green, M P; Gruszko, J; Guiseppe, V E; Gusev, K; Hallin, A L; Hazama, R; Hegai, A; Henning, R; Hoppe, E W; Howard, S; Howe, M A; Keeter, K J; Kidd, M F; Kochetov, O; Konovalov, S I; Kouzes, R T; LaFerriere, B D; Leon, J; Leviner, L E; Loach, J C; MacMullin, J; MacMullin, S; Mertens, S; Mizouni, L; Nomachi, M; Orrell, J L; O'Shaughnessy, C; Overman, N R; Phillips, D G; Poon, A W P; Pushkin, K; Radford, D C; Rielage, K; Robertson, R G H; Romero-Romero, E; Ronquest, M C; Schubert, A G; Shanks, B; Shima, T; Shirchenko, M; Snavely, K J; Snyder, N; Soin, A; Suriano, A M; Thompson, J; Timkin, V; Tornow, W; Varner, R L; Vasilyev, S; Vetter, K; Vorren, K; White, B R; Wilkerson, J F; Xu, W; Yakushev, E; Young, A R; Yu, C -H; Yumatov, V

    2013-01-01

    The MAJORANA DEMONSTRATOR neutrinoless double beta-decay experiment is currently under construction at the Sanford Underground Research Facility in South Dakota, USA. An overview and status of the experiment are given.

  3. Lessons Learned from Microgrid Demonstrations Worldwide

    Energy Technology Data Exchange (ETDEWEB)

    Marnay, Chris [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Zhou, Nan [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Qu, Min [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Romankiewicz, John [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)

    2012-01-31

    The survey leads to policy recommendations for starting a microgrid demonstration program and overall development of microgrid and distributed energy. Additionally, specific recommendations have been made for China specifically.

  4. Demonstration and Deployment Strategy Workshop: Summary

    Energy Technology Data Exchange (ETDEWEB)

    none,

    2014-05-01

    This report is based on the proceedings of the U.S. Department of Energy Bioenergy Technologies Office Demonstration and Deployment Strategy Workshop, held on March 12–13, 2014, at Argonne National Laboratory.

  5. Peculiarities of latent inhibition formation in SHR rats in conditioned task of different complexity.

    Science.gov (United States)

    Kostyunina, N V; Loskutova, L V

    2012-05-01

    Inhibition of attention to irrelevant stimuli was studied in SHR rats using latent inhibition test. Latent inhibition was formed in two types of conditioned tasks with different levels of complexity and stress. Passive and active avoidance conditioning was preceded by preexposure to conditioned stimulus consisting of 20 and 100 non-reinforced presentations, respectively. Control Wistar rats demonstrated successful formation of latent inhibition in both tasks. SHR rats showed different degree of disruption of latent inhibition depending on the type of behavioral task. We assume that learning defect in these animals in respect to both novel and preexposed conditioned stimuli is associated with the lack of behavioral inhibition.

  6. Some simple demonstration experiments involving homopolar motors

    OpenAIRE

    Stewart,Seán M.

    2007-01-01

    The ready availability of very strong permanent magnets in the form of rare-earth magnetic alloys such as neodymium-iron-boron has lead to renewed interest in one of the oldest types of electric motors - the homopolar motor. The ease with which a demonstration homopolar motor can now be built and operated when neodymium magnets are used is quite remarkable. In this paper some simple homopolar motors employing neodymium magnets suitable for demonstrational purposes are described and discussed.

  7. Interactive Image Processing demonstrations for the web

    OpenAIRE

    Tella Amo, Marcel

    2011-01-01

    The main goal in this project is to improve the way how image processing developers can test their algorithms, and show them to other people to demonstrate their performance. This diploma thesis aims to provide a framework for developing web applications for ImagePlus, the software develpment platform in C++ of the Image Processing Group of the Technical University of Catalonia (UPC). These web applications are to demonstrate the functionality of the image processing algorithms to any ...

  8. Electrometallurgical treatment demonstration at ANL-West

    Energy Technology Data Exchange (ETDEWEB)

    Goff, K. M.; Benedict, R. W.; Johnson, S. G.; Mariani, R. D.; Simpson, M. F.; Westphal, B. R.

    2000-03-20

    Electrometallurgical treatment (EMT) was developed by Argonne National Laboratory (ANL) to ready sodium-bonded spent nuclear fuel for geological disposal. A demonstration of this technology was successfully completed in August 1999. EMT was used to condition irradiated EBR-II driver and blanket fuel at ANL-West. The results of this demonstration, including the production of radioactive high-level waste forms, are presented.

  9. Demonstratives and the rhetorical structure of discourse

    OpenAIRE

    2009-01-01

    Besides a canonical and extensively studied deictic use, demonstratives contribute to discourse cohesion in various ways. As a consequence of that these elements can be defined as multifunctional cohesion making devices. As pronominal elements, demonstratives help establish referential networks that go beyond the sentence. Thus, they serve to refer to diverse discourse entities such as individuals, events, or even entire fragments of discourse. As discourse deictic and anaphoric elements, dem...

  10. Guidance manual for conducting technology demonstration activities

    Energy Technology Data Exchange (ETDEWEB)

    Jolley, Robert L.; Morris, Michael I.; Singh, Suman P.N.

    1991-12-01

    This demonstration guidance manual has been prepared to assist Martin Marietta Energy Systems, Inc. (Energy Systems), staff in conducting demonstrations. It is prepared in checklist style to facilitate its use and assumes that Energy Systems personnel have project management responsibility. In addition to a detailed step-by-step listing of procedural considerations, a general checklist, logic flow diagram, and several examples of necessary plans are included to assist the user in developing an understanding of the many complex activities required to manage technology demonstrations. Demonstrations are pilot-scale applications of often innovative technologies to determine the commercial viability of the technologies to perform their designed function. Demonstrations are generally conducted on well-defined problems for which existing technologies or processes are less than satisfactory in terms of effectiveness, cost, and/or regulatory compliance. Critically important issues in demonstration management include, but are not limited to, such factors as communications with line and matrix management and with the US Department of Energy (DOE) and Energy Systems staff responsible for management oversight, budgetary and schedule requirements, regulatory compliance, and safety.

  11. Beneficial bacteria inhibit cachexia.

    Science.gov (United States)

    Varian, Bernard J; Goureshetti, Sravya; Poutahidis, Theofilos; Lakritz, Jessica R; Levkovich, Tatiana; Kwok, Caitlin; Teliousis, Konstantinos; Ibrahim, Yassin M; Mirabal, Sheyla; Erdman, Susan E

    2016-03-15

    Muscle wasting, known as cachexia, is a debilitating condition associated with chronic inflammation such as during cancer. Beneficial microbes have been shown to optimize systemic inflammatory tone during good health; however, interactions between microbes and host immunity in the context of cachexia are incompletely understood. Here we use mouse models to test roles for bacteria in muscle wasting syndromes. We find that feeding of a human commensal microbe, Lactobacillus reuteri, to mice is sufficient to lower systemic indices of inflammation and inhibit cachexia. Further, the microbial muscle-building phenomenon extends to normal aging as wild type animals exhibited increased growth hormone levels and up-regulation of transcription factor Forkhead Box N1 [FoxN1] associated with thymus gland retention and longevity. Interestingly, mice with a defective FoxN1 gene (athymic nude) fail to inhibit sarcopenia after L. reuteri therapy, indicating a FoxN1-mediated mechanism. In conclusion, symbiotic bacteria may serve to stimulate FoxN1 and thymic functions that regulate inflammation, offering possible alternatives for cachexia prevention and novel insights into roles for microbiota in mammalian ontogeny and phylogeny.

  12. Silibinin and Paclitaxel Cotreatment Significantly Suppress the Activity and Lung Metastasis of Triple Negative 4T1 Mammary Tumor Cell in Mice

    Directory of Open Access Journals (Sweden)

    Bing-Ying Ho

    2012-10-01

    Full Text Available The in vitro and in vivo bioactivities of silibinin (SB, paclitaxel (PTX and SB and PTX in combination (SB+PTX against murine metastatic mammary 4T1 cancer cell line were investigated. Isobologram and combination index (CI analyses showed that SB and PTX can function synergistically in the inhibition of 4T1 cell proliferation with a CI value<1. Both SB and PTX alone or SB+PTX treatment inhibited 4T1 cell migration and motility possibly through downregulation of the serpin protease nexin-1 (PN-1 and N-cadherin expression, inhibition of matrix metalloprotease (MMP-9 activity, and upregulation of E-cadherin. Flow cytometry and Western blot analyses demonstrated that both drugs deregulated cell-cycle mediators and induced apoptosis in 4T1 cells. A real-time in vivo bioluminescence imaging system to monitor the breast cancer cell metastasis in syngeneic BALB/c mice was established using a stable 4T1pGL−COX−2/Luc cell clone carrying a COX-2 promoter driven-luciferase reporter gene. In vivo study using the allograft 4T1pGL−COX−2/Luc metastatic mouse model indicated that SB co-treated with PTX can significantly suppress lung metastasis of 4T1 cells likely through inhibiting cell proliferation and angiogenesis. Together, this study demonstrates that SB could act synergistically with PTX in 4T1 cells, providing a therapeutic option for highly metastatic triple negative breast cancer.

  13. Sonic hedgehog signaling inhibition provides opportunities for targeted therapy by sulforaphane in regulating pancreatic cancer stem cell self-renewal.

    Directory of Open Access Journals (Sweden)

    Mariana Rodova

    Full Text Available Dysregulation of the sonic hedgehog (Shh signaling pathway has been associated with cancer stem cells (CSC and implicated in the initiation of pancreatic cancer. Pancreatic CSCs are rare tumor cells characterized by their ability to self-renew, and are responsible for tumor recurrence accompanied by resistance to current therapies. The lethality of these incurable, aggressive and invasive pancreatic tumors remains a daunting clinical challenge. Thus, the objective of this study was to investigate the role of Shh pathway in pancreatic cancer and to examine the molecular mechanisms by which sulforaphane (SFN, an active compound in cruciferous vegetables, inhibits self-renewal capacity of human pancreatic CSCs. Interestingly, we demonstrate here that Shh pathway is highly activated in pancreatic CSCs and plays important role in maintaining stemness by regulating the expression of stemness genes. Given the requirement for Hedgehog in pancreatic cancer, we investigated whether hedgehog blockade by SFN could target the stem cell population in pancreatic cancer. In an in vitro model, human pancreatic CSCs derived spheres were significantly inhibited on treatment with SFN, suggesting the clonogenic depletion of the CSCs. Interestingly, SFN inhibited the components of Shh pathway and Gli transcriptional activity. Interference of Shh-Gli signaling significantly blocked SFN-induced inhibitory effects demonstrating the requirement of an active pathway for the growth of pancreatic CSCs. SFN also inhibited downstream targets of Gli transcription by suppressing the expression of pluripotency maintaining factors (Nanog and Oct-4 as well as PDGFRα and Cyclin D1. Furthermore, SFN induced apoptosis by inhibition of BCL-2 and activation of caspases. Our data reveal the essential role of Shh-Gli signaling in controlling the characteristics of pancreatic CSCs. We propose that pancreatic cancer preventative effects of SFN may result from inhibition of the Shh pathway

  14. Topical treatment of all-trans retinoic acid inhibits murine melanoma partly by promoting CD8(+) T-cell immunity.

    Science.gov (United States)

    Yin, Wei; Song, Yan; Liu, Qing; Wu, Yunyun; He, Rui

    2017-10-01

    All-trans retinoic acid (atRA), the main biologically active metabolite of vitamin A, has been implicated in immunoregulation and anti-cancer. A recent finding that vitamin A could decrease the risk of melanoma in humans indicates the beneficial role of atRA in melanoma. However, it remains unknown whether topical application of atRA could inhibit melanoma growth by influencing tumour immunity. We demonstrate topical application of tretinoin ointment (atRA as the active ingredient) effectively inhibited B16F10 melanoma growth. This is accompanied by markedly enhanced CD8(+) T-cell responses, as evidenced by significantly increased proportions of effector CD8(+) T cells expressing granzyme B, tumour necrosis factor-α, or interferon-γ, and Ki67(+) proliferating CD8(+) T cells in atRA-treated tumours compared with vaseline controls. Furthermore, topical atRA treatment promoted the differentiation of effector CD8(+) T cells in draining lymph nodes (DLN) of tumour-bearing mice. Interestingly, atRA did not affect tumoral CD4(+) T-cell response, and even inhibited the differentiation of interferon-γ-expressing T helper type 1 cells in DLN. Importantly, we demonstrated that the tumour-inhibitory effect of atRA was partly dependent on CD8(+) T cells, as CD8(+) T-cell depletion restored tumour volumes in atRA-treated mice, which, however, was still significantly smaller than those in vaseline-treated mice. Finally, we demonstrated that atRA up-regulated MHCI expression in B16F10 cells, and DLN cells from tumour-bearing mice had a significantly higher killing rate when culturing with atRA-treated B16F10 cells. Hence, our study demonstrates that topical atRA treatment effectively inhibits melanoma growth partly by promoting the differentiation and the cytotoxic function of effector CD8(+) T cells. © 2017 John Wiley & Sons Ltd.

  15. Quantitative phosphoproteomics of proteasome inhibition in multiple myeloma cells.

    Directory of Open Access Journals (Sweden)

    Feng Ge

    Full Text Available BACKGROUND: The proteasome inhibitor bortezomib represents an important advance in the treatment of multiple myeloma (MM. Bortezomib inhibits the activity of the 26S proteasome and induces cell death in a variety of tumor cells; however, the mechanism of cytotoxicity is not well understood. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the differential phosphoproteome upon proteasome inhibition by using stable isotope labeling by amino acids in cell culture (SILAC in combination with phosphoprotein enrichment and LC-MS/MS analysis. In total 233 phosphoproteins were identified and 72 phosphoproteins showed a 1.5-fold or greater change upon bortezomib treatment. The phosphoproteins with expression alterations encompass all major protein classes, including a large number of nucleic acid binding proteins. Site-specific phosphopeptide quantitation revealed that Ser38 phosphorylation on stathmin increased upon bortezomib treatment, suggesting new mechanisms associated to bortezomib-induced apoptosis in MM cells. Further studies demonstrated that stathmin phosphorylation profile was modified in response to bortezomib treatment and the regulation of stathmin by phosphorylation at specific Ser/Thr residues participated in the cellular response induced by bortezomib. CONCLUSIONS/SIGNIFICANCE: Our systematic profiling of phosphorylation changes in response to bortezomib treatment not only advanced the global mechanistic understanding of the action of bortezomib on myeloma cells but also identified previously uncharacterized signaling proteins in myeloma cells.

  16. Ginger phytochemicals exhibit synergy to inhibit prostate cancer cell proliferation.

    Science.gov (United States)

    Brahmbhatt, Meera; Gundala, Sushma R; Asif, Ghazia; Shamsi, Shahab A; Aneja, Ritu

    2013-01-01

    Dietary phytochemicals offer nontoxic therapeutic management as well as chemopreventive intervention for slow-growing prostate cancers. However, the limited success of several single-agent clinical trials suggest a paradigm shift that the health benefits of fruits and vegetables are not ascribable to individual phytochemicals, rather may be ascribed to synergistic interactions among them. We recently reported growth-inhibiting and apoptosis-inducing properties of ginger extract (GE) in in vitro and in vivo prostate cancer models. Nevertheless, the nature of interactions among the constituent ginger biophenolics, viz. 6-gingerol, 8-gingerol, 10-gingerol, and 6-shogoal, remains elusive. Here we show antiproliferative efficacy of the most-active GE biophenolics as single-agents and in binary combinations, and investigate the nature of their interactions using the Chou-Talalay combination index (CI) method. Our data demonstrate that binary combinations of ginger phytochemicals synergistically inhibit proliferation of PC-3 cells with CI values ranging from 0.03 to 0.88. To appreciate synergy among phytochemicals present in GE, the natural abundance of ginger biophenolics was quantitated using LC-UV/MS. Interestingly, combining GE with its constituents (in particular, 6-gingerol) resulted in significant augmentation of GE's antiproliferative activity. These data generate compelling grounds for further preclinical evaluation of GE alone and in combination with individual ginger biophenols for prostate cancer management.

  17. Inhibition of bacterial ammonia oxidation by organohydrazines in soil microcosms

    Directory of Open Access Journals (Sweden)

    Yucheng eWu

    2012-01-01

    Full Text Available Hydroxylamine oxidation by hydroxylamine oxidoreductase (HAO is a key step for energy-yielding in support of the growth of ammonia-oxidizing bacteria (AOB. Organohydrazines have been shown to inactivate HAO from Nitrosomonas europaea, and may serve as selective inhibitors to differentiate bacterial from archaeal ammonia oxidation due to the absence of bacterial HAO gene homologue in known ammonia-oxidizing archaea (AOA. In this study, the effects of three organohydrazines on activity, abundance and composition of AOB and AOA were evaluated in soil microcosms. The results indicate that phenylhydrazine and methylhydrazine at the concentration of 100 mol per gram dry weight soil completely suppressed the activity of soil nitrification. DGGE fingerprinting and sequencing analysis of bacterial ammonia monooxygenase subunit A gene (amoA clearly demonstrated that nitrification activity change is well paralleled with the growth of Nitrosomonas europaea-like AOB in soil microcosms. No significant correlation between AOA community structure and nitrification activity was observed among all treatments during the incubation period, although incomplete inhibition of nitrification activity occurred in 2-hydroxyethylhydrazine-amended soil microcosms. These findings show that the HAO-targeted organohydrazines can effectively inhibit bacterial nitrification in soil, and the mechanism of organohydrazine affecting AOA remains unclear.

  18. Grafting MAP peptide to dental polymer inhibits MMP-8 activity.

    Science.gov (United States)

    Dixit, Namrata; Settle, Jenifer K; Ye, Qiang; Berrie, Cindy L; Spencer, Paulette; Laurence, Jennifer S

    2015-02-01

    Matrix metalloproteinases (MMPs) are a class of zinc and calcium-dependent endopeptidases responsible for degrading extracellular matrix (ECM) components. Their activity is critical for both normal biological function and pathological processes (Dejonckheere et al., Cytokine Growth Factor Rev 2011;22:73-81). In dental restorations, the release and subsequent acid activation of MMPs contributes to premature failure. In particular, MMP-8 accelerates degradation by cleaving the collagen matrix within the dentin substrate in incompletely infiltrated aged bonded dentin (Buzalaf et al., Adv Dent Res 2012;24:72-76), hastening the need for replacement of restorations. Therefore, development of a dental adhesive that better resists MMP-8 activity is of significant interest. We hypothesize that modification of the polymer surface with an inhibitor would disable MMP-8 activity. Here, we identify the metal abstraction peptide (MAP) as an inhibitor of MMP-8 and demonstrate that tethering MAP to methacrylate polymers effectively inhibits catalysis. Our findings indicate complete inhibition of MMP-8 is achievable using a grafting approach. This strategy has potential to improve longevity of dental adhesives and other polymers and enable rational design of a new generation of biocompatible materials.

  19. Inhibition of Rho kinase regulates specification of early differentiation events in P19 embryonal carcinoma stem cells.

    Directory of Open Access Journals (Sweden)

    Roman J Krawetz

    Full Text Available BACKGROUND: The Rho kinase pathway plays a key role in many early cell/tissue determination events that take place in embryogenesis. Rho and its downstream effector Rho kinase (ROCK play pivotal roles in cell migration, apoptosis (membrane blebbing, cell proliferation/cell cycle, cell-cell adhesion and gene regulation. We and others have previously demonstrated that inhibition of ROCK blocks endoderm differentiation in embryonal carcinoma stem cells, however, the effect of ROCK inhibition on mesoderm and ectoderm specification has not been fully examined. In this study, the role of ROCK within the specification and differentiation of all three germ layers was examined. METHODOLOGY/PRINCIPAL FINDINGS: P19 cells were treated with the specific ROCK inhibitor Y-27623, and increase in differentiation efficiency into neuro-ectodermal and mesodermal lineages was observed. However, as expected a dramatic decrease in early endodermal markers was observed when ROCK was inhibited. Interestingly, within these ROCK-inhibited RA treated cultures, increased levels of mesodermal or ectodermal markers were not observed, instead it was found that the pluripotent markers SSEA-1 and Oct-4 remained up-regulated similar to that seen in undifferentiated cultures. Using standard and widely accepted methods for reproducible P19 differentiation into all three germ layers, an enhancement of mesoderm and ectoderm differentiation with a concurrent loss of endoderm lineage specification was observed with Y-27632 treatment. Evidence would suggest that this effect is in part mediated through TGF-β and SMAD signaling as ROCK-inhibited cells displayed aberrant SMAD activation and did not return to a 'ground' state after the inhibition had been removed. CONCLUSIONS/SIGNIFICANCE: Given this data and the fact that only a partial rescue of normal differentiation capacity occurred when ROCK inhibition was alleviated, the effect of ROCK inhibition on the differentiation capacity of

  20. Dehydroepiandrosterone (DHEA) inhibits voltage-gated T-type calcium channels.

    Science.gov (United States)

    Chevalier, M; Gilbert, G; Lory, P; Marthan, R; Quignard, J F; Savineau, J P

    2012-06-01

    Dehydroepiandrosterone (DHEA) and its sulfated form, DHEAS, are the most abundant steroid hormones in the mammalian blood flow. DHEA may have beneficial effects in various pathophysiological conditions such as cardiovascular diseases or deterioration of the sense of well-being. However to date, the cellular mechanism underlying DHEA action remains elusive and may involve ion channel modulation. In this study, we have characterized the effect of DHEA on T-type voltage-activated calcium channels (T-channels), which are involved in several cardiovascular and neuronal diseases. Using the whole-cell patch-clamp technique, we demonstrate that DHEA inhibits the three recombinant T-channels (Ca(V)3.1, Ca(V)3.2 and Ca(V)3.3) expressed in NG108-15 cell line, as well as native T-channels in pulmonary artery smooth muscle cells. This effect of DHEA is both concentration (IC(50) between 2 and 7μM) and voltage-dependent and results in a significant shift of the steady-state inactivation curves toward hyperpolarized potentials. Consequently, DHEA reduces window T-current and inhibits membrane potential oscillations induced by Ca(V)3 channels. DHEA inhibition is not dependent on the activation of nuclear androgen or estrogen receptors and implicates a PTX-sensitive Gi protein pathway. Functionally, DHEA and the T-type inhibitor NNC 55-0396 inhibited KCl-induced contraction of pulmonary artery rings and their effect was not cumulative. Altogether, the present data demonstrate that DHEA inhibits T-channels by a Gi protein dependent pathway. DHEA-induced alteration in T-channel activity could thus account for its therapeutic action and/or physiological effects. Copyright © 2012 Elsevier Inc. All rights reserved.

  1. Tribbles 3 inhibits brown adipocyte differentiation and function by suppressing insulin signaling

    Energy Technology Data Exchange (ETDEWEB)

    Jeong, Ha-Won; Choi, Ran Hee; McClellan, Jamie L. [Division of Applied Physiology, Department of Exercise Science, University of South Carolina, Columbia, SC 29208 (United States); Piroli, Gerardo G.; Frizzell, Norma [Department of Pharmacology, Physiology & Neuroscience, University of South Carolina School of Medicine, Columbia, SC 29208 (United States); Tseng, Yu-Hua; Goodyear, Laurie J. [Research Division, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA 02215 (United States); Koh, Ho-Jin, E-mail: kohh@mailbox.sc.edu [Division of Applied Physiology, Department of Exercise Science, University of South Carolina, Columbia, SC 29208 (United States)

    2016-02-19

    Recent studies have demonstrated that adult humans have substantial amounts of functioning brown adipose tissue (BAT). Since BAT has been implicated as an anti-obese and anti-diabetic tissue, it is important to understand the signaling molecules that regulate BAT function. There has been a link between insulin signaling and BAT metabolism as deletion or pharmaceutical inhibition of insulin signaling impairs BAT differentiation and function. Tribbles 3 (TRB3) is a pseudo kinase that has been shown to regulate metabolism and insulin signaling in multiple tissues but the role of TRB3 in BAT has not been studied. In this study, we found that TRB3 expression was present in BAT and overexpression of TRB3 in brown preadipocytes impaired differentiation and decreased expression of BAT markers. Furthermore, TRB3 overexpression resulted in significantly lower oxygen consumption rates for basal and proton leakage, indicating decreased BAT activity. Based on previous studies showing that deletion or pharmaceutical inhibition of insulin signaling impairs BAT differentiation and function, we assessed insulin signaling in brown preadipocytes and BAT in vivo. Overexpression of TRB3 in cells impaired insulin-stimulated IRS1 and Akt phosphorylation, whereas TRB3KO mice displayed improved IRS1 and Akt phosphorylation. Finally, deletion of IRS1 abolished the function of TRB3 to regulate BAT differentiation and metabolism. These data demonstrate that TRB3 inhibits insulin signaling in BAT, resulting in impaired differentiation and function. - Highlights: • TRB3 is expressed in brown adipose tissue and its expression is increased during differentiation. • Overexpression of TRB3 inhibits differentiation and its activity. • Overexpression of TRB3 in brown preadipocytes inhibits insulin signaling. • TRB3KO mice displays improved insulin signaling in brown adipose tissue. • Insulin signaling is required for the effects of TRB3 to regulate brown adipose tissue differentiation and

  2. Inhibition of NF-κB promotes autophagy via JNK signaling pathway in porcine granulosa cells

    Energy Technology Data Exchange (ETDEWEB)

    Gao, Hui; Lin, Lu; Haq, Ihtesham Ul; Zeng, Shen-ming, E-mail: zengshenming@gmail.com

    2016-04-22

    The transcription factor nuclear factor-κB (NF-κB) plays an important role in diverse processes, including cell proliferation and differentiation, apoptosis and inflammation. However, the role of NF-κB in porcine follicle development is not clearly elucidated. In this study, we demonstrated that follicle stimulating hormone (FSH) increased the level of inhibitor of NF-κB (IκB) protein and promoted the cytoplasmic localization of p65, indicating that FSH inhibits the activation of NF-κB in porcine granulosa cells. Moreover, inhibition of NF-κB by FSH or another specific inhibitor of NF-κB, pyrrolidine dithiocarbamate (PDTC), could activate JNK signaling and enhance autophagic activity in porcine granulosa cells. Knockdown of RelA (p65) Subunit of NF-κB by RNA interference abrogated the activation of JNK signaling pathway and the increase of autophagic protein expression by FSH. Meanwhile, the functional significance of FSH or PDTC-mediated autophagy were further investigated. Our results demonstrated that the increased autophagy promoted progesterone secretion in porcine granulosa cells. Blockage of autophagy by chloroquine obviated the FSH or PDTC-induced progesterone production. Taken together, these results indicate that inhibition of NF-κB increased autophagy via JNK signaling, and promote steroidogenesis in porcine granulosa cells. Our results provide new insights into the regulation and function of autophagy in mammalian follicle development. - Highlights: • FSH inhibits the activation of NF-κB in porcine primary granulosa cells. • Inhibition of NF-κB by FSH promotes autophagy via JNK signaling in granulosa cells. • Increased autophagy contributes to progesterone production in granulosa cells. • This is the first report against beclin1 regulation in porcine granulosa cells.

  3. Cerebellar cortical inhibition and classical eyeblink conditioning.

    Science.gov (United States)

    Bao, Shaowen; Chen, Lu; Kim, Jeansok J; Thompson, Richard F

    2002-02-01

    The cerebellum is considered a brain structure in which memories for learned motor responses (e.g., conditioned eyeblink responses) are stored. Within the cerebellum, however, the relative importance of the cortex and the deep nuclei in motor learning/memory is not entirely clear. In this study, we show that the cerebellar cortex exerts both basal and stimulus-activated inhibition to the deep nuclei. Sequential application of a gamma-aminobutyric acid type A receptor (GABA(A)R) agonist and a noncompetitive GABA(A)R antagonist allows selective blockade of stimulus-activated inhibition. By using the same sequential agonist and antagonist methods in behaving animals, we demonstrate that the conditioned response (CR) expression and timing are completely dissociable and involve different inhibitory inputs; although the basal inhibition modulates CR expression, the conditioned stimulus-activated inhibition is required for the proper timing of the CR. In addition, complete blockade of cerebellar deep nuclear GABA(A)Rs prevents CR acquisition. Together, these results suggest that different aspects of the memories for eyeblink CRs are encoded in the cerebellar cortex and the cerebellar deep nuclei.

  4. Acidosis inhibits mineralization in human osteoblasts.

    Science.gov (United States)

    Takeuchi, Shoko; Hirukawa, Koji; Togari, Akifumi

    2013-09-01

    Osteoblasts and osteoclasts maintain bone volume. Acidosis affects the function of these cells including mineral metabolism. We examined the effect of acidosis on the expression of transcription factors and mineralization in human osteoblasts in vitro. Human osteoblasts (SaM-1 cells) derived from the ulnar periosteum were cultured with α-MEM containing 50 μg/ml ascorbic acid and 5 mM β-glycerophosphate (calcifying medium). Acidosis was induced by incubating the SaM-1 cells in 10 % CO₂ (pH approximately 7.0). Mineralization, which was augmented by the calcifying medium, was completely inhibited by acidosis. Acidosis depressed c-Jun mRNA and increased osteoprotegerin (OPG) production in a time-dependent manner. Depressing c-Jun mRNA expression using siRNA increased OPG production and inhibited mineralization. In addition, depressing OPG mRNA expression with siRNA enhanced mineralization in a dose-dependent manner. Acidosis or the OPG protein strongly inhibited mineralization in osteoblasts from neonatal mice. The present study was the first to demonstrate that acidosis inhibited mineralization, depressed c-Jun mRNA expression, and induced OPG production in human osteoblasts. These results suggest that OPG is involved in mineralization via c-Jun in human osteoblasts.

  5. Nickel inhibits mitochondrial fatty acid oxidation.

    Science.gov (United States)

    Uppala, Radha; McKinney, Richard W; Brant, Kelly A; Fabisiak, James P; Goetzman, Eric S

    2015-08-07

    Nickel exposure is associated with changes in cellular energy metabolism which may contribute to its carcinogenic properties. Here, we demonstrate that nickel strongly represses mitochondrial fatty acid oxidation-the pathway by which fatty acids are catabolized for energy-in both primary human lung fibroblasts and mouse embryonic fibroblasts. At the concentrations used, nickel suppresses fatty acid oxidation without globally suppressing mitochondrial function as evidenced by increased glucose oxidation to CO2. Pre-treatment with l-carnitine, previously shown to prevent nickel-induced mitochondrial dysfunction in neuroblastoma cells, did not prevent the inhibition of fatty acid oxidation. The effect of nickel on fatty acid oxidation occurred only with prolonged exposure (>5 h), suggesting that direct inhibition of the active sites of metabolic enzymes is not the mechanism of action. Nickel is a known hypoxia-mimetic that activates hypoxia inducible factor-1α (HIF1α). Nickel-induced inhibition of fatty acid oxidation was blunted in HIF1α knockout fibroblasts, implicating HIF1α as one contributor to the mechanism. Additionally, nickel down-regulated the protein levels of the key fatty acid oxidation enzyme very long-chain acyl-CoA dehydrogenase (VLCAD) in a dose-dependent fashion. In conclusion, inhibition of fatty acid oxidation by nickel, concurrent with increased glucose metabolism, represents a form of metabolic reprogramming that may contribute to nickel-induced carcinogenesis.

  6. Indole and 3-indolylacetonitrile inhibit spore maturation in Paenibacillus alvei

    Directory of Open Access Journals (Sweden)

    Cho Moo

    2011-05-01

    Full Text Available Abstract Background Bacteria use diverse signaling molecules to ensure the survival of the species in environmental niches. A variety of both Gram-positive and Gram-negative bacteria produce large quantities of indole that functions as an intercellular signal controlling diverse aspects of bacterial physiology. Results In this study, we sought a novel role of indole in a Gram-positive bacteria Paenibacillus alvei that can produce extracellular indole at a concentration of up to 300 μM in the stationary phase in Luria-Bertani medium. Unlike previous studies, our data show that the production of indole in P. alvei is strictly controlled by catabolite repression since the addition of glucose and glycerol completely turns off the indole production. The addition of exogenous indole markedly inhibits the heat resistance of P. alvei without affecting cell growth. Observation of cell morphology with electron microscopy shows that indole inhibits the development of spore coats and cortex in P. alvei. As a result of the immature spore formation of P. alvei, indole also decreases P. alvei survival when exposed to antibiotics, low pH, and ethanol. Additionally, indole derivatives also influence the heat resistance; for example, a plant auxin, 3-indolylacetonitrile dramatically (2900-fold decreased the heat resistance of P. alvei, while another auxin 3-indoleacetic acid had a less significant influence on the heat resistance of P. alvei. Conclusions Together, our results demonstrate that indole and plant auxin 3-indolylacetonitrile inhibit spore maturation of P. alvei and that 3-indolylacetonitrile presents an opportunity for the control of heat and antimicrobial resistant spores of Gram-positive bacteria.

  7. Thiamine deficiency induces anorexia by inhibiting hypothalamic AMPK.

    Science.gov (United States)

    Liu, M; Alimov, A P; Wang, H; Frank, J A; Katz, W; Xu, M; Ke, Z-J; Luo, J

    2014-05-16

    Obesity and eating disorders are prevailing health concerns worldwide. It is important to understand the regulation of food intake and energy metabolism. Thiamine (vitamin B1) is an essential nutrient. Thiamine deficiency (TD) can cause a number of disorders in humans, such as Beriberi and Wernicke-Korsakoff syndrome. We demonstrated here that TD caused anorexia in C57BL/6 mice. After feeding a TD diet for 16days, the mice displayed a significant decrease in food intake and an increase in resting energy expenditure (REE), which resulted in a severe weight loss. At the 22nd day, the food intake was reduced by 69% and 74% for male and female mice, respectively in TD group. The REE increased by ninefolds in TD group. The loss of body weight (17-24%) was similar between male and female animals and mainly resulted from the reduction of fat mass (49% decrease). Re-supplementation of thiamine (benfotiamine) restored animal's appetite, leading to a total recovery of body weight. The hypothalamic adenosine monophosphate-activated protein kinase (AMPK) is a critical regulator of food intake. TD inhibited the phosphorylation of AMPK in the arcuate nucleus (ARN) and paraventricular nucleus (PVN) of the hypothalamus without affecting its expression. TD-induced inhibition of AMPK phosphorylation was reversed once thiamine was re-supplemented. In contrast, TD increased AMPK phosphorylation in the skeletal muscle and upregulated the uncoupling protein (UCP)-1 in brown adipose tissues which was consistent with increased basal energy expenditure. Re-administration of thiamine stabilized AMPK phosphorylation in the skeletal muscle as well as energy expenditure. Taken together, TD may induce anorexia by inhibiting hypothalamic AMPK activity. With a simultaneous increase in energy expenditure, TD caused an overall body weight loss. The results suggest that the status of thiamine levels in the body may affect food intake and body weight.

  8. Launch Vehicle Demonstrator Using Shuttle Assets

    Science.gov (United States)

    Threet, Grady E., Jr.; Creech, Dennis M.; Philips, Alan D.; Water, Eric D.

    2011-01-01

    The Marshall Space Flight Center Advanced Concepts Office (ACO) has the leading role for NASA s preliminary conceptual launch vehicle design and performance analysis. Over the past several years the ACO Earth-to-Orbit Team has evaluated thousands of launch vehicle concept variations for a multitude of studies including agency-wide efforts such as the Exploration Systems Architecture Study (ESAS), Constellation, Heavy Lift Launch Vehicle (HLLV), Heavy Lift Propulsion Technology (HLPT), Human Exploration Framework Team (HEFT), and Space Launch System (SLS). NASA plans to continue human space exploration and space station utilization. Launch vehicles used for heavy lift cargo and crew will be needed. One of the current leading concepts for future heavy lift capability is an inline one and a half stage concept using solid rocket boosters (SRB) and based on current Shuttle technology and elements. Potentially, the quickest and most cost-effective path towards an operational vehicle of this configuration is to make use of a demonstrator vehicle fabricated from existing shuttle assets and relying upon the existing STS launch infrastructure. Such a demonstrator would yield valuable proof-of-concept data and would provide a working test platform allowing for validated systems integration. Using shuttle hardware such as existing RS-25D engines and partial MPS, propellant tanks derived from the External Tank (ET) design and tooling, and four-segment SRB s could reduce the associated upfront development costs and schedule when compared to a concept that would rely on new propulsion technology and engine designs. There are potentially several other additional benefits to this demonstrator concept. Since a concept of this type would be based on man-rated flight proven hardware components, this demonstrator has the potential to evolve into the first iteration of heavy lift crew or cargo and serve as a baseline for block upgrades. This vehicle could also serve as a demonstration

  9. Potent inhibition of human neutrophil activations by bractelactone, a novel chalcone from Fissistigma bracteolatum

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Yang-Chang [Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung 807, Taiwan (China); Graduate Institute of Integrated Medicine, College of Chinese Medicine, China Medical University, Taichung 404, Taiwan (China); Sureshbabu, Munisamy; Fang, Yao-Ching; Wu, Yi-Hsiu [Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan (China); Lan, Yu-Hsuan [School of Pharmacy, China Medical University, Taichung 404, Taiwan (China); Chang, Fang-Rong [Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung 807, Taiwan (China); Chang, Ya-Wen [Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan (China); Hwang, Tsong-Long, E-mail: htl@mail.cgu.edu.tw [Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan (China); Chinese Herbal Medicine Research Team, Healthy Aging Research Center, Chang Gung University, Kweishan, Taoyuan 333, Taiwan (China)

    2013-02-01

    Fissistigma bracteolatum is widely used in traditional medicine to treat inflammatory diseases. However, its active components and mechanisms of action remain unclear. In this study, (3Z)-6,7-dihydroxy-4-methoxy-3-(phenylmethylidene)-5-(3-phenylpropanoyl) -1-benzofuran-2(3H) (bractelactone), a novel chalcone from F. bracteolatum, showed potent inhibitory effects against superoxide anion (O{sub 2}{sup ·−}) production, elastase release, and CD11b expression in formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP)-induced human neutrophils. However, bractelactone showed only weak inhibition of phorbol myristate acetate-caused O{sub 2}{sup ·−} production. The peak cytosolic calcium concentration ([Ca{sup 2+}]{sub i}) was unaltered by bractelactone in FMLP-induced neutrophils, but the decay time of [Ca{sup 2+}]{sub i} was significantly shortened. In a calcium-free solution, changes in [Ca{sup 2+}]{sub i} caused by the addition of extracellular Ca{sup 2+} were inhibited by bractelactone in FMLP-activated cells. In addition, bractelactone did not alter the phosphorylation of p38 MAPK, ERK, JNK, or AKT or the concentration of cAMP. These results suggest that bractelactone selectively inhibits store-operated calcium entry (SOCE). In agreement with this concept, bractelactone suppressed sustained [Ca{sup 2+}]{sub i} changes in thapsigargin-activated neutrophils. Furthermore, bractelactone did not alter FMLP-induced formation of inositol 1,4,5-triphosphate. Taken together, our results demonstrate that the anti-inflammatory effects of bractelactone, an active ingredient of F. bracteolatum, in human neutrophils are through the selective inhibition of SOCE. Highlights: ► Bractelactone isolated from Fissistigma bracteolatum. ► Bractelactone inhibited FMLP-induced human neutrophil activations. ► Bractelactone had no effect on IP3 formation. ► Bractelactone did not alter MAPKs, AKT, and cAMP pathways. ► Bractelactone inhibited store-operated calcium entry.

  10. CTRP6 inhibits fibrogenesis in TGF-β1-stimulated human dermal fibroblasts

    Energy Technology Data Exchange (ETDEWEB)

    Fan, Rong-hui, E-mail: fan_ronghuixa@163.com [Department of Burn and Plastic Surgery, Shaanxi Provincial People’s Hospital, Xi’an 710068 (China); Zhu, Xiu-mei; Sun, Yao-wen [Department of Burn and Plastic Surgery, Shaanxi Provincial People’s Hospital, Xi’an 710068 (China); Peng, Hui-zi [Department of Cosmetology Plastic Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi 710061 (China); Wu, Hang-li; Gao, Wen-jie [Department of Burn and Plastic Surgery, Shaanxi Provincial People’s Hospital, Xi’an 710068 (China)

    2016-07-08

    Skin fibrosis is characterized by excessive proliferation of fibroblasts and overproduction of extracellular matrix (ECM). C1q/tumor necrosis factor-related protein 6 (CTRP6), a member of CTRPs, has been involved in the development of cardiac fibrosis. However, the function and detailed regulatory mechanism of CTRP6 in skin fibrosis remain unclear. The aim of this study was to investigate the effect of CTRP6 on the activation of human dermal fibroblasts. Our results showed that CTRP6 was lowly expressed in scar tissues and transforming growth factor-β1 (TGF-β1)-treated dermal fibroblasts. CTRP6 overexpression significantly inhibited the proliferation of dermal fibroblasts, as well as suppressed the expression of ECM in TGF-β1-treated dermal fibroblasts. Furthermore, CTRP6 overexpression markedly inhibited TGF-β1-induced phosphorylation of Smad3 in dermal fibroblasts. In conclusion, the data reported here demonstrate that CTRP6 is able to inhibit the proliferation and ECM expression in human dermal fibroblasts through suppressing the TGF-β1/Smad3 signaling pathway. These findings suggest that CTRP6 may be a potential therapeutic target for the prevention of skin fibrosis. -- Highlights: •CTRP6 expression was decreased in scar tissues and TGF-β1-treated dermal fibroblasts. •CTRP6 inhibits TGF-β1-induced the proliferation of dermal fibroblasts. •CTRP6 inhibits expression of collagen type I and α-SMA. •CTRP6 inhibits the activation of TGF-β1/Smad3 signaling pathway in dermal fibroblasts.

  11. Slit2 inhibits glioma cell invasion in the brain by suppression of Cdc42 activity.

    Science.gov (United States)

    Yiin, Jia-Jean; Hu, Bo; Jarzynka, Michael J; Feng, Haizhong; Liu, Kui-Wei; Wu, Jane Y; Ma, Hsin-I; Cheng, Shi-Yuan

    2009-12-01

    Acquisition of insidious invasiveness by malignant glioma cells involves multiple genetic alterations in signaling pathways. Slit2, a chemorepulsive factor, controls cell migration of neuronal and glial cells during development and inhibits chemotaxic migration of various types of cells in vitro. However, the role of Slit2 in vitro remains controversial, and the biological significance of Slit2 expression in cancer cell invasion in vivo has not yet been determined. In the present study, we characterized the effects of Slit2 expression on the migration and invasion of invasive glioma cells in vitro and in vivo. By reverse transcriptase polymerase chain reaction (PCR) analyses, Slit2 was found to be expressed at lower levels in primary glioma specimens and invasive glioma cells compared with normal human brain cells and astrocytes. Ectopic expression of Slit2 or treatment with recombinant Slit2 on glioma cells attenuates cell migration and invasion through inhibition of Cdc42 activity in vitro. Cellular depletion of Robo1, a cognate receptor for Slit2, prevented Slit2 inhibition of Cdc42 activity and glioma cell migration. In vivo, expression of Slit2 by invasive SNB19 glioma cells markedly inhibited glioma cell infiltration into the brain of mice. Moreover, impediment of glioma cell invasion by Slit2 did not affect the expression of N-cadherin and beta-catenin in glioma cells. These results provide the first evidence demonstrating that Slit2-Robo1 inhibits glioma invasion through attenuating Cdc42 activity in vitro and in the brain. Understanding the mechanisms of Slit2-Robo1 inhibition of glioma cell invasion will foster new treatments for malignant gliomas.

  12. Thymoquinone Inhibits Escherichia coli ATP Synthase and Cell Growth.

    Directory of Open Access Journals (Sweden)

    Zulfiqar Ahmad

    Full Text Available We examined the thymoquinone induced inhibition of purified F1 or membrane bound F1FO E. coli ATP synthase. Both purified F1 and membrane bound F1FO were completely inhibited by thymoquinone with no residual ATPase activity. The process of inhibition was fully reversible and identical in both membrane bound F1Fo and purified F1 preparations. Moreover, thymoquinone induced inhibition of ATP synthase expressing wild-type E. coli cell growth and non-inhibition of ATPase gene deleted null control cells demonstrates that ATP synthase is a molecular target for thymoquinone. This also links the beneficial dietary based antimicrobial and anticancer effects of thymoquinone to its inhibitory action on ATP synthase.

  13. Thymoquinone Inhibits Escherichia coli ATP Synthase and Cell Growth.

    Science.gov (United States)

    Ahmad, Zulfiqar; Laughlin, Thomas F; Kady, Ismail O

    2015-01-01

    We examined the thymoquinone induced inhibition of purified F1 or membrane bound F1FO E. coli ATP synthase. Both purified F1 and membrane bound F1FO were completely inhibited by thymoquinone with no residual ATPase activity. The process of inhibition was fully reversible and identical in both membrane bound F1Fo and purified F1 preparations. Moreover, thymoquinone induced inhibition of ATP synthase expressing wild-type E. coli cell growth and non-inhibition of ATPase gene deleted null control cells demonstrates that ATP synthase is a molecular target for thymoquinone. This also links the beneficial dietary based antimicrobial and anticancer effects of thymoquinone to its inhibitory action on ATP synthase.

  14. Decision support software technology demonstration plan

    Energy Technology Data Exchange (ETDEWEB)

    SULLIVAN,T.; ARMSTRONG,A.

    1998-09-01

    The performance evaluation of innovative and alternative environmental technologies is an integral part of the US Environmental Protection Agency's (EPA) mission. Early efforts focused on evaluating technologies that supported the implementation of the Clean Air and Clean Water Acts. In 1986 the Agency began to demonstrate and evaluate the cost and performance of remediation and monitoring technologies under the Superfund Innovative Technology Evaluation (SITE) program (in response to the mandate in the Superfund Amendments and Reauthorization Act of 1986 (SARA)). In 1990, the US Technology Policy was announced. This policy placed a renewed emphasis on making the best use of technology in achieving the national goals of improved quality of life for all Americans, continued economic growth, and national security. In the spirit of the technology policy, the Agency began to direct a portion of its resources toward the promotion, recognition, acceptance, and use of US-developed innovative environmental technologies both domestically and abroad. Decision Support Software (DSS) packages integrate environmental data and simulation models into a framework for making site characterization, monitoring, and cleanup decisions. To limit the scope which will be addressed in this demonstration, three endpoints have been selected for evaluation: Visualization; Sample Optimization; and Cost/Benefit Analysis. Five topics are covered in this report: the objectives of the demonstration; the elements of the demonstration plan; an overview of the Site Characterization and Monitoring Technology Pilot; an overview of the technology verification process; and the purpose of this demonstration plan.

  15. High energy laser demonstrators for defense applications

    Science.gov (United States)

    Jung, M.; Riesbeck, Th.; Schmitz, J.; Baumgärtel, Th.; Ludewigt, K.; Graf, A.

    2017-01-01

    Rheinmetall Waffe Munition has worked since 30 years in the area of High Energy Laser (HEL) for defence applications, starting from pulsed CO2 to pulsed glass rods lasers. In the last decade Rheinmetall Waffe Munition changed to diode pumped solid state laser (DPSSL) technology and has successfully developed, realised and tested a variety of versatile HEL weapon demonstrators for air- and ground defence scenarios like countering rocket, artillery, mortar, missile (RAMM), unmanned aerial systems (UAS) and unexploded ordnances clearing. By employing beam superimposing technology and a modular laser weapon concept, the total optical power has been successively increased. Stationary weapon platforms, military vehicles and naval platforms have been equipped with high energy laser effectors. The contribution gives a summary of the most recent development stages of Rheinmetalls HEL weapon program. In addition to the stationary 30 kW laser weapon demonstrator, we present vehicle based HEL demonstrators: the 5 kW class Mobile HEL Effector Track V, the 20 kW class Mobile HEL Effector Wheel XX and the 50 kW class Mobile HEL Effector Container L and the latest 10 kW HEL effector integrated in the naval weapon platform MLG 27. We describe the capabilities of these demonstrators against different potential targets. Furthermore, we will show the capability of the 30 kW stationary Laser Weapon Demonstrator integrated into an existing ground based air defence system to defeat saturated attacks of RAMM and UAS targets.

  16. Buried Waste Integrated Demonstration Plan. Revision 1

    Energy Technology Data Exchange (ETDEWEB)

    Kostelnik, K.M.

    1991-12-01

    This document presents the plan of activities for the Buried Waste Integrated Demonstration (BWID) program which supports the environmental restoration (ER) objectives of the Department of Energy (DOE) Complex. Discussed in this plan are the objectives, organization, roles and responsibilities, and the process for implementing and managing BWID. BWID is hosted at the Idaho National Engineering Laboratory (INEL), but involves participants from throughout the DOE Complex, private industry, universities, and the international community. These participants will support, demonstrate, and evaluate a suite of advanced technologies representing a comprehensive remediation system for the effective and efficient remediation of buried waste. The processes for identifying technological needs, screening candidate technologies for applicability and maturity, selecting appropriate technologies for demonstration, field demonstrating, evaluation of results and transferring technologies to environmental restoration programs are also presented. This document further describes the elements of project planning and control that apply to BWID. It addresses the management processes, operating procedures, programmatic and technical objectives, and schedules. Key functions in support of each demonstration such as regulatory coordination, safety analyses, risk evaluations, facility requirements, and data management are presented.

  17. Motivating inhibition - reward prospect speeds up response cancellation.

    Science.gov (United States)

    Boehler, Carsten N; Hopf, Jens-Max; Stoppel, Christian M; Krebs, Ruth M

    2012-12-01

    Reward prospect has been demonstrated to facilitate various cognitive and behavioral operations, particularly by enhancing the speed and vigor of processes linked to approaching reward. Studies in this domain typically employed task regimes in which participants' overt responses are facilitated by prospective rewards. In contrast, we demonstrate here that even the cancellation of a motor response can be accelerated by reward prospect, thus signifying reward-related benefits on restraint rather than approach behavior. Importantly, this facilitation occurred independent of strategy-related adjustments of response speed, which are known to systematically distort the estimation of response-cancellation speed. The fact that motivational factors can indeed facilitate response inhibition is not only relevant for understanding how motivation and response inhibition interact in healthy participants but also for work on various patient groups that display response-inhibition deficits, suggesting that core differences in the ability to inhibit motor responses have to be differentiated from motivational factors.

  18. Attenuation of Telomerase Activity by siRNA Targeted Telomerase RNA Leads to Apoptosis and Inhibition of Proliferation in Human Renal Carcinoma Cells

    Institute of Scientific and Technical Information of China (English)

    Rumin Wen; Junjie Liu; Wang Li; Wenfa Yang; Lijun Mao; Junnian Zheng

    2006-01-01

    OBJECTIVE Telomerase is an attractive molecular target for cancer therapy because the activation of telomerase is one of the key steps in cell immortalization and carcinogenesis. RNA interference using small-interfering RNA (siRNA) has been demonstrated to be an effective method for inhibiting the expression of a given gene in human cells. The aim of the present study was to investigate whether inhibition of telomerase activity by siRNA targeted against human telomerase RNA (hTR) can inhibit proliferation and induce apoptotic cell death in human renal carcinoma cells(HRCCs).METHODS The siRNA duplexes for hTR were synthesized and 786-O HRCCs were transfected with different concentrations of hTR-siRNA. The influence on the hTR mRNA level, telomerase activity, as well as the effect on cell proliferation and apoptosis was examined.RESULTS Anti-hTR siRNA treatment of HRCCs resulted in specific reduction of hTR mRNA and inhibition of telomerase activity. Additionally,significant inhibition of proliferation and induction of apoptosis were observed.CONCLUSION siRNA against the hTR gene can inhibit proliferation and induce apoptosis by blocking telomerase activity of HRCCs. Specific hTR inhibition by siRNA represents a promising new option for renal cancer treatment.

  19. Histaminergic H1 and H2 Receptors Mediate the Effects of Propofol on the Noradrenalin-Inhibited Neurons in Rat Ventrolateral Preoptic Nucleus.

    Science.gov (United States)

    Liu, Yang; Zhang, Yu; Qian, Kun; Zhang, Lin; Yu, Tian

    2017-02-09

    The ventrolateral preoptic nucleus is a sleep-promoting nucleus located in the basal forebrain. A commonly used intravenous anesthetic, propofol, had been reported to induce sleep spindles and augment the firing rate of neurons in ventrolateral preoptic nucleus, but the underlining mechanism is yet to be known. By using patch clamp recording on neuron in acute brain slice, present study tested if histaminergic H1 and H2 receptors play a role in the effect of propofol on the noradrenalin-inhibited neurons in ventrolateral preoptic nucleus. We found that the firing rate of noradrenalin-inhibited neurons were significantly augmented by propofol; the frequency of inhibitory postsynaptic currents of noradrenalin-inhibited neuron were evidently attenuated by propofol; such inhibition effect was suppressed by histamine; and both triprolidine (antagonist for H1 histamine receptor) and ranitidine (antagonist for H2 histamine receptor) were able to increase the inhibition rate of propofol in presence of histamine. Present study demonstrated that propofol-induced inhibition of inhibitory postsynaptic currents on noradrenalin-inhibited neurons were mediated by histaminergic H1 and H2 receptors.

  20. Molecular mechanisms of cholangiocarcinoma cell inhibition by medicinal plants

    Science.gov (United States)

    Leelawat, Surang; Leelawat, Kawin

    2017-01-01

    Cholangiocarcinoma (CCA) is one of the most common causes of cancer-associated mortality in Thailand. Certain phytochemicals have been demonstrated to modulate apoptotic signaling pathways, which may be targeted for the prevention and treatment of cancer. Therefore, the aim of the present study was to investigate the effect of specific medicinal plants on the inhibition of CCA cell proliferation, and to identify the molecular mechanisms underlying this. A WST-1 cell proliferation assay was performed using an RMCCA1 cell line, and apoptotic signaling pathways were also investigated using a PathScan Stress and Apoptosis Signaling Antibody Array Kit. The cell proliferation assay indicated that extracts from the Phyllanthus emblica fruit pulp (PEf), Phyllanthus emblica seed (PEs), Terminalia chebula fruit pulp (TCf), Terminalia chebula seed (TCs), Areca catechu seed (ACs), Curcuma longa (CL) and Moringa oleifera seed (MOs) exerted anti-proliferative activity in RMCCA1 cells. In addition, the PathScan assay revealed that certain pro-apoptotic molecules, including caspase-3, poly (ADP-ribose) polymerase, checkpoint kinase 2 and tumor protein 53, exhibited increased activity in RMCCA1 cells treated with the aforementioned selected plant extracts, with the exception of PEf. The mitogen-activated protein kinase (MAPK) pathways (including ERK1/2 and p38 MAPK) expression level was significantly increased in RMCCA1 cells pre-treated with extracts of PEs, TCf, CL and MOs. The activation of protein kinase B (Akt) was significantly demonstrated in RMCCA1 cells pre-treated with extracts of TCf, ACs and MOs. In summary, the present study demonstrated that extracts of PEs, TCf, TCs, ACs, CL and MOs exhibited anti-proliferative effects in CCA cells by inducing pro-apoptotic signals and modulating signal transduction molecules. Further studies in vivo are required to demonstrate the potential applications of specific plant extracts for the treatment of human cancer.