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Sample records for activation induces close

  1. Solvent-Induced Reversal of Activities between Two Closely Related Heterogeneous Catalysts in the Aldol Reaction

    Energy Technology Data Exchange (ETDEWEB)

    Kandel, Kapil [Ames Laboratory; Althaus, Stacey M [Ames Laboratory; Peeraphatdit, Chorthip [Ames Laboratory; Kobayashi, Takeshi [Ames Laboratory; Trewyn, Brian G [Ames Laboratory; Pruski, Marek [Ames Laboratory; Slowing, Igor I [Ames Laboratory

    2013-01-11

    The relative rates of the aldol reaction catalyzed by supported primary and secondary amines can be inverted by 2 orders of magnitude, depending on the use of hexane or water as a solvent. Our analyses suggest that this dramatic shift in the catalytic behavior of the supported amines does not involve differences in reaction mechanism, but is caused by activation of imine to enamine equilibria and stabilization of iminium species. The effects of solvent polarity and acidity were found to be important to the performance of the catalytic reaction. This study highlights the critical role of solvent in multicomponent heterogeneous catalytic processes.

  2. Activation of Na(+)-K(+)-ATPase with DRm217 attenuates oxidative stress-induced myocardial cell injury via closing Na(+)-K(+)-ATPase/Src/Ros amplifier.

    Science.gov (United States)

    Yan, Xiaofei; Xun, Meng; Dou, Xiaojuan; Wu, Litao; Zhang, Fujun; Zheng, Jin

    2017-04-01

    Reduced Na(+)-K(+)-ATPase activity has close relationship with cardiomyocyte death. Reactive oxygen species (ROS) also plays an important role in cardiac cell damage. It has been proved that Na(+)-K(+)-ATPase and ROS form a feed-forward amplifier. The aim of this study was to explore whether DRm217, a proved Na(+)/K(+)-ATPase's DR-region specific monoclonal antibody and direct activator, could disrupt Na(+)-K(+)-ATPase/ROS amplifier and protect cardiac cells from ROS-induced injury. We found that DRm217 protected myocardial cells against hydrogen peroxide (H2O2)-induced cardiac cell injury and mitochondrial dysfunction. DRm217 also alleviated the effect of H2O2 on inhibition of Na(+)-K(+)-ATPase activity, Na(+)-K(+)-ATPase cell surface expression, and Src phosphorylation. H2O2-treatment increased intracellular ROS, mitochondrial ROS and induced intracellular Ca(2+), mitochondrial Ca(2+) overload. DRm217 closed Na(+)-K(+)-ATPase/ROS amplifier, alleviated Ca(2+) accumulation and finally inhibited ROS and mitochondrial ROS generation. These novel results may help us to understand the important role of the Na(+)-K(+)-ATPase in oxidative stress and oxidative stress-related disease.

  3. Retraction: Open and closed conformations reveal induced fit movements in butyrate kinase 2 activation. J. Diao, Y. D. Ma, and M. S. Hasson.

    Science.gov (United States)

    2012-06-01

    The following article from Proteins: Structure, Function, and Bioinformatics, "Open and closed conformations reveal induced fit movements in butyrate kinase 2 activation," by Jiasheng Diao, Yunglin D. Ma, and Miriam S. Hasson, published online on 21 October 2010 in Wiley Online Library (onlinelibrary.wiley.com), has been retracted by agreement between the journal Editor in Chief, Bertrand Garcia-Moreno, and Wiley Periodicals. The retraction has been agreed because it was established by internal investigation performed by Purdue University that the authors of this article are not the owners of the data and have no right to publication.

  4. Charge induced closing of Dionaea muscipula Ellis trap.

    Science.gov (United States)

    Volkov, Alexander G; Adesina, Tejumade; Jovanov, Emil

    2008-11-01

    In terms of bioelectrochemistry, Venus flytrap responses can be considered in three stages: stimulus perception, electrical signal transmission, and induction of mechanical and biochemical responses. When an insect touches the trigger hairs, these mechanosensors generate receptor potentials, which induce solitary waves activating the motor cells. We found that the electrical charge injected between a midrib and a lobe closes the Venus flytrap leaf by activating motor cells without mechanical stimulation of trigger hairs. The mean electrical charge required for the closure of the Venus flytrap leaf is 13.6 muC. To close the trap, electrical charge can be submitted as a single charge or applied cumulatively by small portions during a short period of time. Ion channel blocker such as Zn(2+) as well as an uncoupler CCCP, dramatically decreases the speed of the trap closing a few hours after treatment of the soil. This effect is reversible. After soil washing by distilled water, the closing time of Venus flytrap treated by CCCP or ZnCl(2) decreases back from 2-5 s to 0.3 s, but higher electrical charge is needed for trap closure. The mechanism behind closing the upper leaf of Venus flytrap is discussed.

  5. 12 CFR 225.129 - Activities closely related to banking.

    Science.gov (United States)

    2010-01-01

    ... 12 Banks and Banking 3 2010-01-01 2010-01-01 false Activities closely related to banking. 225.129 Section 225.129 Banks and Banking FEDERAL RESERVE SYSTEM (CONTINUED) BOARD OF GOVERNORS OF THE FEDERAL... Holding Companies Interpretations § 225.129 Activities closely related to banking. Courier activities. The...

  6. 12 CFR 225.123 - Activities closely related to banking.

    Science.gov (United States)

    2010-01-01

    ... 12 Banks and Banking 3 2010-01-01 2010-01-01 false Activities closely related to banking. 225.123 Section 225.123 Banks and Banking FEDERAL RESERVE SYSTEM (CONTINUED) BOARD OF GOVERNORS OF THE FEDERAL... Holding Companies Interpretations § 225.123 Activities closely related to banking. (a) Effective June 15...

  7. Environment induced time arrow and the Closed Time Path method

    Science.gov (United States)

    Polonyi, Janos

    2013-06-01

    It is shown in the framework of a harmonic system that the thermodynamical time arrow is induced by the environmental initial conditions in a manner similar to spontaneous symmetry breaking. The Closed Time Path formalism is introduced in classical mechanics to handle Green functions for initial condition problems by the action principle, in a systematic manner. The application of this scheme for quantum systems shows the common dynamical origin of the thermodynamical and the quantum time arrows. It is furthermore conjectured that the quantum-classical transition is strongly coupled.

  8. Active fault diagnosis in closed-loop uncertain systems

    DEFF Research Database (Denmark)

    Niemann, Hans Henrik

    2006-01-01

    Fault diagnosis of parametric faults in closed-loop uncertain systems by using an auxiliary input vector is considered in this paper, i.e. active fault diagnosis (AFD). The active fault diagnosis is based directly on the socalled fault signature matrix, related to the YJBK (Youla, Jabr, Bongiorno...... and Kucera) parameterization. Conditions are given for exact detection and isolation of parametric faults in closed-loop uncertain systems....

  9. Climate-induced range overlap among closely related species

    Science.gov (United States)

    Krosby, Meade; Wilsey, Chad B.; McGuire, Jenny L.; Duggan, Jennifer M.; Nogeire, Theresa M.; Heinrichs, Julie A.; Tewksbury, Joshua J.; Lawler, Joshua J.

    2015-09-01

    Contemporary climate change is causing large shifts in biotic distributions, which has the potential to bring previously isolated, closely related species into contact. This has led to concern that hybridization and competition could threaten species persistence. Here, we use bioclimatic models to show that future range overlap by the end of the century is predicted for only 6.4% of isolated, congeneric species pairs of New World birds, mammals and amphibians. Projected rates of climate-induced overlap are higher for birds (11.6%) than for mammals (4.4%) or amphibians (3.6%). As many species will have difficulty tracking shifting climates, actual rates of future overlap are likely to be far lower, suggesting that hybridization and competition impacts may be relatively modest.

  10. Ventricular Septal Defect Spontaneous Close Induced by Transcatheter: A Case Report

    Institute of Scientific and Technical Information of China (English)

    Qilian Xie; Jun Wang; Lei Gao; Zhen Wang; Milin Zhang; Kunshen Liu

    2007-01-01

    Congenital ventricular septal defect (VSD) spontaneous close induced by transcatheter treatment is rare and has not yet been reported.We report on one case of VSD spontaneous close induced by transcatheter treatment in a 10 years old girl.

  11. Closed-Loop and Activity-Guided Optogenetic Control

    Science.gov (United States)

    Grosenick, Logan; Marshel, James H.; Deisseroth, Karl

    2016-01-01

    Advances in optical manipulation and observation of neural activity have set the stage for widespread implementation of closed-loop and activity-guided optical control of neural circuit dynamics. Closing the loop optogenetically (i.e., basing optogenetic stimulation on simultaneously observed dynamics in a principled way) is a powerful strategy for causal investigation of neural circuitry. In particular, observing and feeding back the effects of circuit interventions on physiologically relevant timescales is valuable for directly testing whether inferred models of dynamics, connectivity, and causation are accurate in vivo. Here we highlight technical and theoretical foundations as well as recent advances and opportunities in this area, and we review in detail the known caveats and limitations of optogenetic experimentation in the context of addressing these challenges with closed-loop optogenetic control in behaving animals. PMID:25856490

  12. An active thermal compensator for closed-cycle helium refrigerators

    Science.gov (United States)

    Jennings, D. E.; Hillman, J. J.

    1977-01-01

    A technique was developed for reducing the amplitude of the temperature oscillation in He closed-cyle refrigerators. The device uses a semiconductor diode as a heating element to actively supply a small oscillating input of heat at a point between the laser and the cold-tip to cancel the heat oscillations due to the refrigerator. It was found that the heater diode could drive the temperature of the heat sink more effectively, i.e., with lower current and therefore less heat, if the heat sink was insulated slightly from the rest of the mount. A sine-wave generator was used to drive the programmable supply which provided the offset current to the heater diode. By matching the frequency and phase of the oscillator to that of the refrigerator cycle, and by adjusting the amplitude of the oscillator signal, the temperature fluctuations at the laser could be minimized. Residual fluctuations were about 0.003K peak-to-peak, at an operating temperature of 9.5K.

  13. The effects of close binaries on the magnetic activity of M dwarfs as probed using close white dwarf companions

    Science.gov (United States)

    Morgan, D. P.

    2017-01-01

    I present a study of close white dwarf (WD) and M dwarf (dM) binary systems (WD+dM) to examine the effects that close companions have on magnetic field generation in dMs. Using the Sloan Digital Sky Survey (SDSS) Data Release 8 spectroscopic database, I constructed a sample of 1756 WD+dM high-quality pairs. I show that early-type dMs (M4), where stars become fully convective, the activity fraction and activity lifetimes of WD+dM binary systems become more comparable to those of the field dMs. The implications of having a close binary companion may include: increased stellar rotation through disk disruption, tidal effects, and/or angular momentum exchange. Thus, the similarity in activity between late-type field dMs and late-type dMs with close companions is likely due to the mechanism generating magnetic fields being less sensitive to the effects caused by a close companion; namely, increased stellar rotation. Using a subset of 181 close WD+dM pairs, matched to the time-domain SDSS Stripe 82 catalog, I show that enhanced magnetic activity extends to the flaring behavior of dMs in close binaries. Specifically, early spectral type dMs (M0-M4), in close WD+dM pairs, are two orders of magnitude more likely to flare than field dMs, whereas late-type dMs (M4-M6) in close WD+dM pairs flare as frequently or less than the late-type field dM sample. To test whether the presence of a close companion leads to star-star interactions, I searched for correlations between the WD occultations and flares from the dM member in KOI-256, an eclipsing WD+dM system. I find no correlations between the flaring activity of the dM and the WD occultations, indicating the there are no obvious signs of star-star interactions at work. In addition, the dM member of KOI-256 flares more than any other dM observed by Kepler and shows evidence for solar-like magnetic activity cycles, a feature not seen in many dMs to date.

  14. Induced activation in accelerator components

    Directory of Open Access Journals (Sweden)

    Cristian Bungau

    2014-08-01

    Full Text Available The residual activity induced in particle accelerators is a serious issue from the point of view of radiation safety as the long-lived radionuclides produced by fast or moderated neutrons and impact protons cause problems of radiation exposure for staff involved in the maintenance work and when decommissioning the facility. This paper presents activation studies of the magnets and collimators in the High Energy Beam Transport line of the European Spallation Source due to the backscattered neutrons from the target and also due to the direct proton interactions and their secondaries. An estimate of the radionuclide inventory and induced activation are predicted using the GEANT4 code.

  15. Frequency-induced changes in interlimb interactions: increasing manifestations of closed-loop control.

    Science.gov (United States)

    de Boer, Betteco J; Peper, C Lieke E; Beek, Peter J

    2011-06-20

    In bimanual coordination, interactions between the limbs result in attraction to in-phase and antiphase coordination. Increasing movement frequency leads to decreasing stability of antiphase coordination, often resulting in a transition to the more stable in-phase pattern. It is unknown, however, how this frequency-induced loss of stability is engendered in terms of the interlimb interactions underwriting bimanual coordination. The present study was conducted to help resolve this issue. Using an established method (based on comparison of various unimanual and bimanual tasks involving both passive and active movements), three sources of interlimb interaction were dissociated: (1) integrated timing of feedforward signals, (2) afference-based correction of relative phase errors, and (3) phase entrainment by contralateral afference. Results indicated that phase entrainment strength remained unaffected by frequency and that the stabilizing effects of error correction and integrated timing decreased with increasing frequency. Their contributions, however, reflected an interesting interplay as frequency increased. For moderate frequencies coordinative stability was predominantly secured by integrated timing processes. However, at high frequencies, the stabilization of the antiphase pattern required combined contributions of both integrated timing and error correction. In sum, increasing frequency was found to induce a shift from predominantly open-loop control to more closed-loop control. The results may be accounted for by means of an internal forward model for sensorimotor integration in which the sensory signals are compared to values predicted on the basis of efference copies.

  16. Activation of high and low affinity dopamine receptors generates a closed loop that maintains a conductance ratio and its activity correlate

    Directory of Open Access Journals (Sweden)

    Wulf-Dieter Christian Krenz

    2013-10-01

    Full Text Available Neuromodulators alter network output and have the potential to destabilize a circuit. The mechanisms maintaining stability in the face of neuromodulation are not well described. Using the pyloric network in the crustacean stomatogastric nervous system, we show that dopamine (DA does not simply alter circuit output, but activates a closed loop in which DA-induced alterations in circuit output consequently drive a change in an ionic conductance to preserve a conductance ratio and its activity correlate. DA acted at low affinity type 1 receptors (D1Rs to induce an immediate modulatory decrease in the transient potassium current (IA of a pyloric neuron. This, in turn, advanced the activity phase of that component neuron, which disrupted its network function and thereby destabilized the circuit. DA simultaneously acted at high affinity D1Rs on the same neuron to confer activity-dependence upon the hyperpolarization activated current (Ih such that the DA-induced changes in activity subsequently reduced Ih. This DA-enabled, activity-dependent, intrinsic plasticity exactly compensated for the modulatory decrease in IA to restore the IA:Ih ratio and neuronal activity phase, thereby closing an open loop created by the modulator. Activation of closed loops to preserve conductance ratios may represent a fundamental operating principle neuromodulatory systems use to ensure stability in their target networks.

  17. 12 CFR 225.126 - Activities not closely related to banking.

    Science.gov (United States)

    2010-01-01

    ... 12 Banks and Banking 3 2010-01-01 2010-01-01 false Activities not closely related to banking. 225.126 Section 225.126 Banks and Banking FEDERAL RESERVE SYSTEM (CONTINUED) BOARD OF GOVERNORS OF THE... Financial Holding Companies Interpretations § 225.126 Activities not closely related to banking. Pursuant to...

  18. Chromospherically Active Low-Mass Close Binary: KIC 9761199

    CERN Document Server

    Yoldas, Ezgi

    2016-01-01

    In this study, we present the results obtained from KIC 9761199's the photometrical data acquired by the Kepler Mission. The light curve of the system, the sinusoidal variation out-of-eclipses and instant-short term flare events in the entire light curves were analyzed. The temperature of the secondary component was found to be 3891+-1 K, while the mass ratio of the components (q) was found to be 0.69+-0.01, and the orbital inclination (i) was computed as 77.4+-0.1 degrees. The sinusoidal variation is caused by the stellar spots of two active regions separated by about 180 degrees longitudinally located around the latitudes of +47 and +30 degrees. In addition, 94 flares were detected and their parameters were computed. The OPEA model was derived for these flares and its parameters were computed. The Plateau value as saturation level for the active component was found to be 1.951+-0.069 s, while the half-life value was found to be 1014 s. The flare frequency N1 was found to be 0.01351 per hour, while the flare...

  19. Close stars and accretion in Low Luminosity Active Galactic Nuclei

    CERN Document Server

    Nayakshin, S

    2004-01-01

    Quasar accretion disks are believed to form stars by self-gravity. Low Luminosity Active Galactic Nuclei (LLAGN) are much dimmer galactic centers, and are often believed to be quasars that ran out of gaseous fuel. LLAGN accretion disks should thus co-exist with thousands to millions of stars or proto-stars left from the previous stronger accretion activity. In principle, these stars may produce several important effects: (i) contribute to the optical/UV spectra of some LLAGN; (ii) reprocessing of the stellar radiation in the dusty disks could dominate the LLAGN infra-red spectra; (iii) deplete the (accretion) gas disk much faster than it can accrete onto the supper-massive black hole (SMBH); (iv) stars, individually or in groups, may slow down and modulate the accretion flow significantly due to their inertia. In this way they may produce the LLAGN cut-off disks; (v) alternatively, frequent enough stellar collisions and resulting stellar disruptions could keep the inner disk empty. Here we explore these ideas...

  20. The Chromospherically Active Low-Mass Close Binary KIC 9761199

    Science.gov (United States)

    Yoldaş, E.; Dal, H. A.

    2017-04-01

    We present the results obtained from the analyses of KIC 9761199's light variation acquired by the Kepler Mission. The temperature of the secondary component was found to be 3891±1 K, and the mass ratio was found to be 0.69±0.01 with an orbital inclination of 77°.4± 0°.1. Stellar spots separated by about 180° longitudinally were found around the latitudes of +47° and +30°. In addition, the OPEA model was derived for 94 detected flares. The plateau value was found to be 1.951±0.069 s, while the half-life value was found to be 1014 s. The flare frequency N1 was 0.01351 h-1, while the flare frequency N2 was 0.00006. Maximum flare rise time was 1118.098 s, while maximum flare total time was 6767.72 s. The chromospheric activity level of KIC 9761199 is at the expected level according to a B-V of 1m.303.

  1. Recombinant covalently closed circular hepatitis B virus DNA induces prolonged viral persistence in immunocompetent mice.

    Science.gov (United States)

    Qi, Zhihua; Li, Gaiyun; Hu, Hao; Yang, Chunhui; Zhang, Xiaoming; Leng, Qibin; Xie, Youhua; Yu, Demin; Zhang, Xinxin; Gao, Yueqiu; Lan, Ke; Deng, Qiang

    2014-07-01

    It remains crucial to develop a laboratory model for studying hepatitis B virus (HBV) chronic infection. We hereby produced a recombinant covalently closed circular DNA (rcccDNA) in view of the key role of cccDNA in HBV persistence. A loxP-chimeric intron was engineered into a monomeric HBV genome in a precursor plasmid (prcccDNA), which was excised using Cre/loxP-mediated DNA recombination into a 3.3-kb rcccDNA in the nuclei of hepatocytes. The chimeric intron was spliced from RNA transcripts without interrupting the HBV life cycle. In cultured hepatoma cells, cotransfection of prcccDNA and pCMV-Cre (encoding Cre recombinase) resulted in accumulation of nuclear rcccDNA that was heat stable and epigenetically organized as a minichromosome. A mouse model of HBV infection was developed by hydrodynamic injection of prcccDNA. In the presence of Cre recombinase, rcccDNA was induced in the mouse liver with effective viral replication and expression, triggering a compromised T-cell response against HBV. Significant T-cell hyporesponsiveness occurred in mice receiving 4 μg prcccDNA, resulting in prolonged HBV antigenemia for up to 9 weeks. Persistent liver injury was observed as elevated alanine transaminase activity in serum and sustained inflammatory infiltration in the liver. Although a T-cell dysfunction was induced similarly, mice injected with a plasmid containing a linear HBV replicon showed rapid viral clearance within 2 weeks. Collectively, our study provides an innovative approach for producing a cccDNA surrogate that established HBV persistence in immunocompetent mice. It also represents a useful model system in vitro and in vivo for evaluating antiviral treatments against HBV cccDNA. Importance: (i) Unlike plasmids that contain a linear HBV replicon, rcccDNA established HBV persistence with sustained liver injury in immunocompetent mice. This method could be a prototype for developing a mouse model of chronic HBV infection. (ii) An exogenous intron was

  2. Chaotic diffusion of the Vesta family induced by close encounters with massive asteroids

    CERN Document Server

    Delisle, J -B

    2011-01-01

    We numerically estimate the semi-major axis chaotic diffusion of the Vesta family asteroids induced by close encounters with 11 massive main belt asteroids : (1) Ceres, (2) Pallas, (3) Juno, (4) Vesta, (7) Iris, (10) Hygiea, (15) Eunomia, (19) Fortuna, (324) Bamberga, (532) Herculina, (704) Interamnia. We find that most of the diffusion is due to Ceres and Vesta. By extrapolating our results, we are able to constrain the global effect of close encounters with all the main belt asteroids. A comparison of this drift estimate with the one expected for the Yarkovsky effect shows that for asteroids whose diameter is larger than about 40 km, close encounters dominate the Yarkovsky effect. Overall, our findings confirm the standard scenario for the history of the Vesta family.

  3. Methods for determining enzymatic activity comprising heating and agitation of closed volumes

    Energy Technology Data Exchange (ETDEWEB)

    Thompson, David Neil; Henriksen, Emily DeCrescenzo; Reed, David William; Jensen, Jill Renee

    2016-03-15

    Methods for determining thermophilic enzymatic activity include heating a substrate solution in a plurality of closed volumes to a predetermined reaction temperature. Without opening the closed volumes, at least one enzyme is added, substantially simultaneously, to the closed volumes. At the predetermined reaction temperature, the closed volumes are agitated and then the activity of the at least one enzyme is determined. The methods are conducive for characterizing enzymes of high-temperature reactions, with insoluble substrates, with substrates and enzymes that do not readily intermix, and with low volumes of substrate and enzyme. Systems for characterizing the enzymes are also disclosed.

  4. Methods for determining enzymatic activity comprising heating and agitation of closed volumes

    Energy Technology Data Exchange (ETDEWEB)

    Thompson, David Neil; Henriksen, Emily DeCrescenzo; Reed, David William; Jensen, Jill Renee

    2016-03-15

    Methods for determining thermophilic enzymatic activity include heating a substrate solution in a plurality of closed volumes to a predetermined reaction temperature. Without opening the closed volumes, at least one enzyme is added, substantially simultaneously, to the closed volumes. At the predetermined reaction temperature, the closed volumes are agitated and then the activity of the at least one enzyme is determined. The methods are conducive for characterizing enzymes of high-temperature reactions, with insoluble substrates, with substrates and enzymes that do not readily intermix, and with low volumes of substrate and enzyme. Systems for characterizing the enzymes are also disclosed.

  5. Modelling stellar proton event-induced particle radiation dose on close-in exoplanets

    Science.gov (United States)

    Atri, Dimitra

    2017-02-01

    Kepler observations have uncovered the existence of a large number of close-in exoplanets and serendipitously of stellar superflares with emissions several orders of magnitude higher than those observed on the Sun. The interaction between the two and their implications on planetary habitability are of great interest to the community. Stellar proton events (SPEs) interact with planetary atmospheres, generate secondary particles and increase the radiation dose on the surface. This effect is amplified for close-in exoplanets and can be a serious threat to potential planetary life. Monte Carlo simulations are used to model the SPE-induced particle radiation dose on the surface of such exoplanets. The results show a wide range of surface radiation doses on planets in close-in configurations with varying atmospheric column depths, magnetic moments and orbital radii. It can be concluded that for close-in exoplanets with sizable atmospheres and magnetospheres, the radiation dose contributed by stellar superflares may not be high enough to sterilize a planet (for life as we know it) but can result in frequent extinction level events. In light of recent reports, the interaction of hard-spectrum SPEs with the atmosphere of Proxima Centauri b is modelled and their implications on its habitability are discussed.

  6. Insensitivity to pain induced by a potent selective closed-state Nav1.7 inhibitor

    Science.gov (United States)

    Flinspach, M.; Xu, Q.; Piekarz, A. D.; Fellows, R.; Hagan, R.; Gibbs, A.; Liu, Y.; Neff, R. A.; Freedman, J.; Eckert, W. A.; Zhou, M.; Bonesteel, R.; Pennington, M. W.; Eddinger, K. A.; Yaksh, T. L.; Hunter, M.; Swanson, R. V.; Wickenden, A. D.

    2017-01-01

    Pain places a devastating burden on patients and society and current pain therapeutics exhibit limitations in efficacy, unwanted side effects and the potential for drug abuse and diversion. Although genetic evidence has clearly demonstrated that the voltage-gated sodium channel, Nav1.7, is critical to pain sensation in mammals, pharmacological inhibitors of Nav1.7 have not yet fully recapitulated the dramatic analgesia observed in Nav1.7-null subjects. Using the tarantula venom-peptide ProTX-II as a scaffold, we engineered a library of over 1500 venom-derived peptides and identified JNJ63955918 as a potent, highly selective, closed-state Nav1.7 blocking peptide. Here we show that JNJ63955918 induces a pharmacological insensitivity to pain that closely recapitulates key features of the Nav1.7-null phenotype seen in mice and humans. Our findings demonstrate that a high degree of selectivity, coupled with a closed-state dependent mechanism of action is required for strong efficacy and indicate that peptides such as JNJ63955918 and other suitably optimized Nav1.7 inhibitors may represent viable non-opioid alternatives for the pharmacological treatment of severe pain. PMID:28045073

  7. Activity Budgets of Impala (Aepyceros melampus in Closed Environments: The Mukuvisi Woodland Experience, Zimbabwe

    Directory of Open Access Journals (Sweden)

    Muposhi Victor Kurauwone

    2013-01-01

    Full Text Available Activity pattern plasticity in ungulates serves as an evolutionary adaptation to optimize fitness in inconsistent environments. Given that time is a limited and valuable resource for foraging wildlife species, provisioning and attraction may affect the activity pattern plasticity and reduce complexities of time partitioning for different activities by impala in closed environments. We assessed activity budgets of free-ranging impala social groups in a closed environment. Social group type had an influence on the activity budgets of impala except for foraging and moving activity states. Both the harem and bachelor groups spent more than 30% of their daily time foraging. Bachelor groups spent more time exhibiting vigilance tendencies than the harem groups. Season influenced the activity budgets of social groups other than vigilance and foraging activity states. Foraging time was highly correlated with vigilance, resting, and grooming. We concluded that provisioning and attraction may have reduced the influence of seasonality on the proportion of time spent on different activity states by impala social groups. There is a need to establish long-term socioecological, physiological, and reproductive consequences of provisioning and habituation on impala under closed environments.

  8. Embryoid Body-Explant Outgrowth Cultivation from Induced Pluripotent Stem Cells in an Automated Closed Platform

    Science.gov (United States)

    Tone, Hiroshi; Yoshioka, Saeko; Akiyama, Hirokazu; Nishimura, Akira; Ichimura, Masaki; Nakatani, Masaru; Kiyono, Tohru

    2016-01-01

    Automation of cell culture would facilitate stable cell expansion with consistent quality. In the present study, feasibility of an automated closed-cell culture system “P 4C S” for an embryoid body- (EB-) explant outgrowth culture was investigated as a model case for explant culture. After placing the induced pluripotent stem cell- (iPSC-) derived EBs into the system, the EBs successfully adhered to the culture surface and the cell outgrowth was clearly observed surrounding the adherent EBs. After confirming the outgrowth, we carried out subculture manipulation, in which the detached cells were simply dispersed by shaking the culture flask, leading to uniform cell distribution. This enabled continuous stable cell expansion, resulting in a cell yield of 3.1 × 107. There was no evidence of bacterial contamination throughout the cell culture experiments. We herewith developed the automated cultivation platform for EB-explant outgrowth cells. PMID:27648449

  9. Hydroxyl Radical Induced Apoptosis Is Closely Related to Changes in Cellular Energy/Redox Metabolism

    Institute of Scientific and Technical Information of China (English)

    贺雨虹; 陈晶; 任建国; 隋森芳; 蔡国平

    2003-01-01

    Reactive oxygen species (ROS), including the hydroxyl radical (·OH), are known to be potential modulators of apoptosis.However, the biochemical mechanisms underlying apoptosis induced by·OH, namely how the radical induces a cell to die, are poorly understood.The present work highlights the changes of the energy/redox status during apoptosis by exogenous· OH-treatment.HeLa cells were induced to undergo typical apoptosis by·OH generated directly via the Fe2+-mediated Fenton reaction.The thermodynamics study indicated that the· OH-treatment increased the cellular heat output in the first hours, and then the cellular thermodynamics shifted to endothermic.The data demonstrates that the mitochondria are actively involved in· OH-treatment induced apoptosis, with the cellular oxygen consumption rapidly decreasing after the·OH-treatment for only 0.5 h.But DNA fragmentation, which is the major characteristic of apoptosis, took place 16 h after · OH-treatment.The results suggest that alteration of the energy/redox metabolism and the energy/redox status may be the primary causes among the early events of· OH-induced apoptosis.

  10. Induction of sperm activation in open and closed thelycum penaeoid shrimps

    NARCIS (Netherlands)

    Alfaro Montoya, J.; Munoz, N.; Vargas, M.; Komen, J.

    2003-01-01

    A modified egg water (EW) technique for in vitro induction of sperm activation was applied to Trachypenaeus byrdi, Xiphopenaeus riveti (closed thelycum shrimps), and Litopenaeus occidentalis (open thelycum) from a tropical estuary, Golfo de Nicoya, Costa Rica. The study was designed to investigate t

  11. An evolutionary vaccination game in the modified activity driven network by considering the closeness

    Science.gov (United States)

    Han, Dun; Sun, Mei

    2016-02-01

    In this paper, we explore an evolutionary vaccination game in the modified activity driven network by considering the closeness. We set a closeness parameter p which is used to describe the way of connection between two individuals. The simulation results show that the closeness p may have an active role in weakening both the spreading of epidemic and the vaccination. Besides, when vaccination is not allowed, the final recovered density increases with the value of the ratio of the infection rate to the recovery rate λ / μ. However, when vaccination is allowed the final density of recovered individual first increases and then decreases with the value of λ / μ. Two variables are designed to identify the relation between the individuals' activities and their states. The results draw that both recovered and vaccinated frequency increase with the increase of the individuals' activities. Meanwhile, the immune fee has less impact on the individuals' vaccination than the closeness. While the λ / μ is in a certain range, with the increase of the value of λ / μ, the recovered frequency of the whole crowds reduces. Our results, therefore, reveal the fact that the best of intentions may lead to backfire.

  12. The Effects of Close Companions (and Rotation) on the Magnetic Activity of M Dwarfs

    CERN Document Server

    Morgan, Dylan P; Garcés, Ane; Catalán, Silvia; Dhital, Saurav; Fuchs, Miriam; Silvestri, Nicole M

    2012-01-01

    We present a study of close white dwarf and M dwarf (WD+dM) binary systems and examine the effect that a close companion has on the magnetic field generation in M dwarfs. We use a base sample of 1602 white dwarf -- main sequence binaries from Rebassa et al. to develop a set of color cuts in GALEX, SDSS, UKIDSS, and 2MASS color space to construct a sample of 1756 WD+dM high-quality pairs from the SDSS DR8 spectroscopic database. We separate the individual WD and dM from each spectrum using an iterative technique that compares the WD and dM components to best-fit templates. Using the absolute height above the Galactic plane as a proxy for age, and the H{\\alpha} emission line as an indicator for magnetic activity, we investigate the age-activity relation for our sample for spectral types \\leqM7. Our results show that early-type M dwarfs (\\leqM4) in close binary systems are more likely to be active and have longer activity lifetimes compared to their field counterparts. However, at a spectral type of M5 (just pas...

  13. Comparative Analysis of Methods to Induce Myocardial Infarction in a Closed-Chest Rabbit Model

    Directory of Open Access Journals (Sweden)

    Marc-Antoine Isorni

    2015-01-01

    Full Text Available Objective. To develop a rabbit model of closed-chest catheter-induced myocardial infarction. Background. Limitations of rodent and large animal models justify the search for clinically relevant alternatives. Methods. Microcatheterization of the heart was performed in 47 anesthetized 3-4 kg New Zealand rabbits to test five techniques of myocardial ischemia: free coils (n=4, interlocking coils (n=4, thrombogenic gelatin sponge (n=4, balloon occlusion (n=4, and alcohol injection (n=8. In order to limit ventricular fibrillation, an antiarrhythmic protocol was implemented, with beta-blockers/amiodarone before and xylocaine infusion during the procedure. Clinical, angiographic, and echographic data were gathered. End points included demonstration of vessel occlusion (TIMI flow grades 0 and 1 on the angiogram, impairment of left ventricular function at 2 weeks after procedure (by echocardiography, and pathologically confirmed myocardial infarction. Results. The best arterial access was determined to be through the right carotid artery. The internal mammary guiding catheter 4-Fr was selected as the optimal device for selective intracoronary injection. Free coils deployed prematurely and tended to prolapse into the aorta. Interlocking coils did not deploy completely and failed to provide reliable results. Gelatin sponge was difficult to handle, adhered to the catheter, and could not be clearly visualized by fluoroscopy. Balloon occlusion yielded inconsistent results. Alcohol injection was the most efficient and reproducible method for inducing myocardial infarction (4 out of 6 animals, the extent of which could be fine-tuned by using a coaxial balloon catheter as a microcatheter (0.52 mm to achieve a superselective injection of 0.2 mL of alcohol. This approach resulted in a 20% decrease in LVEF and infarcted myocardium was confirmed histologically. Conclusions. By following a stepwise approach, a minimally invasive, effective, and reproducible

  14. Calpain Activator Dibucaine Induces Platelet Apoptosis

    Directory of Open Access Journals (Sweden)

    Jun Liu

    2011-03-01

    Full Text Available Calcium-dependent calpains are a family of cysteine proteases that have been demonstrated to play key roles in both platelet glycoprotein Ibα shedding and platelet activation and altered calpain activity is associated with thrombotic thrombocytopenic purpura. Calpain activators induce apoptosis in several types of nucleated cells. However, it is not clear whether calpain activators induce platelet apoptosis. Here we show that the calpain activator dibucaine induced several platelet apoptotic events including depolarization of the mitochondrial inner transmembrane potential, up-regulation of Bax and Bak, down-regulation of Bcl-2 and Bcl-XL, caspase-3 activation and phosphatidylserine exposure. Platelet apoptosis elicited by dibucaine was not affected by the broad spectrum metalloproteinase inhibitor GM6001. Furthermore, dibucaine did not induce platelet activation as detected by P-selectin expression and PAC-1 binding. However, platelet aggregation induced by ristocetin or α-thrombin, platelet adhesion and spreading on von Willebrand factor were significantly inhibited in platelets treated with dibucaine. Taken together, these data indicate that dibucaine induces platelet apoptosis and platelet dysfunction.

  15. Stresslets induced by active swimmers

    CERN Document Server

    Lauga, Eric

    2016-01-01

    Active particles disturb the fluid around them as force dipoles, or stresslets, which govern their collective dynamics. Unlike swimming speeds, the stresslets of active particles are rarely determined due to the lack of a suitable theoretical framework for arbitrary geometry. We propose a general method, based on the reciprocal theorem of Stokes flows, to compute stresslets as integrals of the velocities on the particle's surface, which we illustrate for spheroidal chemically-active particles. Our method will allow tuning the stresslet of artificial swimmers and tailoring their collective motion in complex environments.

  16. Closed-loop neural stimulation for pentylenetetrazole-induced seizures in zebrafish

    Directory of Open Access Journals (Sweden)

    Ricardo Pineda

    2013-01-01

    Neural stimulation can reduce the frequency of seizures in persons with epilepsy, but rates of seizure-free outcome are low. Vagus nerve stimulation prevents seizures by continuously activating noradrenergic projections from the brainstem to the cortex. Cortical norepinephrine then increases GABAergic transmission and increases seizure threshold. Another approach, responsive nervous stimulation, prevents seizures by reactively shocking the seizure onset zone in precise synchrony with seizure onset. The electrical shocks abort seizures before they can spread and manifest clinically. The goal of this study was to determine whether a hybrid platform in which brainstem activation triggered in response to impending seizure activity could prevent seizures. We chose the zebrafish as a model organism for this study because of its ability to recapitulate human disease, in conjunction with its innate capacity for tightly controlled high-throughput experimentation. We first set out to determine whether electrical stimulation of the zebrafish hindbrain could have an anticonvulsant effect. We found that pulse train electrical stimulation of the hindbrain significantly increased the latency to onset of pentylenetetrazole-induced seizures, and that this apparent anticonvulsant effect was blocked by noradrenergic antagonists, as is also the case with rodents and humans. We also found that the anticonvulsant effect of hindbrain stimulation could be potentiated by reactive triggering of single pulse electrical stimulations in response to impending seizure activity. Finally, we found that the rate of stimulation triggering was directly proportional to pentylenetetrazole concentration and that the stimulation rate was reduced by the anticonvulsant valproic acid and by larger stimulation currents. Taken as a whole, these results show that that the anticonvulsant effect of brainstem activation can be efficiently utilized by reactive triggering, which suggests that alternative

  17. Wave induced density modification in RF sheaths and close to wave launchers

    Energy Technology Data Exchange (ETDEWEB)

    Van Eester, D., E-mail: d.van.eester@fz-juelich.de [Laboratory for Plasma Physics, ERM/KMS, EUROfusion Consortium Member, Brussels (Belgium); Crombé, K. [Laboratory for Plasma Physics, ERM/KMS, EUROfusion Consortium Member, Brussels (Belgium); Department of Applied Physics, Ghent University, Ghent (Belgium); Lu, Ling-Feng [CEA, IRFM, F-13108 Saint-Paul-Lez-Durance (France)

    2015-12-10

    With the return to full metal walls - a necessary step towards viable fusion machines - and due to the high power densities of current-day ICRH (Ion Cyclotron Resonance Heating) or RF (radio frequency) antennas, there is ample renewed interest in exploring the reasons for wave-induced sputtering and formation of hot spots. Moreover, there is experimental evidence on various machines that RF waves influence the density profile close to the wave launchers so that waves indirectly influence their own coupling efficiency. The present study presents a return to first principles and describes the wave-particle interaction using a 2-time scale model involving the equation of motion, the continuity equation and the wave equation on each of the time scales. Through the changing density pattern, the fast time scale dynamics is affected by the slow time scale events. In turn, the slow time scale density and flows are modified by the presence of the RF waves through quasilinear terms. Although finite zero order flows are identified, the usual cold plasma dielectric tensor - ignoring such flows - is adopted as a first approximation to describe the wave response to the RF driver. The resulting set of equations is composed of linear and nonlinear equations and is tackled in 1D in the present paper. Whereas the former can be solved using standard numerical techniques, the latter require special handling. At the price of multiple iterations, a simple ’derivative switch-on’ procedure allows to reformulate the nonlinear problem as a sequence of linear problems. Analytical expressions allow a first crude assessment - revealing that the ponderomotive potential plays a role similar to that of the electrostatic potential arising from charge separation - but numerical implementation is required to get a feeling of the full dynamics. A few tentative examples are provided to illustrate the phenomena involved.

  18. Wave induced density modification in RF sheaths and close to wave launchers

    Science.gov (United States)

    Van Eester, D.; Crombé, K.; Lu, Ling-Feng

    2015-12-01

    With the return to full metal walls - a necessary step towards viable fusion machines - and due to the high power densities of current-day ICRH (Ion Cyclotron Resonance Heating) or RF (radio frequency) antennas, there is ample renewed interest in exploring the reasons for wave-induced sputtering and formation of hot spots. Moreover, there is experimental evidence on various machines that RF waves influence the density profile close to the wave launchers so that waves indirectly influence their own coupling efficiency. The present study presents a return to first principles and describes the wave-particle interaction using a 2-time scale model involving the equation of motion, the continuity equation and the wave equation on each of the time scales. Through the changing density pattern, the fast time scale dynamics is affected by the slow time scale events. In turn, the slow time scale density and flows are modified by the presence of the RF waves through quasilinear terms. Although finite zero order flows are identified, the usual cold plasma dielectric tensor - ignoring such flows - is adopted as a first approximation to describe the wave response to the RF driver. The resulting set of equations is composed of linear and nonlinear equations and is tackled in 1D in the present paper. Whereas the former can be solved using standard numerical techniques, the latter require special handling. At the price of multiple iterations, a simple 'derivative switch-on' procedure allows to reformulate the nonlinear problem as a sequence of linear problems. Analytical expressions allow a first crude assessment - revealing that the ponderomotive potential plays a role similar to that of the electrostatic potential arising from charge separation - but numerical implementation is required to get a feeling of the full dynamics. A few tentative examples are provided to illustrate the phenomena involved.

  19. Synthesis and sonication-induced assembly of Si-DDR particles for close-packed oriented layers.

    Science.gov (United States)

    Kim, Eunjoo; Cai, Wanxi; Baik, Hionsuck; Nam, Jaewook; Choi, Jungkyu

    2013-08-28

    Here, we report a seeded growth protocol for synthesizing monodisperse Si-DDR particles of ~1.3-10 μm by varying the seed amount. These Si-DDR particles were deposited onto porous α-Al2O3 discs via sonication-induced assembly, constituting close-packed h0h-oriented layers.

  20. Small high-speed dynamic target at close range laser active imaging system

    Science.gov (United States)

    Yao, Jun; Wang, Du-yue; Zhang, Zheng; Zhang, Yue; Dai, Qin

    2016-11-01

    In the shooting range measuring, all-weather, high speed, unattended, the new concepts such as the remote control is gradually applied. In this paper, a new type of low cost range measurement system, using FPGA + MCU as electronic control system of laser active illumination and high-speed CMOS camera, data to the rear zone by using optical fiber communications, transmission and realizes the remote control of unmanned, due to the low cost of front-end equipment, can be used as consumables replacement at any time, combined with distributed layout principle, can maximum limit close to the measured with mutilate ability goal, thus to achieve the goal of small high-speed dynamic imaging from close range.

  1. Characterization and restoration of performance of {open_quotes}aged{close_quotes} radioiodine removing activated carbons

    Energy Technology Data Exchange (ETDEWEB)

    Freeman, W.P. [NUCON International, Inc., Columbus, OH (United States)

    1997-08-01

    The degradation of radioiodine removal performance for impregnated activated carbons because of ageing is well established. However, the causes for this degradation remain unclear. One theory is that this reduction in performance from the ageing process results from an oxidation of the surface of the carbon. Radioiodine removing activated carbons that failed radioiodine removal tests showed an oxidized surface that had become hydrophilic compared with new carbons. We attempted to restore the performance of these {open_quotes}failed{close_quotes} carbons with a combination of thermal and chemical treatment. The results of these investigations are presented and discussed with the view of extending the life of radioiodine removing activated carbons. 4 refs., 2 tabs.

  2. An insect-induced novel plant phenotype for sustaining social life in a closed system.

    Science.gov (United States)

    Kutsukake, Mayako; Meng, Xian-Ying; Katayama, Noboru; Nikoh, Naruo; Shibao, Harunobu; Fukatsu, Takema

    2012-01-01

    Foraging, defense and waste disposal are essential for sustaining social insect colonies. Hence, their nest generally has an open structure, wherein specialized castes called workers and soldiers perform these tasks. However, some social aphids form completely closed galls, wherein hundreds to thousands of insects grow and reproduce for several months in isolation. Why these social aphids are not drowned by accumulated honeydew has been an enigma. Here we report a sophisticated biological solution to the waste problem in the closed system: the gall inner surface is specialized for absorbing water, whereby honeydew is promptly removed via the plant vascular system. The water-absorbing closed galls have evolved at least twice independently among social aphids. The plant-mediated waste removal, which entails insect's manipulation of plant morphogenesis and physiology, comprises a previously unknown mechanism of nest cleaning, which can be regarded as 'extended phenotype' and 'indirect social behavior' of the social aphids.

  3. A molecular dynamics study of the BACE1 conformational change from Apo to closed form induced by hydroxyethylamine derived compounds.

    Science.gov (United States)

    Gueto-Tettay, Carlos; Zuchniarz, Joshua; Fortich-Seca, Yeyson; Gueto-Tettay, Luis Roberto; Drosos-Ramirez, Juan Carlos

    2016-11-01

    BACE1 is an aspartyl protease which is a therapeutic target for Alzheimer's disease (AD) because of its participation in the rate-limiting step in the production of Aβ-peptide, the accumulation of which produces senile plaques and, in turn, the neurodegenerative effects associated with AD. The active site of this protease is composed in part by two aspartic residues (Asp93 and Asp289). Additionally, the catalytic site has been found to be covered by an antiparallel hairpin loop called the flap. The dynamics of this flap are fundamental to the catalytic function of the enzyme. When BACE1 is inactive (Apo), the flap adopts an open conformation, allowing a substrate or inhibitor to access the active site. Subsequent interaction with the ligand induces flap closure and the stabilization of the macromolecular complex. Further, the protonation state of the aspartic dyad is affected by the chemical nature of the species entering the active site, so that appropriate selection of protonation states for the ligand and the catalytic residues will permit the elucidation of the inhibitory pathway for BACE1. In the present study, comparative analysis of different combinations of protonation states for the BACE1-hydroxyethylamine (HEA) system is reported. HEAs are potent inhibitors of BACE1 with favorable pharmacological and kinetic properties, as well as oral bioavailability. The results of Molecular Dynamics (MD) simulations and population density calculations using 8 different parameters demonstrate that the LnAsp289 configuration (HEA with a neutral amine and the Asp289 residue protonated) is the only one which permits the expected conformational change in BACE1, from apo to closed form, after flap closure. Additionally, differences in their capacities to establish and maintain interactions with residues such as Asp93, Gly95, Thr133, Asp289, Gly291, and Asn294 during this step allow differentiation among the inhibitory activities of the HEAs. The results and methodology here

  4. [Protein kinase C activation induces platelet apoptosis].

    Science.gov (United States)

    Zhao, Li-Li; Chen, Meng-Xing; Zhang, Ming-Yi; Dai, Ke-Sheng

    2013-10-01

    Platelet apoptosis elucidated by either physical or chemical compound or platelet storage occurs wildly, which might play important roles in controlling the numbers and functions of circulated platelets, or in the development of some platelet-related diseases. However, up to now, a little is known about the regulatory mechanisms of platelet apoptosis. Protein kinase C (PKC) is highly expressed in platelets and plays central roles in regulating platelet functions. Although there is evidence indicating that PKC is involved in the regulation of apoptosis of nucleated cells, it is still unclear whether PKC plays a role in platelet apoptosis. The aim of this study was to investigate the role of PKC in platelet apoptosis. The effects of PKC on mitochondrial membrane potential (ΔΨm), phosphatidylserine (PS) exposure, and caspase-3 activation of platelets were analyzed by flow cytometry and Western blot. The results showed that the ΔΨm depolarization in platelets was induced by PKC activator in time-dependent manner, and the caspase-3 activation in platelets was induced by PKC in concentration-dependent manner. However, the platelets incubated with PKC inhibitor did not results in ΔΨm depolarization and PS exposure. It is concluded that the PKC activation induces platelet apoptosis through influencing the mitochondrial functions and activating caspase 3. The finds suggest a novel mechanism for PKC in regulating platelet numbers and functions, which has important pathophysiological implications for thrombosis and hemostasis.

  5. Madagascine Induces Vasodilatation via Activation of AMPK

    Science.gov (United States)

    Chen, Dapeng; Lv, Bochao; Kobayashi, Sei; Xiong, Yongjian; Sun, Pengyuan; Lin, Yuan; Genovese, Salvatore; Epifano, Francesco; Hou, Shanshan; Tang, Fusheng; Ji, Yunyan; Yu, Dandan

    2016-01-01

    Madagascine (3-isopentenyloxyemodin) can be chemically synthesized or purified from several Rhamnus species, and it is found to have more potent biological activities than the parent compound emodin. The aim of this study is to characterize the vasodilatory effect of madagascine on vasoconstriction and sphingosylphosphorylcholine induced vasospasm in ex vivo and reveal the potential mechanisms in vitro. The effects of madagascine on vasoconstriction of rat mesenteric resistance arteries (MRAs) induced by K+, methoxamine, and endothelin-1 were, respectively, studied. The cholesterol-enriched porcine coronary vascular smooth muscle (VSM) strips were used to investigate the effects of madagascine on abnormal constriction induced by sphingosylphosphorylcholine (SPC) which has a pivotal role in vasospasm. The vasodilatory effect was induced by madagascine (0.3–100 μM) in isolated rat MRAs and the vasodilatory effect was blocked by NO synthase inhibitor L-NAME and AMPK inhibitor compound C. Madagascine (10 μM) also significantly relaxed the abnormal constriction in porcine VSM induced by SPC and the effect was abolished by compound C. Madagascine significantly increased the phosphorylation of endothelial nitric oxide synthase (eNOS) in endothelial cells while decreasing the phosphorylation of myosin phosphatase target subunit 1 (MYPT1) in VSM cells. Madagascine-induced vasodilatation was abrogated using small interfering RNA knockdown of AMPK. In summary, madagascine exerted vasodilatation through activating AMPK, leading to the activation of eNOS in endothelium and inhibition of ROCK/MYPT1 in VSM. This study suggests the potential value of madagascine in amelioration of vasospasm related cardiovascular diseases. PMID:27932979

  6. Ionic changes during experimentally induced seizure activity.

    Science.gov (United States)

    Lux, H D; Heinemann, U

    1978-01-01

    Changes in intra- and extracellular ionic activity and their relation to generation and termination of seizure phenomena can be studied with the help of ion-selective microelectrodes. Transient changes in extracellular potassium activity (aK) of the cortex regularly accompany paroxysmal activity induced by electrical stimulation and pentylenetetrazol injections or occur within active penicillin and aluminum foci. A rise of aK from baseline levels of about 3 mmoles/l up to ceiling levels of 8--12 mmoles/l, followed by subnormal K activity, is typically found during seizure discharge. Extracellular K accumulation during seizures facilitates the spread into extrafocal regions. Ceiling levels of extracellular aK are characterized by pronounced K reabsorption which is probably a limiting mechanism for the rise in extracellular aK. It may be a consequence of a simultaneous rise in intracellular Na activity that an electrogenic Na--K exchange process is involved in the termination of ictal activity. Seizures are also accompanied by significant reductions in extracellular Ca2+ activity (aCa) to as low as 0.7 mmoles/l (resting aCa 1.25 mmoles/l). There is no critical level of lowered aCa at which a seizure ultimately results. However, unlike changes in aK reductions in aCa can precede ictal activity. Thus, a fall of aCa occurs before the onset of paroxysmal periods during cyclical spike driving in a penicillin focus and before seizures induced by pentylenetetrazol. Ca2+-dependent mechanisms may contribute to seizure generation. In addition to changes in aK and aCa, intracellular chloride activity (aCl) can increase during seizure activity, as a result of an impaired chloride extrusion mechanism, which would lead to a reduced efficacy of inhibitory synaptic transmission and, therefore, to facilitation of seizure generation.

  7. An adaptive and generalizable closed-loop system for control of medically induced coma and other states of anesthesia

    Science.gov (United States)

    Yang, Yuxiao; Shanechi, Maryam M.

    2016-12-01

    Objective. Design of closed-loop anesthetic delivery (CLAD) systems is an important topic, particularly for medically induced coma, which needs to be maintained for long periods. Current CLADs for medically induced coma require a separate offline experiment for model parameter estimation, which causes interruption in treatment and is difficult to perform. Also, CLADs may exhibit bias due to inherent time-variation and non-stationarity, and may have large infusion rate variations at steady state. Finally, current CLADs lack theoretical performance guarantees. We develop the first adaptive CLAD for medically induced coma, which addresses these limitations. Further, we extend our adaptive system to be generalizable to other states of anesthesia. Approach. We designed general parametric pharmacodynamic, pharmacokinetic and neural observation models with associated guidelines, and derived a novel adaptive controller. We further penalized large steady-state drug infusion rate variations in the controller. We derived theoretical guarantees that the adaptive system has zero steady-state bias. Using simulations that resembled real time-varying and noisy environments, we tested the closed-loop system for control of two different anesthetic states, burst suppression in medically induced coma and unconsciousness in general anesthesia. Main results. In 1200 simulations, the adaptive system achieved precise control of both anesthetic states despite non-stationarity, time-variation, noise, and no initial parameter knowledge. In both cases, the adaptive system performed close to a baseline system that knew the parameters exactly. In contrast, a non-adaptive system resulted in large steady-state bias and error. The adaptive system also resulted in significantly smaller steady-state infusion rate variations compared to prior systems. Significance. These results have significant implications for clinically viable CLAD design for a wide range of anesthetic states, with potential cost

  8. Analysis of laser generated ultrasonic wave frequency characteristics induced by a partially closed surface-breaking crack.

    Science.gov (United States)

    Li, Jia; Zhang, Hongchao; Ni, Chenyin; Shen, Zhonghua

    2013-06-20

    This research focuses on analyzing the frequency characteristics of ultrasonic waves induced by a partially closed surface-breaking crack. When acoustic waves interact with the crack, transmission, reflection, and mode conversions occur and the frequency characteristics of signals perform obvious changes. A pulsed laser line source is used to generate ultrasonic waves in the sample with a partially closed surface-breaking crack, and one can see how the frequency characteristics of detected signals change as the pulsed laser beam scans across the sample surface. The optical deflection beam method is developed to detect the ultrasonic signals experimentally. The fast Fourier transform (FFT) is used to analyze the time-domain data, and the FFT data are visualized by a B-scan plot. A clear disruption in the B-scan can be observed when the laser beam illuminates directly onto the crack, which is due to the changes of frequency characteristics induced by the partially closed crack. A frequency-domain B-scan of numerical simulation results is presented, and the clear disruption can also be observed clearly.

  9. The Extremely Low Activity Comet 209P/LINEAR During Its Extraordinary Close Approach in 2014

    CERN Document Server

    Schleicher, David G

    2016-01-01

    We present results from our observing campaign of Comet 209P/LINEAR during its exceptionally close approach to Earth during May of 2014, the third smallest perigee of any comet in two centuries. These circumstances permitted us to pursue several studies of this intrinsically faint object, including measurements of gas and dust production rates, searching for coma morphology, and direct detection of the nucleus to measure its properties. Indeed, we successfully measured the lowest water production rates of an intact comet in over 35 years and a corresponding smallest active area, ~0.007 km^2. When combined with the nucleus size found from radar (Howell et al. 2014), this also yields the smallest active fraction for any comet, ~0.024%. In all, this strongly suggests that 209P/LINEAR is on its way to becoming an inert object. The nucleus was detected but could not easily be disentangled from the inner coma due to seeing variations and changing spatial scales. Even so, we were able to measure a double-peaked ligh...

  10. New Atglistatin closely related analogues: Synthesis and structure-activity relationship towards adipose triglyceride lipase inhibition.

    Science.gov (United States)

    Roy, Pierre-Philippe; D'Souza, Kenneth; Cuperlovic-Culf, Miroslava; Kienesberger, Petra C; Touaibia, Mohamed

    2016-08-01

    Adipose Triglyceride Lipase (ATGL) performs the first and rate-limiting step in lipolysis by hydrolyzing triacylglycerols stored in lipid droplets to diacylglycerols. By mediating lipolysis in adipose and non-adipose tissues, ATGL is a major regulator of overall energy metabolism and plasma lipid levels. Since chronically high levels of plasma lipids are linked to metabolic disorders including insulin resistance and type 2 diabetes, ATGL is an interesting therapeutic target. In the present study, fourteen closely related analogues of Atglistatin (1), a newly discovered ATGL inhibitor, were synthesized, and their ATGL inhibitory activity was evaluated. The effect of these analogues on lipolysis in 3T3-L1 adipocytes clearly shows that inhibition of the enzyme by Atglistatin (1) is due to the presence of the carbamate and N,N-dimethyl moieties on the biaryl central core at meta and para position, respectively. Mono carbamate-substituted analogue C2, in which the carbamate group was in the meta position as in Atglistatin (1), showed slight inhibition. Low dipole moment of Atglistatin (1) compared to the synthesized analogues possibly explains the lower inhibitory activities.

  11. Induced recrystallization of CdTe thin films deposited by close-spaced sublimation

    Science.gov (United States)

    Moutinho, H. R.; Dhere, R. G.; Al-Jassim, M. M.; Mayo, B.; Levi, D. H.; Kazmerski, L. L.

    1999-03-01

    We have deposited CdTe thin films by close-spaced sublimation at two different temperature ranges. The films deposited at the lower temperature partially recrystallized after CdCl2 treatment at 350 °C and completely recrystallized after the same treatment at 400 °C. The films deposited at higher temperature did not recrystallize at these two temperatures. These results confirmed that the mechanisms responsible for changes in physical properties of CdTe films treated with CdCl2 are recrystallization and grain growth, and provided an alternative method to deposit CSS films using lower temperatures.

  12. Induced Recrystallization of CdTe Thin Films Deposited by Close-Spaced Sublimation

    Energy Technology Data Exchange (ETDEWEB)

    Moutinho, H. R.; Dhere, R. G.; Al-Jassim, M. M.; Levi, D. H.; Kazmerski, L. L. (National Renewable Energy Laboratory); Mayo, B. (Southern University and A& M College, Baton Rouge, LA)

    1998-10-26

    We have deposited CdTe thin films by close-spaced sublimation at two different temperature ranges. The films deposited at the lower temperature partially recrystallized after CdCl2 treatment at 350 C and completely recrystallized after the same treatment at 400 C. The films deposited at higher temperature did not recrystallize at these two temperatures. These results confirmed that the mechanisms responsible for changes in physical properties of CdTe films treated with CdCl2 are recrystallization and grain growth, and provided an alternative method to deposit CSS films using lower temperatures.

  13. Induced Recrystallization of CdTe Thin Films Deposited by Close-Spaced Sublimation

    Energy Technology Data Exchange (ETDEWEB)

    Moutinho, H. R.; Dhere, R. G.; Al-Jassim, M. M.; Levi, D. H.; Kazmerski, L. L. (National Renewable Energy Laboratory); Mayo, B. (Southern University and A& M College, LA)

    1998-10-29

    We have deposited CdTe thin films by close-spaced sublimation at two different temperature ranges. The films deposited at the lower temperature partially recrystallized after CdCl{sub 2} treatment at 350 C and completely recrystallized after the same treatment at 400 C. The films deposited at higher temperature did not recrystallize at these two temperatures. These results confirmed that the mechanisms responsible for changes in physical properties of CdTe films treated with CdCl{sub 2} are recrystallization and grain growth, and provided an alternative method to deposit CSS films using lower temperatures.

  14. Counteraction of tetherin antiviral activity by two closely related SIVs differing by the presence of a Vpu gene.

    Directory of Open Access Journals (Sweden)

    Kristina Nikovics

    Full Text Available In different primate lentiviruses, three proteins (Vpu, Env and Nef have been shown to have anti-tetherin activities. SIVden is a primate lentivirus harbored by a Cercopithecus denti (C. denti whose genome code for a Vpu gene. We have compared the activity of HIV-1 Vpu and of SIVden Vpu on tetherin proteins from humans, from C. denti and from Cercopithecus neglectus (C. neglectus, a monkey species that is naturally infected by SIVdeb, a virus closely related to SIVden but which does not encode a Vpu protein. Here, we demonstrate that SIVden Vpu, is active against C. denti tetherin, but not against human tetherin. Interestingly, C. neglectus tetherin was more sensitive to SIVden Vpu than to HIV-1 Vpu. We also identify residues in the tetherin transmembrane domains that are responsible for the species-specific Vpu effect. Simultaneous mutation (P40L and T45I of human tetherin conferred sensitivity to SIVden Vpu, while abolishing its sensitivity to HIV-1 Vpu. We next analyzed the anti-tetherin activity of the Nef proteins from HIV-1, SIVden and SIVdeb. All three Nef proteins were unable to rescue virus release in the presence of human or C. denti tetherin. Conversely, SIVdeb Nef enhanced virus release in the presence of C. neglectus tetherin, suggesting that SIVdeb relies on Nef in its natural host. Finally, while HIV-1 Vpu not only removed human tetherin from the cell surface but also directed it for degradation, SIVden Vpu only induced the redistribution of both C. denti and C. neglectus tetherins, resulting in a predominantly perinuclear localization.

  15. STELLAR WIND INDUCED SOFT X-RAY EMISSION FROM CLOSE-IN EXOPLANETS

    Energy Technology Data Exchange (ETDEWEB)

    Kislyakova, K. G.; Lammer, H. [Space Research Institute, Austrian Academy of Sciences, Graz (Austria); Fossati, L. [Argelander-Institut für Astronomie der Universität Bonn, Bonn (Germany); Johnstone, C. P. [Department of Astrophysics, University of Vienna, Vienna (Austria); Holmström, M. [Swedish Institute of Space Physics, Kiruna (Sweden); Zaitsev, V. V., E-mail: kristina.kislyakova@oeaw.ac.at [Institute of Applied Physics, Russian Academy of Sciences, Nizhny Novgorod (Russian Federation)

    2015-01-30

    In this Letter, we estimate the X-ray emission from close-in exoplanets. We show that the Solar/Stellar Wind Charge Exchange Mechanism (SWCX), which produces soft X-ray emission, is very effective for hot Jupiters. In this mechanism, X-ray photons are emitted as a result of the charge exchange between heavy ions in the solar wind and the atmospheric neutral particles. In the solar system, comets produce X-rays mostly through the SWCX mechanism, but it has also been shown to operate in the heliosphere, in the terrestrial magnetosheath, and on Mars, Venus, and the Moon. Since the number of emitted photons is proportional to the solar wind mass flux, this mechanism is not very effective for the solar system giants. Here we present a simple estimate of the X-ray emission intensity that can be produced by close-in extrasolar giant planets due to charge exchange with the heavy ions of the stellar wind. Using the example of HD 209458b, we show that this mechanism alone can be responsible for an X-ray emission of ≈10{sup 22} erg s{sup –1}, which is 10{sup 6} times stronger than the emission from the Jovian aurora. We discuss also the possibility of observing the predicted soft X-ray flux of hot Jupiters and show that despite high emission intensities they are unobservable with current facilities.

  16. Stelllar wind induced soft X-ray emission from close-in exoplanets

    Science.gov (United States)

    Kislyakova, Kristina; Fossati, Luca; Johnstone, Colin P.; Holmström, Mats; Zaitsev, Valery V.; Lammer, Helmut

    2016-04-01

    We estimate the X-ray emission from close-in exoplanets. We show that the Solar/Stellar Wind Charge Exchange Mechanism (SWCX) which produces soft X-ray radiation is very effective for hot Jupiters. In this mechanism, X-ray photons are produces by charge exchange between heavy ions in the solar wind and the atmospheric neutral particles. This mechanism is know to generate X-ray emission of comets in the Solar system. It has also been shown to operate in the heliosphere, in the terrestrial magnetosheath, and on Mars, Venus and Moon. Since the number of emitted photons is proportional to the solar wind mass flux, this mechanism is not effective for the Solar system giants. We present a simple estimate of the X-ray emission intensity that can be produced by close-in extrasolar Hot Jupiters due to charge exchange with the heavy ions of the stellar wind. Using the example of HD 209458b, we show that this mechanism alone can be responsible for an X-ray emission of ≈ 1022 erg s-1, which is 106 times stronger than the emission from the Jovian aurora. We discuss the possibility to observe the predicted soft X-ray flux of hot Jupiters and show that despite high emission intensities they are unobservable with current facilities.

  17. Stellar wind induced soft X-ray emission from close-in exoplanets

    CERN Document Server

    Kislyakova, K G; Johnstone, C P; Holmström, M; Zaitsev, V V; Lammer, H

    2015-01-01

    In this paper, we estimate the X-ray emission from close-in exoplanets. We show that the Solar/Stellar Wind Charge Exchange Mechanism (SWCX) which produces soft X-ray emission is very effective for hot Jupiters. In this mechanism, X-ray photons are emitted as a result of the charge exchange between heavy ions in the solar wind and the atmospheric neutral particles. In the Solar System, comets produce X-rays mostly through the SWCX mechanism, but it has also been shown to operate in the heliosphere, in the terrestrial magnetosheath, and on Mars, Venus and Moon. Since the number of emitted photons is proportional to the solar wind mass flux, this mechanism is not very effective for the Solar system giants. Here we present a simple estimate of the X-ray emission intensity that can be produced by close-in extrasolar giant planets due to charge exchange with the heavy ions of the stellar wind. Using the example of HD~209458b, we show that this mechanism alone can be responsible for an X-ray emission of $\\approx 10...

  18. Plastic Changes in Human Motor Cortical Output Induced by Random but not Closed-Loop Peripheral Stimulation: the Curse of Causality

    Directory of Open Access Journals (Sweden)

    Kenneth I Brown

    2016-11-01

    Full Text Available Previous work showed that repetitive peripheral nerve stimulation can induce plastic changes in motor cortical output. Triggering electrical stimulation of central structures from natural activity can also generate plasticity. In this study, we tested whether triggering peripheral nerve stimulation from muscle activity would likewise induce changes in motor output. We developed a wearable electronic device capable of recording electromyogram (EMG and delivering electrical stimulation under closed-loop control. This allowed paired stimuli to be delivered over longer periods than standard laboratory-based protocols.We tested this device in healthy human volunteers. Motor cortical output in relaxed thenar muscles was first assessed via the recruitment curve of responses to contralateral transcranial magnetic stimulation. The wearable device was then configured to record thenar EMG and stimulate the median nerve at the wrist (intensity around motor threshold, rate ~0.66 Hz. Subjects carried out normal daily activities for 4-7 hours, before returning to the laboratory for repeated recruitment curve assessment. Four stimulation protocols were tested (9-14 subjects each: No Stim, no stimuli delivered; Activity, stimuli triggered by EMG activity above threshold; Saved, stimuli timed according to a previous Activity session in the same subject; Rest, stimuli given when EMG was silent. As expected, No Stim did not modify the recruitment curve. Activity and Rest conditions produced no significant effects across subjects, although there were changes in some individuals. Saved produced a significant and substantial increase, with average responses 2.14 times larger at 30% stimulator intensity above threshold.We argue that unavoidable delays in the closed loop feedback, due mainly to central and peripheral conduction times, mean that stimuli in the Activity paradigm arrived too late after cortical activation to generate consistent plastic changes. By contrast

  19. Specificity of herbivore-induced hormonal signaling and defensive traits in five closely related milkweeds (Asclepias spp.).

    Science.gov (United States)

    Agrawal, Anurag A; Hastings, Amy P; Patrick, Eamonn T; Knight, Anna C

    2014-07-01

    Despite the recognition that phytohormonal signaling mediates induced responses to herbivory, we still have little understanding of how such signaling varies among closely related species and may generate herbivore-specific induced responses. We studied closely related milkweeds (Asclepias) to link: 1) plant damage by two specialist chewing herbivores (milkweed leaf beetles Labidomera clivicolis and monarch caterpillars Danaus plexippus); 2) production of the phytohormones jasmonic acid (JA), salicylic acid (SA), and abscisic acid (ABA); 3) induction of defensive cardenolides and latex; and 4) impacts on Danaus caterpillars. We first show that A. syriaca exhibits induced resistance following monarch herbivory (i.e., reduced monarch growth on previously damaged plants), while the defensively dissimilar A. tuberosa does not. We next worked with a broader group of five Asclepias, including these two species, that are highly divergent in defensive traits yet from the same clade. Three of the five species showed herbivore-induced changes in cardenolides, while induced latex was found in four species. Among the phytohormones, JA and ABA showed specific responses (although they generally increased) to insect species and among the plant species. In contrast, SA responses were consistent among plant and herbivore species, showing a decline following herbivore attack. Jasmonic acid showed a positive quantitative relationship only with latex, and this was strongest in plants damaged by D. plexippus. Although phytohormones showed qualitative tradeoffs (i.e., treatments that enhanced JA reduced SA), the few significant individual plant-level correlations among hormones were positive, and these were strongest between JA and ABA in monarch damaged plants. We conclude that: 1) latex exudation is positively associated with endogenous JA levels, even among low-latex species; 2) correlations among milkweed hormones are generally positive, although herbivore damage induces a

  20. Reaction mechanisms in collisions induced by $^{8}$B beam close to the barrier

    CERN Multimedia

    The aim of the proposed experiment is to investigate the reaction dynamics of proton-halo induced collisions at energies around the Coulomb barrier where coupling to continuum effects are expected to be important. We propose to measure the $^{8}$B + $^{64}$Zn elastic scattering angular distribution together with the measurement, for the first time, of p - $^{7}$Be coincidences coming from transfer and/or break-up of $^{8}$B. The latter will allow a better understanding of the relative contribution of elastic $\\textit{vs}$ non-elastic break-up in reactions induced by extremely weakly-bound nuclei. We believe that with the availability of the post accelerated $^{8}$B beam at REX-ISOLDE we will be able to collect for the first time high quality data for the study of such an important topic.

  1. Close-range photogrammetry enables documentation of environment-induced deformation of architectural heritage

    OpenAIRE

    Suziedelyte-Visockiene, J; Bagdziunaite, R; Malys, N.; Maliene, V

    2015-01-01

    Deformation, damage and permanent loss of heritage assets due to various physical and environmental factors has always been a major problem. As the availability of funds for conservation and restoration is limited, the digital documentation of heritage objects and monitoring of environment-induced deformations are increasingly important for cultural heritage preservation. Our study elucidates developments in the digital image capturing and processing for recording architectural heritage objec...

  2. Induced recrystallization of CdTe thin films deposited by close-spaced sublimation

    Energy Technology Data Exchange (ETDEWEB)

    Moutinho, H.R.; Dhere, R.G.; Al-Jassim, M.M.; Levi, D.H.; Kazmerski, L.L. [National Renewable Energy Laboratory, 1617 Cole Blvd., Golden, Colorado 80401 (United States); Mayo, B. [Southern University and AM College, Harding Boulevard, Baton Rouge, Louisiana 70813 (United States)

    1999-03-01

    We have deposited CdTe thin films by close-spaced sublimation at two different temperature ranges. The films deposited at the lower temperature partially recrystallized after CdCl{sub 2} treatment at 350&hthinsp;{degree}C and completely recrystallized after the same treatment at 400&hthinsp;{degree}C. The films deposited at higher temperature did not recrystallize at these two temperatures. These results confirmed that the mechanisms responsible for changes in physical properties of CdTe films treated with CdCl{sub 2} are recrystallization and grain growth, and provided an alternative method to deposit CSS films using lower temperatures. {copyright} {ital 1999 American Institute of Physics.}

  3. A mouse model of ocular blast injury that induces closed globe anterior and posterior pole damage

    Science.gov (United States)

    Hines-Beard, Jessica; Marchetta, Jeffrey; Gordon, Sarah; Chaum, Edward; Geisert, Eldon E.; Rex, Tonia S.

    2012-01-01

    We developed and characterized a mouse model of primary ocular blast injury. The device consists of: a pressurized air tank attached to a regulated paintball gun with a machined barrel; a chamber that protects the mouse from direct injury and recoil, while exposing the eye; and a secure platform that enables fine, controlled movement of the chamber in relation to the barrel. Expected pressures were calculated and the optimal pressure transducer, based on the predicted pressures, was positioned to measure output pressures at the location where the mouse eye would be placed. Mice were exposed to one of three blast pressures (23.6, 26.4, or 30.4psi). Gross pathology, intraocular pressure, optical coherence tomography, and visual acuity were assessed 0, 3, 7, 14, and 28 days after exposure. Contralateral eyes and non-blast exposed mice were used as controls. We detected increased damage with increased pressures and a shift in the damage profile over time. Gross pathology included corneal edema, corneal abrasions, and optic nerve avulsion. Retinal damage was detected by optical coherence tomography and a deficit in visual acuity was detected by optokinetics. Our findings are comparable to those identified in Veterans of the recent wars with closed eye injuries as a result of blast exposure. In summary, this is a relatively simple system that creates injuries with features similar to those seen in patients with ocular blast trauma. This is an important new model for testing the short-term and long-term spectrum of closed globe blast injuries and potential therapeutic interventions. PMID:22504073

  4. Research and Technology Activities Supporting Closed-Brayton-Cycle Power Conversion System Development

    Science.gov (United States)

    Barrett, Michael J.

    2004-01-01

    The elements of Brayton technology development emphasize power conversion system risk mitigation. Risk mitigation is achieved by demonstrating system integration feasibility, subsystem/component life capability (particularly in the context of material creep) and overall spacecraft mass reduction. Closed-Brayton-cycle (CBC) power conversion technology is viewed as relatively mature. At the 2-kWe power level, a CBC conversion system Technology Readiness Level (TRL) of six (6) was achieved during the Solar Dynamic Ground Test Demonstration (SD-GTD) in 1998. A TRL 5 was demonstrated for 10 kWe-class CBC components during the development of the Brayton Rotating Unit (BRU) from 1968 to 1976. Components currently in terrestrial (open cycle) Brayton machines represent TRL 4 for similar uses in 100 kWe-class CBC space systems. Because of the baseline component and subsystem technology maturity, much of the Brayton technology task is focused on issues related to systems integration. A brief description of ongoing technology activities is given.

  5. Postnatal changes of local neuronal circuits involved in activation of jaw-closing muscles.

    Science.gov (United States)

    Inoue, Tomio; Nakamura, Shiro; Takamatsu, Junichi; Tokita, Kenichi; Gemba, Akiko; Nakayama, Kiyomi

    2007-04-01

    Feeding behaviour in mammals changes from suckling to mastication during postnatal development and the neuronal circuits controlling feeding behaviour should change in parallel to the development of orofacial structures. In this review we discuss the location of excitatory premotor neurons for jaw-closing motoneurons (JCMNs) and postnatal changes of excitatory synaptic transmission from the supratrigeminal region (SupV) to JCMNs. We show that neurons located in SupV and the reticular formation dorsal to the facial nucleus most likely excite JCMNs. Excitatory inputs from SupV to JCMNs are mediated by activation of glutamate and glycine receptors in neonatal rats, whereas glycinergic inputs from SupV to JCMNs become inhibitory with age. We also show that the incidence of post-spike afterdepolarization increases during postnatal development, whereas the amplitude and half-duration of the medium-duration afterhyperpolarization decrease with age. Such postnatal changes in synaptic transmission from SupV to JCMNs and membrane properties of JCMNs might be involved in the transition from suckling to mastication.

  6. Novel Methods for Prioritizing "Close-In" Analogs from Structure-Activity Relationship Matrices.

    Science.gov (United States)

    Zhang, Liying; Johnson, Kjell; Starr, Jeremy; Milbank, Jared; Kuhn, Andrew M; Poss, Christopher; Stanton, Robert V; Shanmugasundaram, Veerabahu

    2017-07-24

    Here we describe the development of novel methods for compound evaluation and prioritization based on the structure-activity relationship matrix (SARM) framework. The SARM data structure allows automatic and exhaustive extraction of SAR patterns from data sets and their organization into a chemically intuitive scaffold/functional-group format. While SARMs have been used in the retrospective analysis of SAR discontinuity and identifying underexplored regions of chemistry space, there have been only a few attempts to apply SARMs prospectively in the prioritization of "close-in" analogs. In this work, three new ways of prioritizing virtual compounds based on SARMs are described: (1) matrix pattern-based prioritization, (2) similarity weighted, matrix pattern-based prioritization, and (3) analysis of variance based prioritization (ANV). All of these methods yielded high predictive power for six benchmark data sets (prediction accuracy R(2) range from 0.63 to 0.82), yielding confidence in their application to new design ideas. In particular, the ANV method outperformed the previously reported SARM based method for five out of the six data sets tested. The impact of various SARM parameters were investigated and the reasons why SARM-based compound prioritization methods provide higher predictive power are discussed.

  7. A Distant Echo of Milky Way Central Activity closes the Galaxy's Baryon Census

    CERN Document Server

    Nicastro, F; Krongold, Y; Mathur, S; Elvis, M

    2016-01-01

    We report on the presence of large amounts of million-degree gas in the Milky Way's interstellar and circum-galactic medium. This gas (1) permeates both the Galactic plane and the halo, (2) extends to distances larger than 60-200 kpc from the center, and (3) its mass is sufficient to close the Galaxy's baryon census. Moreover, we show that a vast, $\\sim 6$ kpc radius, spherically-symmetric central region of the Milky Way above and below the 0.16 kpc thick plane, has either been emptied of hot gas or the density of this gas within the cavity has a peculiar profile, increasing from the center up to a radius of $\\sim 6$ kpc, and then decreasing with a typical halo density profile. This, and several other converging pieces of evidence, suggest that the current surface of the cavity, at 6 kpc from the Galaxy's center, traces the distant echo of a period of strong nuclear activity of our super-massive black-hole, occurred about 6 Myrs ago.

  8. Active ammonia oxidizers in an acidic soil are phylogenetically closely related to neutrophilic archaeon.

    Science.gov (United States)

    Wang, Baozhan; Zheng, Yan; Huang, Rong; Zhou, Xue; Wang, Dongmei; He, Yuanqiu; Jia, Zhongjun

    2014-03-01

    All cultivated ammonia-oxidizing archaea (AOA) within the Nitrososphaera cluster (former soil group 1.1b) are neutrophilic. Molecular surveys also indicate the existence of Nitrososphaera-like phylotypes in acidic soil, but their ecological roles are poorly understood. In this study, we present molecular evidence for the chemolithoautotrophic growth of Nitrososphaera-like AOA in an acidic soil with pH 4.92 using DNA-based stable isotope probing (SIP). Soil microcosm incubations demonstrated that nitrification was stimulated by urea fertilization and accompanied by a significant increase in the abundance of AOA rather than ammonia-oxidizing bacteria (AOB). Real-time PCR analysis of amoA genes as a function of the buoyant density of the DNA gradient following the ultracentrifugation of the total DNA extracted from SIP microcosms indicated a substantial growth of soil AOA during nitrification. Pyrosequencing of the total 16S rRNA genes in the "heavy" DNA fractions suggested that archaeal communities were labeled to a much greater extent than soil AOB. Acetylene inhibition further showed that (13)CO2 assimilation by nitrifying communities depended solely on ammonia oxidation activity, suggesting a chemolithoautotrophic lifestyle. Phylogenetic analysis of both (13)C-labeled amoA and 16S rRNA genes revealed that most of the active AOA were phylogenetically closely related to the neutrophilic strains Nitrososphaera viennensis EN76 and JG1 within the Nitrososphaera cluster. Our results provide strong evidence for the adaptive growth of Nitrososphaera-like AOA in acidic soil, suggesting a greater metabolic versatility of soil AOA than previously appreciated.

  9. Walk on Floor Eyes Closed Test: A Unique Test of Spaceflight Induced Ataxia

    Science.gov (United States)

    Reschke, M. F.; Fisher, E. A.; Kofman, I. S.; Cerisano, J. M.; Harm, D. L.; Bloomberg, J. J.

    2011-01-01

    Measurement and quantification of posture and locomotion following spaceflight is an evolving process. Based on the data obtained from the current investigation we believe that the walk on the floor line test with the eyes closed (WOFEC) provides a unique procedure for quantifying postflight ataxia. As a part of an ongoing investigation designed to look at functional changes in astronauts returning from spaceflight seven astronauts (5 short duration with flights of 12-16 days; 2 long duration crewmembers with flights of 6 months) were tested twice before flight, on landing day (short duration only), and 1, 6, and 30 days after flight. The WOFEC consisted of walking for 10 steps (repeated twice) with the feet heel to toe in tandem, arms folded across the chest and the eyes closed. The performance metric (scored by three examiners from video) was the percentage of correct steps completed over the three trials. A step was not counted as correct if the crewmember side-stepped, opened their eyes, or paused for more than three seconds between steps. The data reveled a significant decrease in percentage of correct steps on landing day (short duration crew) and on the first day following landing (long duration) with partial recovery the following day, and full recovery beginning on day sixth after flight. Both short and long duration fliers appeared to be unaware of foot position relative to their bodies or the floor. Postflight, deviation from a straight path was common, and seemed to be determined by the angle of foot placement relative to their body. While deviation from a straight line could be either left or right, primary deviations were observed to occur to the right. Furthermore, the test for two crewmembers elicited motion sickness symptoms. These data clearly demonstrate the sensorimotor challenges facing crewmembers after returning from spaceflight. The WOFEC test has value providing the investigator or crew surgeon with a simple method to quantify vestibular

  10. Surface modification-induced phase transformation of hexagonal close-packed gold square sheets

    KAUST Repository

    Fan, Zhanxi

    2015-03-13

    Conventionally, the phase transformation of inorganic nanocrystals is realized under extreme conditions (for example, high temperature or high pressure). Here we report the complete phase transformation of Au square sheets (AuSSs) from hexagonal close-packed (hcp) to face-centered cubic (fcc) structures at ambient conditions via surface ligand exchange, resulting in the formation of (100)f-oriented fcc AuSSs. Importantly, the phase transformation can also be realized through the coating of a thin metal film (for example, Ag) on hcp AuSSs. Depending on the surfactants used during the metal coating process, two transformation pathways are observed, leading to the formation of (100)f-oriented fcc Au@Ag core-shell square sheets and (110)h/(101)f-oriented hcp/fcc mixed Au@Ag nanosheets. Furthermore, monochromated electron energy loss spectroscopy reveals the strong surface plasmon resonance absorption of fcc AuSS and Au@Ag square sheet in the infrared region. Our findings may offer a new route for the crystal-phase and shape-controlled synthesis of inorganic nanocrystals. © 2015 Macmillan Publishers Limited. All rights reserved.

  11. Chemical reactions induced by high-velocity molecular impacts: challenges for closed-source mass spectrometry

    Science.gov (United States)

    Austin, Daniel

    2016-07-01

    Analysis of upper atmosphere composition using closed-source neutral mass spectrometers (e.g., Cassini INMS, MAVEN NGIMS) is subject to error due to chemical reactions caused by the high-velocity impacts of neutral molecules on the source surfaces. In addition to species traditionally considered "surface reactive" (e.g., O, N) it is likely that many or all impacting molecules are vibrationally excited to the point that chemical changes can occur. Dissociation, fragmentation, formation of radicals and ions, and other reactions likely obscure analysis of the native atmospheric composition, particularly of organic compounds. Existing techniques are not capable of recreating the relevant impact chemistry in the lab. We report on the development of a new capability allowing reactions of high-velocity neutrals impacting surfaces to be characterized directly. Molecules introduced into a vacuum chamber are impacted at several km/s by the surface of a high-speed rotor. These molecules subsequently impact multiple times on other surfaces within the vacuum chamber until they are thermalized, after which they are cryogenically collected and analyzed. Reaction pathways and thermodynamics for volatile compounds are then determined. We will present current results on this project, including data from low- and mid-range velocity experiments. This type of information is critical to clarify prior flight results and plan for future missions. Finally, we present a new type of inlet intended to significantly reduce fragmentation for impact velocities typical of a fly-by mission. Theoretical analysis indicates that this new inlet may reduce fragmentation by more than an order of magnitude for any encounter velocity.

  12. Open and closed cortico-subcortical loops: A neuro-computational account of access to consciousness in the distractor-induced blindness paradigm.

    Science.gov (United States)

    Ebner, Christian; Schroll, Henning; Winther, Gesche; Niedeggen, Michael; Hamker, Fred H

    2015-09-01

    How the brain decides which information to process 'consciously' has been debated over for decades without a simple explanation at hand. While most experiments manipulate the perceptual energy of presented stimuli, the distractor-induced blindness task is a prototypical paradigm to investigate gating of information into consciousness without or with only minor visual manipulation. In this paradigm, subjects are asked to report intervals of coherent dot motion in a rapid serial visual presentation (RSVP) stream, whenever these are preceded by a particular color stimulus in a different RSVP stream. If distractors (i.e., intervals of coherent dot motion prior to the color stimulus) are shown, subjects' abilities to perceive and report intervals of target dot motion decrease, particularly with short delays between intervals of target color and target motion. We propose a biologically plausible neuro-computational model of how the brain controls access to consciousness to explain how distractor-induced blindness originates from information processing in the cortex and basal ganglia. The model suggests that conscious perception requires reverberation of activity in cortico-subcortical loops and that basal-ganglia pathways can either allow or inhibit this reverberation. In the distractor-induced blindness paradigm, inadequate distractor-induced response tendencies are suppressed by the inhibitory 'hyperdirect' pathway of the basal ganglia. If a target follows such a distractor closely, temporal aftereffects of distractor suppression prevent target identification. The model reproduces experimental data on how delays between target color and target motion affect the probability of target detection.

  13. Benzoylureas as removable cis amide inducers: synthesis of cyclic amides via ring closing metathesis (RCM).

    Science.gov (United States)

    Brady, Ryan M; Khakham, Yelena; Lessene, Guillaume; Baell, Jonathan B

    2011-02-07

    Rapid and high yielding synthesis of medium ring lactams was made possible through the use of a benzoylurea auxiliary that serves to stabilize a cisoid amide conformation, facilitating cyclization. The auxiliary is released after activation under the mild conditions required to deprotect a primary amine, such as acidolysis of a Boc group in the examples given here. This methodology is a promising tool for the synthesis of medium ring lactams, macrocyclic natural products and peptides.

  14. A close link between metabolic activity and functional connectivity in the resting human brain

    Energy Technology Data Exchange (ETDEWEB)

    Passow, Susanne [Department of Biological and Medical Psychology, University of Bergen (Norway); NORMENT Center of Excellence, University of Oslo (Norway); Specht, Karsten [Department of Biological and Medical Psychology, University of Bergen (Norway); Department of Clinical Engineering, Haukeland University Hospital, Bergen (Norway); Adamsen, Tom Christian [Department of Radiology, Haukeland University Hospital, Bergen (Norway); Department of Chemistry, University of Bergen (Norway); Biermann, Martin; Brekke, Njål [Department of Radiology, Haukeland University Hospital, Bergen (Norway); Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen (Norway); Craven, Alexander Richard [Department of Biological and Medical Psychology, University of Bergen (Norway); NORMENT Center of Excellence, University of Oslo (Norway); Ersland, Lars [Department of Clinical Engineering, Haukeland University Hospital, Bergen (Norway); NORMENT Center of Excellence, University of Oslo (Norway); Grüner, Renate [Department of Radiology, Haukeland University Hospital, Bergen (Norway); Department of Physics and Technology, University of Bergen (Norway); NORMENT Center of Excellence, University of Oslo (Norway); Kleven-Madsen, Nina [Department of Radiology, Haukeland University Hospital, Bergen (Norway); Department of Physics and Technology, University of Bergen (Norway); Kvernenes, Ole-Heine [Department of Radiology, Haukeland University Hospital, Bergen (Norway); Schwarzlmüller, Thomas [Department of Radiology, Haukeland University Hospital, Bergen (Norway); Department of Clinical Medicine, University of Bergen (Norway); Olesen, Rasmus [Center of Functionally Integrative Neuroscience and MINDLab, Aarhus University, Aarhus (Denmark); Hugdahl, Kenneth [Department of Biological and Medical Psychology, University of Bergen (Norway); Department of Radiology, Haukeland University Hospital, Bergen (Norway); Division of Psychiatry, Haukeland University Hospital, Bergen (Norway); NORMENT Center of Excellence, University of Oslo (Norway)

    2015-05-18

    Default-mode network (DMN) functional connectivity and its task-dependent down-regulation have attracted a lot of attention in the field of neuroscience. Nevertheless, the exact underlying mechanisms of DMN functional connectivity, or more specifically, the blood oxygen level-dependent (BOLD) signal, are still not completely understood. To investigate more directly the association between local glucose consumption, local glutamatergic neurotransmission and DMN functional connectivity during rest, the present study combined for the first time 2-Deoxy-2-[18F]fluoroglucose positron emission tomography (FDG-PET), proton magnetic resonance spectroscopy (1H-MRS), and resting-state functional magnetic resonance imaging (rs-fMRI). Seed-based correlation analyses, using a key region of the DMN i.e. the dorsal posterior cingulate cortex as seed, revealed overall striking spatial similarities between fluctuations in FDG-uptake and the BOLD signal. More specifically, a conjunction analysis across both modalities showed that DMN areas as the inferior parietal lobe, angular gyrus, precuneus, middle and medial frontal gyrus were positively correlated with the dorsal posterior cingulate cortex. Furthermore, we could demonstrate that local glucose consumption in the medial frontal gyrus, posterior cingulate cortex and left angular gyrus was associated with functional connectivity within the DMN. We did not find a relationship between glutamatergic neurotransmission and functional connectivity. In line with very recent findings, our results provide further evidence for a close association between local metabolic activity and functional connectivity and enable further insights towards a better understanding of the underlying mechanisms of the BOLD signal.

  15. Comparison of body-powered voluntary opening and voluntary closing prehensor for activities of daily life

    OpenAIRE

    Kelsey Berning; Sarah Cohick; Reva Johnson, MS; Laura Ann Miller, PhD, CP; Jonathon W. Sensinger, PhD

    2014-01-01

    Persons with an upper-limb amputation who use a body-powered prosthesis typically control the prehensor through contralateral shoulder movement, which is transmitted through a Bowden cable. Increased cable tension either opens or closes the prehensor; when tension is released, some passive element, such as a spring, returns the prehensor to the default state (closed or open). In this study, we used the Southampton Hand Assessment Procedure to examine functional differences between these two t...

  16. Laser-induced transformation of GaS and GaSe nanosheets to onion structures with closed cages

    Indian Academy of Sciences (India)

    K Vasu

    2014-10-01

    Experimental evidence for the transformation of nanosheets of GaS and GaSe into onion structures on UV excimer pulsed laser irradiation is presented. Few-layer GaS and GaSe on Si substrates were exposed to KrF pulsed laser with wavelength of 248 nm and the effect was studied as a function of number of laser pulses. Laser-induced dewetting of the layers results in the formation of spherical nanoparticles after 50 laser pulses. HREM images of these particles reveal the formation of onions with several concentric layers. The initial thickness of the layers controls the size of the onion cages. A mechanism of transformation of few layers to closed cage onions on UV pulsed laser irradiation is presented.

  17. Fre-2, a locus closely linked to Fv-2, is rearranged in some erythroleukemias induced by Friend murine leukemia virus.

    Science.gov (United States)

    Eisel, D; Veit, M; Friedrich, U; Pass, M; Sels, F T; Friedrich, R W

    1997-04-01

    Friend murine leukemia virus (F-MuLV) induces leukemia by integration into the cellular genome, thereby changing the structure of expression of cellular oncogenes. Here we describe a new F-MuLV integration site Fre-2 isolated from splenic DNA of an erythroleukemic animal. This site has been found rearranged in 5 out of 63 additional tumors; however, no F-MuLV proviruses could be detected in the vicinity of the rearrangement sites in these 5 cases. The rearrangements represented closely clustered chromosomal breakpoints, presumably chromosomal translocations. Exons transcribed into differentially spliced mRNAs of 1.9 and 3.7 kb have been found near the breakpoint. No sequences that are homologous to Fre-2 could be found in databases.

  18. Closed-loop control of boundary layer streaks induced by free-stream turbulence

    Science.gov (United States)

    Papadakis, George; Lu, Liang; Ricco, Pierre

    2016-08-01

    The central aim of the paper is to carry out a theoretical and numerical study of active wall transpiration control of streaks generated within an incompressible boundary layer by free-stream turbulence. The disturbance flow model is based on the linearized unsteady boundary-region (LUBR) equations, studied by Leib, Wundrow, and Goldstein [J. Fluid Mech. 380, 169 (1999), 10.1017/S0022112098003504], which are the rigorous asymptotic limit of the Navier-Stokes equations for low-frequency and long-streamwise wavelength. The mathematical formulation of the problem directly incorporates the random forcing into the equations in a consistent way. Due to linearity, this forcing is factored out and appears as a multiplicative factor. It is shown that the cost function (integral of kinetic energy in the domain) is properly defined as the expectation of a random quadratic function only after integration in wave number space. This operation naturally introduces the free-stream turbulence spectral tensor into the cost function. The controller gains for each wave number are independent of the spectral tensor and, in that sense, universal. Asymptotic matching of the LUBR equations with the free-stream conditions results in an additional forcing term in the state-space system whose presence necessitates the reformulation of the control problem and the rederivation of its solution. It is proved that the solution can be obtained analytically using an extension of the sweep method used in control theory to obtain the standard Riccati equation. The control signal consists of two components, a feedback part and a feed-forward part (that depends explicitly on the forcing term). Explicit recursive equations that provide these two components are derived. It is shown that the feed-forward part makes a negligible contribution to the control signal. We also derive an explicit expression that a priori (i.e., before solving the control problem) leads to the minimum of the objective cost

  19. Neck Flexion Induces Larger Deformation of the Brain Than Extension at a Rotational Acceleration, Closed Head Trauma

    Directory of Open Access Journals (Sweden)

    Hans-Arne Hansson

    2014-01-01

    Full Text Available A closed head trauma induces incompletely characterized temporary movement and deformation of the brain, contributing to the primary traumatic brain injury. We used the pressure patterns recorded with light-operated miniature sensors in anaesthetized adult rabbits exposed to a sagittal plane rotational acceleration of the head, lasting 1 ms, as a measure of brain deformation. Two exposure levels were used and scaled to correspond to force levels reported to cause mild and moderate diffuse injury in an adult man, respectively. Flexion induced transient, strong, extended, and predominantly negative pressures while extension generated a short positive pressure peak followed by a minor negative peak. Low level flexion caused as strong, extended negative pressures as did high level extension. Time differences were demonstrated between the deformation of the cerebrum, brainstem, and cerebellum. Available X-ray and MRI techniques do not have as high time resolution as pressure recordings in demonstrating complex, sequential compression and stretching of the brain during a trauma. The exposure to flexion caused more protracted and extensive deformation of the brain than extension, in agreement with a published histopathological report. The severity and extent of the brain deformation generated at a head trauma thus related to the direction at equal force.

  20. BAF Complex Is Closely Related to and Interacts with NF1/CTF and RNA Polymerase Ⅱ in Gene Transcriptional Activation

    Institute of Scientific and Technical Information of China (English)

    Li-Hui ZHAO; Xue-Qing BA; Xiao-Guang WANG; Xiao-Juan ZHU; Li WANG; Xian-Lu ZENG

    2005-01-01

    Brg- or hBrm-associated factor (BAF) complexes, a chromatin-remodeling complex family of mammalian cells, facilitate transcriptional activity by remodeling nucleosome structure. Brg 1 is the core subunit of Brg-associated factor complexes. In the present study, we investigated the spatial relationship between Brg1 and nuclear factor 1 (NF1/CTF) and RNA polymerase Ⅱ (RNAP Ⅱ) upon gene transcriptional activation in vivo by employing immuno-gold labeling. The data showed that Brg1 was closely co-localized with NF1/CTF and RNAP Ⅱ in HeLa cells. Moreover, the co-immunoprecipitation assay further revealed that Brg1 can be isolated together with NF1/CTF and RNAP Ⅱ in the ConA-stimulated, but not the resting,T lymphocyte. The combined results suggested that BAF complexes can interact with NF1/CTF and RNAP Ⅱ, and this interaction is closely dependent on the activation of gene transcription.

  1. Comparison of body-powered voluntary opening and voluntary closing prehensor for activities of daily life

    Directory of Open Access Journals (Sweden)

    Kelsey Berning

    2014-05-01

    Full Text Available Persons with an upper-limb amputation who use a body-powered prosthesis typically control the prehensor through contralateral shoulder movement, which is transmitted through a Bowden cable. Increased cable tension either opens or closes the prehensor; when tension is released, some passive element, such as a spring, returns the prehensor to the default state (closed or open. In this study, we used the Southampton Hand Assessment Procedure to examine functional differences between these two types of prehensors in 29 nondisabled subjects (who used a body-powered bypass prosthesis and 2 persons with unilateral transradial amputations (who used a conventional body-powered device. We also administered a survey to determine whether subjects preferred one prehensor or the other for specific tasks, with a long-term goal of assessing whether a prehensor that could switch between both modes would be advantageous. We found that using the voluntary closing prehensor was 1.3 s faster (p = 0.02 than using the voluntary opening prehensor, across tasks, and that there was consensus among subjects on which types of tasks they preferred to do with each prehensor type. Twenty-five subjects wanted a device that could switch between the two modes in order to perform particular tasks.

  2. Comparison of body-powered voluntary opening and voluntary closing prehensor for activities of daily life.

    Science.gov (United States)

    Berning, Kelsey; Cohick, Sarah; Johnson, Reva; Miller, Laura Ann; Sensinger, Jonathon W

    2014-01-01

    Persons with an upper-limb amputation who use a body-powered prosthesis typically control the prehensor through contralateral shoulder movement, which is transmitted through a Bowden cable. Increased cable tension either opens or closes the prehensor; when tension is released, some passive element, such as a spring, returns the prehensor to the default state (closed or open). In this study, we used the Southampton Hand Assessment Procedure to examine functional differences between these two types of prehensors in 29 nondisabled subjects (who used a body-powered bypass prosthesis) and 2 persons with unilateral transradial amputations (who used a conventional body-powered device). We also administered a survey to determine whether subjects preferred one prehensor or the other for specific tasks, with a long-term goal of assessing whether a prehensor that could switch between both modes would be advantageous. We found that using the voluntary closing prehensor was 1.3 s faster (p = 0.02) than using the voluntary opening prehensor, across tasks, and that there was consensus among subjects on which types of tasks they preferred to do with each prehensor type. Twenty-five subjects wanted a device that could switch between the two modes in order to perform particular tasks.

  3. The Close-Up Imager Onboard the ESA ExoMars Rover: Objectives, Description, Operations, and Science Validation Activities

    Science.gov (United States)

    Josset, Jean-Luc; Westall, Frances; Hofmann, Beda A.; Spray, John; Cockell, Charles; Kempe, Stephan; Griffiths, Andrew D.; De Sanctis, Maria Cristina; Colangeli, Luigi; Koschny, Detlef; Föllmi, Karl; Verrecchia, Eric; Diamond, Larryn; Josset, Marie; Javaux, Emmanuelle J.; Esposito, Francesca; Gunn, Matthew; Souchon-Leitner, Audrey L.; Bontognali, Tomaso R. R.; Korablev, Oleg; Erkman, Suren; Paar, Gerhard; Ulamec, Stephan; Foucher, Frédéric; Martin, Philippe; Verhaeghe, Antoine; Tanevski, Mitko; Vago, Jorge L.

    2017-07-01

    The Close-Up Imager (CLUPI) onboard the ESA ExoMars Rover is a powerful high-resolution color camera specifically designed for close-up observations. Its accommodation on the movable drill allows multiple positioning. The science objectives of the instrument are geological characterization of rocks in terms of texture, structure, and color and the search for potential morphological biosignatures. We present the CLUPI science objectives, performance, and technical description, followed by a description of the instrument's planned operations strategy during the mission on Mars. CLUPI will contribute to the rover mission by surveying the geological environment, acquiring close-up images of outcrops, observing the drilling area, inspecting the top portion of the drill borehole (and deposited fines), monitoring drilling operations, and imaging samples collected by the drill. A status of the current development and planned science validation activities is also given.

  4. Study towards diversity oriented synthesis of optically active substituted cyclopentane fused carbocyclic and oxacyclic medium-sized rings: Competition between Grubbs-II catalyzed ring closing olefin metathesis and ring closing carbonyl-olefin metathesis

    Indian Academy of Sciences (India)

    P CHAKRABORTY; S C ROY

    2016-12-01

    A study towards diversity-oriented synthesis of optically active cyclopentane fused bicyclic frameworks has been accomplished. The common intermediate was prepared from commercially available starting material (S)-carvone. The observations on competition between Grubbs-II catalyzed ring closing metathesis (RCM) and ring closing carbonyl-olefin metathesis (RCCOM) were the key features of the study.

  5. 2D and 3D imaging of the gas phase close to an operating model catalyst by planar laser induced fluorescence.

    Science.gov (United States)

    Blomberg, Sara; Zhou, Jianfeng; Gustafson, Johan; Zetterberg, Johan; Lundgren, Edvin

    2016-11-16

    In recent years, efforts have been made in catalysis related surface science studies to explore the possibilities to perform experiments at conditions closer to those of a technical catalyst, in particular at increased pressures. Techniques such as high pressure scanning tunneling/atomic force microscopy (HPSTM/AFM), near ambient pressure x-ray photoemission spectroscopy (NAPXPS), surface x-ray diffraction (SXRD) and polarization-modulation infrared reflection absorption spectroscopy (PM-IRAS) at semi-realistic conditions have been used to study the surface structure of model catalysts under reaction conditions, combined with simultaneous mass spectrometry (MS). These studies have provided an increased understanding of the surface dynamics and the structure of the active phase of surfaces and nano particles as a reaction occurs, providing novel information on the structure/activity relationship. However, the surface structure detected during the reaction is sensitive to the composition of the gas phase close to the catalyst surface. Therefore, the catalytic activity of the sample itself will act as a gas-source or gas-sink, and will affect the surface structure, which in turn may complicate the assignment of the active phase. For this reason, we have applied planar laser induced fluorescence (PLIF) to the gas phase in the vicinity of an active model catalysts. Our measurements demonstrate that the gas composition differs significantly close to the catalyst and at the position of the MS, which indeed should have a profound effect on the surface structure. However, PLIF applied to catalytic reactions presents several beneficial properties in addition to investigate the effect of the catalyst on the effective gas composition close to the model catalyst. The high spatial and temporal resolution of PLIF provides a unique tool to visualize the on-set of catalytic reactions and to compare different model catalysts in the same reactive environment. The technique can be

  6. 2D and 3D imaging of the gas phase close to an operating model catalyst by planar laser induced fluorescence

    Science.gov (United States)

    Blomberg, Sara; Zhou, Jianfeng; Gustafson, Johan; Zetterberg, Johan; Lundgren, Edvin

    2016-11-01

    In recent years, efforts have been made in catalysis related surface science studies to explore the possibilities to perform experiments at conditions closer to those of a technical catalyst, in particular at increased pressures. Techniques such as high pressure scanning tunneling/atomic force microscopy (HPSTM/AFM), near ambient pressure x-ray photoemission spectroscopy (NAPXPS), surface x-ray diffraction (SXRD) and polarization-modulation infrared reflection absorption spectroscopy (PM-IRAS) at semi-realistic conditions have been used to study the surface structure of model catalysts under reaction conditions, combined with simultaneous mass spectrometry (MS). These studies have provided an increased understanding of the surface dynamics and the structure of the active phase of surfaces and nano particles as a reaction occurs, providing novel information on the structure/activity relationship. However, the surface structure detected during the reaction is sensitive to the composition of the gas phase close to the catalyst surface. Therefore, the catalytic activity of the sample itself will act as a gas-source or gas-sink, and will affect the surface structure, which in turn may complicate the assignment of the active phase. For this reason, we have applied planar laser induced fluorescence (PLIF) to the gas phase in the vicinity of an active model catalysts. Our measurements demonstrate that the gas composition differs significantly close to the catalyst and at the position of the MS, which indeed should have a profound effect on the surface structure. However, PLIF applied to catalytic reactions presents several beneficial properties in addition to investigate the effect of the catalyst on the effective gas composition close to the model catalyst. The high spatial and temporal resolution of PLIF provides a unique tool to visualize the on-set of catalytic reactions and to compare different model catalysts in the same reactive environment. The technique can be

  7. Closed Loop Control of Active Damped Small DC-link Capacitor Based Drive

    DEFF Research Database (Denmark)

    Maheshwari, Ram Krishan; Munk-Nielsen, Stig

    2010-01-01

    A new method of active damping for small DC-link capacitor based drive system is implemented in stator flux oriented control for an induction machine. The active damping technique is based on a detailed model of the drive system which leads to a very simple implementation. The active damping can...

  8. Reelin induces EphB activation

    Institute of Scientific and Technical Information of China (English)

    Elisabeth Bouché; Mario I Romero-Ortega; Mark Henkemeyer; Timothy Catchpole; Jost Leemhuis; Michael Frotscher; Petra May

    2013-01-01

    The integration of newborn neurons into functional neuronal networks requires migration of cells to their final position in the developing brain,the growth and arborization of neuronal processes and the formation of synaptic contacts with other neurons.A central player among the signals that coordinate this complex sequence of differentiation events is the secreted glycoprotein Reelin,which also modulates synaptic plasticity,learning and memory formation in the adult brain.Binding of Reelin to ApoER2 and VLDL receptor,two members of the LDL receptor family,initiates a signaling cascade involving tyrosine phosphorylation of the intracellular cytoplasmic adaptor protein Disabled-l,which targets the neuronal cytoskeleton and ultimately controls the positioning of neurons throughout the developing brain.However,it is possible that Reelin signals interact with other receptor-mediated signaling cascades to regulate different aspects of brain development and plasticity.EphB tyrosine kinases regulate cell adhesion and repulsion-dependent processes via bidirectional signaling through ephrin B transmembrane proteins.Here,we demonstrate that Reelin binds to the extracellular domains of EphB transmembrane proteins,inducing receptor clustering and activation of EphB forward signaling in neurons,independently of the ‘classical' Reelin receptors,ApoER2 and VLDLR.Accordingly,mice lacking EphB1 and EphB2 display a positioning defect of CA3 hippocampal pyramidal neurons,similar to that in Reelin-deficient mice,and this cell migration defect depends on the kinase activity of EphB proteins.Together,our data provide biochemical and functional evidence for signal integration between Reelin and EphB forward signaling.

  9. Experimental investigation of the vortical activity in the close wake of a simplified military transport aircraft

    Science.gov (United States)

    Bury, Yannick; Jardin, Thierry; Klöckner, Andreas

    2013-05-01

    This paper focuses on the experimental characterization of the vortex structures that develop in the aft fuselage region and in the wake of a simplified geometry of a military transport aircraft. It comes within the framework of the military applications of airflow influence on airdrop operations. This work relies on particle image velocimetry measurements combined with a vortex-tracking approach. Complex vortex dynamics is revealed, in terms of vortex positions, intensities, sizes, shapes and fluctuation levels, for both closed and opened cargo-door and ramp airdrop configurations.

  10. Irregular persistent activity induced by synaptic excitatory feedback

    Directory of Open Access Journals (Sweden)

    Francesca Barbieri

    2007-11-01

    Full Text Available Neurophysiological experiments on monkeys have reported highly irregular persistent activity during the performance of an oculomotor delayed-response task. These experiments show that during the delay period the coefficient of variation (CV of interspike intervals (ISI of prefrontal neurons is above 1, on average, and larger than during the fixation period. In the present paper, we show that this feature can be reproduced in a network in which persistent activity is induced by excitatory feedback, provided that (i the post-spike reset is close enough to threshold , (ii synaptic efficacies are a non-linear function of the pre-synaptic firing rate. Non-linearity between presynaptic rate and effective synaptic strength is implemented by a standard short-term depression mechanism (STD. First, we consider the simplest possible network with excitatory feedback: a fully connected homogeneous network of excitatory leaky integrate-and-fire neurons, using both numerical simulations and analytical techniques. The results are then confirmed in a network with selective excitatory neurons and inhibition. In both the cases there is a large range of values of the synaptic efficacies for which the statistics of firing of single cells is similar to experimental data.

  11. Estrus Traits Derived from Activity Measurements are Heritable and Closely Related to Conventional

    DEFF Research Database (Denmark)

    Ismael, Ahmed Ismael Sayed; Kargo, Morten; Fogh, Anders

    This study was aimed at assessing the genetic parameters for fertility-related traits, comparing the interval from calving to first insemination (ICF) to physical activity traits, especially days from calving to first high activity, DFHA. Data from commercial Holstein herds included insemination...

  12. Caregiving activities closely associated with the development of low-back pain among female family caregivers.

    Science.gov (United States)

    Suzuki, Kishiko; Tamakoshi, Koji; Sakakibara, Hisataka

    2016-08-01

    To describe what effects low back pain has on the daily lives of female family caregivers and to elucidate the caregiving factors associated with its development. Low back pain is a common musculoskeletal symptom in caregivers. However, few detailed studies have examined the association of low back pain with the daily lives of female family caregivers or which caregiving activities lead to their low back pain. The elucidation of these issues will contribute to the prevention and treatment of their low back pain. A cross-sectional study. Japanese female family caregivers (n = 156) completed a self-administered questionnaire assessing lifestyle, health status, daily activity and caregiving situation. Correlation analysis measured the association between low back pain and daily activity. Logistic regression analysis identified care activities related to low back pain. Thirty-five (22·4%) participants almost always experienced low back pain. The severity of low back pain was significantly and positively associated with difficulty in daily activities, especially bending and extending the lower back. As for care situation factors and caregiving activities, night care, assisting the family member to stand up and to lie down, dealing with problem behaviours, and taking medication were associated with the development of low back pain. After reclassifying the respective caregiving activities, those involving body repositioning and those mainly performed in a static position showed significant associations. Low back pain in female family caregivers negatively affects their daily activities and certain caregiving activities are involved in the development of low back pain. Clinical nurses understand the situation of female caregivers and could prevent the development of low back pain with early intervention by providing adequate strategies to alleviate the burden of identified care activities related to low back pain. © 2016 John Wiley & Sons Ltd.

  13. Photonic activation of plasminogen induced by low dose UVB.

    Directory of Open Access Journals (Sweden)

    Manuel Correia

    Full Text Available Activation of plasminogen to its active form plasmin is essential for several key mechanisms, including the dissolution of blood clots. Activation occurs naturally via enzymatic proteolysis. We report that activation can be achieved with 280 nm light. A 2.6 fold increase in proteolytic activity was observed after 10 min illumination of human plasminogen. Irradiance levels used are in the same order of magnitude of the UVB solar irradiance. Activation is correlated with light induced disruption of disulphide bridges upon UVB excitation of the aromatic residues and with the formation of photochemical products, e.g. dityrosine and N-formylkynurenine. Most of the protein fold is maintained after 10 min illumination since no major changes are observed in the near-UV CD spectrum. Far-UV CD shows loss of secondary structure after illumination (33.4% signal loss at 206 nm. Thermal unfolding CD studies show that plasminogen retains a native like cooperative transition at ~70 ºC after UV-illumination. We propose that UVB activation of plasminogen occurs upon photo-cleavage of a functional allosteric disulphide bond, Cys737-Cys765, located in the catalytic domain and in van der Waals contact with Trp761 (4.3 Å. Such proximity makes its disruption very likely, which may occur upon electron transfer from excited Trp761. Reduction of Cys737-Cys765 will result in likely conformational changes in the catalytic site. Molecular dynamics simulations reveal that reduction of Cys737-Cys765 in plasminogen leads to an increase of the fluctuations of loop 760-765, the S1-entrance frame located close to the active site. These fluctuations affect the range of solvent exposure of the catalytic triad, particularly of Asp646 and Ser74, which acquire an exposure profile similar to the values in plasmin. The presented photonic mechanism of plasminogen activation has the potential to be used in clinical applications, possibly together with other enzymatic treatments for the

  14. Estrus Traits Derived from Activity Measurements are Heritable and Closely Related to Conventional

    DEFF Research Database (Denmark)

    Ismael, Ahmed Ismael Sayed; Kargo, Morten; Fogh, Anders

    This study was aimed at assessing the genetic parameters for fertility-related traits, comparing the interval from calving to first insemination (ICF) to physical activity traits, especially days from calving to first high activity, DFHA. Data from commercial Holstein herds included insemination...... dates of 11,363 cows for ICF. The activity traits were derived from electronic activity tags for 3533 Holstein cows. Estimates of heritability were 0.05 for ICF and 0.15 for DFHA. The genetic correlation between ICF and DFHA was strong (0.92). The high heritability estimate and the strong genetic...... correlation between ICF and DFHA suggest that genetic gain in ICF can be improved by including DFHA as a supplementary trait in the genetic evaluation of female fertility...

  15. Physical Activity Capture Technology With Potential for Incorporation Into Closed-Loop Control for Type 1 Diabetes.

    Science.gov (United States)

    Dadlani, Vikash; Levine, James A; McCrady-Spitzer, Shelly K; Dassau, Eyal; Kudva, Yogish C

    2015-10-18

    Physical activity is an important determinant of glucose variability in type 1 diabetes (T1D). It has been incorporated as a nonglucose input into closed-loop control (CLC) protocols for T1D during the last 4 years mainly by 3 research groups in single center based controlled clinical trials involving a maximum of 18 subjects in any 1 study. Although physical activity data capture may have clinical benefit in patients with T1D by impacting cardiovascular fitness and optimal body weight achievement and maintenance, limited number of such studies have been conducted to date. Clinical trial registries provide information about a single small sample size 2 center prospective study incorporating physical activity data input to modulate closed-loop control in T1D that are seeking to build on prior studies. We expect an increase in such studies especially since the NIH has expanded support of this type of research with additional grants starting in the second half of 2015. Studies (1) involving patients with other disorders that have lasted 12 weeks or longer and tracked physical activity and (2) including both aerobic and resistance activity may offer insights about the user experience and device optimization even as single input CLC heads into real-world clinical trials over the next few years and nonglucose input is introduced as the next advance.

  16. Laser Induced Selective Activation For Subsequent Autocatalytic Electroless Plating

    DEFF Research Database (Denmark)

    Zhang, Yang

    The subject of this PhD thesis is “Laser induced selective activation for subsequent autocatalytic electroless plating.” The objective of the project is to investigate the process chains for micro structuring of polymer surfaces for selective micro metallization. Laser induced selective activation...

  17. Highly Active Chiral Ruthenium Catalysts for Asymmetric Ring-Closing Olefin Metathesis

    Science.gov (United States)

    Funk, Timothy W.; Berlin, Jacob M.

    2008-01-01

    The synthesis of olefin metathesis catalysts containing chiral, monodentate N-heterocyclic carbenes and their application to asymmetric ring-closing metathesis (ARCM) is reported. These catalysts retain the high levels of reactivity found in the related achiral variants (1a and 1b). Using the parent chiral catalysts 2a and 2b and derivatives that contain steric bulk in the meta positions of the N-bound aryl rings (catalysts 3-5), five- through seven-membered rings were formed in up to 92% ee. The addition of sodium iodide to catalysts 2a-4a (to form 2b-4bin situ) caused a dramatic increase in enantioselectivity for many substrates. Catalyst 5a, which gave high enantiomeric excesses for certain substrates without the addition of NaI, could be used in loadings of ≤1 mol %. Mechanistic explanations for the large sodium iodide effect as well as possible mechanistic pathways leading to the observed products are discussed. PMID:16464082

  18. Vibration criteria for transit systems in close proximity to university research activities

    Science.gov (United States)

    Wolf, Steven

    2001-05-01

    As some of the newer LRT projects get closer to research facilities the question arisesi ``how do you assess the potential impact of train operations on the activities within these types of facilities?'' There are several new LRT projects that have proposed alignments near or under university research facilities. The traditional ground vibration analysis at these locations is no longer valid but requires a more sophisticated approach to identifying both criteria and impact. APTA, ISO, IES, and FTA vibration criteria may not be adequate for the most sensitive activities involving single cell and nano technology research. The use of existing ambient vibration levels is evaluated as a potential criteria. A statistical approach is used to better understand how the train vibration would affect the ambient vibration levels.

  19. Testing the Role of p21-Activated Kinases in Schwannoma Formation Using a Novel Genetically Engineered Murine Model that Closely Phenocopies Human NF2 Disease

    Science.gov (United States)

    2015-06-01

    Kinases in Schwannoma Formation Using a Novel Genetically Engineered Murine Model that Closely Phenocopies Human NF2 Disease The views, opinions and...TITLE AND SUBTITLE Testing the Role of p21-Activated Kinases in Schwannoma Formation Using a Novel Genetically Engineered Murine Model that Closely...1.20 calendar Testing the Role of p21 Activated Kinases in Schwannoma Formation Using a Novel Genetically Engineered Murine Model that Closely

  20. Tumorigenesis induced by the HHV8-encoded chemokine receptor requires ligand modulation of high constitutive activity

    DEFF Research Database (Denmark)

    Holst, P J; Rosenkilde, M M; Manfra, D;

    2001-01-01

    ORF74 (or KSHV-vGPCR) is a highly constitutively active G protein-coupled receptor encoded by HHV8 that is regulated both positively and negatively by endogenous chemokines. When expressed in transgenic mice, this chemokine receptor induces an angioproliferative disease closely resembling Kaposi...... sarcoma (KS). Here we demonstrate that several lines of mice carrying mutated receptors deficient in either constitutive activity or chemokine regulation fail to develop KS-like disease. In addition, animals expressing a receptor that preserves chemokine binding and constitutive activity but that does...

  1. Analysis of active closed cross-section slender beams based on asymptotically correct thin-wall beam theory

    Science.gov (United States)

    Khouli, F.; Langlois, R. G.; Afagh, F. F.

    2007-02-01

    An asymptotically correct theory for multi-cell thin-wall anisotropic slender beams that includes the shell bending strain measures is extended to include embedded active fibre composites (AFCs). A closed-form solution of the asymptotically correct cross-sectional actuation force and moments is obtained. Active thin-wall beam theories found in the literature neglect the shell bending strains, which lead to incorrect predictions for certain cross-sections, while the theory presented is shown to overcome this shortcoming. The theory is implemented and verified against single-cell examples that were solved using the University of Michigan/Variational Beam Sectional Analysis (UM/VABS) software. The stiffness constants and the actuation vector are obtained for two-cell and three-cell active cross-sections. The theory is argued to be reliable for efficient initial design analysis and interdisciplinary parametric or optimization studies of thin-wall closed cross-section slender beams with no initial twist or obliqueness.

  2. Methane Emissions from Landfill: Isotopic Evidence for Low Percentage of Oxidation from Gas Wells, Active and Closed Cells

    Science.gov (United States)

    Lowry, David; Fisher, Rebecca; Zazzeri, Giulia; al-Shalaan, Aalia; France, James; Lanoisellé, Mathias; Nisbet, Euan

    2017-04-01

    Large landfill sites remain a significant source of methane emissions in developed and developing countries, with a global estimated flux of 29 Tg / yr in the EDGAR 2008 database. This is significantly lower than 20 years ago due to the introduction of gas extraction systems, but active cells still emit significant amounts of methane before the gas is ready for extraction. Historically the methane was either passively oxidized through topsoil layers or flared. Oxidation is still the primary method of methane removal in many countries, and covered, remediated cells across the world continue to emit small quantities of methane. The isotopic signatures of methane from landfill gas wells, and that emitted from active and closed cells have been characterized for more than 20 UK landfills since 2011, with more recent work in Kuwait and Hong Kong. Since 2013 the emission plumes have been identified by a mobile measurement system (Zazzeri et al., 2015). Emissions in all 3 countries have a characteristic δ13C signature of -58 ± 3 ‰ dominated by emissions from the active cells, despite the hot, dry conditions of Kuwait and the hot, humid conditions of Hong Kong. Gas well samples define a similar range. Surface emissions from closed cells and closed landfills are mostly in the range -56 to -52 ‰Ṫhese are much more depleted values than those observed in the 1990s (up to -35 ) when soil oxidation was the dominant mechanism of methane removal. Calculations using isotopic signatures of the amount of methane oxidised in these closed areas before emission to atmosphere range from 5 to 15%, but average less than 10%, and are too small to calculate from the high-emitting active cells. Compared to other major methane sources, landfills have the most consistent isotopic signature globally, and are distinct from the more 13C-enriched natural gas, combustion and biomass burning sources. Zazzeri, G. et al. (2015) Plume mapping and isotopic characterization of anthropogenic methane

  3. Near Infrared Activity Close to the Crab Pulsar Correlated with Giant Gamma-ray Flares

    Science.gov (United States)

    Rudy, Alexander R.; Max, Claire E.; Weisskopf, Martin C.

    2014-01-01

    We describe activity observed in the near-infrared correlated with a giant gamma-ray flare in the Crab Pulsar. The Crab Pulsar has been observed by the Fermi and AGILE satellites to flare for a period of 3 to 7 days, once every 1-1.5 years, increasing in brightness by a factor of 3-10 between 100MeV and 1GeV. We used Keck NIRC2 laser guide star adaptive optics imaging to observe the Crab Pulsar and environs before and during the March 2013 flare. We discuss the evidence for the knot as the location of the flares, and the theoretical implications of these observations. Ongoing target-of-opportunity programs hope to confirm this correlation for future flares.

  4. Definition of EGF-like, closely interacting modules that bear activation epitopes in integrin beta subunits.

    Science.gov (United States)

    Takagi, J; Beglova, N; Yalamanchili, P; Blacklow, S C; Springer, T A

    2001-09-25

    Integrin beta subunits contain four cysteine-rich repeats in a long extracellular stalk that connects the headpiece to the membrane. Most mAbs to integrin activation epitopes map to these repeats, and they are important in propagating conformational signals from the membrane/cytosol to the ligand-binding headpiece. Sequence analysis of a protein containing only 10 integrin-like, cysteine-rich repeats suggests that these repeats start one cysteine earlier than previously reported. By using the new repeat boundaries, statistically significant sequence homology to epidermal growth factor-like domains is found, and a disulfide bond connectivity of the eight cysteines is predicted that differs in three of four disulfides from a previous prediction of epidermal growth factor-like modules [Berg, R. W., Leung, E., Gough, S., Morris, C., Yao, W.-P., Wang, S.-x., Ni, J. & Krissansen, G. W. (1999) Genomics 56, 169-178]. N-terminally truncated beta2 integrin stalk fragments were well expressed and secreted from 293 T cells when they began at repeat boundaries but not when they began one cysteine earlier or later. Furthermore, peptides that correspond to module 3 or modules 2 + 3 were expressed in bacteria and refolded. The module 2 + 3 fragment was as reactive with three mAbs to activation epitopes as a beta2 fragment expressed in eukaryotic cells, indicating a native fold. Only one residue intervenes between the last cysteine of one module and the first cysteine of the next. This arrangement is consistent with a tight intermodule connection, a prerequisite for signal propagation from the membrane to the ligand binding headpiece.

  5. Mass-transfer induced activity in galaxies

    Science.gov (United States)

    Shlosman, Isaac

    Current research on the origin and evolution of active galaxies is comprehensively surveyed in this collaborative volume. Both of the proposed types of central activity --- active galactic nuclei and nuclear starbursts --- are analyzed with a particular emphasis on their relationship to the large-scale properties of the host galaxy. The crucial question is what triggers and fuels nuclear activity now and at earlier epochs. The topics covered here are gas flows near to massive black holes, the circumnuclear galactic regions, and the large-scale bars in disk galaxies. Aspects of nuclear bursts of star formation and the relationship between central activity and the gas and stellar dynamics of the host galaxy are addressed as well. The contributors of this book for professionals and graduate students are world experts on galaxy evolution.

  6. Activation-Induced Cytidine Deaminase Contributes to Pancreatic Tumorigenesis by Inducing Tumor-Related Gene Mutations.

    Science.gov (United States)

    Sawai, Yugo; Kodama, Yuzo; Shimizu, Takahiro; Ota, Yuji; Maruno, Takahisa; Eso, Yuji; Kurita, Akira; Shiokawa, Masahiro; Tsuji, Yoshihisa; Uza, Norimitsu; Matsumoto, Yuko; Masui, Toshihiko; Uemoto, Shinji; Marusawa, Hiroyuki; Chiba, Tsutomu

    2015-08-15

    Pancreatic ductal adenocarcinoma (PDAC) develops via an accumulation of various gene mutations. The mechanism underlying the mutations in PDAC development, however, is not fully understood. Recent insight into the close association between the mutation pattern of various cancers and specific mutagens led us to investigate the possible involvement of activation-induced cytidine deaminase (AID), a DNA editing enzyme, in pancreatic tumorigenesis. Our immunohistochemical findings revealed AID protein expression in human acinar ductal metaplasia, pancreatic intraepithelial neoplasia, and PDAC. Both the amount and intensity of the AID protein expression increased with the progression from precancerous to cancerous lesions in human PDAC tissues. To further assess the significance of ectopic epithelial AID expression in pancreatic tumorigenesis, we analyzed the phenotype of AID transgenic (AID Tg) mice. Consistent with our hypothesis that AID is involved in the mechanism of the mutations underlying pancreatic tumorigenesis, we found precancerous lesions developing in the pancreas of AID Tg mice. Using deep sequencing, we also detected Kras and c-Myc mutations in our analysis of the whole pancreas of AID Tg mice. In addition, Sanger sequencing confirmed the presence of Kras, c-Myc, and Smad4 mutations, with the typical mutational footprint of AID in precancerous lesions in AID Tg mice separated by laser capture microdissection. Taken together, our findings suggest that AID contributes to the development of pancreatic precancerous lesions by inducing tumor-related gene mutations. Our new mouse model without intentional manipulation of specific tumor-related genes provides a powerful system for analyzing the mutations involved in PDAC.

  7. Mechanisms of macrophage activation in obesity-induced insulin resistance

    OpenAIRE

    Odegaard, Justin I.; Chawla, Ajay

    2008-01-01

    Chronic inflammation is now recognized as a key step in the pathogenesis of obesity-induced insulin resistance and type 2 diabetes mellitus. This low-grade inflammation is mediated by the inflammatory (classical) activation of recruited and resident macrophages that populate metabolic tissues, including adipose tissue and liver. These findings have led to the concept that infiltration and activation of adipose tissue macrophages is causally linked to obesity-induced insulin resistance. Studie...

  8. A chloride capturing system via proton-induced structure transformation between opened- and closed-forms of dodecavanadates.

    Science.gov (United States)

    Inoue, Yoshitaka; Kikukawa, Yuji; Kuwajima, Sho; Hayashi, Yoshihito

    2016-05-01

    Chloride-incorporated dodecavanadates show two distinct structures of the monoprotonated-form [HV12O32(Cl)](4-) (closed-V12) with a spherical closed-structure and the opened-form [V12O32(Cl)](5-) (opened-V12). The reaction of closed-V12 with a stoichiometric amount of ethylenediamine drives the structure transformation reaction to opened-V12, quantitatively. From time dependent observations of (51)V NMR, a tube-type intermediate [V12O32(Cl)](5-) (tube-V12) was observed in the transformation process. Isolation of the intermediate was achieved by the deprotonation reaction of closed-V12 with diethylamine, and the structure transformation was confirmed by using the isolated intermediate. The reverse transformation from opened-V12 to closed-V12 was also achieved by addition of trifluoroacetic acid. The geometrical difference between closed-V12 and opened-V12 is reflected in the reactivity difference to the external reagents, and this was demonstrated by examining the chloride removal reaction by using a silver cation. The incorporated chloride was preserved in the closed-V12 cage even in the presence of a silver cation. In contrast, the chloride in opened-V12 was removed as AgCl by the silver cation. In addition, by the reaction of chloride-free opened-V12 with a quantitative amount of {Et4N}Cl retrieved opened-V12, showing the capability of opened-V12 to recapture a guest chloride in the cavity. This transformation between two isomeric dodecavanadate structures is regarded as the movement of a molecular mitt to catch a ball and secure it.

  9. TRAIL-Induced Caspase Activation Is a Prerequisite for Activation of the Endoplasmic Reticulum Stress-Induced Signal Transduction Pathways.

    Science.gov (United States)

    Lee, Dae-Hee; Sung, Ki Sa; Guo, Zong Sheng; Kwon, William Taehyung; Bartlett, David L; Oh, Sang Cheul; Kwon, Yong Tae; Lee, Yong J

    2016-05-01

    It is well known that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis can be initially triggered by surface death receptors (the extrinsic pathway) and subsequently amplified through mitochondrial dysfunction (the intrinsic pathway). However, little is known about signaling pathways activated by the TRAIL-induced endoplasmic reticulum (ER) stress response. In this study, we report that TRAIL-induced apoptosis is associated with the endoplasmic reticulum (ER) stress response. Human colorectal carcinoma HCT116 cells were treated with TRAIL and the ER stress-induced signal transduction pathway was investigated. During TRAIL treatment, expression of ER stress marker genes, in particular the BiP (binding immunoglobulin protein) gene, was increased and activation of the PERK (PKR-like ER kinase)-eIF2α (eukaryotic initiation factor 2α)-ATF4 (activating transcription factor 4)-CHOP (CCAAT-enhancer-binding protein homologous protein) apoptotic signal transduction pathway occurred. Experimental data from use of a siRNA (small interfering RNA) technique, caspase inhibitor, and caspase-3-deficient cell line revealed that TRAIL-induced caspase activation is a prerequisite for the TRAIL-induced ER stress response. TRAIL-induced ER stress was triggered by caspase-8-mediated cleavage of BAP31 (B cell receptor-associated protein 31). The involvement of the proapoptotic PERK-CHOP pathway in TRAIL-induced apoptosis was verified by using a PERK knockout (PERK(-/-)) mouse embryo fibroblast (MEF) cell line and a CHOP(-/-) MEF cell line. These results suggest that TRAIL-induced the activation of ER stress response plays a role in TRAIL-induced apoptotic death.

  10. Design information verification (DIV) of closed geological repositories (SAGOR activity 3c)[Nuclear waste disposal; Security; Monitoring

    Energy Technology Data Exchange (ETDEWEB)

    Myatt, J

    1998-02-01

    Following IAEA Advisory and Consultants Group meetings in September 1988 and in May 1991 respectively an IAEA multi-national Support Programme Task was initiated to consider the 'Development of Safeguards for Final Disposal of Spent Fuel in Geological Repositories' (SAGOR). A 'Technical Coordination Committee' (TCC) was set up with invited representatives from those Member State Support Programmes wishing to be involved. The joint programme, through the TCC, was given the task of studying the safeguards requirements in: conditioning plant (where the spent fuel is prepared for transfer to the repository); operating repositories (i.e., those in which the fuel is being emplaced); closed repositories. At the first meeting of the TCC in Washington in July 1994 the UK undertook to provide a study of the Design Information Verification (DIV) required in all three areas. For this activity the requirements, techniques and procedures for the Design Information Verification (DIV) of closed repositories have been considered. In completing the study the findings reported for activities 1b/c and 2c (descriptions of a Model Repository and Potential Diversion Paths, respectively) have been used in formulating any conclusions reached. It is also debatable as to whether this activity is strictly speaking DIV or is one of surveillance. As undeclared access can only be made to the emplacement areas of the repository by altering the physical makeup of the surrounding area; i.e. physically changing the 'design' of the surrounding area, however, this is deemed to be DIV. Although the techniques used appear to be those of surveillance they are being applied in this case as the tools of DIV. As with any facility there are a number of stages in its lifetime. For the purposes of this report the operating life of a repository is defined as being the time from inception to when it is finally decommissioned and sealed with the ground surface returned to being a

  11. A Comparative Analysis between Active and Passive Techniques for Underwater 3D Reconstruction of Close-Range Objects

    Directory of Open Access Journals (Sweden)

    Maurizio Muzzupappa

    2013-08-01

    Full Text Available In some application fields, such as underwater archaeology or marine biology, there is the need to collect three-dimensional, close-range data from objects that cannot be removed from their site. In particular, 3D imaging techniques are widely employed for close-range acquisitions in underwater environment. In this work we have compared in water two 3D imaging techniques based on active and passive approaches, respectively, and whole-field acquisition. The comparison is performed under poor visibility conditions, produced in the laboratory by suspending different quantities of clay in a water tank. For a fair comparison, a stereo configuration has been adopted for both the techniques, using the same setup, working distance, calibration, and objects. At the moment, the proposed setup is not suitable for real world applications, but it allowed us to conduct a preliminary analysis on the performances of the two techniques and to understand their capability to acquire 3D points in presence of turbidity. The performances have been evaluated in terms of accuracy and density of the acquired 3D points. Our results can be used as a reference for further comparisons in the analysis of other 3D techniques and algorithms.

  12. A preliminary census of engineering activities located in Sicily (Southern Italy) which may "potentially" induce seismicity

    Science.gov (United States)

    Aloisi, Marco; Briffa, Emanuela; Cannata, Andrea; Cannavò, Flavio; Gambino, Salvatore; Maiolino, Vincenza; Maugeri, Roberto; Palano, Mimmo; Privitera, Eugenio; Scaltrito, Antonio; Spampinato, Salvatore; Ursino, Andrea; Velardita, Rosanna

    2015-04-01

    The seismic events caused by human engineering activities are commonly termed as "triggered" and "induced". This class of earthquakes, though characterized by low-to-moderate magnitude, have significant social and economical implications since they occur close to the engineering activity responsible for triggering/inducing them and can be felt by the inhabitants living nearby, and may even produce damage. One of the first well-documented examples of induced seismicity was observed in 1932 in Algeria, when a shallow magnitude 3.0 earthquake occurred close to the Oued Fodda Dam. By the continuous global improvement of seismic monitoring networks, numerous other examples of human-induced earthquakes have been identified. Induced earthquakes occur at shallow depths and are related to a number of human activities, such as fluid injection under high pressure (e.g. waste-water disposal in deep wells, hydrofracturing activities in enhanced geothermal systems and oil recovery, shale-gas fracking, natural and CO2 gas storage), hydrocarbon exploitation, groundwater extraction, deep underground mining, large water impoundments and underground nuclear tests. In Italy, induced/triggered seismicity is suspected to have contributed to the disaster of the Vajont dam in 1963. Despite this suspected case and the presence in the Italian territory of a large amount of engineering activities "capable" of inducing seismicity, no extensive researches on this topic have been conducted to date. Hence, in order to improve knowledge and correctly assess the potential hazard at a specific location in the future, here we started a preliminary study on the entire range of engineering activities currently located in Sicily (Southern Italy) which may "potentially" induce seismicity. To this end, we performed: • a preliminary census of all engineering activities located in the study area by collecting all the useful information coming from available on-line catalogues; • a detailed compilation

  13. Closed bore XMR (CBXMR) systems for aortic valve replacement: Active magnetic shielding of x-ray tubes

    Energy Technology Data Exchange (ETDEWEB)

    Bracken, John A.; DeCrescenzo, Giovanni; Komljenovic, Philip; Lillaney, Prasheel V.; Fahrig, Rebecca; Rowlands, J. A. [Department of Medical Biophysics and Sunnybrook Health Sciences Center, University of Toronto, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5 (Canada); Department of Radiology, Stanford University, Stanford, California 94305 (United States); Department of Medical Biophysics and Sunnybrook Health Sciences Center, University of Toronto, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5 (Canada)

    2009-05-15

    Hybrid closed bore x-ray/MRI systems are being developed to improve the safety and efficacy of percutaneous aortic valve replacement procedures by harnessing the complementary strengths of the x-ray and MRI modalities in a single interventional suite without requiring patient transfer between two rooms. These systems are composed of an x-ray C-arm in close proximity ({approx_equal}1 m) to an MRI scanner. The MRI magnetic fringe field can cause the electron beam in the x-ray tube to deflect. The deflection causes the x-ray field of view to shift position on the detector receptacle. This could result in unnecessary radiation exposure to the patient and the staff in the cardiac catheterization laboratory. Therefore, the electron beam deflection must be corrected. The authors developed an active magnetic shielding system that can correct for electron beam deflection to within an accuracy of 5% without truncating the field of view or increasing exposure to the patient. This system was able to automatically adjust to different field strengths as the external magnetic field acting on the x-ray tube was changed. Although a small torque was observed on the shielding coils of the active shielding system when they were placed in a magnetic field, this torque will not impact their performance if they are securely mounted on the x-ray tube and the C-arm. The heating of the coils of the shielding system for use in the clinic caused by electric current was found to be slow enough not to require a dedicated cooling system for one percutaneous aortic valve replacement procedure. However, a cooling system will be required if multiple procedures are performed in one session.

  14. Citicoline protects brain against closed head injury in rats through suppressing oxidative stress and calpain over-activation.

    Science.gov (United States)

    Qian, Ke; Gu, Yi; Zhao, Yumei; Li, Zhenzong; Sun, Ming

    2014-07-01

    Citicoline, a natural compound that functions as an intermediate in the biosynthesis of cell membrane phospholipids, is essential for membrane integrity and repair. It has been reported to protect brain against trauma. This study was designed to investigate the protective effects of citicoline on closed head injury (CHI) in rats. Citicoline (250 mg/kg i.v. 30 min and 4 h after CHI) lessened body weight loss, and improved neurological functions significantly at 7 days after CHI. It markedly lowered brain edema and blood-brain barrier permeability, enhanced the activities of superoxide dismutase and the levels of glutathione, reduced the levels of malondialdehyde and lactic acid. Moreover, citicoline suppressed the activities of calpain, and enhanced the levels of calpastatin, myelin basic protein and αII-spectrin in traumatic tissue 24 h after CHI. Also, it attenuated the axonal and myelin sheath damage in corpus callosum and the neuronal cell death in hippocampal CA1 and CA3 subfields 7 days after CHI. These data demonstrate the protection of citicoline against white matter and grey matter damage due to CHI through suppressing oxidative stress and calpain over-activation, providing additional support to the application of citicoline for the treatment of traumatic brain injury.

  15. c-Myc-Induced Extrachromosomal Elements Carry Active Chromatin

    Directory of Open Access Journals (Sweden)

    Greg Smith

    2003-03-01

    Full Text Available Murine Pre-13 lymphocytes with experimentally activated MycER show both chromosomal and extrachromosomal gene amplification. In this report, we have elucidated the size, structure, functional components of c-Myc-induced extrachromosomal elements (EEs. Scanning electron microscopy revealed that EEs isolated from MycER-activated Pre-B+ cells are an average of 10 times larger than EEs isolated from non-MycER-activated control Pre-B- cells. We demonstrate that these large c-Myc-induced EEs are associated with histone proteins, whereas EEs of non-MycER-activated Pre B- cells are not. Immunohistochemistry and Western blot analyses using pan -histone-specific, histone H3 phosphorylation-specific, histone H4 acetylation-specific antibodies indicate that a significant proportion of EEs analyzed from MycER-activated cells harbors transcriptionally competent and/or active chromatin. Moreover, these large, c-Myc-induced EEs carry genes. Whereas the total genetic make-up of these c-Myc-induced EEs is unknown, we found that 30.2% of them contain the dihydrofolate reductase (DHFR gene, whereas cyclin C (CCNC was absent. In addition, 50% of these c-Myc-activated Pre-B+ EEs incorporated bromodeoxyuridine (BrdU, identifying them as genetic structures that self-propagate. In contrast, EEs isolated from non-Myc-activated cells neither carry the DHFR gene nor incorporate BrdU, suggesting that c-Myc deregulation generates a new class of EEs.

  16. Regulation of Activation Induced Deaminase (AID) by Estrogen.

    Science.gov (United States)

    Pauklin, Siim

    2016-01-01

    Regulation of Activation Induced Deaminase (AID) by the hormone estrogen has important implications for understanding adaptive immune responses as well as the involvement of AID in autoimmune diseases and tumorigenesis. This chapter describes the general laboratory techniques for analyzing AID expression and activity induced by estrogen, focusing on the isolation and preparation of cells for hormone treatment and the subsequent analysis of AID responsiveness to estrogen at the RNA level and for determining the regulation of AID activity via estrogen by analyzing Ig switch circle transcripts and mutations in switch region loci.

  17. Suppressed expression of mitogen-activated protein kinases in hyperthermia induced defective neural tube.

    Science.gov (United States)

    Zhang, Tianliang; Leng, Zhaoting; Liu, Wenjing; Wang, Xia; Yan, Xue; Yu, Li

    2015-05-06

    Neural tube defects (NTDs) are common congenital malformations. Mitogen-activated protein kinases (MAPKs) pathway is involved in many physiological processes. HMGB1 has been showed closely associated with neurulation and NTDs induced by hyperthermia and could activate MAPKs pathway. Since hyperthermia caused increased activation of MAPKs in many systems, the present study aims to investigate whether HMGB1 contributes to hyperthermia induced NTDs through MAPKs pathway. The mRNA levels of MAPKs and HMGB1 between embryonic day 8.5 and 10 (E8.5-10) in hyperthermia induced defective neural tube were detected by real-time quantitative polymerase chain reaction (qPCR). By immunofluorescence and western blotting, the expressions of HMGB1 and phosphorylated MAPKs (ERK1/2, JNK and p38) in neural tubes after hyperthermia were studied. The mRNA levels of MAPKs and HMGB1, as well as the expressions of HMGB1 along with phosphorylated JNK, p38 and ERK, were downregulated in NTDs groups induced by hyperthermia compared with control. The findings suggested that HMGB1 may contribute to hyperthermia induced NTDs formation through decreased cell proliferation due to inhibited phosphorylated ERK1/2 MAPK.

  18. Active ocular vergence improves postural control in elderly as close viewing distance with or without a single cognitive task.

    Science.gov (United States)

    Matheron, Eric; Yang, Qing; Delpit-Baraut, Vincent; Dailly, Olivier; Kapoula, Zoï

    2016-01-01

    Performance of the vestibular, visual, and somatosensory systems decreases with age, reducing the capacity of postural control, and increasing the risk of falling. The purpose of this study is to measure the effects of vision, active vergence eye movements, viewing distance/vergence angle and a simple cognitive task on postural control during an upright stance, in completely autonomous elderly individuals. Participated in the study, 23 elderly subjects (73.4 ± 6.8 years) who were enrolled in a center dedicated to the prevention of falling. Their body oscillations were measured with the DynaPort(®) device, with three accelerometers, placed at the lumbosacral level, near the center of mass. The conditions were the following: eyes open fixating on LED at 20 cm or 150 cm (vergence angle 17.0° and 2.3° respectively) with or without additional cognitive tasks (counting down from one hundred), performing active vergence by alternating the fixation between the far and the near LED (convergence and divergence), eyes closed after having fixated the far LED. The results showed that the postural stability significantly decreased when fixating on the LED at a far distance (weak convergence angle) with or without cognitive tasks; active convergence-divergence between the LEDs improved the postural stability while eye closure decreased it. The privilege of proximity (with increased convergence at near), previously established with foot posturography, is shown here to be valid for accelerometry with the center of mass in elderly. Another major result is the beneficial contribution of active vergence eye movements to better postural stability. The results bring new perspectives for the role of eye movement training to preserve postural control and autonomy in elderly.

  19. Activation of Nrf2 protects against triptolide-induced hepatotoxicity.

    Directory of Open Access Journals (Sweden)

    Jia Li

    Full Text Available Triptolide, the major active component of Tripterygium wilfordii Hook f. (TWHF, has a wide range of pharmacological activities. However, the toxicities of triptolide, particularly the hepatotoxicity, limit its clinical application. The hepatotoxicity of triptolide has not been well characterized yet. The aim of this study was to investigate the role of NF-E2-related factor 2 (Nrf2 in triptolide-induced toxicity and whether activation of Nrf2 could protect against triptolide-induced hepatotoxicity. The results showed that triptolide caused oxidative stress and cell damage in HepG2 cells, and these toxic effects could be aggravated by Nrf2 knockdown or be counteracted by overexpression of Nrf2. Treatment with a typical Nrf2 agonist, sulforaphane (SFN, attenuated triptolide-induced liver dysfunction, structural damage, glutathione depletion and decrease in antioxidant enzymes in BALB/C mice. Moreover, the hepatoprotective effect of SFN on triptolide-induced liver injury was associated with the activation of Nrf2 and its downstream targets. Collectively, these results indicate that Nrf2 activation protects against triptolide-induced hepatotoxicity.

  20. A closed-loop dynamic simulation-based design method for articulated heavy vehicles with active trailer steering systems

    Science.gov (United States)

    Manjurul Islam, Md.; Ding, Xuejun; He, Yuping

    2012-05-01

    This paper presents a closed-loop dynamic simulation-based design method for articulated heavy vehicles (AHVs) with active trailer steering (ATS) systems. AHVs have poor manoeuvrability at low speeds and exhibit low lateral stability at high speeds. From the design point of view, there exists a trade-off relationship between AHVs' manoeuvrability and stability. For example, fewer articulation points and longer wheelbases will improve high-speed lateral stability, but they will degrade low-speed manoeuvrability. To tackle this conflicting design problem, a systematic method is proposed for the design of AHVs with ATS systems. In order to evaluate vehicle performance measures under a well-defined testing manoeuvre, a driver model is introduced and it 'drivers' the vehicle model to follow a prescribed route at a given speed. Considering the interactions between the mechanical trailer and the ATS system, the proposed design method simultaneously optimises the active design variables of the controllers and passive design variables of the trailer in a single design loop (SDL). Through the design optimisation of an ATS system for an AHV with a truck and a drawbar trailer combination, this SDL method is compared against a published two design loop method. The benchmark investigation shows that the former can determine better trade-off design solutions than those derived by the latter. This SDL method provides an effective approach to automatically implement the design synthesis of AHVs with ATS systems.

  1. Activating PTEN by COX-2 inhibitors antagonizes radiation-induced AKT activation contributing to radiosensitization

    Energy Technology Data Exchange (ETDEWEB)

    Meng, Zhen [Central Laboratory, Peking University School and Hospital of Stomatology, 22 Zhongguancun Avenue South, Haidian District, Beijing 100081 (China); Department of Oral & Maxillofacial Surgery, Peking University School and Hospital of Stomatology, 22 Zhongguancun Avenue South, Haidian District, Beijing 100081 (China); Gan, Ye-Hua, E-mail: kqyehuagan@bjmu.edu.cn [Central Laboratory, Peking University School and Hospital of Stomatology, 22 Zhongguancun Avenue South, Haidian District, Beijing 100081 (China); Department of Oral & Maxillofacial Surgery, Peking University School and Hospital of Stomatology, 22 Zhongguancun Avenue South, Haidian District, Beijing 100081 (China)

    2015-05-01

    Radiotherapy is still one of the most effective nonsurgical treatments for many tumors. However, radioresistance remains a major impediment to radiotherapy. Although COX-2 inhibitors can induce radiosensitization, the underlying mechanism is not fully understood. In this study, we showed that COX-2 selective inhibitor celecoxib enhanced the radiation-induced inhibition of cell proliferation and apoptosis in HeLa and SACC-83 cells. Treatment with celecoxib alone dephosphorylated phosphatase and tensin homolog deleted on chromosome ten (PTEN), promoted PTEN membrane translocation or activation, and correspondingly dephosphorylated or inactivated protein kinase B (AKT). By contrast, treatment with radiation alone increased PTEN phosphorylation, inhibited PTEN membrane translocation and correspondingly activated AKT in the two cell lines. However, treatment with celecoxib or another COX-2 selective inhibitor (valdecoxib) completely blocked radiation-induced increase of PTEN phosphorylation, rescued radiation-induced decrease in PTEN membrane translocation, and correspondingly inactivated AKT. Moreover, celecoxib could also upregulate PTEN protein expression by downregulating Sp1 expression, thereby leading to the activation of PTEN transcription. Our results suggested that COX-2 inhibitors could enhance radiosensitization at least partially by activating PTEN to antagonize radiation-induced AKT activation. - Highlights: • COX-2 inhibitor, celecoxib, could enhance radiosensitization. • Radiation induced PTEN inactivation (phosphorylation) and AKT activation. • COX-2 inhibitor induced PTEN expression and activation, and inactivated AKT. • COX-2 inhibitor enhanced radiosensitization through activating PTEN.

  2. Feedback activation of neurofibromin terminates growth factor-induced Ras activation

    OpenAIRE

    Hennig, Anne; Markwart, Robby; Wolff, Katharina; Schubert, Katja; Cui, Yan; Ian A Prior; Manuel A Esparza-Franco; Ladds, Graham; Rubio, Ignacio

    2016-01-01

    This is the final published version. It first appeared at http://biosignaling.biomedcentral.com/articles/10.1186/s12964-016-0128-z. Background Growth factors induce a characteristically short-lived Ras activation in cells emerging from quiescence. Extensive work has shown that transient as opposed to sustained Ras activation is critical for the induction of mitogenic programs. Mitogen-induced accumulation of active Ras-GTP results from increased nucleotide exchange driven by the nucleo...

  3. Cold suppresses agonist-induced activation of TRPV1.

    Science.gov (United States)

    Chung, M-K; Wang, S

    2011-09-01

    Cold therapy is frequently used to reduce pain and edema following acute injury or surgery such as tooth extraction. However, the neurobiological mechanisms of cold therapy are not completely understood. Transient receptor potential vanilloid 1 (TRPV1) is a capsaicin- and heat-gated nociceptive ion channel implicated in thermosensation and pathological pain under conditions of inflammation or injury. Although capsaicin-induced nociception, neuropeptide release, and ionic currents are suppressed by cold, it is not known if cold suppresses agonist-induced activation of recombinant TRPV1. We demonstrate that cold strongly suppressed the activation of recombinant TRPV1 by multiple agonists and capsaicin-evoked currents in trigeminal ganglia neurons under normal and phosphorylated conditions. Cold-induced suppression was partially impaired in a TRPV1 mutant that lacked heat-mediated activation and potentiation. These results suggest that cold-induced suppression of TRPV1 may share a common molecular basis with heat-induced potentiation, and that allosteric inhibition may contribute, in part, to the cold-induced suppression. We also show that combination of cold and a specific antagonist of TRPV1 can produce an additive suppression. Our results provide a mechanistic basis for cold therapy and may enhance anti-nociceptive approaches that target TRPV1 for managing pain under inflammation and tissue injury, including that from tooth extraction.

  4. Mucin-like peptides from Echinococcus granulosus induce antitumor activity.

    Science.gov (United States)

    Noya, Verónica; Bay, Sylvie; Festari, María Florencia; García, Enrique P; Rodriguez, Ernesto; Chiale, Carolina; Ganneau, Christelle; Baleux, Françoise; Astrada, Soledad; Bollati-Fogolín, Mariela; Osinaga, Eduardo; Freire, Teresa

    2013-09-01

    There is substantial evidence suggesting that certain parasites can have antitumor properties. We evaluated mucin peptides derived from the helminth Echinococcus granulosus (denominated Egmuc) as potential inducers of antitumor activity. We present data showing that Egmuc peptides were capable of inducing an increase of activated NK cells in the spleen of immunized mice, a fact that was correlated with the capacity of splenocytes to mediate killing of tumor cells. We demonstrated that Egmuc peptides enhance LPS-induced maturation of dendritic cells in vitro by increasing the production of IL-12p40p70 and IL-6 and that Egmuc-treated DCs may activate NK cells, as judged by an increased expression of CD69. This evidence may contribute to the design of tumor vaccines and open new horizons in the use of parasite-derived molecules in the fight against cancer.

  5. Aldehyde-induced xanthine oxidase activity in raw milk.

    Science.gov (United States)

    Steffensen, Charlotte L; Andersen, Henrik J; Nielsen, Jacob H

    2002-12-04

    In the present study, the aldehyde-induced pro-oxidative activity of xanthine oxidase was followed in an accelerated raw milk system using spin-trap electron spin resonance (ESR) spectroscopy. The aldehydes acetaldehyde, propanal, hexanal, trans-2-hexenal, trans-2-heptenal, trans-2-nonenal, and 3-methyl-2-butenal were all found to initiate radical reactions when added to milk. Formation of superoxide through aldehyde-induced xanthine oxidase activity is suggested as the initial reaction, as all tested aldehydes were shown to trigger superoxide formation in an ultrahigh temperature (UHT) milk model system with added xanthine oxidase. It was found that addition of aldehydes to milk initially increased the ascorbyl radical concentration with a subsequent decay due to ascorbate depletion, which renders the formation of superoxide in milk with added aldehyde. The present study shows for the first time potential acceleration of oxidative events in milk through aldehyde-induced xanthine oxidase activity.

  6. Saturation of retinol-binding protein correlates closely to the severity of alcohol-induced liver disease

    DEFF Research Database (Denmark)

    Wagnerberger, S.; Schäfer, C.; Bode, C.;

    2006-01-01

    Impaired metabolism of retinol has been shown to occur in alcohol-induced liver disease (ALD). The purpose of the present study was to investigate the saturation of retinol-binding protein (RBP) in 6 patients with different stages of ALD. Hospitalized alcohol consumers (n=118) with different stages......: 43.5+/-6.2%; ALD3: 29.0+/-5.1%). The present study indicates that plasma concentrations of retinol and RBP per se do not correlate to severity of ALD, but rather that the retinol/RBP ratio links to the severity of alcohol-induced liver damage. From these results, a reduced availability of retinol...

  7. Borrelia burgdorferi Spirochetes Induce Mast Cell Activation and Cytokine Release

    Science.gov (United States)

    Talkington, Jeffrey; Nickell, Steven P.

    1999-01-01

    The Lyme disease spirochete, Borrelia burgdorferi, is introduced into human hosts via tick bites. Among the cell types present in the skin which may initially contact spirochetes are mast cells. Since spirochetes are known to activate a variety of cell types in vitro, we tested whether B. burgdorferi spirochetes could activate mast cells. We report here that freshly isolated rat peritoneal mast cells or mouse MC/9 mast cells cultured in vitro with live or freeze-thawed B. burgdorferi spirochetes undergo low but detectable degranulation, as measured by [5-3H] hydroxytryptamine release, and they synthesize and secrete the proinflammatory cytokine tumor necrosis factor alpha (TNF-α). In contrast to findings in previous studies, where B. burgdorferi-associated activity was shown to be dependent upon protein lipidation, mast cell TNF-α release was not induced by either lipidated or unlipidated recombinant OspA. This activity was additionally shown to be protease sensitive and surface expressed. Finally, comparisons of TNF-α-inducing activity in known low-, intermediate-, and high-passage B. burgdorferi B31 isolates demonstrated passage-dependent loss of activity, indicating that the activity is probably plasmid encoded. These findings document the presence in low-passage B. burgdorferi spirochetes of a novel lipidation-independent activity capable of inducing cytokine release from host cells. PMID:10024550

  8. Proteases induce secretion of collagenase and plasminogen activator by fibroblasts

    Energy Technology Data Exchange (ETDEWEB)

    Werb, Z.; Aggeler, J.

    1978-04-01

    We have observed that treatment of rabbit synovial fibroblasts with proteolytic enzymes can induce secretion of collagenase (EC 3.4.24.7) and plasminogen activator (EC 3.4.21.-). Cells treated for 2 to 24 hr with plasmin, trypsin, chymotrypsin, pancreatic elastase, papain, bromelain, thermolysin, or ..cap alpha..-protease but not with thrombin or neuraminidase secreted detectable amounts of collagenase within 16 to 48 hr. Treatment of fibroblasts with trypsin also induced secretion of plasminogen activator. Proteases initiated secretion of collagenase (up to 20 units per 10/sup 6/ cells per 24 hr) only when treatment produced decreased cell adhesion. Collagenase production did not depend on continued presence of proteolytic activity or on subsequent cell adhesion, spreading, or proliferation. Routine subculturing with crude trypsin also induced collagenase secretion by cells. Secretion of collagenase was prevented and normal spreading was obtained if the trypsinized cells were placed into medium containing fetal calf serum. Soybean trypsin inhibitor, ..cap alpha../sub 1/-antitrypsin, bovine serum albumin, collagen, and fibronectin did not inhibit collagenase production. Although proteases that induced collagenase secretion also removed surface glycoprotein, the kinetics of induction of cell protease secretion were different from those for removal of fibronectin. Physiological inducers of secretion of collagenase and plasminogen activator by cells have not been identified. These results suggest that extracellular proteases in conjunction with plasma proteins may govern protease secretion by cells.

  9. Low-dose effect of ethanol on locomotor activity induced by activation of the mesolimbic system.

    Science.gov (United States)

    Milton, G V; Randall, P K; Erickson, C K

    1995-06-01

    Four experiments were designed to study the ability of 0.5 g/kg ethanol (EtOH) intraperitoneally to modify locomotor activity induced by drugs that interact with different sites in the mesolimbic system (MLS) of male Sprague-Dawley rats. Locomotor activity was measured in a doughnut-shaped circular arena after various treatments. EtOH alone did not alter locomotor activity in any of the experiments. Amphetamine (AMP, intraperitoneally or intraaccumbens) increased locomotor activity in a dose-dependent manner, and the presence of EtOH attenuated AMP-induced locomotor activity. Bilateral infusion of GABAA antagonist picrotoxin (PIC) into the ventral tegmental area also increased locomotor activity in a dose-dependent manner, and the presence of EtOH attenuated PIC-induced locomotor activity. On the other hand, the interaction between bilateral infusion of mu-receptor agonist Tyr-D-Ala-Gly-NMe-Phe-Gly-ol (DAGO) and EtOH on locomotor activity is complex. The highest dose of DAGO that significantly increased locomotor activity was not affected by the presence of EtOH. But, with lower doses of DAGO that either had no effect or a small increase in locomotor activity, the combination of EtOH and DAGO increased and attenuated locomotor activity, respectively. Results from this study support our hypothesis that a low dose of EtOH that does not modify behavior can interact with neurotransmitter systems in the brain and modify drug-induced locomotor activity. Modification of this drug-induced locomotor activity by a low dose of EtOH is dependent on the rate of ongoing locomotor behavior induced by drug and the neurotransmitter substrate that the drug modified to induce locomotor behavior.(ABSTRACT TRUNCATED AT 250 WORDS)

  10. On the effect of water film on flow-induced pulsations in closed side branches in tandem configuration

    NARCIS (Netherlands)

    Sanna, F.; Golliard, J.; Belfroid, S.P.C.

    2015-01-01

    Previous studies demonstrate that the presence of liquid strongly influences the pressure pulsation amplitudes of flow induced pulsations. In particular, in case of annular flow (thin liquid film on the walls) the pulsations can be eliminated. The present study aims at evaluating the contribution of

  11. Activation-induced resetting of cerebral oxygen and glucose uptake in the rat

    DEFF Research Database (Denmark)

    Madsen, P L; Linde, R; Hasselbalch, S G

    1998-01-01

    In the clinical setting it has been shown that activation will increase cerebral glucose uptake in excess of cerebral oxygen uptake. To study this phenomenon further, this study presents an experimental setup that enables precise determination of the ratio between cerebral uptake of glucose...... and oxygen in the awake rat. Global CBF was measured by the Kety-Schmidt technique, and the ratio between cerebral uptake rates for oxygen, glucose, and lactate was calculated from cerebral arterial-venous differences. During baseline conditions, rats were kept in a closed box designed to minimize...... interference. During baseline conditions CBF was 1.08 +/- 0.25 mL x g(-1) x minute(-1), and the cerebral oxygen to glucose uptake ratio was 5.5. Activation was induced by opening the sheltering box for 6 minutes. Activation increased CBF to 1.81 mL x g(-1) x minute(-1). During activation cerebral glucose...

  12. Activation-induced force enhancement in human adductor pollicis.

    Science.gov (United States)

    Oskouei, Ali E; Herzog, Walter

    2009-10-01

    It has been known for a long time that the steady-state isometric force after muscle stretch is bigger than the corresponding force obtained in a purely isometric contraction for electrically stimulated and maximal voluntary contractions (MVC). Recent studies using sub-maximal voluntary contractions showed that force enhancement only occurred in a sub-group of subjects suggesting that force enhancement for sub-maximal voluntary contractions has properties different from those of electrically-induced and maximal voluntary contractions. Specifically, force enhancement for sub-maximal voluntary contractions may contain an activation-dependent component that is independent of muscle stretching. To address this hypothesis, we tested for force enhancement using (i) sub-maximal electrically-induced contractions and stretch and (ii) using various activation levels preceding an isometric reference contraction at 30% of MVC (no stretch). All tests were performed on human adductor pollicis muscles. Force enhancement following stretching was found for all subjects (n=10) and all activation levels (10%, 30%, and 60% of MVC) for electrically-induced contractions. In contrast, force enhancement at 30% of MVC, preceded by 6s of 10%, 60%, and 100% of MVC was only found in a sub-set of the subjects and only for the 60% and 100% conditions. This result suggests that there is an activation-dependent force enhancement for some subjects for sub-maximal voluntary contractions. This activation-dependent force enhancement was always smaller than the stretch-induced force enhancement obtained at the corresponding activation levels. Active muscle stretching increased the force enhancement in all subjects, independent whether they showed activation dependence or not. It appears that post-activation potentiation, and the associated phosphorylation of the myosin light chains, might account for the stretch-independent force enhancement observed here.

  13. Uracil DNA glycosylase counteracts APOBEC3G-induced hypermutation of hepatitis B viral genomes: excision repair of covalently closed circular DNA.

    Directory of Open Access Journals (Sweden)

    Kouichi Kitamura

    Full Text Available The covalently closed circular DNA (cccDNA of the hepatitis B virus (HBV plays an essential role in chronic hepatitis. The cellular repair system is proposed to convert cytoplasmic nucleocapsid (NC DNA (partially double-stranded DNA into cccDNA in the nucleus. Recently, antiviral cytidine deaminases, AID/APOBEC proteins, were shown to generate uracil residues in the NC-DNA through deamination, resulting in cytidine-to-uracil (C-to-U hypermutation of the viral genome. We investigated whether uracil residues in hepadnavirus DNA were excised by uracil-DNA glycosylase (UNG, a host factor for base excision repair (BER. When UNG activity was inhibited by the expression of the UNG inhibitory protein (UGI, hypermutation of NC-DNA induced by either APOBEC3G or interferon treatment was enhanced in a human hepatocyte cell line. To assess the effect of UNG on the cccDNA viral intermediate, we used the duck HBV (DHBV replication model. Sequence analyses of DHBV DNAs showed that cccDNA accumulated G-to-A or C-to-T mutations in APOBEC3G-expressing cells, and this was extensively enhanced by UNG inhibition. The cccDNA hypermutation generated many premature stop codons in the P gene. UNG inhibition also enhanced the APOBEC3G-mediated suppression of viral replication, including reduction of NC-DNA, pre-C mRNA, and secreted viral particle-associated DNA in prolonged culture. Enhancement of APOBEC3G-mediated suppression by UNG inhibition was not observed when the catalytic site of APOBEC3G was mutated. Transfection experiments of recloned cccDNAs revealed that the combination of UNG inhibition and APOBEC3G expression reduced the replication ability of cccDNA. Taken together, these data indicate that UNG excises uracil residues from the viral genome during or after cccDNA formation in the nucleus and imply that BER pathway activities decrease the antiviral effect of APOBEC3-mediated hypermutation.

  14. Induced starburst and nuclear activity: Faith, facts, and theory

    Science.gov (United States)

    Shlosman, Isaac

    1990-01-01

    The problem of the origin of starburst and nuclear (nonstellar) activity in galaxies is reviewed. A physical understanding of the mechanism(s) that induce both types of activity requires one to address the following issues: (1) what is the source of fuel that powers starbursts and active galactic nuclei; and (2) how is it channeled towards the central regions of host galaxies? As a possible clue, the author examines the role of non-axisymmetric perturbations of galactic disks and analyzes their potential triggers. Global gravitational instabilities in the gas on scales approx. 100 pc appear to be crucial for fueling the active galactic nuclei.

  15. Antidiabetic activity of Rheum emodi in Alloxan induced diabetic rats.

    Directory of Open Access Journals (Sweden)

    Radhika.R

    2010-09-01

    Full Text Available The present study was carried out to evaluate the antidiabetic effect of Rheum emodi rhizome extract and to study the activities of hexokinase, aldolase and phosphoglucoisomerase, and gluconeogenic enzymes such as glucose-6- phosphatase and fructose 1,6-diphosphatase in liver and kidney of normal and alloxan induced diabetic rats. Oral administration of 75 % ethanolic extract of R. emodi (250 mg/kg body weight for 30 days, resulted in decrease inthe activities of glucose-6-phosphatase, fructose-1,6-disphosphatase, aldolase and an increase in the activity of phosphoglucoisomerase and hexokinase in tissues. The study clearly shows that the R.emodi possesses antidiabetic activity.

  16. [Administration of premedication with fexofenadine for paclitaxel-induced hypersensitive reactions in breast cancer patients complicated with closed-angle glaucoma].

    Science.gov (United States)

    Komatsubara, Kazuo; Miyoshi, Kyoko; Kogure, Yuuki; Matsuhisa, Tetsuaki; Eguchi, Hisae

    2010-01-01

    Paclitaxel (PTX) is one of the most important breast cancer treatment drugs. However, severe hypersensitivity reactions such as decreases in blood pressure and impaired breathing occur with high frequency. For the prevention of such hypersensitivity reactions, administration of a premedication composed of three components, diphenhydramine, ranitidine (or famotidine), and dexamethasone, has been advised in package insert information of medicine. Administration of diphenhydramine is difficult in breast cancer patients complicated with closed-angle glaucoma, because diphenhydramine has a weak anticholinergic adverse effect which can induce mydriasis and glaucoma attack. We studied the prevention of severe hypersensitivity reactions and of glaucoma attack in 2 breast cancer patients complicated with closed angle glaucoma at our hospital from April 2007 to March 2008. We switched from diphenhydramine to fexofenadine as the medicine to prevent hypersensitivity reactions. Hypersensitivity reactions were not observed throughout all courses in both patients, and no glaucoma attack was observed.

  17. CHD1 regulates cell fate determination by activation of differentiation-induced genes

    DEFF Research Database (Denmark)

    Baumgart, Simon J; Najafova, Zeynab; Hossan, Tareq

    2017-01-01

    . Furthermore, we observed that CHD1-dependent genes are mainly induced during osteoblast differentiation and are characterized by higher levels of CHD1 occupancy around the TSS. Interestingly, CHD1 depletion resulted in increased pausing of RNA Polymerase II (RNAPII) and decreased H2A.Z occupancy close......The coordinated temporal and spatial activation of gene expression is essential for proper stem cell differentiation. The Chromodomain Helicase DNA-binding protein 1 (CHD1) is a chromatin remodeler closely associated with transcription and nucleosome turnover downstream of the transcriptional start...... to the TSS, but not at enhancer regions. These findings reveal a novel role for CHD1 during osteoblast differentiation and provide further insights into the intricacies of epigenetic regulatory mechanisms controlling cell fate determination....

  18. Nonpathogenic, environmental fungi induce activation and degranulation of human eosinophils.

    Science.gov (United States)

    Inoue, Yoshinari; Matsuwaki, Yoshinori; Shin, Seung-Heon; Ponikau, Jens U; Kita, Hirohito

    2005-10-15

    Eosinophils and their products are probably important in the pathophysiology of allergic diseases, such as bronchial asthma, and in host immunity to certain organisms. An association between environmental fungal exposure and asthma has been long recognized clinically. Although products of microorganisms (e.g., lipopolysaccharides) directly activate certain inflammatory cells (e.g., macrophages), the mechanism(s) that triggers eosinophil degranulation is unknown. In this study we investigated whether human eosinophils have an innate immune response to certain fungal organisms. We incubated human eosinophils with extracts from seven environmental airborne fungi (Alternaria alternata, Aspergillus versicolor, Bipolaris sorokiniana, Candida albicans, Cladosporium herbarum, Curvularia spicifera, and Penicillium notatum). Alternaria and Penicillium induced calcium-dependent exocytosis (e.g., eosinophil-derived neurotoxin release) in eosinophils from normal individuals. Alternaria also strongly induced other activation events in eosinophils, including increases in intracellular calcium concentration, cell surface expression of CD63 and CD11b, and production of IL-8. Other fungi did not induce eosinophil degranulation, and Alternaria did not induce neutrophil activation, suggesting specificity for fungal species and cell type. The Alternaria-induced eosinophil degranulation was pertussis toxin sensitive and desensitized by preincubating cells with G protein-coupled receptor agonists, platelet-activating factor, or FMLP. The eosinophil-stimulating activity in Alternaria extract was highly heat labile and had an M(r) of approximately 60 kDa. Thus, eosinophils, but not neutrophils, possess G protein-dependent cellular activation machinery that directly responds to an Alternaria protein product(s). This innate response by eosinophils to certain environmental fungi may be important in host defense and in the exacerbation of inflammation in asthma and allergic diseases.

  19. Enhanced surface plasmon polariton propagation induced by active dielectrics

    OpenAIRE

    Athanasopoulos, C.; Mattheakis, M.; Tsironis, G. P.

    2013-01-01

    We present numerical simulations for the propagation of surface plasmon polaritons in a dielectric-metal-dielectric waveguide using COMSOL multiphysics software. We show that the use of an active dielectric with gain that compensates metal absorption losses enhances substantially plasmon propagation. Furthermore, the introduction of the active material induces, for a specific gain value, a root in the imaginary part of the propagation constant leading to infinite propagation of the surface pl...

  20. The influence of experimentally induced pain on shoulder muscle activity

    DEFF Research Database (Denmark)

    Diederichsen, L.P.; Winther, A.; Dyhre-Poulsen, P.

    2009-01-01

    muscles. EMG was recorded before pain, during pain and after pain had subsided and pain intensity was continuously scored on a visual analog scale (VAS). During abduction, experimentally induced pain in the supraspinatus muscle caused a significant decrease in activity of the anterior deltoid, upper...... in a way that protects the painful structure. Further, the changes in muscle activity following subacromial pain induction tend to expand the subacromial space and thereby decrease the load on the painful structures Udgivelsesdato: 2009/4...

  1. The influence of experimentally induced pain on shoulder muscle activity

    DEFF Research Database (Denmark)

    Diederichsen, Louise Pyndt; Winther, Annika; Dyhre-Poulsen, Poul

    2009-01-01

    . EMG was recorded before pain, during pain and after pain had subsided and pain intensity was continuously scored on a visual analog scale (VAS). During abduction, experimentally induced pain in the supraspinatus muscle caused a significant decrease in activity of the anterior deltoid, upper trapezius...... the painful structure. Further, the changes in muscle activity following subacromial pain induction tend to expand the subacromial space and thereby decrease the load on the painful structures....

  2. Activation-Induced Cytidine Deaminase Links Ovulation-Induced Inflammation and Serous Carcinogenesis

    Directory of Open Access Journals (Sweden)

    Stav Sapoznik

    2016-02-01

    Full Text Available In recent years, the notion that ovarian carcinoma results from ovulation-induced inflammation of the fallopian tube epithelial cells (FTECs has gained evidence. However, the mechanistic pathway for this process has not been revealed yet. In the current study, we propose the mutator protein activation-induced cytidine deaminase (AID as a link between ovulation-induced inflammation in FTECs and genotoxic damage leading to ovarian carcinogenesis. We show that AID, previously shown to be functional only in B lymphocytes, is expressed in FTECs under physiological conditions, and is induced in vitro upon ovulatory-like stimulation and in vivo in carcinoma-associated FTECs. We also report that AID activity results in epigenetic, genetic and genomic damage in FTECs. Overall, our data provides new insights into the etiology of ovarian carcinogenesis and may set the ground for innovative approaches aimed at prevention and early detection.

  3. Lotus hairy roots expressing inducible arginine decarboxylase activity.

    Science.gov (United States)

    Chiesa, María A; Ruiz, Oscar A; Sánchez, Diego H

    2004-05-01

    Biotechnological uses of plant cell-tissue culture usually rely on constitutive transgene expression. However, such expression of transgenes may not always be desirable. In those cases, the use of an inducible promoter could be an alternative approach. To test this hypothesis, we developed two binary vectors harboring a stress-inducible promoter from Arabidopsis thaliana, driving the beta-glucuronidase reporter gene and the oat arginine decarboxylase. Transgenic hairy roots of Lotus corniculatus were obtained with osmotic- and cold-inducible beta-glucuronidase and arginine decarboxylase activities. The increase in the activity of the latter was accompanied by a significant rise in total free polyamines level. Through an organogenesis process, we obtained L. corniculatus transgenic plants avoiding deleterious phenotypes frequently associated with the constitutive over-expression of arginine decarboxylation and putrescine accumulation.

  4. Caspase-9 mediates Puma activation in UCN-01-induced apoptosis.

    Science.gov (United States)

    Nie, C; Luo, Y; Zhao, X; Luo, N; Tong, A; Liu, X; Yuan, Z; Wang, C; Wei, Y

    2014-10-30

    The protein kinase inhibitor 7-hydroxystaurosporine (UCN-01) is one of the most potent and frequently used proapoptotic stimuli. The BH3-only molecule of Bcl-2 family proteins has been reported to contribute to UCN-01-induced apoptosis. Here we have found that UCN-01 triggers Puma-induced mitochondrial apoptosis pathway. Our data confirmed that Akt-FoxO3a pathway mediated Puma activation. Importantly, we elucidate the detailed mechanisms of Puma-induced apoptosis. Our data have also demonstrated that caspase-9 is a decisive molecule of Puma induction after UCN-01 treatment. Caspase-9 mediates apoptosis through two kinds of feedback loops. On the one hand, caspase-9 enhances Puma activation by cleaving Bcl-2 and Bcl-xL independent of caspase-3. On the other hand, caspase-9 directly activated caspase-3 in the presence of caspase-3. Caspase-3 could cleave XIAP in an another positive feedback loop to further sensitize cancer cells to UCN-01-induced apoptosis. Therefore, caspase-9 mediates Puma activation to determine the threshold for overcoming chemoresistance in cancer cells.

  5. Early autophagy activation inhibits podocytes from apoptosis induced by aldosterone

    Institute of Scientific and Technical Information of China (English)

    王文琰

    2013-01-01

    Objective To explore the protection of early autoph-agy activation on podocyte injury induced by aldosterone.Methods In vitro cultured mouse podocyte clones(MPC5) were treated with aldosterone for 6,12,24,48 hrespectively. Apoptosis of podocytes was detected by

  6. Relationship between ascorbyl radical intensity and apoptosis-inducing activity.

    Science.gov (United States)

    Sakagami, H; Satoh, K; Ohata, H; Takahashi, H; Yoshida, H; Iida, M; Kuribayashi, N; Sakagami, T; Momose, K; Takeda, M

    1996-01-01

    Ascorbic acid and its related compounds were compared for their ascorbyl radical intensity and apoptosis-inducing activity. Sodium L-ascorbate, L-ascorbic acid, D-isoascorbic acid, sodium 6-beta-O-galactosyl-L-ascorbate and sodium 5,6-benzylidene-L-ascorbate, at the concentration of 1-10 mM, induced apoptotic cell death characterized by cell shrinkage, nuclear fragmentation and internucleosomal DNA cleavage in human promyelocytic leukemic HL-60 cells. On the other hand, L-ascorbic acid-2-phosphate magnesium salt and L-ascorbic acid 2-sulfate did not induce any of these apoptosis-associated characteristics. ESR measurements revealed that all the active compounds were progressively degraded, producing the ascorbyl radical (g = 2.0064, hfc = 0.17 mT) in culture medium, whereas the inactive compounds were stable and did not produce the ascorbyl radical. Cytotoxicity began to appear when the radical intensity exceeded a certain threshold level. In the presence of N-acetyl-L-cysteine, both ascorbyl radical intensity and apoptosis-inducing activity were significantly reduced. These data suggest the possible involvement of the ascorbyl radical in apoptosis induction by ascorbic acid-related compounds. Exposure of HL-60 cells to ascorbic acid or its active derivatives resulted in the rapid elevation of intracellular Ca2+ concentration, which might serve as the initial signal leading to the cell death pathway.

  7. [Closing diastemas].

    Science.gov (United States)

    Vieira, L C; Pereira, J C; Coradazzi, J L; Francischone, C E

    1990-01-01

    The authors describe a clinical case of closing upper central incisives diastema, reconstructiva of a conoid upper lateral and the rechaping of an upper canine to a lateral incisive. The material used was composite resin.

  8. Lipoprotein-induced phenoloxidase-activity in tarantula hemocyanin.

    Science.gov (United States)

    Schenk, Sven; Schmidt, Juliane; Hoeger, Ulrich; Decker, Heinz

    2015-08-01

    Phenoloxidases play vital roles in invertebrate innate immune reactions, wound closure and sclerotization processes in arthropods. In chelicerates, where phenoloxidases are lacking, phenoloxidase-activity can be induced in the oxygen carrier hemocyanin in vitro by proteolytic cleavage, incubation with the artificial inducer SDS, or lipids. The role of protein-protein interaction has up to now received little attention. This is remarkable, as lipoproteins - complexes of proteins and lipids - are present at high concentrations in arthropod hemolymph. We characterized the three lipoproteins present in tarantula hemolymph, two high-density lipoproteins and one very high-density lipoprotein, and show that the two high-density lipoproteins have distinct structures: the more abundant high-density lipoprotein is an ellipsoid particle with axes of ~22.5 nm and ~16.8 nm, respectively. The second high-density lipoprotein, present only in trace amount, is a large discoidal lipoprotein with a diameter of ~38.4 nm and an on-edge thickness of ~7.1 nm. We further demonstrate that the interaction between lipoproteins and hemocyanin induces phenoloxidase activity in hemocyanin, and propose that this activation is due to protein-protein interaction rather than protein-lipid interaction, as neither lipid micelles nor lipid monomers were found to be activating. Activation was strongest in the presence of high-density lipoproteins; very high-density lipoproteins were found to be non-activating. This is the first time that the ability of lipoproteins to induce phenoloxidase activity of hemocyanin has been demonstrated, thus adding novel aspects to the function of lipoproteins apart from their known role in nutrient supply. Copyright © 2015 Elsevier B.V. All rights reserved.

  9. Jealousy increased by induced relative left frontal cortical activity.

    Science.gov (United States)

    Kelley, Nicholas J; Eastwick, Paul W; Harmon-Jones, Eddie; Schmeichel, Brandon J

    2015-10-01

    Asymmetric frontal cortical activity may be one key to the process linking social exclusion to jealous feelings. The current research examined the causal role of asymmetric frontal brain activity in modulating jealousy in response to social exclusion. Transcranial direct-current stimulation (tDCS) over the frontal cortex to manipulate asymmetric frontal cortical activity was combined with a modified version of the Cyberball paradigm designed to induce jealousy. After receiving 15 min of tDCS, participants were excluded by a desired partner and reported how jealous they felt. Among individuals who were excluded, tDCS to increase relative left frontal cortical activity caused greater levels of self-reported jealousy compared to tDCS to increase relative right frontal cortical activity or sham stimulation. Limitations concerning the specificity of this effect and implications for the role of the asymmetric prefrontal cortical activity in motivated behaviors are discussed.

  10. Antimicrobial Activity of UV-Induced Phenylamides from Rice Leaves

    Directory of Open Access Journals (Sweden)

    Hye Lin Park

    2014-11-01

    Full Text Available Rice produces a wide array of phytoalexins in response to pathogen attacks and UV-irradiation. Except for the flavonoid sakuranetin, most phytoalexins identified in rice are diterpenoid compounds. Analysis of phenolic-enriched fractions from UV-treated rice leaves showed that several phenolic compounds in addition to sakuranetin accumulated remarkably in rice leaves. We isolated two compounds from UV-treated rice leaves using silica gel column chromatography and preparative HPLC. The isolated phenolic compounds were identified as phenylamide compounds: N-trans-cinnamoyltryptamine and N-p-coumaroylserotonin. Expression analysis of biosynthetic genes demonstrated that genes for arylamine biosynthesis were upregulated by UV irradiation. This result suggested that phenylamide biosynthetic pathways are activated in rice leaves by UV treatment. To unravel the role of UV-induced phenylamides as phytoalexins, we examined their antimicrobial activity against rice fungal and bacterial pathogens. N-trans-Cinnamoyltryptamine inhibited the growth of rice brown spot fungus (Bipolaris oryzae. In addition to the known antifungal activity to the blast fungus, sakuranetin had antimicrobial activity toward B. oryzae and Rhizoctonia solani (rice sheath blight fungus. UV-induced phenylamides and sakuranetin also had antimicrobial activity against rice bacterial pathogens for grain rot (Burkholderia glumae, blight (Xanthomonas oryzae pv. oryzae and leaf streak (X. oryzae pv. oryzicola diseases. These findings suggested that the UV-induced phenylamides in rice are phytoalexins against a diverse array of pathogens.

  11. Calciumreleasing activity induced by nuclei of mouse fertilized early embryos

    Institute of Scientific and Technical Information of China (English)

    2003-01-01

    At fertilization, repetitive transient rises of intracellular calcium concentration occur in all mammals studied so far. It has been shown that calcium rises could be induced when mouse fertilized 1-, 2-cell nuclei were transplanted into unfertilized eggs and that the reconstituted embryo could be activated. However, whether the capability of inducing calcium rises occurs in all stages of mammalian embryos remains unknown. In this study, by using the nuclear transplantation technique and measurement of intracellular calcium rises in living cells, we showed that only the nuclei from mouse fertilized 1-cell and 2-cell embryos, neither the nuclei from 4-, 8-cell and ethanol activated parthenogenetic embryos nor 2 or 3 nuclei of electrofused 4-cell stage syncytium, have calcium-releasing activity when they were transferred into unfertilized mature oocytes. Our results indicate that the calcium-releasing activity in nuclei of 1-, 2-cell embryos is produced during fertilization and exists at the special stage of fertilized early embryos. These suggested that the capacity of inducing calcium release activity in fertilized early embryos is important for normal embryonic development.

  12. Characteristics of induced activity from medical linear accelerators.

    Science.gov (United States)

    Wang, Yi Zhen; Evans, Michael D C; Podgorsak, Ervin B

    2005-09-01

    A study of the induced activity in a medical linear accelerator (linac) room was carried out on several linac installations. Higher beam energy, higher dose rate, and larger field size generally result in higher activation levels at a given point of interest, while the use of multileaf collimators (MLC) can also increase the activation level at the isocenter. Both theoretical and experimental studies reveal that the activation level in the morning before any clinical work increases from Monday to Saturday and then decreases during the weekend. This weekly activation picture keeps stable from one week to another during standard clinical operation of the linac. An effective half-life for a given point in the treatment room can be determined from the measured or calculated activity decay curves. The effective half-life for points inside the treatment field is longer than that for points outside of the field in the patient plane, while a larger field and longer irradiation time can also make the effective half-life longer. The activation level reaches its practical saturation value after a 30 min continuous irradiation, corresponding to 12 000 MU at a "dose rate" of 400 MU/min. A "dose" of 300 MU was given 20 times in 15 min intervals to determine the trends in the activation level in a typical clinical mode. As well, a long-term (85 h over a long weekend) decay curve was measured to evaluate the long-term decay of room activation after a typical day of clinical linac use. A mathematical model for the activation level at the isocenter has been established and shown to be useful in explaining and predicting the induced activity levels for typical clinical and experimental conditions. The activation level for a 22 MeV electron beam was also measured and the result shows it is essentially negligible.

  13. Mild closed head traumatic brain injury-induced changes in monoamine neurotransmitters in the trigeminal subnuclei of a rat model: mechanisms underlying orofacial allodynias and headache

    Directory of Open Access Journals (Sweden)

    Golam Mustafa

    2017-01-01

    Full Text Available Our recent findings have demonstrated that rodent models of closed head traumatic brain injury exhibit comprehensive evidence of progressive and enduring orofacial allodynias, a hypersensitive pain response induced by non-painful stimulation. These allodynias, tested using thermal hyperalgesia, correlated with changes in several known pain signaling receptors and molecules along the trigeminal pain pathway, especially in the trigeminal nucleus caudalis. This study focused to extend our previous work to investigate the changes in monoamine neurotransmitter immunoreactivity changes in spinal trigeminal nucleus oralis, pars interpolaris and nucleus tractus solitaries following mild to moderate closed head traumatic brain injury, which are related to tactile allodynia, touch-pressure sensitivity, and visceral pain. Our results exhibited significant alterations in the excitatory monoamine, serotonin, in spinal trigeminal nucleus oralis and pars interpolaris which usually modulate tactile and mechanical sensitivity in addition to the thermal sensitivity. Moreover, we also detected a robust alteration in the expression of serotonin, and inhibitory molecule norepinephrine in the nucleus tractus solitaries, which might indicate the possibility of an alteration in visceral pain, and existence of other morbidities related to solitary nucleus dysfunction in this rodent model of mild to moderate closed head traumatic brain injury. Collectively, widespread changes in monoamine neurotransmitter may be related to orofacial allodynhias and headache after traumatic brain injury.

  14. Influence of induced magnetic field and heat transfer on the peristaltic motion of a Jeffrey fluid in an asymmetric channel: Closed form solutions

    Energy Technology Data Exchange (ETDEWEB)

    Akram, Safia, E-mail: safia_akram@yahoo.com [Department of Humanities and Basic Sciences, Military College of Signals, National University of Sciences and Technology, Rawalpindi 46000 (Pakistan); Department of Mathematics, Quaid-i-Azam University 45320, Islamabad 44000 (Pakistan); Nadeem, S. [Department of Mathematics, Quaid-i-Azam University 45320, Islamabad 44000 (Pakistan)

    2013-02-15

    We discuss the peristaltic motion of a two dimensional Jeffrey fluid in an asymmetric channel under the effects of induced magnetic field and heat transfer. The problem is simplified by using long wave length and low Reynolds approximations. Exact and closed form Adomian solutions are presented. Expressions for the velocity, stream function, magnetic force function, temperature, pressure gradient and pressure rise are computed. The results of pertinent parameters are discussed. Finally, the trapping phenomena for different wave shapes are discussed. It is observed that the pressure rise for sinusoidal wave is less than trapezoidal wave and greater than triangular in a Jeffrey fluid. - Highlights: Black-Right-Pointing-Pointer The effects of induced magnetic field and heat transfer in peristaltic motion of a two dimensional Jeffrey fluid are discussed. Black-Right-Pointing-Pointer In this paper exact and closed form Adomian solutions are presented. Black-Right-Pointing-Pointer Different wave shapes are considered to observe the behavior of pressure rise and trapping phenomena.

  15. Acupuncture inhibits cue-induced heroin craving and brain activation

    Institute of Scientific and Technical Information of China (English)

    Xinghui Cai; Xiaoge Song; Chuanfu Li; Chunsheng Xu; Xiliang Li; Qi Lu

    2012-01-01

    Previous research using functional MRI has shown that specific brain regions associated with drug dependence and cue-elicited heroin craving are activated by environmental cues.Craving is an important trigger of heroin relapse,and acupuncture may inhibit craving.In this study,we performed functional MRI in heroin addicts and control subjects.We compared differences in brain activation between the two groups during heroin cue exposure,heroin cue exposure plus acupuncture at the Zusanli point(ST36)without twirling of the needle,and heroin cue exposure plus acupuncture at the Zusanli point with twirling of the needle.Heroin cue exposure elicited significant activation in craving-related brain regions mainly in the frontal lobes and callosal gyri.Acupuncture without twirling did not significantly affect the range of brain activation induced by heroin cue exposure,but significantly changed the extent of the activation in the heroin addicts group.Acupuncture at the Zusanli.point with twirling of the needle significantly decreased both the range and extent of activation induced by heroin cue exposure compared with heroin cue exposure plus acupuncture without twirling of the needle.These experimental findings indicate that presentation of heroin cues can induce activation in craving-related brain regions,which are involved in reward,learning and memory,cognition and emotion.Acupuncture at the Zusanli point can rapidly suppress the activation of specific brain regions related to craving,supporting its potential as an intervention for drug craving.

  16. Nrf2 activation prevents cadmium-induced acute liver injury

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Kai C. [Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS (United States); Liu, Jie J. [Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS (United States); Klaassen, Curtis D., E-mail: cklaasse@kumc.edu [Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS (United States)

    2012-08-15

    Oxidative stress plays an important role in cadmium-induced liver injury. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that up-regulates cytoprotective genes in response to oxidative stress. To investigate the role of Nrf2 in cadmium-induced hepatotoxicity, Nrf2-null mice, wild-type mice, kelch-like ECH-associated protein 1-knockdown (Keap1-KD) mice with enhanced Nrf2, and Keap1-hepatocyte knockout (Keap1-HKO) mice with maximum Nrf2 activation were treated with cadmium chloride (3.5 mg Cd/kg, i.p.). Blood and liver samples were collected 8 h thereafter. Cadmium increased serum alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) activities, and caused extensive hepatic hemorrhage and necrosis in the Nrf2-null mice. In contrast, Nrf2-enhanced mice had lower serum ALT and LDH activities and less morphological alternations in the livers than wild-type mice. H{sub 2}DCFDA (2′,7′-dichlorodihydrofluoresein diacetate) staining of primary hepatocytes isolated from the four genotypes of mice indicated that oxidative stress was higher in Nrf2-null cells, and lower in Nrf2-enhanced cells than in wild-type cells. To further investigate the mechanism of the protective effect of Nrf2, mRNA of metallothionein (MT) and other cytoprotective genes were determined. Cadmium markedly induced MT-1 and MT-2 in livers of all four genotypes of mice. In contrast, genes involved in glutathione synthesis and reducing reactive oxygen species, including glutamate-cysteine ligase (Gclc), glutathione peroxidase-2 (Gpx2), and sulfiredoxin-1 (Srxn-1) were only induced in Nrf2-enhanced mice, but not in Nrf2-null mice. In conclusion, the present study shows that Nrf2 activation prevents cadmium-induced oxidative stress and liver injury through induction of genes involved in antioxidant defense rather than genes that scavenge Cd. -- Highlights: ► Cadmium caused extensive hepatic hemorrhage and necrosis in Nrf2-null mice. ► Keap1-KD and Keap1-HKO mice

  17. Reducing friction-induced vibration using intelligent active force control (AFC) with piezoelectric actuators

    Indian Academy of Sciences (India)

    S M Hashemi-Dehkordi; A R Abu-Bakar; M Mailah

    2012-12-01

    In this paper, a novel approach to reduce the effect of mode coupling that causes friction induced vibration (FIV) is proposed by applying an intelligent active force control (AFC)-based strategy employing piezoelectric actuators with hysteresis effect to a simplified two degree-of-freedom mathematical model of a friction-induced vibration system. At first, the model is simulated and analysed using a closed loop pure Proportional-Integral-Derivative (PID) controller. Later, it is integrated with the intelligent AFC with fuzzy logic (FL) estimator and simulated under similar operating condition. After running several tests with different sets of operating and loading conditions, the results both in time and frequency domains show that the PID controller with the intelligent AFC is much more effective in reducing the vibration, compared to the pure PID controller alone.

  18. Ionizing radiation induces astrocyte gliosis through microglia activation.

    Science.gov (United States)

    Hwang, So-Young; Jung, Jae-Seob; Kim, Tae-Hyun; Lim, Soo-Jeong; Oh, Eok-Soo; Kim, Joo-Young; Ji, Kyung-Ae; Joe, Eun-Hye; Cho, Kwan-Ho; Han, Inn-Oc

    2006-03-01

    The aim of this study was to investigate the role of microglia in radiation-induced astrocyte gliosis. We found that a single dose of 15 Gy radiation to a whole rat brain increased immunostaining of glial fibrillary acidic protein in astrocytes 6 h later, and even more so 24 h later, indicating the initiation of gliosis. While irradiation of cultured rat astrocytes had little effect, irradiation of microglia-astrocyte mixed-cultures displayed altered astrocyte phenotype into more processed, which is another characteristic of gliosis. Experiments using microglia-conditioned media indicated this astrocyte change was due to factors released from irradiated microglia. Irradiation of cultured mouse microglial cells induced a dose-dependent increase in mRNA levels for cyclooxygenase-2 (COX-2), interleukin (IL)-1beta, IL-6, IL-18, tumor necrosis factor-alpha and interferon-gamma-inducible protein-10, which are usually associated with microglia activation. Consistent with these findings, irradiation of microglia activated NF-kappaB, a transcription factor that regulates microglial activation. Addition of prostaglandin E2 (PGE2: a metabolic product of the COX-2 enzyme) to primary cultured rat astrocytes resulted in phenotypic changes similar to those observed in mixed-culture experiments. Therefore, it appears that PGE(2) released from irradiated microglia is a key mediator of irradiation-induced gliosis or astrocyte phenotype change. These data suggest that radiation-induced microglial activation and resultant production of PGE2 seems to be associated with an underlying cause of inflammatory complications associated with radiation therapy for malignant gliomas.

  19. Identity, regulation, and activity of inducible diterpenoid phytoalexins in maize.

    Science.gov (United States)

    Schmelz, Eric A; Kaplan, Fatma; Huffaker, Alisa; Dafoe, Nicole J; Vaughan, Martha M; Ni, Xinzhi; Rocca, James R; Alborn, Hans T; Teal, Peter E

    2011-03-29

    Phytoalexins constitute a broad category of pathogen- and insect-inducible biochemicals that locally protect plant tissues. Because of their agronomic significance, maize and rice have been extensively investigated for their terpenoid-based defenses, which include insect-inducible monoterpene and sesquiterpene volatiles. Rice also produces a complex array of pathogen-inducible diterpenoid phytoalexins. Despite the demonstration of fungal-induced ent-kaur-15-ene production in maize over 30 y ago, the identity of functionally analogous maize diterpenoid phytoalexins has remained elusive. In response to stem attack by the European corn borer (Ostrinia nubilalis) and fungi, we observed the induced accumulation of six ent-kaurane-related diterpenoids, collectively termed kauralexins. Isolation and identification of the predominant Rhizopus microsporus-induced metabolites revealed ent-kaur-19-al-17-oic acid and the unique analog ent-kaur-15-en-19-al-17-oic acid, assigned as kauralexins A3 and B3, respectively. Encoding an ent-copalyl diphosphate synthase, fungal-induced An2 transcript accumulation precedes highly localized kauralexin production, which can eventually exceed 100 μg · g(-1) fresh weight. Pharmacological applications of jasmonic acid and ethylene also synergize the induced accumulation of kauralexins. Occurring at elevated levels in the scutella of all inbred lines examined, kauralexins appear ubiquitous in maize. At concentrations as low as 10 μg · mL(-1), kauralexin B3 significantly inhibited the growth of the opportunistic necrotroph R. microsporus and the causal agent of anthracnose stalk rot, Colletotrichum graminicola. Kauralexins also exhibited significant O. nubilalis antifeedant activity. Our work establishes the presence of diterpenoid defenses in maize and enables a more detailed analysis of their biosynthetic pathways, regulation, and crop defense function.

  20. Involvement of lipid rafts in adhesion-induced activation of Met and EGFR

    Directory of Open Access Journals (Sweden)

    Lu Ying-Che

    2011-10-01

    Full Text Available Abstract Background Cell adhesion has been shown to induce activation of certain growth factor receptors in a ligand-independent manner. However, the mechanism for such activation remains obscure. Methods Human epidermal carcinoma A431 cells were used as a model to examine the mechanism for adhesion-induced activation of hepatocyte growth factor receptor Met and epidermal growth factor receptor (EGFR. The cells were suspended and replated on culture dishes under various conditions. The phosphorylation of Met at Y1234/1235 and EGFR at Y1173 were used as indicators for their activation. The distribution of the receptors and lipid rafts on the plasma membrane were visualized by confocal fluorescent microscopy and total internal reflection microscopy. Results We demonstrate that Met and EGFR are constitutively activated in A431 cells, which confers proliferative and invasive potentials to the cells. The ligand-independent activation of Met and EGFR in A431 cells relies on cell adhesion to a substratum, but is independent of cell spreading, extracellular matrix proteins, and substratum stiffness. This adhesion-induced activation of Met and EGFR cannot be attributed to Src activation, production of reactive oxygen species, and the integrity of the cytoskeleton. In addition, we demonstrate that Met and EGFR are independently activated upon cell adhesion. However, partial depletion of Met and EGFR prevents their activation upon cell adhesion, suggesting that overexpression of the receptors is a prerequisite for their self-activation upon cell adhesion. Although Met and EGFR are largely distributed in 0.04% Triton-insoluble fractions (i.e. raft fraction, their activated forms are detected mainly in 0.04% Triton-soluble fractions (i.e. non-raft fraction. Upon cell adhesion, lipid rafts are accumulated at the cell surface close to the cell-substratum interface, while Met and EGFR are mostly excluded from the membrane enriched by lipid rafts. Conclusions

  1. Different activation signals induce distinct mast cell degranulation strategies

    Science.gov (United States)

    Sibilano, Riccardo; Marichal, Thomas; Reber, Laurent L.; Cenac, Nicolas; McNeil, Benjamin D.; Dong, Xinzhong; Hernandez, Joseph D.; Sagi-Eisenberg, Ronit; Hammel, Ilan; Roers, Axel; Valitutti, Salvatore; Tsai, Mindy

    2016-01-01

    Mast cells (MCs) influence intercellular communication during inflammation by secreting cytoplasmic granules that contain diverse mediators. Here, we have demonstrated that MCs decode different activation stimuli into spatially and temporally distinct patterns of granule secretion. Certain signals, including substance P, the complement anaphylatoxins C3a and C5a, and endothelin 1, induced human MCs rapidly to secrete small and relatively spherical granule structures, a pattern consistent with the secretion of individual granules. Conversely, activating MCs with anti-IgE increased the time partition between signaling and secretion, which was associated with a period of sustained elevation of intracellular calcium and formation of larger and more heterogeneously shaped granule structures that underwent prolonged exteriorization. Pharmacological inhibition of IKK-β during IgE-dependent stimulation strongly reduced the time partition between signaling and secretion, inhibited SNAP23/STX4 complex formation, and switched the degranulation pattern into one that resembled degranulation induced by substance P. IgE-dependent and substance P–dependent activation in vivo also induced different patterns of mouse MC degranulation that were associated with distinct local and systemic pathophysiological responses. These findings show that cytoplasmic granule secretion from MCs that occurs in response to different activating stimuli can exhibit distinct dynamics and features that are associated with distinct patterns of MC-dependent inflammation. PMID:27643442

  2. The influence of experimentally induced pain on shoulder muscle activity.

    Science.gov (United States)

    Diederichsen, Louise Pyndt; Winther, Annika; Dyhre-Poulsen, Poul; Krogsgaard, Michael R; Nørregaard, Jesper

    2009-04-01

    Muscle function is altered in painful shoulder conditions. However, the influence of shoulder pain on muscle coordination of the shoulder has not been fully clarified. The aim of the present study was to examine the effect of experimentally induced shoulder pain on shoulder muscle function. Eleven healthy men (range 22-27 years), with no history of shoulder or cervical problems, were included in the study. Pain was induced by 5% hypertonic saline injections into the supraspinatus muscle or subacromially. Seated in a shoulder machine, subjects performed standardized concentric abduction (0 degrees -105 degrees) at a speed of approximately 120 degrees/s, controlled by a metronome. During abduction, electromyographic (EMG) activity was recorded by intramuscular wire electrodes inserted in two deeply located shoulder muscles and by surface-electrodes over six superficially located shoulder muscles. EMG was recorded before pain, during pain and after pain had subsided and pain intensity was continuously scored on a visual analog scale (VAS). During abduction, experimentally induced pain in the supraspinatus muscle caused a significant decrease in activity of the anterior deltoid, upper trapezius and the infraspinatus and an increase in activity of lower trapezius and latissimus dorsi muscles. Following subacromial injection a significantly increased muscle activity was seen in the lower trapezius, the serratus anterior and the latissimus dorsi muscles. In conclusion, this study shows that acute pain both subacromially and in the supraspinatus muscle modulates coordination of the shoulder muscles during voluntary movements. During painful conditions, an increased activity was detected in the antagonist (latissimus), which support the idea that localized pain affects muscle activation in a way that protects the painful structure. Further, the changes in muscle activity following subacromial pain induction tend to expand the subacromial space and thereby decrease the load

  3. Etoposide Induces ATM-Dependent Mitochondrial Biogenesis through AMPK Activation

    Science.gov (United States)

    Lyu, Yi Lisa; Liu, Leroy F.; Qi, Haiyan

    2008-01-01

    Background DNA damage such as double-stranded DNA breaks (DSBs) has been reported to stimulate mitochondrial biogenesis. However, the underlying mechanism is poorly understood. The major player in response to DSBs is ATM (ataxia telangiectasia mutated). Upon sensing DSBs, ATM is activated through autophosphorylation and phosphorylates a number of substrates for DNA repair, cell cycle regulation and apoptosis. ATM has been reported to phosphorylate the α subunit of AMP-activated protein kinase (AMPK), which senses AMP/ATP ratio in cells, and can be activated by upstream kinases. Here we provide evidence for a novel role of ATM in mitochondrial biogenesis through AMPK activation in response to etoposide-induced DNA damage. Methodology/Principal Findings Three pairs of human ATM+ and ATM- cells were employed. Cells treated with etoposide exhibited an ATM-dependent increase in mitochondrial mass as measured by 10-N-Nonyl-Acridine Orange and MitoTracker Green FM staining, as well as an increase in mitochondrial DNA content. In addition, the expression of several known mitochondrial biogenesis regulators such as the major mitochondrial transcription factor NRF-1, PGC-1α and TFAM was also elevated in response to etoposide treatment as monitored by RT-PCR. Three pieces of evidence suggest that etoposide-induced mitochondrial biogenesis is due to ATM-dependent activation of AMPK. First, etoposide induced ATM-dependent phosphorylation of AMPK α subunit at Thr172, indicative of AMPK activation. Second, inhibition of AMPK blocked etoposide-induced mitochondrial biogenesis. Third, activation of AMPK by AICAR (an AMP analogue) stimulated mitochondrial biogenesis in an ATM-dependent manner, suggesting that ATM may be an upstream kinase of AMPK in the mitochondrial biogenesis pathway. Conclusions/Significance These results suggest that activation of ATM by etoposide can lead to mitochondrial biogenesis through AMPK activation. We propose that ATM-dependent mitochondrial

  4. Etoposide induces ATM-dependent mitochondrial biogenesis through AMPK activation.

    Directory of Open Access Journals (Sweden)

    Xuan Fu

    Full Text Available BACKGROUND: DNA damage such as double-stranded DNA breaks (DSBs has been reported to stimulate mitochondrial biogenesis. However, the underlying mechanism is poorly understood. The major player in response to DSBs is ATM (ataxia telangiectasia mutated. Upon sensing DSBs, ATM is activated through autophosphorylation and phosphorylates a number of substrates for DNA repair, cell cycle regulation and apoptosis. ATM has been reported to phosphorylate the alpha subunit of AMP-activated protein kinase (AMPK, which senses AMP/ATP ratio in cells, and can be activated by upstream kinases. Here we provide evidence for a novel role of ATM in mitochondrial biogenesis through AMPK activation in response to etoposide-induced DNA damage. METHODOLOGY/PRINCIPAL FINDINGS: Three pairs of human ATM+ and ATM- cells were employed. Cells treated with etoposide exhibited an ATM-dependent increase in mitochondrial mass as measured by 10-N-Nonyl-Acridine Orange and MitoTracker Green FM staining, as well as an increase in mitochondrial DNA content. In addition, the expression of several known mitochondrial biogenesis regulators such as the major mitochondrial transcription factor NRF-1, PGC-1alpha and TFAM was also elevated in response to etoposide treatment as monitored by RT-PCR. Three pieces of evidence suggest that etoposide-induced mitochondrial biogenesis is due to ATM-dependent activation of AMPK. First, etoposide induced ATM-dependent phosphorylation of AMPK alpha subunit at Thr172, indicative of AMPK activation. Second, inhibition of AMPK blocked etoposide-induced mitochondrial biogenesis. Third, activation of AMPK by AICAR (an AMP analogue stimulated mitochondrial biogenesis in an ATM-dependent manner, suggesting that ATM may be an upstream kinase of AMPK in the mitochondrial biogenesis pathway. CONCLUSIONS/SIGNIFICANCE: These results suggest that activation of ATM by etoposide can lead to mitochondrial biogenesis through AMPK activation. We propose that ATM

  5. Protein kinase C-associated kinase regulates NF-κB activation through inducing IKK activation.

    Science.gov (United States)

    Kim, Sang-Woo; Schifano, Matthew; Oleksyn, David; Jordan, Craig T; Ryan, Daniel; Insel, Richard; Zhao, Jiyong; Chen, Luojing

    2014-10-01

    Activation of the transcription factor NF-κB induced by extracellular stimuli requires IKKα and IKKβ kinase activity. How IKKα and IKKβ are activated by various upstream signaling molecules is not fully understood. We previously showed that protein kinase C-associated kinase (PKK, also known as DIK/RIP4), which belongs to the receptor-interacting protein (RIP) kinase family, mediates the B cell activating factor of the TNF family (BAFF)-induced NF-κB activation in diffuse large B cell lymphoma (DLBCL) cell lines. Here we have investigated the mechanism underlying NF-κB activation regulated by PKK. Our results suggest that PKK can activate both the classical and the alternative NF-κB activation pathways. PKK associates with IKKα and IKKβ in mammalian cells and induces activation of both IKKα and IKKβ via phosphorylation of their serine residues 176/180 and 177/181, respectively. Unlike other members of the RIP family that activate NF-κB through a kinase-independent pathway, PKK appears to activate IKK and NF-κB mainly in a kinase-dependent manner. Suppression of PKK expression by RNA interference inhibits phosphorylation of IKKα and IKKβ as well as activation of NF-κB in human cancer cell lines. Thus, PKK regulates NF-κB activation by modulating activation of IKKα and IKKβ in mammalian cells. We propose that PKK may provide a critical link between IKK activation and various upstream signaling cascades, and may represent a potential target for inhibiting abnormal NF-κB activation in human cancers.

  6. Acetaminophen induces human neuroblastoma cell death through NFKB activation.

    Directory of Open Access Journals (Sweden)

    Inmaculada Posadas

    Full Text Available Neuroblastoma resistance to apoptosis may contribute to the aggressive behavior of this tumor. Therefore, it would be relevant to activate endogenous cellular death mechanisms as a way to improve neuroblastoma therapy. We used the neuroblastoma SH-SY5Y cell line as a model to study the mechanisms involved in acetaminophen (AAP-mediated toxicity by measuring CYP2E1 enzymatic activity, NFkB p65 subunit activation and translocation to the nucleus, Bax accumulation into the mitochondria, cytochrome c release and caspase activation. AAP activates the intrinsic death pathway in the SH-SY5Y human neuroblastoma cell line. AAP metabolism is partially responsible for this activation, because blockade of the cytochrome CYP2E1 significantly reduced but did not totally prevent, AAP-induced SH-SY5Y cell death. AAP also induced NFkB p65 activation by phosphorylation and its translocation to the nucleus, where NFkB p65 increased IL-1β production. This increase contributed to neuroblastoma cell death through a mechanism involving Bax accumulation into the mitochondria, cytochrome c release and caspase3 activation. Blockade of NFkB translocation to the nucleus by the peptide SN50 prevented AAP-mediated cell death and IL-1β production. Moreover, overexpression of the antiapoptotic protein Bcl-x(L did not decrease AAP-mediated IL-1β production, but prevented both AAP and IL-1β-mediated cell death. We also confirmed the AAP toxic actions on SK-N-MC neuroepithelioma and U87MG glioblastoma cell lines. The results presented here suggest that AAP activates the intrinsic death pathway in neuroblastoma cells through a mechanism involving NFkB and IL-1β.

  7. Tau oligomers and fibrils induce activation of microglial cells.

    Science.gov (United States)

    Morales, Inelia; Jiménez, José M; Mancilla, Marcela; Maccioni, Ricardo B

    2013-01-01

    Neuroinflammation is a process related to the onset of several neurodegenerative disorders, including Alzheimer's disease (AD). Increasing sets of evidence support the major role of deregulation of the interaction patterns between glial cells and neurons in the pathway toward neuronal degeneration, a process we are calling neuroimmunomodulation in AD. On the basis of the hypothesis that pathological tau aggregates induce microglial activation with the subsequent events of the neuroinflammatory cascade, we have studied the effects of tau oligomeric species and filamentous structures over microglial cells in vitro. Tau oligomers and fibrils were induced by arachidonic acid and then their actions assayed upon addition to microglial cells. We showed activation of the microglia, with significant morphological alterations as analyzed by immunofluorescence. The augmentation of nitrites and the proinflammatory cytokine IL-6 was evaluated in ELISA assays. Furthermore, conditioned media of stimulated microglia cells were exposed to hippocampal neurons generating altered patterns in these cells, including shortening of neuritic processes and cytoskeleton reorganization.

  8. Evidence for Planet-induced Chromospheric Activity on HD 179949

    CERN Document Server

    Shkolnik, E; Bohlender, D A; Shkolnik, Evgenya; Walker, Gordon A.H.; Bohlender, David A.

    2003-01-01

    We have detected the synchronous enhancement of Ca II H & K emission with the short-period planetary orbit in HD 179949. High-resolution spectra taken on three observing runs extending more than a year show the enhancement coincides with phi ~ 0 (the sub-planetary point) of the 3.093-day orbit with the effect persisting for more than 100 orbits. The synchronous enhancement is consistent with planet-induced chromospheric heating by magnetic rather than tidal interaction. Something which can only be confirmed by further observations. Independent observations are needed to determine whether the stellar rotation is sychronous with the planet's orbit. Of the five 51 Peg-type systems monitored, HD 179949 shows the greatest chromospheric H & K activity. Three others show significant nightly variations but the lack of any phase coherence prevents us saying whether the activity is induced by the planet. Our two standards, tau Ceti and the Sun, show no such nightly variations.

  9. Antioxidant activity of simvastatin prevents ifosfamide-induced nephrotoxicity.

    Science.gov (United States)

    Mhaidat, Nizar Mahmoud; Ali, Reem Mustafa; Shotar, Ali Muhammad; Alkaraki, Almuthanna Khalaf

    2016-03-01

    Ifosfamide is an anticancer agent used largely in treatment of solid tumors. The mainstay dose-limiting toxicity of ifosfamide is nephrotoxicity. This is largely believde to be a result of ifosfamide-induced oxidative stress. In this study, we investigated the antioxidant activity of simvastatin and the possible protective role of simvastatin against ifosfamide induced nephrotoxicity. Thirty Sprague-Dawely rats were divided into five groups and given orally different drug combinations. Group I and II were regarded as control groups and received 0.1% DMSO and normal saline, respectively. Group III received ifosfamide at 50 mg/kg, group IV received simvastatin at 0.3 mg/kg and group V received both ifosfamide and simvastatin. All animals were decapitated 2 days after the last ifosfamide administration. Findings revealed that ifosfamide induced nephrotoxicity as indicated by a significant increase in plasma creatinine and lipid per oxidation. This increase was significantly inhibited in animals pretreated with simvastatin. Histopathological observations were in correlation with the biochemical parameters in that simvastatin minimized ifosfamide-induced renal tubular damage. The above results promote a future use of simvastatin in combination with ifosfamide in treatment of cancer patients to indicate that simvastatin protectics against ifosfamide-induced nephrotoxicity in terms of oxidative stress and might be given in combination.

  10. Overinhibition of Mitogen-Activated Protein Kinase Inducing Tau Hyperphosphorylation

    Institute of Scientific and Technical Information of China (English)

    LI Hong-lian; CHEN Juan; LIU Shi-jie; ZHANG Jia-yu; WANG Qun; WANG Jian-zhi

    2005-01-01

    To reveal the relationship between mitogen-activated protein kinase (MAPK) and tau phosphorylation, we used different concentration of PD98059, an inhibitor of MEK (MAPK kinase), to treat mice neuroblastma (N2a) cell line for 6 h. It showed that the activity of MAPK decreased in a dose-dependent manner. But Western blot and immunofluorescence revealed that just when the cells were treated with 16 μmol/L PD98059, tau was hyperphosphorylated at Ser396/404 and Ser199/202 sites. We obtained the conclusion that overinhibited MAPK induced tau hyperphosphorylation at Ser396/404 and Ser199/202 sites.

  11. Activation-induced cell death in B lymphocytes

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    Upon encountering the antigen (Ag), the immune system can either develop a specific immune response or enter a specific state of unresponsiveness, tolerance. The response of B cells to their specific Ag can be activation and proliferation, leading to the immune response, or anergy and activation-induced cell death (AICD), leading to tolerance. AICD in B lymphocytes is a highly regulated event initiated by crosslinking of the B cell receptor (BCR). BCR engagement initiates several signaling events such as activation of PLCγ, Ras, and PI3K, which generally speaking, lead to survival However, in the absence of survival signals (CD40 or IL-4R engagement), BCR crosslinking can also promote apoptotic signal transduction pathways such as activation of effector caspases, expression of pro-apoptotic genes, and inhibition of pro-survival genes. The complex interplay between survival and death signals determines the B cell fate and, consequently, the immune response.

  12. Interleukin-25 fails to activate STAT6 and induce alternatively activated macrophages.

    Science.gov (United States)

    Stolfi, Carmine; Caruso, Roberta; Franzè, Eleonora; Sarra, Massimiliano; De Nitto, Daniela; Rizzo, Angelamaria; Pallone, Francesco; Monteleone, Giovanni

    2011-01-01

    Interleukin-25 (IL-25), a T helper type 2 (Th2) -related factor, inhibits the production of inflammatory cytokines by monocytes/macrophages. Since Th2 cytokines antagonize classically activated monocytes/macrophages by inducing alternatively activated macrophages (AAMs), we here assessed the effect of IL-25 on the alternative activation of human monocytes/macrophages. The interleukins IL-25, IL-4 and IL-13 were effective in reducing the expression of inflammatory chemokines in monocytes. This effect was paralleled by induction of AAMs in cultures added with IL-4 or IL-13 but not with IL-25, regardless of whether cells were stimulated with lipopolysaccharide or interferon-γ. Moreover, pre-incubation of cells with IL-25 did not alter the ability of both IL-4 and IL-13 to induce AAMs. Both IL-4 and IL-13 activated signal transducer and activator of transcription 6 (STAT6), and silencing of this transcription factor markedly reduced the IL-4/IL-13-driven induction of AAMs. In contrast, IL-25 failed to trigger STAT6 activation. Among Th2 cytokines, only IL-25 and IL-10 were able to activate p38 mitogen-activated protein kinase. These results collectively indicate that IL-25 fails to induce AAMs and that Th2-type cytokines suppress inflammatory responses in human monocytes by activating different intracellular signalling pathways.

  13. Tandem halogenation/Michael-initiated ring-closing reaction of α,β-unsaturated nitriles and activated methylene compounds: one-pot diastereoselective synthesis of functionalized cyclopropanes.

    Science.gov (United States)

    Xin, Xiaoqing; Zhang, Qian; Liang, Yongjiu; Zhang, Rui; Dong, Dewen

    2014-04-21

    An efficient one-pot synthetic route to highly substituted cyclopropanes has been developed from readily available α,β-unsaturated nitriles and doubly activated methylene compounds under very mild conditions in a highly diastereoselective manner, which involves halogenation, Michael addition and intramolecular ring-closing reaction sequences.

  14. Creatine kinase activity in dogs with experimentally induced acute inflammation

    Directory of Open Access Journals (Sweden)

    Dimitrinka Zapryanova

    2013-01-01

    Full Text Available The main purpose of this study was to investigate the effect of acute inflammation on total creatine kinase (CK activity in dogs. In these animals, CK is an enzyme found predominantly in skeletal muscle and significantly elevated serum activity is largely associated with muscle damage. Plasma increases in dogs are associated with cell membrane leakage and will therefore be seen in any condition associated with muscular inflammation. The study was induced in 15 mongrel male dogs (n=9 in experimental group and n=6 in control group at the age of two years and body weight 12-15 kg. The inflammation was reproduced by inoculation of 2 ml turpentine oil subcutaneously in lumbar region. The plasma activity of creatine kinase was evaluated at 0, 6, 24, 48, 72 hours after inoculation and on days 7, 14 and 21 by a kit from Hospitex Diagnostics. In the experimental group, the plasma concentrations of the CK-activity were increased at the 48th hour (97.48±6.92 U/L and remained significantly higher (p<0.05 at the 72 hour (97.43±2.93 U/L compared to the control group (77.08±5.27 U/L. The results of this study suggest that the evaluation of creatine kinase in dogs with experimentally induced acute inflammation has a limited diagnostic value. It was observed that the creatine kinase activity is slightly affected by the experimentally induced acute inflammation in dogs.

  15. Bullous pemphigoid autoantibodies directly induce blister formation without complement activation.

    Science.gov (United States)

    Ujiie, Hideyuki; Sasaoka, Tetsumasa; Izumi, Kentaro; Nishie, Wataru; Shinkuma, Satoru; Natsuga, Ken; Nakamura, Hideki; Shibaki, Akihiko; Shimizu, Hiroshi

    2014-11-01

    Complement activation and subsequent recruitment of inflammatory cells at the dermal/epidermal junction are thought to be essential for blister formation in bullous pemphigoid (BP), an autoimmune blistering disease induced by autoantibodies against type XVII collagen (COL17); however, this theory does not fully explain the pathological features of BP. Recently, the involvement of complement-independent pathways has been proposed. To directly address the question of the necessity of the complement activation in blister formation, we generated C3-deficient COL17-humanized mice. First, we show that passive transfer of autoantibodies from BP patients induced blister formation in neonatal C3-deficient COL17-humanized mice without complement activation. By using newly generated human and murine mAbs against the pathogenic noncollagenous 16A domain of COL17 with high (human IgG1, murine IgG2), low (murine IgG1), or no (human IgG4) complement activation abilities, we demonstrate that the deposition of Abs, and not complements, is relevant to the induction of blister formation in neonatal and adult mice. Notably, passive transfer of BP autoantibodies reduced the amount of COL17 in lesional mice skin, as observed in cultured normal human keratinocytes treated with the same Abs. Moreover, the COL17 depletion was associated with a ubiquitin/proteasome pathway. In conclusion, the COL17 depletion induced by BP autoantibodies, and not complement activation, is essential for the blister formation under our experimental system. Copyright © 2014 by The American Association of Immunologists, Inc.

  16. Active harmonic filtering using current-controlled, grid-connected DG units with closed-loop power control

    DEFF Research Database (Denmark)

    He, Jinwei; Li, Yun Wei; Blaabjerg, Frede

    2014-01-01

    voltage detection are not necessary for the proposed harmonic compensation method. Moreover, a closed-loop power control scheme is employed to directly derive the fundamental current reference without using any phase-locked loops (PLL). The proposed power control scheme effectively eliminates the impacts...

  17. Activation-induced cytidine deaminase induces reproducible DNA breaks at many non-Ig Loci in activated B cells.

    Science.gov (United States)

    Staszewski, Ori; Baker, Richard E; Ucher, Anna J; Martier, Raygene; Stavnezer, Janet; Guikema, Jeroen E J

    2011-01-21

    After immunization or infection, activation-induced cytidine deaminase (AID) initiates diversification of immunoglobulin (Ig) genes in B cells, introducing mutations within the antigen-binding V regions (somatic hypermutation, SHM) and double-strand DNA breaks (DSBs) into switch (S) regions, leading to antibody class switch recombination (CSR). We asked if, during B cell activation, AID also induces DNA breaks at genes other than IgH genes. Using a nonbiased genome-wide approach, we have identified hundreds of reproducible, AID-dependent DSBs in mouse splenic B cells shortly after induction of CSR in culture. Most interestingly, AID induces DSBs at sites syntenic with sites of translocations, deletions, and amplifications found in human B cell lymphomas, including within the oncogene B cell lymphoma11a (bcl11a)/evi9. Unlike AID-induced DSBs in Ig genes, genome-wide AID-dependent DSBs are not restricted to transcribed regions and frequently occur within repeated sequence elements, including CA repeats, non-CA tandem repeats, and SINEs.

  18. Inhibitory Effects of Ecklonia cava Extract on High Glucose-Induced Hepatic Stellate Cell Activation

    Directory of Open Access Journals (Sweden)

    Akiko Kojima-Yuasa

    2011-12-01

    Full Text Available Nonalcoholic steatohepatitis (NASH is a disease closely associated with obesity and diabetes. A prevalence of type 2 diabetes and a high body mass index in cryptogenic cirrhosis may imply that obesity leads to cirrhosis. Here, we examined the effects of an extract of Ecklonia cava, a brown algae, on the activation of high glucose-induced hepatic stellate cells (HSCs, key players in hepatic fibrosis. Isolated HSCs were incubated with or without a high glucose concentration. Ecklonia cava extract (ECE was added to the culture simultaneously with the high glucose. Treatment with high glucose stimulated expression of type I collagen and α-smooth muscle actin, which are markers of activation in HSCs, in a dose-dependent manner. The activation of high glucose-treated HSCs was suppressed by the ECE. An increase in the formation of intracellular reactive oxygen species (ROS and a decrease in intracellular glutathione levels were observed soon after treatment with high glucose, and these changes were suppressed by the simultaneous addition of ECE. High glucose levels stimulated the secretion of bioactive transforming growth factor-β (TGF-β from the cells, and the stimulation was also suppressed by treating the HSCs with ECE. These results suggest that the suppression of high glucose-induced HSC activation by ECE is mediated through the inhibition of ROS and/or GSH and the downregulation of TGF-β secretion. ECE is useful for preventing the development of diabetic liver fibrosis.

  19. Investigation of induced recrystallization and stress in close-spaced sublimated and radio-frequency magnetron sputtered CdTe thin films

    Energy Technology Data Exchange (ETDEWEB)

    Moutinho, H.R.; Dhere, R.G.; Al-Jassim, M.M.; Levi, D.H.; Kazmerski, L.L. [National Renewable Energy Laboratory, 1617 Cole Boulevard, Golden, Colorado 80401 (United States)

    1999-07-01

    We have induced recrystallization of small grain CdTe thin films deposited at low temperatures by close-spaced sublimation (CSS), using a standard CdCl{sub 2} annealing treatment. We also studied the changes in the physical properties of CdTe films deposited by radio-frequency magnetron sputtering after the same post-deposition processing. We demonstrated that the effects of CdCl{sub 2} on the physical properties of CdTe films are similar, and independent of the deposition method. The recrystallization process is linked directly to the grain size and stress in the films. These studies indicated the feasibility of using lower-temperature processes in fabricating efficient CSS CdTe solar cells. We believe that, after the optimization of the parameters of the chemical treatment, these films can attain a quality similar to CSS films grown using current standard conditions. {copyright} {ital 1999 American Vacuum Society.}

  20. A closed concept of extractive whole cell microbial transformation of benzaldehyde into L-phenylacetylcarbinol by Saccharomyces cerevisiae in novel polyethylene-glycol-induced cloud-point system.

    Science.gov (United States)

    Wang, Zhilong; Liang, Rui; Xu, Jian-He; Liu, Yubo; Qi, Hanshi

    2010-03-01

    Extractive microbial transformation of benzaldehyde into L-phenylacetylcarbinol (L-PAC) by Saccharomyces cerevisiae (Baker's yeast) has been carried out in a novel polyethylene-glycol-induced cloud-point system (PEG-CPS). The extractive microbial transformation in the PEG-CPS and a downstream process for stripping of the product from the microbial transformation broth with microemulsion extraction are demonstrated. The results indicate that the PEG-CPS maintains the advantage of CPS for in situ extraction of polar product in the microbial transformation. At the same time, the utilization of hydrophilic nonionic surfactant in the PEG-CPS is favorable for stripping of product from the nonionic surfactant in the microbial transformation broth by Winsor I microemulsion extraction. Thus, a closed concept of in situ extraction of polar product in microbial transformation and its downstream process of product recovery are fulfilled at the same time.

  1. Passive vs. active touch-induced activity in the developing whisker pathway.

    Science.gov (United States)

    Mosconi, Tony; Woolsey, Thomas A; Jacquin, Mark F

    2010-10-01

    The mouse trigeminal (V) system undergoes significant postnatal structural and functional developmental changes. Histological modules (barrelettes, barreloids and barrels) in the brainstem, thalamus and cortex related to actively moved (whisking) tactile hairs (vibrissae) on the face allow detailed studies of development. High-resolution [(3) H]2-deoxyglucose (2DG) emulsion autoradiography with cytochrome oxidase histochemistry was used to analyze neuronal activity changes related to specific whisker modules in the developing and mature mouse V system provoked by passive (experimenter-induced) and active (animal-induced) displacements of a single whisker (D4). We tested the hypothesis that neuronal activity patterns change in relation to the onset of active touch (whisking) on postnatal day (P)14. Quantitative image analyses revealed: (i) on P7, when whisker-like patterns of modules are clear, heightened 2DG activity in all appropriate modules in the brainstem, thalamus and cortex; (ii) on P14, a transitory activity pattern coincident with the emergence of whisking behavior that presages (iii) strong labeling of the spinal V subnucleus interpolaris and barrel cortex produced by single-whisker-mediated active touch in adults and (iv) at all above-listed ages and structures, significant suppression of baseline activity in some modules surrounding those representing the stimulated whisker. Differences in activity patterns before and after the onset of whisking behavior may be caused by neuronal activity induced by whisking, and by strengthening of modulatory projections that alter the activity of subcortical inputs produced by whisking behavior during active touch. © 2010 The Authors. European Journal of Neuroscience © 2010 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

  2. GP130 activation induces myeloma and collaborates with MYC

    Science.gov (United States)

    Dechow, Tobias; Steidle, Sabine; Götze, Katharina S.; Rudelius, Martina; Behnke, Kerstin; Pechloff, Konstanze; Kratzat, Susanne; Bullinger, Lars; Fend, Falko; Soberon, Valeria; Mitova, Nadya; Li, Zhoulei; Thaler, Markus; Bauer, Jan; Pietschmann, Elke; Albers, Corinna; Grundler, Rebekka; Schmidt-Supprian, Marc; Ruland, Jürgen; Peschel, Christian; Duyster, Justus; Rose-John, Stefan; Bassermann, Florian; Keller, Ulrich

    2014-01-01

    Multiple myeloma (MM) is a plasma cell neoplasm that results from clonal expansion of an Ig-secreting terminally differentiated B cell. Advanced MM is characterized by tissue damage that involves bone, kidney, and other organs and is typically associated with recurrent genetic abnormalities. IL-6 signaling via the IL-6 signal transducer GP130 has been implicated as an important driver of MM pathogenesis. Here, we demonstrated that ectopic expression of constitutively active GP130 (L-GP130) in a murine retroviral transduction-transplantation model induces rapid MM development of high penetrance. L-GP130–expressing mice recapitulated all of the characteristics of human disease, including monoclonal gammopathy, BM infiltration with lytic bone lesions, and protein deposition in the kidney. Moreover, the disease was easily transplantable and allowed different therapeutic options to be evaluated in vitro and in vivo. Using this model, we determined that GP130 signaling collaborated with MYC to induce MM and was responsible and sufficient for directing the plasma cell phenotype. Accordingly, we identified Myc aberrations in the L-GP130 MM model. Evaluation of human MM samples revealed recurrent activation of STAT3, a downstream target of GP130 signaling. Together, our results indicate that deregulated GP130 activity contributes to MM pathogenesis and that pathways downstream of GP130 activity have potential as therapeutic targets in MM. PMID:25384216

  3. Ginsenoside Rb1 attenuates activated microglia-induced neuronal damage

    Institute of Scientific and Technical Information of China (English)

    Lining Ke; Wei Guo; Jianwen Xu; Guodong Zhang; Wei Wang; Wenhua Huang

    2014-01-01

    The microglia-mediated inlfammatory reaction promotes neuronal damage under cerebral isch-emia/hypoxia conditions. We therefore speculated that inhibition of hypoxia-induced microglial activation may alleviate neuronal damage. To test this hypothesis, we co-cultured ginsenoside Rb1, an active component of ginseng, and cortical neurons. Ginsenoside Rb1 protected neuronal morphology and structure in a single hypoxic culture system and in a hypoxic co-culture system with microglia, and reduced neuronal apoptosis and caspase-3 production. The protective effect was observable prior to placing in co-culture. Additionally, ginsenoside Rb1 inhibited levels of tumor necrosis factor-αin a co-culture system containing activated N9 microglial cells. Ginse-noside Rb1 also signiifcantly decreased nitric oxide and superoxide production induced by N9 microglia. Our ifndings indicate that ginsenoside Rb1 attenuates damage to cerebral cortex neu-rons by downregulation of nitric oxide, superoxide, and tumor necrosis factor-αexpression in hypoxia-activated microglia.

  4. Copper is required for cobalt-induced transcriptional activity of hypoxia-inducible factor-1.

    Science.gov (United States)

    Qiu, Liying; Ding, Xueqin; Zhang, Zhen; Kang, Y James

    2012-08-01

    Cobalt inhibits prolyl hydroxylases, leading to the accumulation of hypoxia-inducible factor-1α (HIF-1α) and a concomitant increase in the transcriptional activity of HIF-1. Therefore, cobalt has been under development as a drug for activating HIF-1 under some disease conditions. However, it has been shown that ischemic conditions resulted in the loss of copper, and the activation of HIF-1 would not occur unless copper was supplemented. The present study was undertaken to test the hypothesis that copper is also required for the cobalt activation of HIF-1 transcriptional activity. Human umbilical vein endothelial cells subjected to treatment with cobalt chloride (CoCl(2)) at concentrations above 25 μM for 2 h resulted in an accumulation of HIF-1α, which was determined by Western blot analysis, and an increase in the expression of vascular endothelial growth factor (VEGF), which was determined by real-time reverse transcription-polymerase chain reaction analysis for mRNA levels and enzyme-linked immunosorbent assay analysis for protein levels. The copper chelator tetraethylenepentamine at 25 μM did not significantly affect the accumulation of HIF-1α but blocked increases in VEGF mRNA and protein levels, an effect that could be reversed by the addition of 25 μM copper sulfate (CuSO(4)). In addition, gene silencing of the copper chaperone for Cu,Zn-superoxide dismutase blocked VEGF expression with little effect on cobalt-induced HIF-1α accumulation. The present study thus demonstrates that copper was required for cobalt-activated transcriptional activity of HIF-1, although copper did not affect cobalt-induced accumulation of HIF-1α in the cells.

  5. Platelet-Activating Factor Induces Th17 Cell Differentiation

    Directory of Open Access Journals (Sweden)

    Anne-Marie Drolet

    2011-01-01

    Full Text Available Th17 cells have been implicated in a number of inflammatory and autoimmune diseases. The phospholipid mediator platelet-activating factor (PAF is found in increased concentrations in inflammatory lesions and has been shown to induce IL-6 production. We investigated whether PAF could affect the development of Th17 cells. Picomolar concentrations of PAF induced IL-23, IL-6, and IL-1β expression in monocyte-derived Langerhans cells (LCs and in keratinocytes. Moreover, when LC were pretreated with PAF and then cocultured with anti-CD3- and anti-CD28-activated T cells, the latter developed a Th17 phenotype, with a significant increase in the expression of the transcriptional regulator RORγt and enhanced expression of IL-17, IL-21, and IL-22. PAF-induced Th17 development was prevented by the PAF receptor antagonist WEB2086 and by neutralizing antibodies to IL-23 and IL-6R. This may constitute a previously unknown stimulus for the development and persistence of inflammatory processes that could be amenable to pharmacologic intervention.

  6. CREB is activated in EPO induced HEL cells

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    cAMP response element binding protein (CREB) is a transcription factor in nucleus. The activating CREB can specifically bind to the cAMP response element (CRE). The present result showed that erythropoietin (EPO) could induce the phosphorylation of CREB on Serine133(Pser133), as detected by Western blot analysis. In addition, the EPO-dependent activation of CREB binding to CRE element was demonstrated by electrophoretic mobility shift assay. However, the binding of CREB to CRE element could be inhibited by anti-CREB-Pser133antibody. The data obtained suggested that the EPO-mediated CREB phosphorylation might be critical to both the binding of CREB to the CRE element and the activation of the CREB transcription factor.

  7. Closed-loop feedback control and bifurcation analysis of epileptiform activity via optogenetic stimulation in a mathematical model of human cortex

    Science.gov (United States)

    Selvaraj, Prashanth; Sleigh, Jamie W.; Kirsch, Heidi E.; Szeri, Andrew J.

    2016-01-01

    Optogenetics provides a method of neuron stimulation that has high spatial, temporal, and cell-type specificity. Here we present a model of optogenetic feedback control that targets the inhibitory population, which expresses light-sensitive channelrhodopsin-2 channels, in a mean-field model of undifferentiated cortex that is driven to seizures. The inhibitory population is illuminated with an intensity that is a function of electrode measurements obtained via the cortical model. We test the efficacy of this control method on seizurelike activity observed in two parameter spaces of the cortical model that most closely correspond to seizures observed in patients. We also compare the effect of closed-loop and open-loop control on seizurelike activity using a less-complicated ordinary differential equation model of the undifferentiated cortex in parameter space. Seizurelike activity is successfully suppressed in both parameter planes using optimal illumination intensities less likely to have adverse effects on cortical tissue.

  8. Dihydrotestosterone Potentiates EGF-Induced ERK Activation by Inducing SRC in Fetal Lung Fibroblasts

    Science.gov (United States)

    Smith, Susan M.; Murray, Sandy; Pham, Lucia D.; Minoo, Parviz; Nielsen, Heber C.

    2014-01-01

    Lung maturation is regulated by interactions between mesenchymal and epithelial cells, and is delayed by androgens. Fibroblast–Type II cell communications are dependent on extracellular signal-regulated kinases (ERK) 1/2 activation by the ErbB receptor ligands epidermal growth factor (EGF), transforming growth factor (TGF)-α, and neuregulin (Nrg). In other tissues, dihydrotestosterone (DHT) has been shown to activate SRC by a novel nontranscriptional mechanism, which phosphorylates EGF receptors to potentiate EGF-induced ERK1/2 activation. This study sought to determine if DHT potentiates EGFR signaling by a nontranscriptional mechanism. Embryonic day (E)17 fetal lung cells were isolated from dams treated with or without DHT since E12. Cells were exposed to 30 ng/ml DHT for periods of 30 minutes to 3 days before being stimulated with 100 ng/ml EGF, TGF-α, or Nrg for up to 30 minutes. Lysates were immunoblotted for ErbB and SRC pathway signaling intermediates. DHT increased ERK1/2 activation by EGF, TGF-α, and Nrg in fibroblasts and Type II cells. Characterization in fibroblasts showed that potentiation of the EGF pathway was significant after 60 minutes of DHT exposure and persisted in the presence of the translational inhibitor cycloheximide. SRC and EGF receptor phosphorylation was increased by DHT, as was EGF-induced SHC1 phosphorylation and subsequent association with GRB2. Finally, SRC silencing, SRC inhibition with PP2, and overexpression of a dominant-negative SRC each prevented DHT from increasing EGF-induced ERK1/2 phosphorylation. These results suggest that DHT activates SRC to potentiate the signaling pathway leading from the EGF receptor to ERK activation in primary fetal lung fibroblasts. PMID:24484548

  9. Effect of low potassium concentration on cadmium induced epileptiform activity of leech retzius neurons

    Directory of Open Access Journals (Sweden)

    Milićević Nebojša

    2016-01-01

    Full Text Available Epilepsies have a large significance and require detailed investigation of cellular mechanisms that lead to this disorder. Environmental, especially industrial, toxins are having increasingly more prominent role in these investigations. The aim of our research was to investigate the significance of Cd2+ in generation of epileptiform electrical activity of neurons, and the role of Na+/K+ pump in mechanisms that lead to cessation of this activity. Experiments were performed on Retzius nerve cells of the leech Haemopis sanguisuga. Intracellularly placed microelectrodes were used to measure membrane potential changes upon administration of Cd2+ (100 µmol/l, and the same concentration of Cd2+ in low K+ (1 mmol/l solution. In our experiments Cd2+ led to generation of rhythmic repetitive oscillatory activity. This activity closely resembles paroxysmal depolarizing shifts (PDS which represent the cellular basis of epilepsy. Cd2+ induced epileptiform activity had the following characteristics: frequency of 3.9±0.8 PDS/minute, PDS duration of 4.0±0.3 s, and PDS amplitude of 8.1±0.7 mV. Cd2+ induces effects similar to those of Ni2+ and Co2+, but in 30 times smaller concentration. Application of Cd2+ in low K+ solution led to a significant reduction of PDS frequency (by 2.34±0.55 PDS/minute, p<0.05, Student's t-test, highly significant increase in PDS duration (by 2.84±0.23 s, p<0.01, Student's t-test and highly significant reduction in PDS amplitude (by 1.91±0.33 mV, p=0.01, Student's t-test. Our results show that Cd2+ is a potent initiator of epileptiform activity, and that Na+/K+ pump significantly affects this activity and has a potentially important role in mechanisms that lead to its cessation.

  10. Electron beam induced surface activation of oxide surfaces for nanofabrication

    Energy Technology Data Exchange (ETDEWEB)

    Vollnhals, Florian; Seiler, Steffen; Walz, Marie-Madeleine; Steinrueck, Hans-Peter; Marbach, Hubertus [Lehrstuhl fuer Physikalische Chemie II and Interdisciplinary Center for Molecular Materials (ICMM), Friedrich-Alexander-Universitaet Erlangen-Nuernberg, Erlangen (Germany); Woolcot, Tom; Thornton, Geoff [London Centre for Nanotechnology and Department of Chemistry, University College London (United Kingdom)

    2012-07-01

    The controlled fabrication of structures on the nanoscale is a major challenge in science and engineering. Direct-write techniques like Electron Beam Induced Deposition (EBID) were shown to be suitable tools in this context. Recently, Electron Beam Induced Surface Activation (EBISA) has been introduced as a new focused electron beam technique. In EBISA, a surface, e.g. SiO{sub 2}, is irradiated by a focused electron beam, resulting in an activation of the exposed area. The activated area can then react and decompose precursor gases like iron pentacarbonyl, Fe(CO){sub 5}. This leads to a primary deposit, which continues to grow autocatalytically as long as Fe(CO){sub 5} is supplied, resulting in pure (> 90 % at.), crystalline iron nanostructures. We expand the use of this concept by exploring EBISA to produce metallic nanostructures on TiO{sub 2}(110) in UHV; atomistic insight into the process is obtained via Scanning Tunneling Microscopy (STM) and chemical insight via Auger Electron Spectroscopy (AES).

  11. Catechin-induced activation of the LKB1/AMP-activated protein kinase pathway.

    Science.gov (United States)

    Murase, Takatoshi; Misawa, Koichi; Haramizu, Satoshi; Hase, Tadashi

    2009-07-01

    Catechins are abundant in green tea and induce a variety of biologic actions, including anti-cancer, anti-obesity, and anti-diabetes effects, and their clinical application has been widely investigated. To clarify the underlying molecular mechanisms of these actions, we examined the effect of catechins on AMP-activated protein kinase (AMPK) in cultured cells and in mice. In Hepa 1-6, L6, and 3T3-L1 cells, epigallocatechin gallate (EGCG) induced increases in AMPKalpha and the downstream target acetyl-CoA carboxylase (ACC) phosphorylation, and AMPKalpha activity. Analysis of the molecular specificity of eight naturally occurring catechins revealed that catechins with a gallocatechin moiety or a galloyl residue act as AMPK activators. In addition, phosphorylation of LKB1, which is a tumor-suppressor protein and a major AMPK-kinase, was increased by catechin treatment. EGCG-induced phosphorylation of LKB1 and AMPKalpha was suppressed by treatment with catalase, suggesting that reactive oxygen species are involved in EGCG-induced activation of the LKB1/AMPK pathway. Oral administration of EGCG (200mg/kg body weight) to BALB/c mice induced an increase in AMPKalpha activity in the liver concomitant with a significant increase in AMPKalpha and ACC phosphorylation. EGCG administration also increased oxygen consumption and fat oxidation, as determined by indirect calorimetry. These findings suggest that multiple effects of catechins, including anti-obesity and anti-cancer effects, are mediated, at least in part, by the activation of LKB1/AMPK in various tissues, and that these effects vary according to the catechin structure.

  12. Survivin S81A Enhanced TRAIL's Activity in Inducing Apoptosis

    Directory of Open Access Journals (Sweden)

    Ferry Sandra

    2010-12-01

    Full Text Available BACKGROUND: Survivin is rarely expressed in normal healthy adult tissues, however, it is upregulated in the majority of cancers. Survivin, which belongs to IAPs family, has been widely reported to protect cells from apoptosis by inhibiting caspases pathway. Survivin’s mitotic activity is modulated by many kinases, and its phosphor status can also influence its ability to inhibit apoptosis. There are several important survivin’s phosphorylation sites, such as S20 and T34. We have continued our investigation on other potential survivin’s phosphorylation sites that could be important site for regulating survivin’s cyto-protection. METHODS: By assuming that S81 could be a potential target to modify activity of survivin, wild-type survivin (Survivin, antisense survivin (Survivin-AS, mutated-survivin Thr34Ala (Survivin-T34A and mutated-survivin Ser81Ala (Survivin-S81A were constructed and inserted into pMSCV-IRES-GFP vector with cytomegalovirus (CMV promoter. Each retroviral product was produced in BOSC23 cells. LY294002 pretreatment and TRAIL treatment along with infection of retroviral products were performed in murine fibrosarcoma L929 cells. For analysis, flow cytometric apoptosis assay and western blot were performed. RESULTS: In our present study, survivin for providing cytoprotection was regulated by PI3K. The results showed that LY294002, an inhibitor of PI3K, effectively suppressed survivin-modulated cytoprotection in a TRAIL-induced apoptotic model. In addition, mutated survivin S81A showed marked suppression on survivin’s cytoprotection. Along with that, TRAIL’s apoptotic activity was enhanced for inducing apoptosis. CONCLUSIONS: We suggested that survivin could inhibit apoptosis through PI3K and S81A could be another potential target in order to inhibit Survivin-modulated cytoprotection as well as to sensitize efficacy of TRAIL or other related apoptotic inducers. KEYWORDS: apoptosis, survivin, TRAIL, S81A, L929, LY294002.

  13. New classification of landslide-inducing anthropogenic activities

    Science.gov (United States)

    Michoud, C.; Jaboyedoff, M.; Derron, M.-H.; Nadim, F.; Leroi, E.

    2012-04-01

    Although landslides are usually considered typical examples of natural hazards, they can be influenced by human activities. Many examples can be found in the literature about slope instabilities induced by anthropogenic activities, ranging from small superficial landslides to rock avalanches. Research on this topic is of primary importance for understanding and mitigation of landslide risk. Indeed, slope stabilities influenced by human actions contribute significantly to the risk level because, by definition, they are located where elements at risk and people are present. Within the framework of the European project SafeLand "Living with Landslide Risk in Europe", the authors analyzed the landslides induced by anthropogenic factors in Europe and elsewhere (SafeLand deliverable D1.6). During the bibliographical research, it appeared that a complete and illustrated classification on human activities influencing slope stabilities does not yet exist. Therefore, a new classification was introduced by Michoud et al. (2011) about anthropogenic activities affecting slope stability conditions. This classification takes into account conceptual processes leading to landslides (Terzaghi, 1950; Jaboyedoff and Derron, 2005) and the distinction between destabilization factors and triggering factors (Vaunat et al., 1994; Leroueil et al., 1996). The classification was tested and improved through fifty-eight well-documented case studies, even lots of large landslides, such as Elm, Aberfan, Namsos and Rissa landslides, etc. Furthermore, the boundary between natural and "anthropogenic" landslide triggers (e.g. water run-off modified by new land-uses, creating landslides some km farther), and the time during which changes and reactions are to be considered as direct consequences of human activities were highlighted. Finally, anthropogenic influences can also be positive and examples of (non-voluntary) positive human impacts on slope stability are presented. Jaboyedoff, M. and Derron, M

  14. Neutron distribution and induced activity inside a Linac treatment room.

    Science.gov (United States)

    Juste, B; Miró, R; Verdú, G; Díez, S; Campayo, J M

    2015-01-01

    Induced radioactivity and photoneutron contamination inside a radiation therapy bunker of a medical linear accelerator (Linac) is investigated in this work. The Linac studied is an Elekta Precise electron accelerator which maximum treatment photon energy is 15 MeV. This energy exceeds the photonuclear reaction threshold (around 7 MeV for high atomic number metals). The Monte Carlo code MCNP6 has been used for quantifying the neutron contamination inside the treatment room for different gantry rotation configuration. Walls activation processes have also been simulated. The approach described in this paper is useful to prevent the overexposure of patients and medical staff.

  15. Activation-Induced Cell Death in T Cells and Autoimmunity

    Institute of Scientific and Technical Information of China (English)

    Jian Zhang; Xuemei Xu; Yong Liu

    2004-01-01

    Activation-induced cell death (AICD), which results from the interaction between Fas and Fas ligand, is responsible for maintaining tolerance to self-antigen. A defect in AICD may lead to development of autoimmunity. During the last several years, much progress has been made in understanding the mechanism(s) of AICD and its potential role in the pathogenesis of autoimmune diseases. In this review, we summarize the most recent progress on the regulation of the susceptibility of T cells to AICD and its possible involvement in autoimmune diseases.

  16. Terpenoids from Diplophyllum taxifolium with quinone reductase-inducing activity.

    Science.gov (United States)

    Wang, Xiao; Zhang, Jiao-Zhen; Zhou, Jin-Chuan; Shen, Tao; Lou, Hong-Xiang

    2016-03-01

    Two new ent-prenylaromadendrane-type diterpenoids, diplotaxifols A (1) and B (2), a new ent-eudesmol, ent-eudesma-4(15),11(13)-dien-6α,12-diol (3), eight new eudesmanolides enantiomers (4-11) of the corresponding compounds from higher plants along with four known ent-eudesmanolides (12-15) were isolated from the 95% EtOH extract of Chinese liverwort Diplophyllum taxifolium. Their structures were elucidated on the basis of MS, NMR and IR spectral data, and confirmed by single-crystal X-ray diffraction analysis. The quinone reductase-inducing activity of the compounds was evaluated.

  17. LSD-induced entropic brain activity predicts subsequent personality change.

    Science.gov (United States)

    Lebedev, A V; Kaelen, M; Lövdén, M; Nilsson, J; Feilding, A; Nutt, D J; Carhart-Harris, R L

    2016-09-01

    Personality is known to be relatively stable throughout adulthood. Nevertheless, it has been shown that major life events with high personal significance, including experiences engendered by psychedelic drugs, can have an enduring impact on some core facets of personality. In the present, balanced-order, placebo-controlled study, we investigated biological predictors of post-lysergic acid diethylamide (LSD) changes in personality. Nineteen healthy adults underwent resting state functional MRI scans under LSD (75µg, I.V.) and placebo (saline I.V.). The Revised NEO Personality Inventory (NEO-PI-R) was completed at screening and 2 weeks after LSD/placebo. Scanning sessions consisted of three 7.5-min eyes-closed resting-state scans, one of which involved music listening. A standardized preprocessing pipeline was used to extract measures of sample entropy, which characterizes the predictability of an fMRI time-series. Mixed-effects models were used to evaluate drug-induced shifts in brain entropy and their relationship with the observed increases in the personality trait openness at the 2-week follow-up. Overall, LSD had a pronounced global effect on brain entropy, increasing it in both sensory and hierarchically higher networks across multiple time scales. These shifts predicted enduring increases in trait openness. Moreover, the predictive power of the entropy increases was greatest for the music-listening scans and when "ego-dissolution" was reported during the acute experience. These results shed new light on how LSD-induced shifts in brain dynamics and concomitant subjective experience can be predictive of lasting changes in personality. Hum Brain Mapp 37:3203-3213, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  18. Opioid-Induced Glial Activation: Mechanisms of Activation and Implications for Opioid Analgesia, Dependence, and Reward

    Directory of Open Access Journals (Sweden)

    Mark R. Hutchinson

    2007-01-01

    Full Text Available This review will introduce the concept of toll-like receptor (TLR–mediated glial activation as central to all of the following: neuropathic pain, compromised acute opioid analgesia, and unwanted opioid side effects (tolerance, dependence, and reward. Attenuation of glial activation has previously been demonstrated both to alleviate exaggerated pain states induced by experimental pain models and to reduce the development of opioid tolerance. Here we demonstrate that selective acute antagonism of TLR4 results in reversal of neuropathic pain as well as potentiation of opioid analgesia. Attenuating central nervous system glial activation was also found to reduce the development of opioid dependence, and opioid reward at a behavioral (conditioned place preference and neurochemical (nucleus accumbens microdialysis of morphine-induced elevations in dopamine level of analysis. Moreover, a novel antagonism of TLR4 by (+- and (˗-isomer opioid antagonists has now been characterized, and both antiallodynic and morphine analgesia potentiating activity shown. Opioid agonists were found to also possess TLR4 agonistic activity, predictive of glial activation. Targeting glial activation is a novel and as yet clinically unexploited method for treatment of neuropathic pain. Moreover, these data indicate that attenuation of glial activation, by general or selective TLR antagonistic mechanisms, may also be a clinical method for separating the beneficial (analgesia and unwanted (tolerance, dependence, and reward actions of opioids, thereby improving the safety and efficacy of their use.

  19. Fission and spallation data evaluation using induced-activity method

    CERN Document Server

    Karapetyan, G S

    2015-01-01

    The induced-activity investigations in off-line analysis performed in different experiments, concerning pre-actinide and actinide nuclei, are here presented and discussed. Generalized expressions for the determination of independent yields/cross sections of radioactive nuclei, formed in the targets, are derived and analysed. The fragment mass distribution from U-238, Th-232 and Ta-181 photofission at the bremsstrahlung end-point energies of 50 and 3500 MeV, and from Am-241, U-238 and Np-237 fission induced by 660-MeV protons, are scrutinized from the point of view of the multimodal fission approach. The results of these studies are hence compared with theoretical model calculations using the CRISP code. We subsequently discuss the complex particle-induced reaction, such as heavy-ions and deuterons, by using the thick-target thick-catcher technique and the two-step vector model framework as well. This is accomplished in order to present the investigation of the main processes (fission, spallation and (multi)fr...

  20. Aspirin-triggered resolvin D1 inhibits TGF-β1-induced EMT through the inhibition of the mTOR pathway by reducing the expression of PKM2 and is closely linked to oxidative stress.

    Science.gov (United States)

    Liu, Yu; Yuan, Xiaolong; Li, Wenhui; Cao, Qianqian; Shu, Yusheng

    2016-10-01

    Transforming growth factor-β1 (TGF-β1) is a potent stimulator of the epithelial-to-mesenchymal transition (EMT), which is a key event in the initiation of tumor cell metastasis. Aspirin-triggered resolvin D1 (AT-RvD1) is known to be involved in the resolution of inflammation; however, whether AT-RvD1 exerts effects on TGF-β1-induced EMT remains unclear. Thus, we first explored the effects of AT-RvD1 on the EMT of lung cancer cells. Treatment with TGF-β1 increased the level of reactive oxygen species (ROS) and reduced the expression of nuclear factor (erythroid-derived 2)-like 2 (Nrf2). The expression of E-cadherin in A549 lung cancer cells was reduced, and the expression of vimentin was enhanced. AT-RvD1 enhanced the expression of E-cadherin in a concentration‑dependent manner and suppressed the expression of Nrf2 and vimentin. AT-RvD1 did not affect the proliferation of A549 lung cancer cells whereas it suppressed the TGF-β1‑induced migration and invasion of A549 cells. The expression of pyruvate kinase M2 (Pkm2), which is associated with TGF-β-induced factor homeobox 2 (TGIF2), was significantly increased during the TGF-β1-induced EMT of A549 lung cancer cells. The mTOR pathway is known to regulate the expression of various glycolytic enzymes including Pkm2. We examined the involvement of the mTOR pathway in the suppressive effects of AT-RvD1 on Pkm2 expression in A549 cells. The mTOR activator restored the expression of Pkm2 and partially downregulated the expression of E-cadherin. However, the mTOR activator had no clear effect on the TGF-β1-induced EMT. These results suggest that AT-RvD1 is closely linked to oxidative stress and partially inhibits TGF-β1-induced EMT through the inhibition of the mTOR pathway by reducing the expression of Pkm2.

  1. ACTIVATION OF VASTUS MEDIALIS OBLIQUES AT DIFFERENT KNEE ANGLES IN CLOSED KINETIC CHAIN AND OPEN KINETIC CHAIN POSITION IN SUBJECTS WITH PATELLO FEMORAL PAIN SYNDROME

    Directory of Open Access Journals (Sweden)

    Ujwal Bhattacharya

    2015-06-01

    Full Text Available Background: Patello femoral pain syndrome is one of the most common musculoskeletal disorders and is reported to affect 15% - 33% of an active adult population and 21%-45% of adolescents thereby decreasing the work capacity of an individual. Patello femoral pain syndrome as implicated is due to inappropriate neural control of the quadriceps femoris muscle. Since Vastus medialis muscle is regarded as the dynamic medial stabilizer of patella so it’s important to understand the activation of Vastus Medialis Oblique’s in patients with patello femoral pain syndrome The purpose of this study is to assess the activation of Vastus Medialis Oblique’s at different knee angles between closed kinetic chain position and open kinetic chain position and the information thus gained can be used to design training program aimed at controlling patello femoral joint dysfunction. Methods: Thirty subjects with patello femoral pain syndrome (assessed through history and examination were assigned to two groups. Group A was made to perform open kinetic chain activity(i.e. sitting on high plinth and Group B was made to perform a closed kinetic chain activity(i.e. standing The outcome measure were amplitude and duration. Analyses were performed using independent t-Test. Results: Significant difference was found between the groups for amplitude and duration at varying angles. Amplitude: 0 degree (p=0.004, 60 degrees (p=0.015, 90 degrees (p=0.004. Duration: 0 degree (p=0.007, 60 degrees (p=0.008,90 degrees (p=0.002 Conclusion: Based on the outcome of the study it’s concluded that there is greater activation of Vastus Medialis Oblique’s muscle while performing close kinetic chain activity than in open kinetic chain.

  2. Efficient Room-Temperature Methane Activation by the Closed-Shell, Metal-Free Cluster [OSiOH](+) : A Novel Mechanistic Variant.

    Science.gov (United States)

    Sun, Xiaoyan; Zhou, Shaodong; Schlangen, Maria; Schwarz, Helmut

    2016-09-26

    The closed-shell cluster ion [OSiOH](+) is generated in the gas phase and its reactivity towards the thermal activation of CH4 has been examined using Fourier transform-ion cyclotron resonance (FT-ICR) mass spectrometry in conjunction with state-of-the-art quantum chemical calculations. Quite unexpectedly at room temperature, [OSiOH](+) efficiently mediates C-H bond activation, giving rise to [SiOH](+) and [SiOCH3 ](+) with the concomitant formation of methanol and water, respectively. Mechanistic aspects for this unprecedented reactivity pattern are presented, and the properties of the [OSiOH](+) /CH4 couple are compared with those of the closed-shell systems [OCOH](+) /CH4 and [MgOH](+) /CH4 ; the last two couples exhibit an entirely different reactivity scenario. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  3. Angiotensin-converting enzyme inhibitor captopril prevents activation-induced apoptosis by interfering with T cell activation signals

    Science.gov (United States)

    Odaka, C; Mizuochi, T

    2000-01-01

    Captopril is an orally active inhibitor of angiotensin-converting enzyme (ACE) which is widely used as an anti-hypertensive agent. In addition to its ability to reduce blood pressure, captopril has a number of other biological activities. Recently the drug was shown to inhibit Fas-induced apoptosis in human activated peripheral T cells and human lung epithelial cells. In this study, we investigated whether captopril blocks activation-induced apoptosis in murine T cell hybridomas, and found that captopril inhibited IL-2 synthesis and apoptotic cell death upon activation with anti-CD3 antibody. In addition, captopril inhibited an inducible caspase-3-like activity during activation-induced apoptosis. On the other hand, captopril did not interfere with Fas signalling, since anti-Fas antibody-induced apoptosis in Fas+ Jurkat cells was unaffected by the drug. Furthermore, we examined whether captopril blocks activation-induced apoptosis by interfering with expression of Fas, Fas ligand (FasL), or both on T cell hybridomas. FasL expression on activated T cells was significantly inhibited by captopril, whereas up-expression of Fas was partially inhibited, as assessed by cell surface staining. Taking all data together, we conclude that captopril prevents activation-induced apoptosis in T cell hybridomas by interfering with T cell activation signals. Captopril has been reported to induce systemic lupus erythematosus syndrome, and our findings may be useful for elucidating the mechanism of captopril-induced autoimmunity. PMID:10971519

  4. Mitigating Induced Seismicity Through Active Pressure Management in Numerical Simulations

    Science.gov (United States)

    Kroll, K.; Richards-Dinger, K. B.; White, J. A.

    2016-12-01

    The recent upturn of seismicity rates in the Central and Eastern United States and Canada has been attributed to industrial operations such as waste-water disposal, hydraulic fracturing, and subsurface carbon storage. We couple the 3D, physics-based earthquake simulator, RSQSim, to a reservoir model to investigate the space-time characteristics of earthquakes induced by pore-fluid pressure increases and/or poroelastic stresses during injection. RSQSim employs rate-state friction, which gives rise to spatiotemporal earthquake clustering. The simulator generates long catalogs of seismicity based on stress changes due to fault interaction and external stress perturbations with great computational efficiency, allowing for multiple simulations to systematically explore the parameters that control induced seismicity. These simulations provide physics-based statistical data that may contribute to the formalization of optimal injection operations designed to minimize risk of seismicity at a given industrial site. Industrial operators may modify injection rates as an active seismicity mitigation tool to either reduce the total number of earthquakes or attempt to reduce the likelihood of future large events. To explore the efficacy of this approach, we use RSQSim to explore how sequences of induced earthquakes respond to changes in injection schedule. We simulate induced seismicity on a single optimally oriented fault with fractally distributed initial shear stresses and compare results from models with/without along-strike fault permeability and poroelastic stress changes. We investigate the seismic response to several injection schedules that lie between two end-member scenarios, 1) constant injection at low rates, and 2) periodic injection at high rates. We evaluate the cumulative number of events, total seismic moment release, and the spatio-temporal characteristics of seismicity including the time/location of the next large event after adjusting injection rates

  5. Hyaluronic acid induces activation of the κ-opioid receptor.

    Directory of Open Access Journals (Sweden)

    Barbara Zavan

    Full Text Available INTRODUCTION: Nociceptive pain is one of the most common types of pain that originates from an injury involving nociceptors. Approximately 60% of the knee joint innervations are classified as nociceptive. The specific biological mechanism underlying the regulation of nociceptors is relevant for the treatment of symptoms affecting the knee joint. Intra-articular administration of exogenous hyaluronic acid (HA in patients with osteoarthritis (OA appears to be particularly effective in reducing pain and improving patient function. METHODS: We performed an in vitro study conducted in CHO cells that expressed a panel of opioid receptors and in primary rat dorsal root ganglion (DRG neurons to determine if HA induces the activation of opioid peptide receptors (OPr using both aequorin and the fluorescent dye Fura-2/AM. RESULTS: Selective agonists and antagonists for each OPr expressed on CHO cells were used to test the efficacy of our in vitro model followed by stimulation with HA. The results showed that HA induces stimulatory effects on the κ receptor (KOP. These effects of HA were also confirmed in rat DRG neurons, which express endogenously the OPr. CONCLUSIONS: HA activates the KOP receptor in a concentration dependent manner, with a pEC(50 value of 7.57.

  6. Active Control Does Not Eliminate Motion-Induced Illusory Displacement

    Directory of Open Access Journals (Sweden)

    Ian M. Thornton

    2011-05-01

    Full Text Available When the sine-wave grating of a Gabor patch drifts to the left or right, the perceived position of the entire object is shifted in the direction of local motion. In the current work we explored whether active control of the physical position of the patch overcomes such motion induced illusory displacement. In Experiment 1 we created a simple computer game and asked participants to continuously guide a Gabor patch along a randomly curving path using a joystick. When the grating inside the Gabor patch was stationary, participants could perform this task without error. When the grating drifted to either left or right, we observed systematic errors consistent with previous reports of motion-induced illusory displacement. In Experiment 2 we created an iPad application where the built-in accelerometer tilt control was used to steer the patch through as series of “gates”. Again, we observed systematic guidance errors that depended on the direction and speed of local motion. In conclusion, we found no evidence that participants could adapt or compensate for illusory displacement given active control of the target.

  7. Single substitutions to closely related amino acids contribute to the functional diversification of an insect-inducible, positively selected plant cystatin.

    Science.gov (United States)

    Rasoolizadeh, Asieh; Goulet, Marie-Claire; Sainsbury, Frank; Cloutier, Conrad; Michaud, Dominique

    2016-04-01

    A causal link has been reported between positively selected amino acids in plant cystatins and the inhibitory range of these proteins against insect digestive cysteine (Cys) proteases. Here we assessed the impact of single substitutions to closely related amino acids on the contribution of positive selection to cystatin diversification. Cystatin sequence alignments, while confirming hypervariability, indicated a preference for related amino acids at positively selected sites. For example, the non-polar residues leucine (Leu), isoleucine (Ile) and valine (Val) were shown to predominate at positively selected site 2 in the N-terminal region, unlike selected sites 6 and 10, where polar residues are preferred. The model cystatin SlCYS8 and single variants with Leu, Ile or Val at position 2 were compared with regard to their ability to bind digestive proteases of the coleopteran pest Leptinotarsa decemlineata and to induce compensatory responses in this insect. A functional proteomics procedure to capture target Cys proteases in midgut extracts allowed confirmation of distinct binding profiles for the cystatin variants. A shotgun proteomics procedure to monitor whole Cys protease complements revealed protease family specific compensatory responses in the insect, dependent on the variant ingested. Our data confirm the contribution of closely related amino acids to the functional diversity of positively selected plant cystatins in a broader structure/function context imposing physicochemical constraints to primary structure alterations. They also underline the complexity of protease/inhibitor interactions in plant-insect systems, and the challenges still to be met in order to harness the full potential of ectopically expressed protease inhibitors in crop protection.

  8. Activation of phospholipase D activity in transforming growth factor—beta—induced cell growth inhibition

    Institute of Scientific and Technical Information of China (English)

    ZHOUBINGHONG; JUNSONGCHEN; 等

    2000-01-01

    Cells regulate phospholipase D(PLD) activity in response to numerous extracellular signals.Here,we investigated the involvement of PLD activity in transforming growth factor-β(TGF-β1)-mediated growth inhibition of epithelial cells.TGF-β1)-mediated growth inhibition of epithelial cells.TGF-β1 inhibits the growth of MDCK,Mv1Lu,and A-549 cells.In the presence of 0.4% butanol,TGF-β1 induces an increase in the formation of phosphatidylbutanol,a unique product catalyzed by PLD.TGF-β1 also induces an increase in phosphatidic acid (PA) level in A-549 and MDCK cells.TGF-β1 induces an increase in the levels of DAG labeled with [3H]-myristic acid in A-549 and MDCK cells but not in Mv1Lu cells.No increase of DAG was observed in cells prelabeled with [3H]-arachidonic acid.The data presented suggest that PLD activation is involved in the TGF-β1-induced cell growth inhibition.

  9. Novel Principles of Gamma-Retroviral Insertional Transcription Activation in Murine Leukemia Virus-induced End-stage Tumors

    DEFF Research Database (Denmark)

    Sokol, Martin; Wabl, Matthias; Rius Ruiz, Irene;

    2014-01-01

    Background Insertional mutagenesis screens of retrovirus-induced mouse tumors have proven valuable in human cancer research and for understanding adverse effects of retroviral-based gene therapies. In previous studies, the assignment of mouse genes to individual retroviral integration sites has...... been based on close proximity and expression patterns of annotated genes at target positions in the genome. We here employed next-generation RNA sequencing to map retroviral-mouse chimeric junctions genome-wide, and to identify local patterns of transcription activation in T-lymphomas induced...... than 2,000 mice was examined. Results We detected several novel mechanisms of retroviral insertional mutagenesis: bidirectional activation of mouse transcripts on opposite sides of a provirus including transcription of unannotated mouse sequence; sense/antisense-type activation of genes located...

  10. Dural administration of inflammatory soup or Complete Freund's Adjuvant induces activation and inflammatory response in the rat trigeminal ganglion

    DEFF Research Database (Denmark)

    Lukács, M; Haanes, K A; Majláth, Zs

    2015-01-01

    induces inflammatory activation in the trigeminal ganglion. METHODS: We performed topical administration of inflammatory soup (IS) or Complete Freund's Adjuvant (CFA) onto an exposed area of the rat dura mater in vivo for 20 min. The window was closed and the rats were sacrificed after 4 h and up to 7...... days. Myography was performed on middle meningeal arteries. The trigeminal ganglia were removed and processed for immunohistochemistry or Western blot. RESULTS: Both CFA and IS induced enhanced expression of pERK1/2, IL-1β and CGRP in the trigeminal ganglia. The pERK1/2 immunoreactivity was mainly seen...... vasoconstrictor response to IS, but not to CFA. CONCLUSIONS: These results suggest that the application of IS or CFA onto the dura mater causes long-term activation of the TG and demonstrate the importance of the neuro-glial interaction in the activation of the trigeminovascular system....

  11. The changes in telomerase activity and telomere length in HeLa cells undergoing apop- tosis induced by sodium butyrate

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    The changes in telomerase activity and telomere length during apoptosis in HeLa cells as induced by sodium butyrate (SB) have been studied. After a 48 h SB treatment, HeLa cells demonstrated characteristic apoptotic hallmarks including chromatin condensation, formation of apoptotic bodies and DNA Laddering which were caused by the cleavage and degradation of DNA between nucleosomes. There were no significant changes in telomerase activity of apoptotic cells, while the telomere length shortened markedly. In the meanwhile, cells became more susceptible to apoptotic stimuli and telomere became more vulnerable to degradation after telomerase activity was inhibited. All the results suggest that the apoptosis induced by SB is closely related to telomere shortening, while telomerase enhances resistance of HeLa cells to apoptotic stimuli by protecting telomere.

  12. N-terminal aromatic residues closely impact the cytolytic activity of cupiennin 1a, a major spider venom peptide.

    Science.gov (United States)

    Kuhn-Nentwig, Lucia; Sheynis, Tania; Kolusheva, Sofiya; Nentwig, Wolfgang; Jelinek, Raz

    2013-12-01

    Cupiennins are small cationic α-helical peptides from the venom of the ctenid spider Cupiennius salei which are characterized by high bactericidal as well as hemolytic activities. To gain insight into the determinants responsible for the broad cytolytic activities, two analogues of cupiennin 1a with different N-terminal hydrophobicities were designed. The insecticidal, bactericidal and hemolytic activities of these analogues were assayed and compared to the native peptide. Specifically, substitution of two N-terminal Phe residues by Ala results in less pronounced insecticidal and cytolytic activity, whereas a substitution by Lys reduces strongly its bactericidal activity and completely diminishes its hemolytic activity up to very high tested concentrations. Biophysical analyses of peptide/bilayer membrane interactions point to distinct interactions of the analogues with lipid bilayers, and dependence upon membrane surface charge. Indeed, we find that lower hemolytic activity was correlated with less surface association of the analogues. In contrast, our data indicate that the reduced bactericidal activity of the two cupiennin 1a analogues likely correspond to greater bilayer-surface localization of the peptides. Overall, ultimate insertion and destruction of the host cell membrane is highly dependent on the presence of Phe-2 and Phe-6 (Cu 1a) or Leu-6 (Cu 2a) in the N-terminal sequences of native cupiennins.

  13. [Ginsenoside Rh₂ induces apoptosis and autophagy of K562 cells by activating p38].

    Science.gov (United States)

    Liu, Xiao-Xia; Xia, Jing; Tang, Jia-Feng; Zhou, Ming-Hua; Chen, Di-Long; Liu, Ze-Hong

    2017-01-01

    To study the effect of ginseng saponin Rh₂ in inducing apoptosis of human leukemia K562 cells, and explore its mechanism from the aspect of autophagy pathway. CCK-8 assay was used to examine the growth inhibition of human leukemia cell lines K562 treated with ginsenoside Rh₂; flow cytometry (FCM) was used to detect cell apoptosis; Hoechst staining was used to observe the changes of cell morphological apoptosis; Acridine and MDC staining were used to detect the effects of the Rh₂ on autophagy; Western blot and RT-PCR were used to detect the expression levels of the proteins closely associated with autophagy and apoptosis. In order to study the effect of autophagy in proliferation and apoptosis, we used the autophagy inhibitor (3-MA).CCK-8 indicated that Rh₂ at low concentration could effectively inhibit the proliferation of leukemia cellsin dose- and time-dependent manners in K562 cells; FCM indicated that Rh₂ induced apoptosis; Hoechest staining showed that K562 cells had typical apoptotic morphological changes by treated Rh₂; Acridine and MDC staining showed that Rh₂ enhanced the green fluorescence and a large number of acidic autophagy vesicles were present; Western blot and RT-PCR results showed that Rh₂ increased the expression levels of Beclin-1, LC3A, LC3B, activated Caspase-3 and p-p38 in K562 cells; application of autophagy inhibitors(3-MA) could weaken the inhibition effect of Rh₂ on proliferation and induction effect on apoptosis in K562 cells. Ginsenoside Rh₂ inhibited the proliferation and induced apoptosis probably through activating p-p38, and inducing cell autophagy signaling pathway in K562 cells. Copyright© by the Chinese Pharmaceutical Association.

  14. Adaptation strategies of two closely related Desmodesmus armatus (green alga) strains contained different amounts of cadmium: a study with light-induced synchronized cultures of algae.

    Science.gov (United States)

    Pokora, Wojciech; Baścik-Remisiewicz, Agnieszka; Tukaj, Stefan; Kalinowska, Renata; Pawlik-Skowrońska, Barbara; Dziadziuszko, Małgorzata; Tukaj, Zbigniew

    2014-01-15

    During the Desmodesmus armatus cell cycle, 8-celled coenobia of 276-4d strain accumulated a much lower amounts of cadmium than unicells of B1-76 strain. Cadmium reduced growth and photosynthesis in the cells of strain B1-76, but not those of 276-4d strain. Cells of 276-4d strain revealed a higher activity of superoxide dismutase (SOD) isoforms, in particular the activity and protein content of Fe-SOD. Cu/Zn-SOD was earlier and much stronger induced by cadmium in 276-4d than in B1-76 strain, whereas Fe- and Mn-SOD activity and Fe-SOD synthesis were induced only in 276-4d strain. Cadmium did not affect the heat shock protein 70 synthesis in B1-76 strain, but significantly stimulated this process in 276-4d strain. The level of glutathione increased 30-fold during cell development of Cd-exposed 276-4d strain, while in B1-76 it increased about 12 timed. Matured cells of both strains exposed to cadmium produced comparable amounts of phytochelatins and other thiol peptides, but their production in young cells of B1-76 strain was much higher than in 276-4d strain. In conclusion, a complex of internal detoxification mechanisms appeared to be more efficient in cells of 276-4d strain than B1-76 one.

  15. hERG S4-S5 linker acts as a voltage-dependent ligand that binds to the activation gate and locks it in a closed state.

    Science.gov (United States)

    Malak, Olfat A; Es-Salah-Lamoureux, Zeineb; Loussouarn, Gildas

    2017-12-01

    Delayed-rectifier potassium channels (hERG and KCNQ1) play a major role in cardiac repolarization. These channels are formed by a tetrameric pore (S5-S6) surrounded by four voltage sensor domains (S1-S4). Coupling between voltage sensor domains and the pore activation gate is critical for channel voltage-dependence. However, molecular mechanisms remain elusive. Herein, we demonstrate that covalently binding, through a disulfide bridge, a peptide mimicking the S4-S5 linker (S4-S5L) to the channel S6 C-terminus (S6T) completely inhibits hERG. This shows that channel S4-S5L is sufficient to stabilize the pore activation gate in its closed state. Conversely, covalently binding a peptide mimicking S6T to the channel S4-S5L prevents its inhibiting effect and renders the channel almost completely voltage-independent. This shows that the channel S4-S5L is necessary to stabilize the activation gate in its closed state. Altogether, our results provide chemical evidence that S4-S5L acts as a voltage-controlled ligand that binds S6T to lock the channel in a closed state, elucidating the coupling between voltage sensors and the gate in delayed rectifier potassium channels and potentially other voltage-gated channels.

  16. Multiscale modeling of the active site of [Fe] hydrogenase: the H₂ binding site in open and closed protein conformations.

    Science.gov (United States)

    Hedegård, Erik Donovan; Kongsted, Jacob; Ryde, Ulf

    2015-05-18

    A series of QM/MM optimizations of the full protein of [Fe] hydrogenase were performed. The FeGP cofactor has been optimized in the water-bound resting state (1), with a side-on bound dihydrogen (2), or as a hydride intermediate (3). For inclusion of H4MPT in the closed structure, advanced multiscale modeling appears to be necessary, especially to obtain reliable distances between CH-H4MPT(+) and the dihydrogen (H2) or hydride (H(-)) ligand in the FeGP cofactor. Inclusion of the full protein is further important for the relative energies of the two intermediates 2 and 3. We finally find that hydride transfer from 3 has a significantly higher barrier than found in previous studies neglecting the full protein environment.

  17. Experimental autoimmune prostatitis induces microglial activation in the spinal cord

    Science.gov (United States)

    Wong, Larry; Done, Joseph D.; Schaeffer, Anthony J.; Thumbikat, Praveen

    2014-01-01

    Background The pathogenesis of chronic prostatitis/chronic pelvic pain syndrome is unknown and factors including the host’s immune response and the nervous system have been attributed to the development of CP/CPPS. We previously demonstrated that mast cells and chemokines such as CCL2 and CCL3 play an important role in mediating prostatitis. Here, we examined the role of neuroinflammation and microglia in the CNS in the development of chronic pelvic pain. Methods Experimental autoimmune prostatitis (EAP) was induced using a subcutaneous injection of rat prostate antigen. Sacral spinal cord tissue (segments S4–S5) was isolated and utilized for immunofluorescence or QRT-PCR analysis. Tactile allodynia was measured at baseline and at various points during EAP using Von Frey fibers as a function for pelvic pain. EAP mice were treated with minocycline after 30 days of prostatitis to test the efficacy of microglial inhibition on pelvic pain. Results Prostatitis induced the expansion and activation of microglia and the development of inflammation in the spinal cord as determined by increased expression levels of CCL3, IL-1β, Iba1, and ERK1/2 phosphorylation. Microglial activation in mice with prostatitis resulted in increased expression of P2X4R and elevated levels of BDNF, two molecular markers associated with chronic pain. Pharmacological inhibition of microglia alleviated pain in mice with prostatitis and resulted in decreased expression of IL-1β, P2X4R, and BDNF. Conclusion Our data shows that prostatitis leads to inflammation in the spinal cord and the activation and expansion of microglia, mechanisms that may contribute to the development and maintenance of chronic pelvic pain. PMID:25263093

  18. Curcumin attenuates diet-induced hepatic steatosis by activating AMP-activated protein kinase.

    Science.gov (United States)

    Um, Min Young; Hwang, Kwang Hyun; Ahn, Jiyun; Ha, Tae Youl

    2013-09-01

    Curcumin is a well-known component of traditional turmeric (Curcuma longa), which has been reported to prevent obesity and diabetes. However, the effect of curcumin on hepatic lipid metabolism remains unclear. The aim of this study was to examine the effects of curcumin on hepatic steatosis in high-fat/cholesterol diet (HFD)-induced obese mice. Male C57BL/6J mice were fed a normal diet (ND), HFD or HFD with 0.15% curcumin (HFD+C) for 11 weeks. We found that curcumin significantly lowered the body-weight and adipose tissue weight of mice in the HFD+C group compared with the findings for the HFD group (p cholesterol, fasting glucose and insulin in serum were decreased, and HFD-induced impairment of insulin sensitivity was improved by curcumin supplementation (p Curcumin protected against the development of hepatic steatosis by reducing hepatic fat accumulation. Moreover, curcumin activated AMP-activated protein kinase (AMPK) and elevated the gene expression of peroxisome proliferator-activated receptor alpha. By contrast, curcumin suppressed the HFD-mediated increases in sterol regulatory element-binding protein-1, acetyl-CoA carboxylase 1, fatty acid synthase and cluster of differentiation 36 expression. Taken together, these findings indicate that curcumin attenuates HFD-induced hepatic steatosis by regulating hepatic lipid metabolism via AMPK activation, suggesting its use as a therapeutic for hepatic steatosis.

  19. Paclitaxel-induced activation of murine peritoneal macrophage in vitro

    Institute of Scientific and Technical Information of China (English)

    Li Zhongxiang; Wang Fufeng; Qiao Yuhuan

    2004-01-01

    Objective: To study the effects of paclitaxel on macrophage activation. Methods:Mouse macrophages were isolated by peritoneal lavage and cultured in RPMI 1640 medium according to the following groups: paclitaxel (5μmol/L) group, IFN-γ (5U/L) group, paclitaxel (5μmol/L) and IFN-γ (5U/L) combination group, and control group(without paclitaxel and IFNγ) .24 hours later, supematants were collected for nitric oxide(NO) assessment using the Griess reagent, and ttanor necrosis factor-α(TNF-α) assessment using the enzyme linked immunosorbent assay. Antibody-dependent cell-mediated cytotoxicity(ADCC) of the macrophages was assessed using the method of hemoglobin-enzyme release assay (Hb-ERA). Results: Paclitaxel induced the production of higher levels of NO(8.86 ± 1.16μmol/L) and TNF-α(120.2 ± 10.2pg/ml) ,and enhanced the ADCC of macrophages[ (20.61 + 1.13)% ]. The differences were significant compared with the control group[no NO and TNF-α detected,ADCC (15.37 + 1.93)% ](P < 0.01). Paclitaxel and IFN-γ in combination induced the production of higher levels of NO(22.85 ± 0.91μmol/L) and TNF-α(358.6 ± 27 .5pg/ml), and enhanced the ADCC of macrophages[ (42.49 + 3.09) % ]. The differences were significant compared with paclitaxel or IFN-γ[NO 8.09 ± 1.13μmol/L, TNF-α1 24.8 + 9.6pg/ml, ADCC(23.32 ± 2.63) % ] alone (P<0.01). Conclusion: These findings indicate that paclitaxel can promote NO and TNF-α production,enhance ADCC of macrophages, and induce macrophage activation. The active effects are more significant with paclitaxel and IFN-γcombination.

  20. Biological function of activation-induced cytidine deaminase (AID

    Directory of Open Access Journals (Sweden)

    Ritu Kumar

    2014-10-01

    Full Text Available Activation-induced Cytidine Deaminase (AID is an essential regulator of B cell diversification, but its full range of action has until recently been an enigma. Based on homology, it was originally proposed to be an RNA-editing enzyme, but so far, no RNA substrates are known. Rather, it functions by deaminating cytidine, and in this manner, coupled with base-excision repair or mismatch repair machinery, it is a natural mutator. This allows it to play a central role in adaptive immunity, whereby it initiates the processes of class switch recombination and somatic hypermutation to help generate a diverse and high-affinity repertoire of immunoglobulin isotypes. More recently, it has been appreciated that methylated cytidine, already known as a key epigenetic mark on DNA controlling gene expression, can also be a target for AID modification. Coupled with repair machinery, this can facilitate the active removal of methylated DNA. This activity can impact the process of cellular reprogramming, including transition of a somatic cell to pluripotency, which requires major reshuffling of epigenetic memory. Thus, seemingly disparate roles for AID in controlling immune diversity and epigenetic memory have a common mechanistic basis. However, the very activity that is so useful for B cell diversity and cellular reprogramming is dangerous for the integrity of the genome. Thus, AID expression and activity is tightly regulated, and deregulation is associated with diseases including cancer. Here, we review the range of AID functions with a focus on its mechanisms of action and regulation. Major questions remain to be answered concerning how and when AID is targeted to specific loci and how this impacts development and disease.

  1. Biological function of activation-induced cytidine deaminase (AID).

    Science.gov (United States)

    Kumar, Ritu; DiMenna, Lauren J; Chaudhuri, Jayanta; Evans, Todd

    2014-01-01

    Activation-induced Cytidine Deaminase (AID) is an essential regulator of B cell diversification, but its full range of action has until recently been an enigma. Based on homology, it was originally proposed to be an RNA-editing enzyme, but so far, no RNA substrates are known. Rather, it functions by deaminating cytidine, and in this manner, coupled with base-excision repair or mismatch repair machinery, it is a natural mutator. This allows it to play a central role in adaptive immunity, whereby it initiates the processes of class switch recombination and somatic hypermutation to help generate a diverse and high-affinity repertoire of immunoglobulin isotypes. More recently, it has been appreciated that methylated cytidine, already known as a key epigenetic mark on DNA controlling gene expression, can also be a target for AID modification. Coupled with repair machinery, this can facilitate the active removal of methylated DNA. This activity can impact the process of cellular reprogramming, including transition of a somatic cell to pluripotency, which requires major reshuffling of epigenetic memory. Thus, seemingly disparate roles for AID in controlling immune diversity and epigenetic memory have a common mechanistic basis. However, the very activity that is so useful for B cell diversity and cellular reprogramming is dangerous for the integrity of the genome. Thus, AID expression and activity is tightly regulated, and deregulation is associated with diseases including cancer. Here, we review the range of AID functions with a focus on its mechanisms of action and regulation. Major questions remain to be answered concerning how and when AID is targeted to specific loci and how this impacts development and disease.

  2. Closed headpiece of integrin [alpah]IIb[beta]3 and its complex with an [alpha]IIb[beta]3-specific antagonist that does not induce opening

    Energy Technology Data Exchange (ETDEWEB)

    Zhu, Jieqing; Zhu, Jianghai; Negri, Ana; Provasi, Davide; Filizola, Marta; Coller, Barry S.; Springer, Timothy A. (Sinai); (Rockefeller); (CH-Boston)

    2011-08-24

    The platelet integrin {alpha}{sub IIb}{beta}{sub 3} is essential for hemostasis and thrombosis through its binding of adhesive plasma proteins. We have determined crystal structures of the {alpha}{sub IIb}{beta}{sub 3} headpiece in the absence of ligand and after soaking in RUC-1, a novel small molecule antagonist. In the absence of ligand, the {alpha}{sub IIb}{beta}{sub 3} headpiece is in a closed conformation, distinct from the open conformation visualized in presence of Arg-Gly-Asp (RGD) antagonists. In contrast to RGD antagonists, RUC-1 binds only to the {alpha}{sub IIb} subunit. Molecular dynamics revealed nearly identical binding. Two species-specific residues, {alpha}{sub IIb} Y190 and {alpha}{sub aIIb} D232, in the RUC-1 binding site were confirmed as important by mutagenesis. In sharp contrast to RGD-based antagonists, RUC-1 did not induce {alpha}{sub IIb}{beta}{sub 3} to adopt an open conformation, as determined by gel filtration and dynamic light scattering. These studies provide insights into the factors that regulate integrin headpiece opening, and demonstrate the molecular basis for a novel mechanism of integrin antagonism.

  3. Activation tagging of the two closely linked genes LEP and VAS independently affects vascular cell number

    DEFF Research Database (Denmark)

    van der Graaff, Eric; Hooykaas, Paul J J; Keller, Beat

    2002-01-01

    report that in addition to this leafy petiole phenotype, the size of the vascular bundles is increased in all aerial organs in let as a result of an increase in the number of xylem, phloem (pro)cambial and pericycle cells. This vascular phenotype is caused by activation tagging of the two genes VASCULAR...... TISSUE SIZE (VAS) and LEP. These genes are closely linked and arranged in tandem. Activation tagging of LEP only caused a specific increase in the number of xylem cells. This increased xylem cell number, together with the ectopic leaf blade formation, indicates that LEP functions as a cell division......-promoting factor. The activation tagging of VAS only resulted in a specific increase in phloem (pro)cambial and pericycle cells. We conclude that activation tagging of LEP and VAS results in additive phenotypes. Insertional mutants for LEP and VAS display wild-type vascular development, indicating the relevance...

  4. Cisplatin induces cytotoxicity through the mitogen-activated protein kinase pathways and activating transcription factor 3.

    Science.gov (United States)

    St Germain, Carly; Niknejad, Nima; Ma, Laurie; Garbuio, Kyla; Hai, Tsonwin; Dimitroulakos, Jim

    2010-07-01

    The mechanisms underlying the proapoptotic effect of the chemotherapeutic agent, cisplatin, are largely undefined. Understanding the mechanisms regulating cisplatin cytotoxicity may uncover strategies to enhance the efficacy of this important therapeutic agent. This study evaluates the role of activating transcription factor 3 (ATF3) as a mediator of cisplatin-induced cytotoxicity. Cytotoxic doses of cisplatin and carboplatin treatments consistently induced ATF3 expression in five tumor-derived cell lines. Characterization of this induction revealed a p53, BRCA1, and integrated stress response-independent mechanism, all previously implicated in stress-mediated ATF3 induction. Analysis of mitogen-activated protein kinase (MAPK) pathway involvement in ATF3 induction by cisplatin revealed a MAPK-dependent mechanism. Cisplatin treatment combined with specific inhibitors to each MAPK pathway (c-Jun N-terminal kinase, extracellular signal-regulated kinase, and p38) resulted in decreased ATF3 induction at the protein level. MAPK pathway inhibition led to decreased ATF3 messenger RNA expression and reduced cytotoxic effects of cisplatin as measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide cell viability assay. In A549 lung carcinoma cells, targeting ATF3 with specific small hairpin RNA also attenuated the cytotoxic effects of cisplatin. Similarly, ATF3-/- murine embryonic fibroblasts (MEFs) were shown to be less sensitive to cisplatin-induced cytotoxicity compared with ATF3+/+ MEFs. This study identifies cisplatin as a MAPK pathway-dependent inducer of ATF3, whose expression influences cisplatin's cytotoxic effects.

  5. Mechanism of Hydrophilicity by Radiation-Induced Surface Activation

    Science.gov (United States)

    Honjo, Yoshio; Furuya, Masahiro; Takamasa, Tomoji; Okamoto, Koji

    When a metal oxide is irradiated by gamma rays, the irradiated surface becomes hydrophilic. This surface phenomenon is called as radiation-induced surface activation (RISA) hydrophilicity. In order to investigate gamma ray-induced and photoinduced hydrophilicity, the contact angles of water droplets on a titanium dioxide surface were measured in terms of irradiation intensity and time for gamma rays of cobalt-60 and for ultraviolet rays. Reciprocals of the contact angles increased in proportion to the irradiation time before the contact angles reached its super-hydrophilic state. The irradiation time dependency is equal to each other qualitatively. In addition, an effect of ambient gas was investigated. In pure argon gas, the contact angle remains the same against the irradiation time. This clearly indicates that certain humidity is required in ambient gas to take place of RISA hydrophilicity. A single crystal titanium dioxide (100) surface was analyzed by X-ray photoelectron spectrometry (XPS). After irradiation with gamma rays, a peak was found in the O1s spectrum, which indicates the adsorption of dissociative water to a surface 5-fold coordinate titanium site, and the formation of a surface hydroxyl group. We conclude that the RISA hydrophilicity is caused by chemisorption of the hydroxyl group on the surface.

  6. Load-Induced Confinement Activates Diamond Lubrication by Water

    Science.gov (United States)

    Zilibotti, G.; Corni, S.; Righi, M. C.

    2013-10-01

    Tribochemical reactions are chemical processes, usually involving lubricant or environment molecules, activated at the interface between two solids in relative motion. They are difficult to be monitored in situ, which leaves a gap in the atomistic understanding required for their control. Here we report the real-time atomistic description of the tribochemical reactions occurring at the interface between two diamond films in relative motion, by means of large scale ab initio molecular dynamics. We show that the load-induced confinement is able to catalyze diamond passivation by water dissociative adsorption. Such passivation decreases the energy of the contacting surfaces and increases their electronic repulsion. At sufficiently high coverages, the latter prevents surface sealing, thus lowering friction. Our findings elucidate effects of the nanoscale confinement on reaction kinetics and surface thermodynamics, which are important for the design of new lubricants.

  7. Active tunable plasmonically induced polarization conversion in the THz regime

    Science.gov (United States)

    Ling, Furi; Yao, Gang; Yao, Jianquan

    2016-01-01

    A plasmon-induced polarization conversion (PIPC) structure based on periodically patterned graphene was demonstrated in the THz regime. By varying the Fermi level of two connected T-shape graphene strips through the electrostatic gating, the peak frequency and the group index in the transparency window can be tuned, which is good agreement with the coupled Lorentz oscillator model. Due to interference between two polarization selective graphene plasmonic resonances coexisting in the planar metamaterial, polarization conversion can be achieved. The linearly polarized THz wave can be converted to elliptically and right circularly polarized THz wave through varying the relaxation time of electrons in graphene. This novel chip-scale active terahertz device promises essential application opportunities in terahertz sensing and terahertz communications. PMID:27734912

  8. Activity deprivation induces neuronal cell death: mediation by tissue-type plasminogen activator.

    Directory of Open Access Journals (Sweden)

    Eldi Schonfeld-Dado

    Full Text Available Spontaneous activity is an essential attribute of neuronal networks and plays a critical role in their development and maintenance. Upon blockade of activity with tetrodotoxin (TTX, neurons degenerate slowly and die in a manner resembling neurodegenerative diseases-induced neuronal cell death. The molecular cascade leading to this type of slow cell death is not entirely clear. Primary post-natal cortical neurons were exposed to TTX for up to two weeks, followed by molecular, biochemical and immunefluorescence analysis. The expression of the neuronal marker, neuron specific enolase (NSE, was down-regulated, as expected, but surprisingly, there was a concomitant and striking elevation in expression of tissue-type plasminogen activator (tPA. Immunofluorescence analysis indicated that tPA was highly elevated inside affected neurons. Transfection of an endogenous tPA inhibitor, plasminogen activator inhibitor-1 (PAI-1, protected the TTX-exposed neurons from dying. These results indicate that tPA is a pivotal player in slowly progressing activity deprivation-induced neurodegeneration.

  9. Bacterial Species-Specific Activity of a Fluoroquinolone against Two Closely Related Pasteurellaceae with Similar MICs: Differential In Vitro Inoculum Effects and In Vivo Efficacies.

    Directory of Open Access Journals (Sweden)

    Guillaume Lhermie

    Full Text Available We investigated the antimicrobial activity of a fluoroquinolone against two genetically close bacterial species belonging to the Pasteurellaceae family. Time-kill experiments were used to measure the in vitro activity of marbofloxacin against two strains of Mannheimia haemolytica and Pasteurella multocida with similar MICs. We observed that marbofloxacin was equally potent against 105 CFU/mL inocula M. haemolytica and P. multocida. However, an inoculum effect was observed with P. multocida, meaning that marbofloxacin activity was decreased against a 108 CFU/mL inoculum, whereas no inoculum effect was observed with M. haemolytica. Marbofloxacin activity was also tested in a lung infection model with immunocompromised mice intratracheally infected with 109 CFU of each bacteria. At the same dose, the clinical and bacteriological outcomes were much better for mice infected with M. haemolytica than for those infected with P. multocida. Moreover, bacteriological eradication was obtained with a lower marbofloxacin dose for mice infected with M. haemolytica. Our results suggest that the differential in vivo marbofloxacin efficacy observed with the two bacterial species of similar MIC could be explained by a differential inoculum effect. Consequently, MICs determined on 105 CFU inocula were not predictive of the differences in antibiotic efficacies against high bacterial inocula of closely related bacterial strains. These results could stimulate further investigations on bacterial species-specific antibiotic doses in a clinical setting.

  10. Bacterial Species-Specific Activity of a Fluoroquinolone against Two Closely Related Pasteurellaceae with Similar MICs: Differential In Vitro Inoculum Effects and In Vivo Efficacies

    Science.gov (United States)

    Lhermie, Guillaume; El Garch, Farid; Toutain, Pierre-Louis; Ferran, Aude A.; Bousquet-Mélou, Alain

    2015-01-01

    We investigated the antimicrobial activity of a fluoroquinolone against two genetically close bacterial species belonging to the Pasteurellaceae family. Time-kill experiments were used to measure the in vitro activity of marbofloxacin against two strains of Mannheimia haemolytica and Pasteurella multocida with similar MICs. We observed that marbofloxacin was equally potent against 105 CFU/mL inocula M. haemolytica and P. multocida. However, an inoculum effect was observed with P. multocida, meaning that marbofloxacin activity was decreased against a 108 CFU/mL inoculum, whereas no inoculum effect was observed with M. haemolytica. Marbofloxacin activity was also tested in a lung infection model with immunocompromised mice intratracheally infected with 109 CFU of each bacteria. At the same dose, the clinical and bacteriological outcomes were much better for mice infected with M. haemolytica than for those infected with P. multocida. Moreover, bacteriological eradication was obtained with a lower marbofloxacin dose for mice infected with M. haemolytica. Our results suggest that the differential in vivo marbofloxacin efficacy observed with the two bacterial species of similar MIC could be explained by a differential inoculum effect. Consequently, MICs determined on 105 CFU inocula were not predictive of the differences in antibiotic efficacies against high bacterial inocula of closely related bacterial strains. These results could stimulate further investigations on bacterial species-specific antibiotic doses in a clinical setting. PMID:26506096

  11. Ginger extract inhibits LPS induced macrophage activation and function

    Directory of Open Access Journals (Sweden)

    Bruch David

    2008-01-01

    Full Text Available Abstract Background Macrophages play a dual role in host defence. They act as the first line of defence by mounting an inflammatory response to antigen exposure and also act as antigen presenting cells and initiate the adaptive immune response. They are also the primary infiltrating cells at the site of inflammation. Inhibition of macrophage activation is one of the possible approaches towards modulating inflammation. Both conventional and alternative approaches are being studied in this regard. Ginger, an herbal product with broad anti inflammatory actions, is used as an alternative medicine in a number of inflammatory conditions like rheumatic disorders. In the present study we examined the effect of ginger extract on macrophage activation in the presence of LPS stimulation. Methods Murine peritoneal macrophages were stimulated by LPS in presence or absence of ginger extract and production of proinflammatory cytokines and chemokines were observed. We also studied the effect of ginger extract on the LPS induced expression of MHC II, B7.1, B7.2 and CD40 molecules. We also studied the antigen presenting function of ginger extract treated macrophages by primary mixed lymphocyte reaction. Results We observed that ginger extract inhibited IL-12, TNF-α, IL-1β (pro inflammatory cytokines and RANTES, MCP-1 (pro inflammatory chemokines production in LPS stimulated macrophages. Ginger extract also down regulated the expression of B7.1, B7.2 and MHC class II molecules. In addition ginger extract negatively affected the antigen presenting function of macrophages and we observed a significant reduction in T cell proliferation in response to allostimulation, when ginger extract treated macrophages were used as APCs. A significant decrease in IFN-γ and IL-2 production by T cells in response to allostimulation was also observed. Conclusion In conclusion ginger extract inhibits macrophage activation and APC function and indirectly inhibits T cell activation.

  12. Guard cell photosynthesis is critical for stomatal turgor production, yet does not directly mediate CO2 - and ABA-induced stomatal closing.

    Science.gov (United States)

    Azoulay-Shemer, Tamar; Palomares, Axxell; Bagheri, Andisheh; Israelsson-Nordstrom, Maria; Engineer, Cawas B; Bargmann, Bastiaan O R; Stephan, Aaron B; Schroeder, Julian I

    2015-08-01

    Stomata mediate gas exchange between the inter-cellular spaces of leaves and the atmosphere. CO2 levels in leaves (Ci) are determined by respiration, photosynthesis, stomatal conductance and atmospheric [CO2 ]. [CO2 ] in leaves mediates stomatal movements. The role of guard cell photosynthesis in stomatal conductance responses is a matter of debate, and genetic approaches are needed. We have generated transgenic Arabidopsis plants that are chlorophyll-deficient in guard cells only, expressing a constitutively active chlorophyllase in a guard cell specific enhancer trap line. Our data show that more than 90% of guard cells were chlorophyll-deficient. Interestingly, approximately 45% of stomata had an unusual, previously not-described, morphology of thin-shaped chlorophyll-less stomata. Nevertheless, stomatal size, stomatal index, plant morphology, and whole-leaf photosynthetic parameters (PSII, qP, qN, FV '/FM' ) were comparable with wild-type plants. Time-resolved intact leaf gas-exchange analyses showed a reduction in stomatal conductance and CO2 -assimilation rates of the transgenic plants. Normalization of CO2 responses showed that stomata of transgenic plants respond to [CO2 ] shifts. Detailed stomatal aperture measurements of normal kidney-shaped stomata, which lack chlorophyll, showed stomatal closing responses to [CO2 ] elevation and abscisic acid (ABA), while thin-shaped stomata were continuously closed. Our present findings show that stomatal movement responses to [CO2 ] and ABA are functional in guard cells that lack chlorophyll. These data suggest that guard cell CO2 and ABA signal transduction are not directly modulated by guard cell photosynthesis/electron transport. Moreover, the finding that chlorophyll-less stomata cause a 'deflated' thin-shaped phenotype, suggests that photosynthesis in guard cells is critical for energization and guard cell turgor production.

  13. Denitrification activity is closely linked to the total ambient Fe concentration in mangrove sediments of Goa, India

    Digital Repository Service at National Institute of Oceanography (India)

    Fernandes, S.O.; Gonsalves, M.J.B.D.; Michotey, V.D.; Bonin, P.C.; LokaBharathi, P.A.

    (Corredor and Morell, 1994) or wastewater treatment (Nedwell, 1975). Chiu et al. (2004) have quantified denitrification and assessed the factors affecting the process in temperate mangrove sediment. Some of the factors influencing the activity...; Corredor and Morell, 1994; Kana et al., 1998) and organic carbon (Mc Carty and Bremner, 1993; Pfenning and Mc Mahon 1997; Ward et al., 2008). Earlier studies in the mangrove swamps of Goa have shown trace metal contamination derived mainly from ferro...

  14. Pd Close Coupled Catalyst

    Institute of Scientific and Technical Information of China (English)

    Zhong Hua SHI; Mao Chu GONG; Yao Qiang CHEN

    2006-01-01

    A catalyst comprised novel high surface area alumina support was prepared to control emission of automobiles. The results showed that prepared catalyst could satisfy the requirements of a high performance close coupled catalyst for its good catalytic activity at low temperature and good stability at high temperature.

  15. Neuronal activity-induced regulation of Lingo-1.

    Science.gov (United States)

    Trifunovski, Alexandra; Josephson, Anna; Ringman, Andreas; Brené, Stefan; Spenger, Christian; Olson, Lars

    2004-10-25

    Axonal regeneration after injury can be limited in the adult CNS by the presence of inhibitory proteins such as Nogo. Nogo binds to a receptor complex that consists of Nogo receptor (NgR), p75NTR, and Lingo-1. Nogo binding activates RhoA, which inhibits axonal outgrowth. Here we assessed Lingo-1 and NgR mRNA levels after delivery of BDNF into the rat hippocampal formation, Lingo-1 mRNA levels in rats subjected to kainic acid (KA) and running in running wheels. Lingo-1 mRNA was not changed by running. However, we found that Lingo-1 mRNA was strongly up-regulated while NgR mRNA was down-regulated in the dentate gyrus in both the BDNF and the KA experiments. Our data demonstrate inverse regulation of NgR and Lingo-1 in these situations, suggesting that Lingo-1 up-regulation is one characteristic of activity-induced neural plasticity responses.

  16. RIP3 induces apoptosis independent of pronecrotic kinase activity.

    Science.gov (United States)

    Mandal, Pratyusha; Berger, Scott B; Pillay, Sirika; Moriwaki, Kenta; Huang, Chunzi; Guo, Hongyan; Lich, John D; Finger, Joshua; Kasparcova, Viera; Votta, Bart; Ouellette, Michael; King, Bryan W; Wisnoski, David; Lakdawala, Ami S; DeMartino, Michael P; Casillas, Linda N; Haile, Pamela A; Sehon, Clark A; Marquis, Robert W; Upton, Jason; Daley-Bauer, Lisa P; Roback, Linda; Ramia, Nancy; Dovey, Cole M; Carette, Jan E; Chan, Francis Ka-Ming; Bertin, John; Gough, Peter J; Mocarski, Edward S; Kaiser, William J

    2014-11-20

    Receptor-interacting protein kinase 3 (RIP3 or RIPK3) has emerged as a central player in necroptosis and a potential target to control inflammatory disease. Here, three selective small-molecule compounds are shown to inhibit RIP3 kinase-dependent necroptosis, although their therapeutic value is undermined by a surprising, concentration-dependent induction of apoptosis. These compounds interact with RIP3 to activate caspase 8 (Casp8) via RHIM-driven recruitment of RIP1 (RIPK1) to assemble a Casp8-FADD-cFLIP complex completely independent of pronecrotic kinase activities and MLKL. RIP3 kinase-dead D161N mutant induces spontaneous apoptosis independent of compound, whereas D161G, D143N, and K51A mutants, like wild-type, only trigger apoptosis when compound is present. Accordingly, RIP3-K51A mutant mice (Rip3(K51A/K51A)) are viable and fertile, in stark contrast to the perinatal lethality of Rip3(D161N/D161N) mice. RIP3 therefore holds both necroptosis and apoptosis in balance through a Ripoptosome-like platform. This work highlights a common mechanism unveiling RHIM-driven apoptosis by therapeutic or genetic perturbation of RIP3.

  17. An Engineered Herpesvirus Activates Dendritic Cells and Induces Protective Immunity

    Science.gov (United States)

    Ma, Yijie; Chen, Min; Jin, Huali; Prabhakar, Bellur S.; Valyi-Nagy, Tibor; He, Bin

    2017-01-01

    Herpes simplex viruses (HSV) are human pathogens that switch between lytic and latent infection. While attenuated HSV is explored for vaccine, the underlying event remains poorly defined. Here we report that recombinant HSV-1 with a mutation in the γ134.5 protein, a virulence factor, stimulates dendritic cell (DC) maturation which is dependent on TANK-binding kinase 1 (TBK1). When exposed to CD11+ DCs, the mutant virus that lacks the amino terminus of γ134.5 undergoes temporal replication without production of infectious virus. Mechanistically, this leads to sequential phosphorylation of interferon regulatory factor 3 (IRF3) and p65/RelA. In correlation, DCs up-regulate the expression of co-stimulatory molecules and cytokines. However, selective inhibition of TBK1 precludes phosphorylation of IRF3 and subsequent DC activation by the γ134.5 mutant. Herein, the γ134.5 mutant is immune-stimulatory and non-destructive to DCs. Remarkably, upon immunization the γ134.5 mutant induces protection against lethal challenge by the wild type virus, indicative of its vaccine potential. Furthermore, CD11+ DCs primed by the γ134.5 mutant in vivo mediate protection upon adoptive transfer. These results suggest that activation of TBK1 by engineered HSV is crucial for DC maturation, which may contribute to protective immunity. PMID:28150813

  18. Light-induced self-assembly of active rectification devices.

    Science.gov (United States)

    Stenhammar, Joakim; Wittkowski, Raphael; Marenduzzo, Davide; Cates, Michael E

    2016-04-01

    Self-propelled colloidal objects, such as motile bacteria or synthetic microswimmers, have microscopically irreversible individual dynamics-a feature they share with all living systems. The incoherent behavior of individual swimmers can be harnessed (or "rectified") by microfluidic devices that create systematic motions that are impossible in equilibrium. We present a computational proof-of-concept study showing that such active rectification devices could be created directly from an unstructured "primordial soup" of light-controlled motile particles, solely by using spatially modulated illumination to control their local propulsion speed. Alongside both microscopic irreversibility and speed modulation, our mechanism requires spatial symmetry breaking, such as a chevron light pattern, and strong interactions between particles, such as volume exclusion, which cause a collisional slowdown at high density. Together, we show how these four factors create a novel, many-body rectification mechanism. Our work suggests that standard spatial light modulator technology might allow the programmable, light-induced self-assembly of active rectification devices from an unstructured particle bath.

  19. Thioredoxin interacting protein inhibits hypoxia-inducible factor transcriptional activity

    Science.gov (United States)

    Farrell, Michael R; Rogers, Lynette K; Liu, Yusen; Welty, Stephen E; Tipple, Trent E

    2010-01-01

    Vascular endothelial growth factor (VEGF) is required for proper lung development and is transcriptionally regulated in alveolar epithelial cells by hypoxia inducible factor (HIF). Previous findings in a newborn mouse model of bronchopulmonary dysplasia (BPD) suggest that thioredoxin interacting protein (Txnip) is a novel regulator of VEGF expression. The present studies were designed to test the hypothesis that Txnip negatively regulates VEGF through effects on HIF-mediated gene expression. To test this hypothesis, we first examined the levels of VEGF and Txnip protein in the lungs of 1 day-old newborn and E19 embryos and detected a significant inverse correlation. To elucidate the mechanisms underlying this relationship, we studied the effects of Txnip overexpression on HIF-mediated transcription using murine lung epithelial (MLE-12) cells. Overexpression of Txnip inhibited HIF-mediated reporter activity in both hypoxia and room air. Suppression of HIF activity by Txnip appeared to be independent of the ability of Txnip to bind to thioredoxin. Thus, our studies support a model in which Txnip is a potentially critical regulator of HIF-mediated gene transcription in the murine lung. Alterations in Txnip expression could alter lung VEGF expression in prematurely born human infants and contribute to the development of BPD. PMID:20692333

  20. p38 Mitogen-Activated Protein Kinase in beryllium-induced dendritic cell activation.

    Science.gov (United States)

    Li, L; Huang, Z; Gillespie, M; Mroz, P M; Maier, L A

    2014-12-01

    Dendritic cells (DC) play a role in the regulation of immune responses to haptens, which in turn impact DC maturation. Whether beryllium (Be) is able to induce DC maturation and if this occurs via the MAPK pathway is not known. Primary monocyte-derived DCs (moDCs) models were generated from Be non-exposed healthy volunteers as a non-sensitized cell model, while PBMCs from BeS (Be sensitized) and CBD (chronic beryllium disease) were used as disease models. The response of these cells to Be was evaluated. The expression of CD40 was increased significantly (pBeSO₄-stimulation. BeSO₄ induced p38MAPK phosphorylation, while IκB-α was degraded in Be-stimulated moDCs. The p38 MAPK inhibitor SB203580 blocked Be-induced NF-κB activation in moDCs, suggesting that p38MAPK and NF-κB are dependently activated by BeSO₄. Furthermore, in BeS and CBD subjects, SB203580 downregulated Be-stimulated proliferation in a dose-dependent manner, and decreased Be-stimulated TNF-α and IFNγ cytokine production. Taken together, this study suggests that Be-induces non-sensitized Glu69+ DCs maturation, and that p38MAPK signaling is important in the Be-stimulated DCs activation as well as subsequent T cell proliferation and cytokine production in BeS and CBD. In total, the MAPK pathway may serve as a potential therapeutic target for human granulomatous lung diseases.

  1. Ring-Closing and Cross-Metathesis with Artificial Metalloenzymes Created by Covalent Active Site-Directed Hybridization of a Lipase.

    Science.gov (United States)

    Basauri-Molina, Manuel; Verhoeven, Dide G A; van Schaik, Arnoldus J; Kleijn, Henk; Klein Gebbink, Robertus J M

    2015-10-26

    A series of Grubbs-type catalysts that contain lipase-inhibiting phosphoester functionalities have been synthesized and reacted with the lipase cutinase, which leads to artificial metalloenzymes for olefin metathesis. The resulting hybrids comprise the organometallic fragment that is covalently bound to the active amino acid residue of the enzyme host in an orthogonal orientation. Differences in reactivity as well as accessibility of the active site by the functionalized inhibitor became evident through variation of the anchoring motif and substituents on the N-heterocyclic carbene ligand. Such observations led to the design of a hybrid that is active in the ring-closing metathesis and the cross-metathesis of N,N-diallyl-p-toluenesulfonamide and allylbenzene, respectively, the latter being the first example of its kind in the field of artificial metalloenzymes.

  2. Fracture-induced mechanophore activation and solvent healing in poly(methyl methacrylate)

    Science.gov (United States)

    Celestine, Asha-Dee N.

    of the crack tip. Control specimens in which the mechanophore is absent or tethered in positions in which no mechanochemical activation is expected are also tested and exhibit no change in color or fluorescence intensity with crack propagation. The relationship between fracture-induced mechanophore activation in rubber toughened SP-PMMA and the strain and stress ahead of the propagating crack is also studied. SP activation is again detected and quantified by in situ fluorescence imaging. Digital Image Correlation (DIC) is used to measure the strain ahead of the crack tip. The corresponding stress is generated through the use of the Hutchinson-Rice-Rosengren (HRR) singularity field equations. Mechanophore activation ahead of the crack tip is shown to follow a power law distribution that is closely aligned with strain. The potential of SP as a damage sensor is explored further by incorporating the spiropyran into the core of rubber nanoparticles. SP-linked rubber nanoparticles are synthesized using a seeded emulsion polymerization process and incorporated into cross-linked PMMA at a concentration of 5 wt%. Cylindrical specimens are torsion tested and the activation of the SP within the nanoparticles is monitored via full field fluorescence imaging. SP activation within the core is shown to increase with shear strain. Autonomous damage repair in PMMA is also investigated. The first demonstration of fully autonomous self-healing in PMMA is achieved through the use of solvent microcapsules. Solvent microcapsules with a PMMA-anisole liquid core are prepared and embedded within a linear PMMA matrix. Specimens of the microcapsule-loaded material are then fabricated for Double Cleavage Drilled Compression (DCDC) fracture testing. The DCDC specimens, containing increasing concentrations of solvent microcapsules, are tested and then allowed to heal for a fixed period of time before a second DCDC test. The healing efficiency of each material system is evaluated based on the

  3. Simplified Fiber-Wireless Distribution of HD Video in Passive and Active W-band Close Proximity Terminals

    DEFF Research Database (Denmark)

    Lebedev, Alexander; Rodes Lopez, Roberto; Yu, Xianbin;

    2012-01-01

    We experimentally demonstrate uncompressed high-definition (HD) video distribution at 84 GHz Radio over Fiber link achieving up to 3 meters of wireless transmission. We experimentally emulate Metro-Access architecture by deploying single/multimode fibers. Passive and active approaches for remote...... antenna unit (RAU) are experimentally investigated. The bit error rate (BER) performance of the optical and wireless channels is reported. A successful transmission of uncompressed HD video in the W-band wireless channel is demonstrated with prospects to pave the way for application-focused fiber...

  4. Accelerated ovum transport in rabbits induced by endotoxin II. Changes in oviductal smooth muscle activity.

    Science.gov (United States)

    Hodgson, B J; Harper, M J; Valenzuela, G

    1978-01-01

    Oviductal mortility, measured with open-ended perfused catheters in anesthetized animals injected with human Chorionic Gonadotropin (hCG), is depressed 2 h following endotoxin injection and returns to control levels by 3 h after endotoxin injection. This decrease in motility is prevented by indomethacin. Endotoxin did not affect spontaneous or phenylephrine (PE)-induced contractions of oviduct when it was added to the bathing medium of in vitro tissues. Oviductal segments removed 2 h after endotoxin (26 h after hCG) showed electrical activity confined to the ampullary-isthmic-junction (AIJ), where ova were located; the dose-response curve for PE was shifted to the right and the maximum contraction was depressed. Activity of tissues removed 4 h after endotoxin more closely resembled control tissues except that the maximum contraction to PE was depressed, ova had passed out of the oviduct and a proovarian bias in the isthmus was not present. The response of the oviduct to prostaglandins (PGs) in vivo is critically dependent on the previous exposure to PGs. In endotoxin-treated animals PGE then PGF levels increase and the decrease in motility coincides with increased PGE levels, but accelerated ovum transport with the return of motility and activation of the isthmus.

  5. Quantifying signaling pathway activation to monitor the quality of induced pluripotent stem cells.

    Science.gov (United States)

    Makarev, Eugene; Fortney, Kristen; Litovchenko, Maria; Braunewell, Karl H; Zhavoronkov, Alex; Atala, Anthony

    2015-09-15

    Many attempts have been made to evaluate the safety and potency of human induced pluripotent stem cells (iPSCs) for clinical applications using transcriptome data, but results so far have been ambiguous or even contradictory. Here, we characterized stem cells at the pathway level, rather than at the gene level as has been the focus of previous work. We meta-analyzed publically-available gene expression data sets and evaluated signaling and metabolic pathway activation profiles for 20 human embryonic stem cell (ESC) lines, 12 human iPSC lines, five embryonic body lines, and six fibroblast cell lines. We demonstrated the close resemblance of iPSCs with ESCs at the pathway level, and provided examples of how pathway activity can be applied to identify iPSC line abnormalities or to predict in vitro differentiation potential. Our results indicate that pathway activation profiling is a promising strategy for evaluating the safety and potency of iPSC lines in translational medicine applications.

  6. Hydrophobic interactions as key determinants to the KCa3.1 channel closed configuration. An analysis of KCa3.1 mutants constitutively active in zero Ca2+.

    Science.gov (United States)

    Garneau, Line; Klein, Hélène; Banderali, Umberto; Longpré-Lauzon, Ariane; Parent, Lucie; Sauvé, Rémy

    2009-01-02

    In this study we present evidence that residue Val282 in the S6 transmembrane segment of the calcium-activated KCa3.1 channel constitutes a key determinant of channel gating. A Gly scan of the S6 transmembrane segment first revealed that the substitutions A279G and V282G cause the channel to become constitutively active in zero Ca2+. Constitutive activity was not observed when residues extending from Cys276 to Ala286, other than Ala279 and Val282, were substituted to Gly. The accessibility of Cys engineered at Val275 deep in the channel cavity was next investigated for the ion-conducting V275C/V282G mutant and closed V275C channel in zero Ca2+ using Ag+ as probe. These experiments demonstrated that internal Ag+ ions have free access to the channel cavity independently of the channel conducting state, arguing against an activation gate located at the S6 segment C-terminal end. Experiments were also conducted where Val282 was substituted by residues differing in size and/or hydrophobicity. We found a strong correlation between constitutive activity in zero Ca2+ and the hydrophobic energy for side chain burial. Single channel recordings showed finally that constitutive activation in zero Ca2+ is better explained by a model where the channel is locked in a low conducting state with a high open probability rather than resulting from a change in the open/closed energy balance that would favor channel openings to a full conducting state in the absence of Ca2+. We conclude that hydrophobic interactions involving Val282 constitute key determinants to KCa3.1 gating by modulating the ion conducting state of the selectivity filter through an effect on the S6 transmembrane segment.

  7. Methoxychlor induces atresia by altering Bcl2 factors and inducing caspase activity in mouse ovarian antral follicles in vitro.

    Science.gov (United States)

    Basavarajappa, Mallikarjuna S; Karman, Bethany N; Wang, Wei; Gupta, Rupesh K; Flaws, Jodi A

    2012-12-01

    Methoxychlor (MXC) is an organochlorine pesticide widely used in many countries against various species of insects that attack crops and domestic animals. MXC reduces fertility by increasing atresia (death) of antral follicles in vivo. MXC also induces atresia of antral follicles after 96 h in vitro. The current work tested the hypothesis that MXC induces morphological atresia at early time points (24 and 48 h) by altering pro-apoptotic (Bax, Bok, Casp3, and caspase activity) and anti-apoptotic (Bcl2 and Bcl-xL) factors in the follicles. The results indicate that at 24 h, MXC increased Bcl-xL and Bax mRNA levels and increased the ratio of Bax/Bcl2. At 48-96 h, MXC induced morphological atresia. At 24-96 h, MXC increased caspase activities. These data suggest that MXC may induce atresia by altering Bcl2 factors and inducing caspase activities in antral follicles.

  8. Recombinant N-Terminal Slit2 Inhibits TGF-β-Induced Fibroblast Activation and Renal Fibrosis.

    Science.gov (United States)

    Yuen, Darren A; Huang, Yi-Wei; Liu, Guang-Ying; Patel, Sajedabanu; Fang, Fei; Zhou, Joyce; Thai, Kerri; Sidiqi, Ahmad; Szeto, Stephen G; Chan, Lauren; Lu, Mingliang; He, Xiaolin; John, Rohan; Gilbert, Richard E; Scholey, James W; Robinson, Lisa A

    2016-09-01

    Fibrosis and inflammation are closely intertwined injury pathways present in nearly all forms of CKD for which few safe and effective therapies exist. Slit glycoproteins signaling through Roundabout (Robo) receptors have been described to have anti-inflammatory effects through regulation of leukocyte cytoskeletal organization. Notably, cytoskeletal reorganization is also required for fibroblast responses to TGF-β Here, we examined whether Slit2 also controls TGF-β-induced renal fibrosis. In cultured renal fibroblasts, which we found to express Slit2 and Robo-1, the bioactive N-terminal fragment of Slit2 inhibited TGF-β-induced collagen synthesis, actin cytoskeletal reorganization, and Smad2/3 transcriptional activity, but the inactive C-terminal fragment of Slit2 did not. In mouse models of postischemic renal fibrosis and obstructive uropathy, treatment with N-terminal Slit2 before or after injury inhibited the development of renal fibrosis and preserved renal function, whereas the C-terminal Slit2 had no effect. Our data suggest that administration of recombinant Slit2 may be a new treatment strategy to arrest chronic injury progression after ischemic and obstructive renal insults by not only attenuating inflammation but also, directly inhibiting renal fibrosis.

  9. Pressure-related activation of inducible nitric oxide synthase

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    A lot of reports suggested that inducible nitric oxide synthase (iNOS) has a very different nature from constitutive NOS including endothelial NOS (eNOS) and neural NOS (nNOS). When exposed to cytokines or bacterial products, iNOS could be greatly activated and produces hundreds or thousands fold more NO than it does usually. Whether iNOS activation is arterial pressure related is not clear. In the present experiment, we studied three groups(n=6) of Sprague Dawley (SD) rats with implanted aorta and venous catheters that were maintained on 1 mEq/d, 12.5 mEq/d and 25 mEq/d of sodium intake respectively. Pulsatile arterial pressure signals from the amplifier were sent to a digital computer and the urine samples were taken every other day for nitrate/nitrite excretion (UNOx) assay using Greiss Reaction. After 6 days infusion, the rats were euthanized with an overdose of sodium pentobarbital, and the renal medullas were rapidly removed and frozen on dry ice for iNOS activity assay. Morever separate groups of hypertensive rats including spontaneously hypertensive rat (SHR, n=6) and High NaCl-induced hypertensive rat (NaHR, n=6) were used to measure renal iNOS protein by Western Blotting. The results showed that the mean arterial pressure (MAP) were significantly increased with the increase intake of sodium, the MAP (mmHg) at day 6 were 99.6±3.5,116.65±4.2 and 125.43±4.5, and the iNOS activity (nmol*g-1 protein*min-1) were 122.3±23.4, 342.4±35.6 and 623.9±65.4 in 1 mEq/d, 12.5 mEq/d and 25 mEq/d of sodium intake-rats respectively. At the same time, UNOx at day 6 were also increased, in turn, to 5 865.6±343.0 (for 12.5 mEq/d intake-rats) and (9 642.8±1 045.3) (for 25 mEq/d sodium intake-rats) nmol/d from (3 834.9±234.8) nmol/d of 1 mEq/d sodium intake-rats respectively. Western blotting showed that the renal medullary iNOS protein in SHR and NaHR were increased by 178%±13% and 104%±9% of normal Wistar rats. The data indicates that elevated arterial pressure

  10. Nf1+/- monocytes/macrophages induce neointima formation via CCR2 activation.

    Science.gov (United States)

    Bessler, Waylan K; Kim, Grace; Hudson, Farlyn Z; Mund, Julie A; Mali, Raghuveer; Menon, Keshav; Kapur, Reuben; Clapp, D Wade; Ingram, David A; Stansfield, Brian K

    2016-03-15

    Persons with neurofibromatosis type 1 (NF1) have a predisposition for premature and severe arterial stenosis. Mutations in the NF1 gene result in decreased expression of neurofibromin, a negative regulator of p21(Ras), and increases Ras signaling. Heterozygous Nf1 (Nf1(+/-)) mice develop a marked arterial stenosis characterized by proliferating smooth muscle cells (SMCs) and a predominance of infiltrating macrophages, which closely resembles arterial lesions from NF1 patients. Interestingly, lineage-restricted inactivation of a single Nf1 allele in monocytes/macrophages is sufficient to recapitulate the phenotype observed in Nf1(+/-) mice and to mobilize proinflammatory CCR2+ monocytes into the peripheral blood. Therefore, we hypothesized that CCR2 receptor activation by its primary ligand monocyte chemotactic protein-1 (MCP-1) is critical for monocyte infiltration into the arterial wall and neointima formation in Nf1(+/-) mice. MCP-1 induces a dose-responsive increase in Nf1(+/-) macrophage migration and proliferation that corresponds with activation of multiple Ras kinases. In addition, Nf1(+/-) SMCs, which express CCR2, demonstrate an enhanced proliferative response to MCP-1 when compared with WT SMCs. To interrogate the role of CCR2 activation on Nf1(+/-) neointima formation, we induced neointima formation by carotid artery ligation in Nf1(+/-) and WT mice with genetic deletion of either MCP1 or CCR2. Loss of MCP-1 or CCR2 expression effectively inhibited Nf1(+/-) neointima formation and reduced macrophage content in the arterial wall. Finally, administration of a CCR2 antagonist significantly reduced Nf1(+/-) neointima formation. These studies identify MCP-1 as a potent chemokine for Nf1(+/-) monocytes/macrophages and CCR2 as a viable therapeutic target for NF1 arterial stenosis.

  11. Damage-induced DNA replication stalling relies on MAPK-activated protein kinase 2 activity

    DEFF Research Database (Denmark)

    Köpper, Frederik; Bierwirth, Cathrin; Schön, Margarete

    2013-01-01

    DNA damage can obstruct replication forks, resulting in replicative stress. By siRNA screening, we identified kinases involved in the accumulation of phosphohistone 2AX (γH2AX) upon UV irradiation-induced replication stress. Surprisingly, the strongest reduction of phosphohistone 2AX followed...... replication impaired by gemcitabine or by Chk1 inhibition. This rescue strictly depended on translesion DNA polymerases. In conclusion, instead of being an unavoidable consequence of DNA damage, alterations of replication speed and origin firing depend on MK2-mediated signaling....... knockdown of the MAP kinase-activated protein kinase 2 (MK2), a kinase currently implicated in p38 stress signaling and G2 arrest. Depletion or inhibition of MK2 also protected cells from DNA damage-induced cell death, and mice deficient for MK2 displayed decreased apoptosis in the skin upon UV irradiation...

  12. Direct Optical Ice Sensing and Closed-Loop Controller Design for Active De-icing of Wind Turbines Using Distributed Heating

    Science.gov (United States)

    Shajiee, Shervin

    Ice accumulation on wind turbines operating in cold regions reduces power generation by degrading aerodynamic efficiency and causes mass imbalance and fatigue loads on the blades. Due to blade rotation and variation of the pitch angle, different locations on the blade experience large variations of Reynolds number, Nusselt number, heat loss, and non-uniform ice distribution. Hence, applying different amounts of heat flux in different blade locations can provide more effective de-icing for the same total power consumption. This large variation of required heat flux motivates using distributed resistive heating, with the capability of locally adjusting thermal power as a function of location on the blade. The main contributions of this research are developing the experimental feasibility of direct ice sensing using an optical sensing technique as well as development of a computational framework for implementation of closed-loop localized active de-icing using distributed sensing. A script-base module was developed in a commercial finite-element software (ANSYS) which provides the capability of (i) Closed-loop de-icing simulations for a distributed network of sensors and actuators, (ii) investigating different closed-loop thermal control schemes and their de-icing efficiency (iii) optimizing thermal actuation for a distributed resistive heating, and (iv) analyzing different faulty scenarios for sensors and thermal actuators under known faults in the network. Different surrogate models were used to enhance the computational efficiency of this approach. The results showed that optimal value of control parameters in a distributed network of heaters depends on convective heat transfer characteristics, layout of heaters and type of closed-loop controller scheme used for thermal actuation. Furthermore, It was shown that closed-loop control provides much faster de-icing than the open-loop constant heat flux thermal actuation. It was observed both experimentally and

  13. Control plasma renin activity and changes in sympathetic tone as determinants of minoxidil-induced increase in plasma renin activity.

    Science.gov (United States)

    O'Malley, K; Velasco, M; Wells, J; McNay, J L

    1975-01-01

    A study was made of the possible mechanism(s) underlying minoxidil-induced increase in plasma renin activity (PRA). 10 patients with essential hypertension were treated with minoxidil and subsequently with a combination of minoxidil plus propranolol. Minoxidil lowered mean arterial pressure 31.6 plus or minus 3.3 mm Hg, mean plus or minus SEM. There was an associated increase in both PRA, 6.26 plus or minus 2.43 NG/ML/H, and heart rate, 21.4 plus or minus 2.7 beats/min. The changes in PRA and heart rate were positively correlated, r, 0.79. Addition of propranolol reduced mean arterial pressure by a further 10.1 plus or minus 1.5 mm Hg and returned heart rate to control levels. Propranolol reduced PRA significantly but not to control levels. Control PRA positively correlated with PRA on minoxidil, r, 0.97, and with PRA on minoxidil plus propranolol, r, 0.98. We conclude that control PRA is a major determinant of change in PRA with minoxidil. Minoxidil increased PRA by at least two mechanisms: (a) an adrenergic mechanism closely related to change in heart rate and blocked by propranolol, and (b) a mechanism(s) not sensitive to propranolol and possibly related to decrease in renal perfusion pressure. PMID:1127099

  14. Differential activities of glucocorticoid-induced leucine zipper protein isoforms.

    Science.gov (United States)

    Soundararajan, Rama; Wang, Jian; Melters, Daniël; Pearce, David

    2007-12-14

    Glucocorticoid-induced leucine zipper protein (GILZ) is expressed in both epithelial and immune tissues and modulates a variety of cellular functions, including proliferation and epithelial sodium channel (ENaC) activity. A number of reports have described various GILZ activities, focusing on a single isoform with molecular mass of approximately 17 kDa, now termed GILZ1. In GILZ immunoblots using a newly developed antiserum, we detected multiple species in extracts from cultured kidney cells. Mass spectrometric analysis revealed that one of these represented a previously uncharacterized distinct isoform of GILZ, GILZ2. Rapid amplification of cDNA ends was used to clone cDNAs corresponding to four isoforms, which, in addition to GILZ1 and GILZ2, included new isoforms GILZ3 and GILZ4. Heterologous expression of these four GILZ isoforms in cultured cells revealed striking functional differences. Notably, GILZ1 was the only isoform that significantly stimulated ENaC-mediated Na+ current in a kidney collecting duct cell line, although GILZ2 and GILZ3 also stimulated ENaC surface expression in HEK 293 cells. GILZ1 and GILZ3, and to a lesser extent GILZ2, inhibited ERK phosphorylation. Interestingly, GILZ4, which had no effect on either ENaC or ERK, potently suppressed cellular proliferation, as did GILZ1, but not GILZ2 or GILZ3. Finally, rat and mouse tissues all expressed multiple GILZ species but varied in the relative abundance of each. These data suggest that multiple GILZ isoforms are expressed in most cells and tissues and that these play distinct roles in regulating key cellular functions, including proliferation and ion transport. Furthermore, GILZ inhibition of ERK appears to play an essential role in stimulation of cell surface ENaC but not in inhibition of proliferation.

  15. Mitogen-Activated Protein Kinases Regulate Susceptibility to Ventilator-Induced Lung Injury

    OpenAIRE

    2008-01-01

    BACKGROUND: Mechanical ventilation causes ventilator-induced lung injury in animals and humans. Mitogen-activated protein kinases have been implicated in ventilator-induced lung injury though their functional significance remains incomplete. We characterize the role of p38 mitogen-activated protein kinase/mitogen activated protein kinase kinase-3 and c-Jun-NH(2)-terminal kinase-1 in ventilator-induced lung injury and investigate novel independent mechanisms contributing to lung injury during ...

  16. Electrophysiological correlates of competitor activation predict retrieval-induced forgetting.

    Science.gov (United States)

    Hellerstedt, Robin; Johansson, Mikael

    2014-06-01

    The very act of retrieval modifies the accessibility of memory for knowledge and past events and can also cause forgetting. A prominent theory of such retrieval-induced forgetting (RIF) holds that retrieval recruits inhibition to overcome interference from competing memories, rendering these memories inaccessible. The present study tested a fundamental tenet of the inhibitory-control account: The competition-dependence assumption. Event-related potentials (ERPs) were recorded while participants engaged in a competitive retrieval task. Competition levels were manipulated within the retrieval task by varying the cue-item associative strength of competing items. In order to temporally separate ERP correlates of competitor activation and target retrieval, memory was probed with the sequential presentation of 2 cues: A category cue, to reactivate competitors, and a target cue. As predicted by the inhibitory-control account, competitors with strong compared with weak cue-competitor association were more susceptible to forgetting. Furthermore, competition-sensitive ERP modulations, elicited by the category cue, were observed over anterior regions and reflected individual differences in ensuing forgetting. The present study demonstrates ERP correlates of the reactivation of tightly bound associated memories (the competitors) and provides support for the inhibitory-control account of RIF.

  17. Ethylene mediates brassinosteroid-induced stomatal closure via Gα protein-activated hydrogen peroxide and nitric oxide production in Arabidopsis.

    Science.gov (United States)

    Shi, Chenyu; Qi, Cheng; Ren, Hongyan; Huang, Aixia; Hei, Shumei; She, Xiaoping

    2015-04-01

    Brassinosteroids (BRs) are essential for plant growth and development; however, whether and how they promote stomatal closure is not fully clear. In this study, we report that 24-epibrassinolide (EBR), a bioactive BR, induces stomatal closure in Arabidopsis (Arabidopsis thaliana) by triggering a signal transduction pathway including ethylene synthesis, the activation of Gα protein, and hydrogen peroxide (H(2)O(2)) and nitric oxide (NO) production. EBR initiated a marked rise in ethylene, H(2)O(2) and NO levels, necessary for stomatal closure in the wild type. These effects were abolished in mutant bri1-301, and EBR failed to close the stomata of gpa1 mutants. Next, we found that both ethylene and Gα mediate the inductive effects of EBR on H(2)O(2) and NO production. EBR-triggered H(2)O(2) and NO accumulation were canceled in the etr1 and gpa1 mutants, but were strengthened in the eto1-1 mutant and the cGα line (constitutively overexpressing the G protein α-subunit AtGPA1). Exogenously applied H(2)O(2) or sodium nitroprusside (SNP) rescued the defects of etr1-3 and gpa1 or etr1 and gpa1 mutants in EBR-induced stomatal closure, whereas the stomata of eto1-1/AtrbohF and cGα/AtrbohF or eto1-1/nia1-2 and cGα/nia1-2 constructs had an analogous response to H(2)O(2) or SNP as those of AtrbohF or Nia1-2 mutants. Moreover, we provided evidence that Gα plays an important role in the responses of guard cells to ethylene. Gα activator CTX largely restored the lesion of the etr1-3 mutant, but ethylene precursor ACC failed to rescue the defects of gpa1 mutants in EBR-induced stomatal closure. Lastly, we demonstrated that Gα-activated H(2)O(2) production is required for NO synthesis. EBR failed to induce NO synthesis in mutant AtrbohF, but it led to H(2)O(2) production in mutant Nia1-2. Exogenously applied SNP rescued the defect of AtrbohF in EBR-induced stomatal closure, but H(2)O(2) did not reverse the lesion of EBR-induced stomatal closure in Nia1-2. Together, our

  18. Trace elements induce predominance among methanogenic activity in anaerobic digestion

    Directory of Open Access Journals (Sweden)

    Babett Wintsche

    2016-12-01

    Full Text Available Trace elements play an essential role in all organisms due to their functions in enzyme complexes. In anaerobic digesters, control and supplementation of trace elements lead to stable and more efficient methane production processes while trace element deficits cause process imbalances. However, the underlying metabolic mechanisms and the adaptation of the affected microbial communities to such deficits are not yet fully understood. Here, we investigated the microbial community dynamics and resulting process changes induced by trace element deprivation. Two identical lab-scale continuous stirred tank reactors fed with distiller’s grains and supplemented with trace elements (cobalt, molybdenum, nickel, tungsten and a commercial iron additive were operated in parallel. After 72 weeks of identical operation, the feeding regime of one reactor was changed by omitting trace element supplements and reducing the amount of iron additive. Both reactors were operated for further 21 weeks. Various process parameters (biogas production and composition, total solids and volatile solids, trace element concentration, volatile fatty acids, total ammonium nitrogen, total organic acids/alkalinity ratio, and pH and the composition and activity of the microbial communities were monitored over the total experimental time. While the methane yield remained stable, the concentrations of hydrogen sulfide, total ammonia nitrogen, and acetate increased in the trace element-depleted reactor compared to the well-supplied control reactor. Methanosarcina and Methanoculleus dominated the methanogenic communities in both reactors. However, the activity ratio of these two genera was shown to depend on trace element supplementation explainable by different trace element requirements of their energy conservation systems. Methanosarcina dominated the well-supplied anaerobic digester, pointing to acetoclastic methanogenesis as the dominant methanogenic pathway. Under trace element

  19. EDITORIAL: Close contact Close contact

    Science.gov (United States)

    Demming, Anna

    2010-07-01

    The development of scanning probe techniques, such as scanning tunnelling microscopy [1], has often been touted as the catalyst for the surge in activity and progress in nanoscale science and technology. Images of nanoscale structural detail have served as an invaluable investigative resource and continue to fascinate with the fantastical reality of an intricate nether world existing all around us, but hidden from view of the naked eye by a disparity in scale. As is so often the case, the invention of the scanning tunnelling microscope heralded far more than just a useful new apparatus, it demonstrated the scope for exploiting the subtleties of electronic contact. The shrinking of electronic devices has been a driving force for research into molecular electronics, in which an understanding of the nature of electronic contact at junctions is crucial. In response, the number of experimental techniques in molecular electronics has increased rapidly in recent years. Scanning tunnelling microscopes have been used to study electron transfer through molecular films on a conducting substrate, and the need to monitor the contact force of scanning tunnelling electrodes led to the use of atomic force microscopy probes coated in a conducting layer as studied by Cui and colleagues in Arizona [2]. In this issue a collaboration of researchers at Delft University and Leiden University in the Netherlands report a new device architecture for the independent mechanical and electrostatic tuning of nanoscale charge transport, which will enable thorough studies of molecular transport in the future [3]. Scanning probes can also be used to pattern surfaces, such as through spatially-localized Suzuki and Heck reactions in chemical scanning probe lithography. Mechanistic aspects of spatially confined Suzuki and Heck chemistry are also reported in this issue by researchers in Oxford [4]. All these developments in molecular electronics fabrication and characterization provide alternative

  20. Involvement of hypothalamic AMP-activated protein kinase in leptin-induced sympathetic nerve activation.

    Directory of Open Access Journals (Sweden)

    Mamoru Tanida

    Full Text Available In mammals, leptin released from the white adipose tissue acts on the central nervous system to control feeding behavior, cardiovascular function, and energy metabolism. Central leptin activates sympathetic nerves that innervate the kidney, adipose tissue, and some abdominal organs in rats. AMP-activated protein kinase (AMPK is essential in the intracellular signaling pathway involving the activation of leptin receptors (ObRb. We investigated the potential of AMPKα2 in the sympathetic effects of leptin using in vivo siRNA injection to knockdown AMPKα2 in rats, to produce reduced hypothalamic AMPKα2 expression. Leptin effects on body weight, food intake, and blood FFA levels were eliminated in AMPKα2 siRNA-treated rats. Leptin-evoked enhancements of the sympathetic nerve outflows to the kidney, brown and white adipose tissues were attenuated in AMPKα2 siRNA-treated rats. To check whether AMPKα2 was specific to sympathetic changes induced by leptin, we examined the effects of injecting MT-II, a melanocortin-3 and -4 receptor agonist, on the sympathetic nerve outflows to the kidney and adipose tissue. MT-II-induced sympatho-excitation in the kidney was unchanged in AMPKα2 siRNA-treated rats. However, responses of neural activities involving adipose tissue to MT-II were attenuated in AMPKα2 siRNA-treated rats. These results suggest that hypothalamic AMPKα2 is involved not only in appetite and body weight regulation but also in the regulation of sympathetic nerve discharges to the kidney and adipose tissue. Thus, AMPK might function not only as an energy sensor, but as a key molecule in the cardiovascular, thermogenic, and lipolytic effects of leptin through the sympathetic nervous system.

  1. Involvement of hypothalamic AMP-activated protein kinase in leptin-induced sympathetic nerve activation.

    Science.gov (United States)

    Tanida, Mamoru; Yamamoto, Naoki; Shibamoto, Toshishige; Rahmouni, Kamal

    2013-01-01

    In mammals, leptin released from the white adipose tissue acts on the central nervous system to control feeding behavior, cardiovascular function, and energy metabolism. Central leptin activates sympathetic nerves that innervate the kidney, adipose tissue, and some abdominal organs in rats. AMP-activated protein kinase (AMPK) is essential in the intracellular signaling pathway involving the activation of leptin receptors (ObRb). We investigated the potential of AMPKα2 in the sympathetic effects of leptin using in vivo siRNA injection to knockdown AMPKα2 in rats, to produce reduced hypothalamic AMPKα2 expression. Leptin effects on body weight, food intake, and blood FFA levels were eliminated in AMPKα2 siRNA-treated rats. Leptin-evoked enhancements of the sympathetic nerve outflows to the kidney, brown and white adipose tissues were attenuated in AMPKα2 siRNA-treated rats. To check whether AMPKα2 was specific to sympathetic changes induced by leptin, we examined the effects of injecting MT-II, a melanocortin-3 and -4 receptor agonist, on the sympathetic nerve outflows to the kidney and adipose tissue. MT-II-induced sympatho-excitation in the kidney was unchanged in AMPKα2 siRNA-treated rats. However, responses of neural activities involving adipose tissue to MT-II were attenuated in AMPKα2 siRNA-treated rats. These results suggest that hypothalamic AMPKα2 is involved not only in appetite and body weight regulation but also in the regulation of sympathetic nerve discharges to the kidney and adipose tissue. Thus, AMPK might function not only as an energy sensor, but as a key molecule in the cardiovascular, thermogenic, and lipolytic effects of leptin through the sympathetic nervous system.

  2. Actively induced platelet-bound IgG associated with thrombocytopenia in the marmoset

    Energy Technology Data Exchange (ETDEWEB)

    Gengozian, N.; McLaughlin, C.L.

    1978-06-01

    Interspecies platelet immunizations among marmosets lead to antibody formation to the donor platelets and a profound thrombocytopenia, which when associated with anemia may result in death of the animal. This actively induced immonologic thrombocytopenia closely resembles two clinical disease entities manifesting autoimmune thrombocytopenia, posttransfusion purpura and idiopathic thrombocytopenic purpura. Although antibody to donor-type platelets could be demonstrated readily, antihost activity was most often nondetectable or, when present, was in very low titer. A consistent finding was the appearance of IgG on the host's platelets shortly after immunization and concomitant with the appearance of antidonor platelet antibody. In 3 of 13 immunized animals thromoocytopenia did not occur even though antibody was formed and the host's platelets became IgG positive. In those animals that recovered from the induced thrombocytopenia IgG-positive platelets were found for periods ranging from 30 to greater than 100 days. Splenectomy before or after immunization did not alter the sequential development of antibody formation, appearance of IgG-positive platelets, and thrombocytopenia. Eluates prepared from IgG-positive platelets contained IgG and platelet antigens; the eluted IgG could attach nonspecifically to platelets of host or donor (immunizing) type, in contrast to the species specificity demonstrated for IgG eluted from platelets that had been reacted in vitro with specific antibody. Platelets in a few normal, nonimmunized marmosets were found to have signficant amounts of IgG on their surface, comparable to that observed in the immunized animal; interestingly, such IgG-positive platelets were found among imported but not laboratory-bred marmosets.

  3. Cisplatin Induces Cytotoxicity through the Mitogen-Activated Protein Kinase Pathways ana Activating Transcription Factor 3

    Directory of Open Access Journals (Sweden)

    Carly St. Germain

    2010-07-01

    Full Text Available The mechanisms underlying the proapoptotic effect of the chemotherapeutic agent, cisplatin, are largely undefined. Understanding the mechanisms regulating cisplatin cytotoxicity may uncover strategies to enhance the efficacy of this important therapeutic agent. This study evaluates the role of activating transcription factor 3 (ATF3 as a mediator of cisplatin-induced cytotoxicity. Cytotoxic doses of cisplatin and carboplatin treatments consistently induced ATF3 expression in five tumor-derived cell lines. Characterization of this induction revealed a p53, BRCA1, and integrated stress response-independent mechanism, all previously implicated in stress-mediated ATF3 induction. Analysis of mitogenactivated protein kinase (MAPK pathway involvement in ATF3 induction by cisplatin revealed a MAPK-dependent mechanism. Cisplatin treatment combined with specific inhibitors to each MAPK pathway (c-Jun N-terminal kinase, extracellularsignal-regulated kinase, and p38 resulted in decreasedATF3 induction at the protein level. MAPK pathway inhibition led to decreased ATF3 messenger RNA expression and reduced cytotoxic effects of cisplatin as measured by the 3-(4,5-dimethylthiazol-2-ylF2,5-diphenyltetrazolium bromide cell viability assay. In A549 lung carcinoma cells, targeting ATF3 with specific small hairpin RNA also attenuated the cytotoxic effects of cisplatin. Similarly, ATF3-/murine embryonic fibroblasts (MEFs were shown to be less sensitive to cisplatin-induced cytotoxicity compared with ATF3+/+ MEFs. This study identifies cisplatin as a MAPK pathway-dependent inducer of ATF3, whose expression influences cisplatin’s cytotoxic effects.

  4. Exercise in Closed-Loop Control : A Major Hurdle

    NARCIS (Netherlands)

    Bon, Arianne C. van; Verbitskiy, Eugeny; Basum, Golo von; Hoekstra, Joost B.L.; Vries, J. Hans de

    2011-01-01

    Background: People with type 1 diabetes mellitus (T1DM) are at risk for exercise-induced hypoglycemia. Prevention of such hypoglycemia in a closed-loop setting is a major challenge. Markers for automated detection of physical activity could be heart rate (HR) and body acceleration counts (AC).

  5. Temporomandibular Joint, Closed

    Science.gov (United States)

    ... Gallery > Oral Health > The Temporomandibular Joint, Closed The Temporomandibular Joint, Closed Main Content Title: The Temporomandibular Joint, Closed Description: The temporomandibular joint connects the lower ...

  6. Activity concentration and spatial distribution of radionuclides in marine sediments close to the estuary of Shatt al-Arab/Arvand Rud River, the Gulf.

    Science.gov (United States)

    Patiris, D L; Tsabaris, C; Anagnostou, C L; Androulakaki, E G; Pappa, F K; Eleftheriou, G; Sgouros, G

    2016-06-01

    Tigris and Euphrates rivers both emerge in eastern Turkey and cross Syria and Iraq. They unite to Shatt al-Arab/Arvand Rud River and discharge in Arabic/Persian Gulf. The activity concentration of natural and anthropogenic radionuclides was measured during the August of 2011 in a number of surficial sediment samples collected from the seabed along an almost straight line beginning near the estuary mouth and extending seaward. The results exhibited low activity concentration levels and an almost homogeneous spatial distribution except locations where sediment of biogenic origin, poor in radionuclides, dilute their concentrations. Dose rates absorbed by reference marine biota were calculated by the ERICA Assessment Tool considering the contribution of 40 K. The results revealed a relatively low impact of 40 K mainly to species living in, on and close to the seabed. Also, statistical association of radionuclides with selected stable elements (Ca, Ba and Sr) did not indicate presence of by-products related with oil and gas exploitation and transportation activities. Moreover, a semi-empirical sedimentology model applied to reproduce seabed granulometric facies based entirely on radionuclides activity concentrations.

  7. Laser-induced periodic surface structures on polymers for formation of gold nanowires and activation of human cells

    Science.gov (United States)

    Barb, R.-A.; Hrelescu, C.; Dong, L.; Heitz, J.; Siegel, J.; Slepicka, P.; Vosmanska, V.; Svorcik, V.; Magnus, B.; Marksteiner, R.; Schernthaner, M.; Groschner, K.

    2014-10-01

    Frequently observed coherent structures in laser-surface processing are ripples, also denoted as laser-induced periodic surface structures (LIPSS). For polyethylene terephthalate (PET) and polystyrene (PS), LIPSS can be induced by irradiation with linearly polarized ns-pulsed UV laser light. Under an angle of incidence of θ, their lateral period is close to the laser wavelength λ divided by ( n eff - sin θ). Here, n eff is the effective refractive index which is 1.32 and 1.23 for PET and PS, respectively. We describe potential applications of LIPSS for alignment and activation of human cells cultivated on polymer substrates, as well as for formation of separated gold nanowires which show pronounced surface plasmon resonances, e.g., at 775 nm for PET.

  8. Photonic Activation of Plasminogen induced by low dose UVB

    DEFF Research Database (Denmark)

    Correia, Manuel Guiherme L.P. Marins; Snabe, Torben; Thiagarajan, Viruthachalam;

    2015-01-01

    Activation of plasminogen to its active form plasmin is essential for several key mechanisms, including the dissolution of blood clots. Activation occurs naturally via enzymatic proteolysis. We report that activation can be achieved with 280 nm light. A 2.6 fold increase in proteolytic activity w...

  9. Predictive lethal proarrhythmic risk evaluation using a closed-loop-circuit cell network with human induced pluripotent stem cells derived cardiomyocytes

    Science.gov (United States)

    Nomura, Fumimasa; Hattori, Akihiro; Terazono, Hideyuki; Kim, Hyonchol; Odaka, Masao; Sugio, Yoshihiro; Yasuda, Kenji

    2016-06-01

    For the prediction of lethal arrhythmia occurrence caused by abnormality of cell-to-cell conduction, we have developed a next-generation in vitro cell-to-cell conduction assay, i.e., a quasi in vivo assay, in which the change in spatial cell-to-cell conduction is quantitatively evaluated from the change in waveforms of the convoluted electrophysiological signals from lined-up cardiomyocytes on a single closed loop of a microelectrode of 1 mm diameter and 20 µm width in a cultivation chip. To evaluate the importance of the closed-loop arrangement of cardiomyocytes for prediction, we compared the change in waveforms of convoluted signals of the responses in the closed-loop circuit arrangement with that of the response of cardiomyocyte clusters using a typical human ether a go-go related gene (hERG) ion channel blocker, E-4031. The results showed that (1) waveform prolongation and fluctuation both in the closed loops and clusters increased depending on the E-4031 concentration increase. However, (2) only the waveform signals in closed loops showed an apparent temporal change in waveforms from ventricular tachycardia (VT) to ventricular fibrillation (VF), which is similar to the most typical cell-to-cell conductance abnormality. The results indicated the usefulness of convoluted waveform signals of a closed-loop cell network for acquiring reproducible results acquisition and more detailed temporal information on cell-to-cell conduction.

  10. Inhibition of aldehyde dehydrogenase 2 activity enhances antimycin-induced rat cardiomyocytes apoptosis through activation of MAPK signaling pathway.

    Science.gov (United States)

    Zhang, Peng; Xu, Danling; Wang, Shijun; Fu, Han; Wang, Keqiang; Zou, Yunzeng; Sun, Aijun; Ge, Junbo

    2011-12-01

    Aldehyde dehydrogenase 2 (ALDH2), a mitochondrial-specific enzyme, has been proved to be involved in oxidative stress-induced cell apoptosis, while little is known in cardiomyocytes. This study was aimed at investigating the role of ALDH2 in antimycin A-induced cardiomyocytes apoptosis by suppressing ALDH2 activity with a specific ALDH2 inhibitor Daidzin. Antimycin A (40μg/ml) was used to induce neonatal cardiomyocytes apoptosis. Daidzin (60μM) effectively inhibited ALDH2 activity by 50% without own effect on cell apoptosis, and significantly enhanced antimycin A-induced cardiomyocytes apoptosis from 33.5±4.4 to 56.5±6.4% (Hochest method, pdaidzin treated cardiomyocytes compared to the cells treated with antimycin A alone. These findings indicated that modifying mitochondrial ALDH2 activity/expression might be a potential therapeutic option on reducing oxidative insults induced cardiomyocytes apoptosis.

  11. Berberine induces caspase-independent cell death in colon tumor cells through activation of apoptosis-inducing factor.

    Directory of Open Access Journals (Sweden)

    Lihong Wang

    Full Text Available Berberine, an isoquinoline alkaloid derived from plants, is a traditional medicine for treating bacterial diarrhea and intestinal parasite infections. Although berberine has recently been shown to suppress growth of several tumor cell lines, information regarding the effect of berberine on colon tumor growth is limited. Here, we investigated the mechanisms underlying the effects of berberine on regulating the fate of colon tumor cells, specifically the mouse immorto-Min colonic epithelial (IMCE cells carrying the Apc(min mutation, and of normal colon epithelial cells, namely young adult mouse colonic epithelium (YAMC cells. Berberine decreased colon tumor colony formation in agar, and induced cell death and LDH release in a time- and concentration-dependent manner in IMCE cells. In contrast, YAMC cells were not sensitive to berberine-induced cell death. Berberine did not stimulate caspase activation, and PARP cleavage and berberine-induced cell death were not affected by a caspase inhibitor in IMCE cells. Rather, berberine stimulated a caspase-independent cell death mediator, apoptosis-inducing factor (AIF release from mitochondria and nuclear translocation in a ROS production-dependent manner. Amelioration of berberine-stimulated ROS production or suppression of AIF expression blocked berberine-induced cell death and LDH release in IMCE cells. Furthermore, two targets of ROS production in cells, cathepsin B release from lysosomes and PARP activation were induced by berberine. Blockage of either of these pathways decreased berberine-induced AIF activation and cell death in IMCE cells. Thus, berberine-stimulated ROS production leads to cathepsin B release and PARP activation-dependent AIF activation, resulting in caspase-independent cell death in colon tumor cells. Notably, normal colon epithelial cells are less susceptible to berberine-induced cell death, which suggests the specific inhibitory effects of berberine on colon tumor cell growth.

  12. Expression and activity of inducible nitric oxide synthase and endothelial nitric oxide synthase correlate with ethanol-induced liver injury

    Institute of Scientific and Technical Information of China (English)

    Guang-Jin Yuan; Xiao-Rong Zhou; Zuo-Jiong Gong; Pin Zhang; Xiao-Mei Sun; Shi-Hua Zheng

    2006-01-01

    AIM: To study the expression and activity of inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) in rats with ethanol-induced liver injury and their relation with liver damage, activation of nuclear factor-KB (NF-кB) and tumor necrosis factor-α (TNF-α)expression in the liver.METHODS: Female Sprague-Dawley rats were given fish oil (0.5 mL) along with ethanol or isocaloric dextrose daily via gastrogavage for 4 or 6 wk. Liver injury was assessed using serum alanine aminotransferase (ALT)activity and pathological analysis. Liver malondialdehyde (MDA), nitric oxide contents, iNOS and eNOS activity were determined. NF-KB p65, iNOS, eNOS and TNF-αprotein or mRNA expression in the liver were detected by immunohistochemistry or reverse transcriptase-polymerase chain reaction (RT-PCR).RESULTS: Chronic ethanol gavage for 4 wk caused steatosis, inflammation and necrosis in the liver, and elevated serum ALT activity. Prolonged ethanol administration (6 wk) enhanced the liver damage. These responses were accompanied with increased lipid peroxidation, NO contents, iNOS activity and reduced eNOS activity. NF-кB p65, iNOS and TNF-α protein or mRNA expression were markedly induced after chronic ethanol gavage, whereas eNOS mRNA expression remained unchanged. The enhanced iNOS activity and expression were positively correlated with the liver damage, especially the necro-inflammation, activation of NF-кB, and TNF-α mRNA expression.CONCLUSION: iNOS expression and activity are induced in the liver after chronic ethanol exposure in rats, which are correlated with the liver damage, especially the necro-inflammation, activation of NF-KB and TNF-αexpression. eNOS activity is reduced, but its mRNA expression is not affected.

  13. Growth hormone-induced insulin resistance in human subjects involves reduced pyruvate dehydrogenase activity

    DEFF Research Database (Denmark)

    Nellemann, Birgitte; Vendelbo, Mikkel H; Nielsen, Thomas S

    2014-01-01

    Insulin resistance induced by growth hormone (GH) is linked to promotion of lipolysis by unknown mechanisms. We hypothesized that suppression of the activity of pyruvate dehydrogenase in the active form (PDHa) underlies GH-induced insulin resistance similar to what is observed during fasting....

  14. Evidence of solar induced cycles of high seismic activity

    Science.gov (United States)

    Duma, G.

    2010-12-01

    100 with Kp. In terms of earthquake statistics, the changes of Kp imply that in N-America during Kp maxima there happen e.g. 1 event M7, 4 events M6 and 30 events M5 per year, instead of only 10 events M5 in years with lowest Kp. For S-America the number of events during Kp maxima is about twice that observed for N-America. It further turns out that in all three regions, the strongest earthquakes with magnitude 7 and even 8 occur during the Kp maxima. In the recent decade, several geophysical models have been tested at the ZAMG and in co-operation with institutes in USA and UK, to interpret the coupling between the solar induced geomagnetic variations and disturbances and its mechanic implications in the Earth’s lithosphere, i.e. in rupture zones. Two such models are briefly introduced, which fit well the observations and indicate high mechanic forces due to electromagnetic induction. The described solar-terrestrial effect significantly affects strong earthquake activity, as outlined above. It is a general geodynamic process which acts in nearly all main seismic regions on the globe. Thus, the results may essentially contribute to a better understanding of earthquake occurrence and hazard assessment.

  15. Activating AMP-activated protein kinase by an α1 selective activator compound 13 attenuates dexamethasone-induced osteoblast cell death

    Energy Technology Data Exchange (ETDEWEB)

    Guo, Shiguang [Department of Intensive Care Unit, Huai' an First People' s Hospital, Nanjing Medical University, Huai' an (China); Mao, Li [Department of Endocrinology, Huai' an First People' s Hospital, Nanjing Medical University, Huai' an (China); Ji, Feng, E-mail: huaiaifengjidr@163.com [Department of Orthopedics, Huai' an First People' s Hospital, Nanjing Medical University, Huai' an (China); Wang, Shouguo; Xie, Yue; Fei, Haodong [Department of Orthopedics, Huai' an First People' s Hospital, Nanjing Medical University, Huai' an (China); Wang, Xiao-dong, E-mail: xiaodongwangsz@163.com [The Center of Diagnosis and Treatment for Children' s Bone Diseases, The Children' s Hospital Affiliated to Soochow University, Suzhou (China)

    2016-03-18

    Excessive glucocorticoid (GC) usage may lead to non-traumatic femoral head osteonecrosis. Dexamethasone (Dex) exerts cytotoxic effect to cultured osteoblasts. Here, we investigated the potential activity of Compound 13 (C13), a novel α1 selective AMP-activated protein kinase (AMPK) activator, against the process. Our data revealed that C13 pretreatment significantly attenuated Dex-induced apoptosis and necrosis in both osteoblastic-like MC3T3-E1 cells and primary murine osteoblasts. AMPK activation mediated C13′ cytoprotective effect in osteoblasts. The AMPK inhibitor Compound C, shRNA-mediated knockdown of AMPKα1, or dominant negative mutation of AMPKα1 (T172A) almost abolished C13-induced AMPK activation and its pro-survival effect in osteoblasts. On the other hand, forced AMPK activation by adding AMPK activator A-769662 or exogenous expression a constitutively-active (ca) AMPKα1 (T172D) mimicked C13's actions and inhibited Dex-induced osteoblast cell death. Meanwhile, A-769662 or ca-AMPKα1 almost nullified C13's activity in osteoblast. Further studies showed that C13 activated AMPK-dependent nicotinamide adenine dinucleotide phosphate (NADPH) pathway to inhibit Dex-induced reactive oxygen species (ROS) production in MC3T3-E1 cells and primary murine osteoblasts. Such effects by C13 were almost reversed by Compound C or AMPKα1 depletion/mutation. Together, these results suggest that C13 alleviates Dex-induced osteoblast cell death via activating AMPK signaling pathway. - Highlights: • Compound 13 (C13) attenuates dexamethasone (Dex)-induced osteoblast cell death. • C13-induced cytoprotective effect against Dex in osteoblasts requires AMPK activation. • Forced AMPK activation protects osteoblasts from Dex, nullifying C13's activities. • C13 increases NADPH activity and inhibits Dex-induced oxidative stress in osteoblasts.

  16. Peroxisome Proliferator-Activated Receptor α Activation Induces Hepatic Steatosis, Suggesting an Adverse Effect

    Science.gov (United States)

    Yan, Fang; Wang, Qi; Xu, Chao; Cao, Mingfeng; Zhou, Xiaoming; Wang, Tingting; Yu, Chunxiao; Jing, Fei; Chen, Wenbin; Gao, Ling; Zhao, Jiajun

    2014-01-01

    Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic triglyceride accumulation, ranging from steatosis to steatohepatitis and cirrhosis. NAFLD is a risk factor for cardiovascular diseases and is associated with metabolic syndrome. Antihyperlipidemic drugs are recommended as part of the treatment for NAFLD patients. Although fibrates activate peroxisome proliferator-activated receptor α (PPARα), leading to the reduction of serum triglyceride levels, the effects of these drugs on NAFLD remain controversial. Clinical studies have reported that PPARα activation does not improve hepatic steatosis. In the present study, we focused on exploring the effect and mechanism of PPARα activation on hepatic triglyceride accumulation and hepatic steatosis. Male C57BL/6J mice, Pparα-null mice and HepG2 cells were treated with fenofibrate, one of the most commonly used fibrate drugs. Both low and high doses of fenofibrate were administered. Hepatic steatosis was detected through oil red O staining and electron microscopy. Notably, in fenofibrate-treated mice, the serum triglyceride levels were reduced and the hepatic triglyceride content was increased in a dose-dependent manner. Oil red O staining of liver sections demonstrated that fenofibrate-fed mice accumulated abundant neutral lipids. Fenofibrate also increased the intracellular triglyceride content in HepG2 cells. The expression of sterol regulatory element-binding protein 1c (SREBP-1c) and the key genes associated with lipogenesis were increased in fenofibrate-treated mouse livers and HepG2 cells in a dose-dependent manner. However, the effect was strongly impaired in Pparα-null mice treated with fenofibrate. Fenofibrate treatment induced mature SREBP-1c expression via the direct binding of PPARα to the DR1 motif of the SREBP-1c gene. Taken together, these findings indicate the molecular mechanism by which PPARα activation increases liver triglyceride accumulation and suggest an adverse effect of

  17. The prediction of induced activity levels in and around NIMROD

    CERN Document Server

    Hack, R C

    1973-01-01

    Comparisons are reported between measured and predicted levels of induced radioactivity for a number of irradiation conditions. Good agreement was found between experimental measurements and fairly simple methods of prediction developed at CERN.

  18. Silica nanoparticles induce endoplasmic reticulum stress response and activate mitogen activated kinase (MAPK signalling

    Directory of Open Access Journals (Sweden)

    Verena Christen

    2016-01-01

    Full Text Available Humans may be exposed to engineered silica nanoparticles (SiO2-NPs but potential adverse effects are poorly understood, in particular in relation to cellular effects and modes of action. Here we studied effects of SiO2-NPs on cellular function in human hepatoma cells (Huh7. Exposure for 24 h to 10 and 50 μg/ml SiO2-NPs led to induction of endoplasmic reticulum (ER stress as demonstrated by transcriptional induction of DNAJB9, GADD34, CHOP, as well as CHOP target genes BIM, CHAC-1, NOXA and PUMA. In addition, CHOP protein was induced. In addition, SiO2-NPs induced an inflammatory response as demonstrated by induction of TNF-α and IL-8. Activation of MAPK signalling was investigated employing a PCR array upon exposure of Huh7 cells to SiO2-NPs. Five of 84 analysed genes, including P21, P19, CFOS, CJUN and KSR1 exhibited significant transcriptional up-regulation, and 18 genes a significant down-regulation. Strongest down-regulation occurred for the proto-oncogene BRAF, MAPK11, one of the four p38 MAPK genes, and for NFATC4. Strong induction of CFOS, CJUN, FRA1 and CMYC was found after exposure to 50 μg/ml SiO2-NPs for 24 h. To analyse for effects derived from up-regulation of TNF-α, Huh7 cells were exposed to SiO2-NPs in the presence of the TNF-α inhibitor sauchinone, which reduced the induction of the TNF-α transcript by about 50%. These data demonstrate that SiO2-NPs induce ER stress, MAPK pathway and lead to inflammatory reaction in human hepatoma cells. Health implications of SiO2-NPs exposure should further be investigated for a risk assessment of these frequently used nanoparticles.

  19. Glucose Enhances Basal or Melanocortin-Induced cAMP-Response Element Activity in Hypothalamic Cells.

    Science.gov (United States)

    Breit, Andreas; Wicht, Kristina; Boekhoff, Ingrid; Glas, Evi; Lauffer, Lisa; Mückter, Harald; Gudermann, Thomas

    2016-07-01

    Melanocyte-stimulating hormone (MSH)-induced activation of the cAMP-response element (CRE) via the CRE-binding protein in hypothalamic cells promotes expression of TRH and thereby restricts food intake and increases energy expenditure. Glucose also induces central anorexigenic effects by acting on hypothalamic neurons, but the underlying mechanisms are not completely understood. It has been proposed that glucose activates the CRE-binding protein-regulated transcriptional coactivator 2 (CRTC-2) in hypothalamic neurons by inhibition of AMP-activated protein kinases (AMPKs), but whether glucose directly affects hypothalamic CRE activity has not yet been shown. Hence, we dissected effects of glucose on basal and MSH-induced CRE activation in terms of kinetics, affinity, and desensitization in murine, hypothalamic mHypoA-2/10-CRE cells that stably express a CRE-dependent reporter gene construct. Physiologically relevant increases in extracellular glucose enhanced basal or MSH-induced CRE-dependent gene transcription, whereas prolonged elevated glucose concentrations reduced the sensitivity of mHypoA-2/10-CRE cells towards glucose. Glucose also induced CRCT-2 translocation into the nucleus and the AMPK activator metformin decreased basal and glucose-induced CRE activity, suggesting a role for AMPK/CRTC-2 in glucose-induced CRE activation. Accordingly, small interfering RNA-induced down-regulation of CRTC-2 expression decreased glucose-induced CRE-dependent reporter activation. Of note, glucose also induced expression of TRH, suggesting that glucose might affect the hypothalamic-pituitary-thyroid axis via the regulation of hypothalamic CRE activity. These findings significantly advance our knowledge about the impact of glucose on hypothalamic signaling and suggest that TRH release might account for the central anorexigenic effects of glucose and could represent a new molecular link between hyperglycaemia and thyroid dysfunction.

  20. Enterovirus 71 2B Induces Cell Apoptosis by Directly Inducing the Conformational Activation of the Proapoptotic Protein Bax.

    Science.gov (United States)

    Cong, Haolong; Du, Ning; Yang, Yang; Song, Lei; Zhang, Wenliang; Tien, Po

    2016-11-01

    To survive and replicate within a host, many viruses have evolved strategies that target crucial components within the apoptotic cascade, leading to either inhibition or induction of cell apoptosis. Enterovirus 71 (EV71) infections have been demonstrated to impact the mitochondrial apoptotic pathway and induce apoptosis in many cell lines. However, the detailed mechanism of EV71-induced apoptosis remains to be elucidated. In this study, we report that EV71 2B protein (2B) localized to the mitochondria and induced cell apoptosis by interacting directly with and activating the proapoptotic protein Bax. 2B recruited Bax to the mitochondria and induced Bax conformational activation. In addition, mitochondria isolated from 2B-expressing cells that were treated with a recombinant Bax showed increased Bax interaction and cytochrome c (Cyt c) release. Importantly, apoptosis in cells with either EV71 infection or 2B expression was dramatically reduced in Bax knockdown cells but not in Bak knockdown cells, suggesting that Bax played a pivotal role in EV71- or 2B-induced apoptosis. Further studies indicate that a hydrophobic region of 18 amino acids (aa) in the C-terminal region of 2B (aa 63 to 80) was responsible for the location of 2B in the mitochondria. A hydrophilic region of 14 aa in the N-terminal region of 2B was functional in Bax interaction and its subsequent activation. Moreover, overexpression of the antiapoptotic protein Bcl-XL abrogates 2B-induced release of Cyt c and caspase activation. Therefore, this study provides direct evidence that EV71 2B induces cell apoptosis and impacts the mitochondrial apoptotic pathway by directly modulating the redistribution and activation of proapoptotic protein Bax. EV71 infections are usually accompanied by severe neurological complications. It has also been postulated that the induction of cell apoptosis resulting from tissue damage is a possible process of EV71-related pathogenesis. In this study, we report that EV71 2B

  1. Influenza a virus induces an immediate cytotoxic activity in all major subsets of peripheral blood mononuclear cells.

    Directory of Open Access Journals (Sweden)

    Sanda Sturlan

    Full Text Available BACKGROUND: A replication defective influenza A vaccine virus (delNS1 virus was developed. Its attenuation is due to potent stimulation of the innate immune system by the virus. Since the innate immune system can also target cancer cells, we reasoned that delNS1 virus induced immune-stimulation should also lead to the induction of innate cytotoxic effects towards cancer cells. METHODOLOGY/PRINCIPAL FINDINGS: Peripheral blood mononuclear cells (PBMCs, isolated CD56+, CD3+, CD14+ and CD19+ subsets and different combinations of the above subsets were stimulated by delNS1, wild type (wt virus or heat inactivated virus and co-cultured with tumor cell lines in the presence or absence of antibodies against the interferon system. Stimulation of PBMCs by the delNS1 virus effectively induced cytotoxicity against different cancer cell lines. Surprisingly, virus induced cytotoxicity was exerted by all major subtypes of PBMCs including CD56+, CD3+, CD14+ and CD19+ cells. Virus induced cytotoxicity in CD3+, CD14+ and CD19+ cells was dependent on virus replication, whereas virus induced cytotoxicity in CD56+ cells was only dependent on the binding of the virus. Virus induced cytotoxicity of isolated cell cultures of CD14+, CD19+ or CD56+ cells could be partially blocked by antibodies against type I and type II (IFN interferon. In contrast, virus induced cytotoxicity in the complete PBMC preparation could not be inhibited by blocking type I or type II IFN, indicating a redundant system of activation in whole blood. CONCLUSIONS/SIGNIFICANCE: Our data suggest that apart from their well known specialized functions all main subsets of peripheral blood cells also initially exert a cytotoxic effect upon virus stimulation. This closely links the innate immune system to the adaptive immune response and renders delNS1 virus a potential therapeutic tool for viro-immunotherapy of cancer.

  2. Protease-activated receptor 1 and 2 contribute to angiotensin II-induced activation of adventitial fibroblasts from rat aorta

    Energy Technology Data Exchange (ETDEWEB)

    He, Rui-Qing; Tang, Xiao-Feng; Zhang, Bao-Li [State Key Laboratory of Medical Genetics, Shanghai Key Laboratory of Hypertension and Department of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (China); Shanghai Institute of Hypertension, Shanghai (China); Li, Xiao-Dong [State Key Laboratory of Medical Genetics, Shanghai Key Laboratory of Hypertension and Department of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (China); Laboratory of Vascular Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai (China); Shanghai Institute of Hypertension, Shanghai (China); Hong, Mo-Na [State Key Laboratory of Medical Genetics, Shanghai Key Laboratory of Hypertension and Department of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (China); Shanghai Institute of Hypertension, Shanghai (China); Chen, Qi-Zhi [Shanghai Institute of Hypertension, Shanghai (China); Han, Wei-Qing, E-mail: whan020@gmail.com [State Key Laboratory of Medical Genetics, Shanghai Key Laboratory of Hypertension and Department of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (China); Laboratory of Vascular Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai (China); Shanghai Institute of Hypertension, Shanghai (China); Gao, Ping-Jin, E-mail: gaopingjin@sibs.ac.cn [State Key Laboratory of Medical Genetics, Shanghai Key Laboratory of Hypertension and Department of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (China); Laboratory of Vascular Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai (China); Shanghai Institute of Hypertension, Shanghai (China)

    2016-04-29

    Adventitial fibroblasts (AFs) can be activated by angiotensin II (Ang II) and exert pro-fibrotic and pro-inflammatory effects in vascular remodeling. Protease-activated receptor (PAR) 1 and 2 play a significant role in fibrogenic and inflammatory diseases. The present study hypothesized that PAR1 and PAR2 are involved in Ang II-induced AF activation and contribute to adventitial remodeling. We found that direct activation of PAR1 and PAR2 with PAR1-AP and PAR2-AP led to AF activation, including proliferation and differentiation of AFs, extracellular matrix synthesis, as well as production of pro-fibrotic cytokine TGF-β and pro-inflammatory cytokines IL-6 and MCP-1. Furthermore, PAR1 and PAR2 mediated Ang II-induced AF activation, since both PAR1 and PAR2 antagonists inhibited Ang II-induced proliferation, migration, differentiation, extracellular matrix synthesis and production of pro-fibrotic and pro-inflammatory cytokines in AFs. Finally, mechanistic study showed that Ang II, via Ang II type I receptor (AT1R), upregulated both PAR1 and PAR2 expression, and transactivated PAR1 and PAR2, as denoted by internalization of both proteins. In conclusion, our results suggest that PAR1 and PAR2 play a critical role in Ang II-induced AF activation, and this may contribute to adventitia-related pathological changes. - Highlights: • Direct activation of PAR1 and PAR2 led to adventitial fibroblast (AF) activation. • PAR1 and PAR2 antagonists attenuated Ang II-induced AF activation. • Ang II induced the upregulation and transactivation of PAR1/PAR2 in AFs.

  3. Patient self-assessed shoulder comfort and function and active motion are not closely related to surgically documented rotator cuff tear integrity.

    Science.gov (United States)

    Hsu, Jason E; Tang, Anna; Matsen, Frederick A

    2017-07-06

    The rationale for rotator cuff repair surgery is that better integrity of the cuff should be associated with better comfort and function. However, in patients with cuff disease, there is not good evidence that the degree of rotator cuff integrity is closely associated with the shoulder's comfort, function, or active motion. The goal of this study was to explore these relationships in shoulders with surgically documented cuff disease. In 55 shoulders having surgery for cuff-related symptoms, we correlated the preoperative Simple Shoulder Test score with the objectively measured preoperative active shoulder motion and with the integrity of the cuff observed at surgery. The 16 shoulders with tendinosis or partial-thickness tears had an average Simple Shoulder Test score of 3.7 ± 3.3, active abduction of 111° ± 38°, and active flexion of 115° ± 36°. The corresponding values were 3.6 ± 2.8, 94° ± 47°, and 94° ± 52° for the 22 full-thickness supraspinatus tears and 3.9 ± 2.7, 89° ± 39°, and 100° ± 39° for the 17 supraspinatus and infraspinatus tears. In this study, surgically observed cuff integrity was not strongly associated with the shoulder's comfort or function. Whereas surgeons often seek to improve the integrity of the rotator cuff, the management of patients with rotator cuff disorders needs to be informed by a better understanding of the factors other than cuff integrity that influence the comfort and functioning of shoulders with cuff disease. Copyright © 2017 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.

  4. Neuroprotective role of pseudoginsenoside-F11 on activated microgfia induced by lipopolysaccharide

    Institute of Scientific and Technical Information of China (English)

    Xiu-liBI; Jing-yuYANG; Ying-xuDONG; LiangYU; Chun-fuWU

    2004-01-01

    AIM: In the present study, the neuroprotective effect and its possible molecular mechanisms of pseudoginsenoside-F11 (PF11),a saponin existed in American ginseng, on activated N9 microglia induced by lipopolysaccharide (LPS) were studied. RESULTS:The results showed that PF11 inhibited the activation of p38 ,p42/44 mitogen-activated protein kinases (MAPKs), and the degradation of IkB alpha (IrBα) induced by LPS. However, it

  5. The power features of Masseter muscle activity in tension-type and migraine without aura headache during open-close clench cycles

    Directory of Open Access Journals (Sweden)

    Behrouz Alizadeh Savareh

    2017-07-01

    Full Text Available Introduction Different types of headaches and TMJ click influence the masseter muscle activity. The aim of this study was to assess the trend of energy level of the electromyography (EMG activity of the masseter muscle during open-close clench cycles in migraine without aura (MOA and tension-type headache (TTH with or without TMJ click. Methods Twenty-five women with MOA and twenty four women with TTH participated in the study. They matched with 25 healthy subjects, in terms of class of occlusion and prevalence of temporomandibular joint (TMJ with click. The EMG of both masseter muscles were recorded during open-close clench cycles at a rate of 80 cycles per minute for 15 seconds. The mouth opening was restricted to two centimeters by mandibular motion frame. Signal processing steps have been done on the EMG as: noise removing, smoothing, feature extraction, and statistical analyzing. The six statistical parameters of energy computed were mean, Variance, Skewness, Kurtosis, and first and second half energy over all signal energy. Results A three-way ANOVA indicated that during all the cycles, the mean of energy was more and there was a delay in showing the peak of energy in the masseter of the left side with clicked TMJ in MOA group compared to the two other groups, while this pattern occurred inversely in the side with no-clicked TMJ (P < 0.009. The variation of energy was significantly less in MOA group compared to the two other groups in the no-clicked TMJ (P < 0.003. However, the proportion of the first or second part of signal energy to all energy showed that TTH group had less energy in the first part and more energy in the second part in comparison to the two other groups (P < 0.05. Conclusion The study showed different changes in the energy distribution of masseter muscle activity during cycles in MOA and TTH. MOA, in contrast to TTH, had lateralization effect on EMG and interacted with TMJ click.

  6. Glucocorticoid-induced impairment of macrophage antimicrobial activity: mechanisms and dependence on the state of activation.

    Science.gov (United States)

    Schaffner, A; Schaffner, T

    1987-01-01

    Experimental observations indicate that tissue macrophages deployed in great numbers at critical anatomic sites such as the liver, spleen, and lung are major targets for glucocorticoids compromising natural resistance of the host. Therapeutic concentrations of glucocorticoids appear to prevent destruction of microorganisms ingested by macrophages without interfering with phagocytosis, phagolysosomal fusion, and/or secretion of reactive oxygen intermediates. These findings indicate that at the cellular level the glucocorticoid target should be sought for in the nonoxidative armature of the phagocyte and that nonoxidative killing systems of resident tissue macrophages play an important role in natural resistance to opportunistic pathogens. Glucocorticoids do not prevent lymphokine-induced activation of oxidative killing systems. Thus, lymphokines such as interferon-gamma can restore the microbicidal activity of macrophages functionally impaired by glucocorticoids. Counterbalance of the suppressive effect of glucocorticoids by lymphokines might only be possible, however, for pathogens susceptible to oxidative killing and not for microorganisms that are more resistant to reactive oxygen intermediates such as Aspergillus spores and Nocardia, opportunists that appear to be particularly associated with hypercortisolism.

  7. Mapping snow depth in complex alpine terrain with close range aerial imagery - estimating the spatial uncertainties of repeat autonomous aerial surveys over an active rock glacier

    Science.gov (United States)

    Goetz, Jason; Marcer, Marco; Bodin, Xavier; Brenning, Alexander

    2017-04-01

    Snow depth mapping in open areas using close range aerial imagery is just one of the many cases where developments in structure-from-motion and multi-view-stereo (SfM-MVS) 3D reconstruction techniques have been applied for geosciences - and with good reason. Our ability to increase the spatial resolution and frequency of observations may allow us to improve our understanding of how snow depth distribution varies through space and time. However, to ensure accurate snow depth observations from close range sensing we must adequately characterize the uncertainty related to our measurement techniques. In this study, we explore the spatial uncertainties of snow elevation models for estimation of snow depth in a complex alpine terrain from close range aerial imagery. We accomplish this by conducting repeat autonomous aerial surveys over a snow-covered active-rock glacier located in the French Alps. The imagery obtained from each flight of an unmanned aerial vehicle (UAV) is used to create an individual digital elevation model (DEM) of the snow surface. As result, we obtain multiple DEMs of the snow surface for the same site. These DEMs are obtained from processing the imagery with the photogrammetry software Agisoft Photoscan. The elevation models are also georeferenced within Photoscan using the geotagged imagery from an onboard GNSS in combination with ground targets placed around the rock glacier, which have been surveyed with highly accurate RTK-GNSS equipment. The random error associated with multi-temporal DEMs of the snow surface is estimated from the repeat aerial survey data. The multiple flights are designed to follow the same flight path and altitude above the ground to simulate the optimal conditions of repeat survey of the site, and thus try to estimate the maximum precision associated with our snow-elevation measurement technique. The bias of the DEMs is assessed with RTK-GNSS survey observations of the snow surface elevation of the area on and surrounding

  8. A Taiwanese Propolis Derivative Induces Apoptosis through Inducing Endoplasmic Reticular Stress and Activating Transcription Factor-3 in Human Hepatoma Cells

    Directory of Open Access Journals (Sweden)

    Fat-Moon Suk

    2013-01-01

    Full Text Available Activating transcription factor-(ATF- 3, a stress-inducible transcription factor, is rapidly upregulated under various stress conditions and plays an important role in inducing cancer cell apoptosis. NBM-TP-007-GS-002 (GS-002 is a Taiwanese propolin G (PPG derivative. In this study, we examined the antitumor effects of GS-002 in human hepatoma Hep3B and HepG2 cells in vitro. First, we found that GS-002 significantly inhibited cell proliferation and induced cell apoptosis in dose-dependent manners. Several main apoptotic indicators were found in GS-002-treated cells, such as the cleaved forms of caspase-3, caspase-9, and poly(ADP-ribose polymerase (PARP. GS-002 also induced endoplasmic reticular (ER stress as evidenced by increases in ER stress-responsive proteins including glucose-regulated protein 78 (GRP78, growth arrest- and DNA damage-inducible gene 153 (GADD153, phosphorylated eukaryotic initiation factor 2α (eIF2α, phosphorylated protein endoplasmic-reticular-resident kinase (PERK, and ATF-3. The induction of ATF-3 expression was mediated by mitogen-activated protein kinase (MAPK signaling pathways in GS-002-treated cells. Furthermore, we found that GS-002 induced more cell apoptosis in ATF-3-overexpressing cells. These results suggest that the induction of apoptosis by the propolis derivative, GS-002, is partially mediated through ER stress and ATF-3-dependent pathways, and GS-002 has the potential for development as an antitumor drug.

  9. ATM increases activation-induced cytidine deaminase activity at downstream S regions during class-switch recombination

    NARCIS (Netherlands)

    Khair, Lyne; Guikema, Jeroen E J; Linehan, Erin K; Ucher, Anna J; Leus, Niek G J; Ogilvie, Colin; Lou, Zhenkun; Schrader, Carol E; Stavnezer, Janet

    2014-01-01

    Activation-induced cytidine deaminase (AID) initiates Ab class-switch recombination (CSR) in activated B cells resulting in exchanging the IgH C region and improved Ab effector function. During CSR, AID instigates DNA double-strand break (DSB) formation in switch (S) regions located upstream of C

  10. Protease-Activated Receptor-2 Activation Contributes to House Dust Mite-Induced IgE Responses in Mice

    NARCIS (Netherlands)

    Post, Sijranke; Heijink, Irene; Petersen, A H; de Bruin, Harold G.; van Oosterhout, Antoon J. M.; Nawijn, Martijn C.

    2014-01-01

    Aeroallergens such as house dust mite (HDM), cockroach, and grass or tree pollen are innocuous substances that can induce allergic sensitization upon inhalation. The serine proteases present in these allergens are thought to activate the protease-activated receptor (PAR)-2, on the airway epithelium,

  11. Protease-activated receptor-2 activation contributes to house dust mite-induced IgE responses in mice

    NARCIS (Netherlands)

    Post, Sijranke; Heijink, Irene H; Petersen, Arjen H; de Bruin, Harold G; van Oosterhout, Antoon J M; Nawijn, Martijn C

    2014-01-01

    Aeroallergens such as house dust mite (HDM), cockroach, and grass or tree pollen are innocuous substances that can induce allergic sensitization upon inhalation. The serine proteases present in these allergens are thought to activate the protease-activated receptor (PAR)-2, on the airway epithelium,

  12. Structure-activity relationship study of dibenzocyclooctadiene lignans isolated from Schisandra chinensis on lipopolysaccharide-induced microglia activation.

    Science.gov (United States)

    Hu, Di; Han, Na; Yao, Xuechun; Liu, Zhihui; Wang, Yu; Yang, Jingyu; Yin, Jun

    2014-06-01

    To explore the relationship of the dibenzocyclooctadiene lignans from Schisandra chinensis to their anti-inflammatory activities, series of dibenzocyclooctadiene lignans were isolated and assessed by testing their inhibitory effects on nitric oxide production in lipopolysaccharide-induced BV2 mouse microglia. It was found, for the first time, that dibenzocyclooctadiene lignans which have S-biphenyl and methylenedioxy groups strongly inhibited LPS-induced microglia activation. The methoxy group on the cyclooctadiene introduced more effectiveness, but the presence of an acetyl group on the cyclooctadiene or hydroxyl group on C-7 decreased the inhibitory activity.

  13. Leu85 in the beta1-beta2 linker of ASIC1 slows activation and decreases the apparent proton affinity by stabilizing a closed conformation.

    Science.gov (United States)

    Li, Tianbo; Yang, Youshan; Canessa, Cecilia M

    2010-07-16

    Acid-sensing ion channels (ASICs) are proton-activated channels expressed in neurons of the central and peripheral nervous systems where they modulate neuronal activity in response to external increases in proton concentration. The size of ASIC1 currents evoked by a given local acidification is determined by the number of channels in the plasma membrane and by the apparent proton affinities for activation and steady-state desensitization of the channel. Thus, the magnitude of the pH drop and the value of the baseline pH both are functionally important. Recent characterization of ASIC1s from an increasing number of species has made evident that proton affinities of these channels vary across vertebrates. We found that in species with high baseline plasma pH, e.g. frog, shark, and fish, ASIC1 has high proton affinity compared with the mammalian channel. The beta1-beta2 linker in the extracellular domain, specifically by the substitution M85L, determines the interspecies differences in proton affinities and also the time course of ASIC1 macroscopic currents. The mechanism underlying these observations is a delay in channel opening after application of protons, most likely by stabilizing a closed conformation that decreases the apparent affinity to protons and also slows the rise and decay phases of the current. Together, the results suggest evolutionary adaptation of ASIC1 to match the value of the species-specific plasma pH. At the molecular level, adaptation is achieved by substitutions of nonionizable residues rather than by modification of the channel proton sensor.

  14. Airflow limitation or static hyperinflation: which is more closely related to dyspnea with activities of daily living in patients with COPD?

    Directory of Open Access Journals (Sweden)

    Nishimura Takashi

    2011-10-01

    Full Text Available Abstract Background Dyspnea while performing the activities of daily living has been suggested to be a better measurement than peak dyspnea during exercise. Furthermore, the inspiratory capacity (IC has been shown to be more closely related to exercise tolerance and dyspnea than the FEV1, because dynamic hyperinflation is the main cause of shortness of breath in patients with COPD. However, breathlessness during exercise is measured in most studies to evaluate this relationship. Purpose To evaluate the correlation between breathlessness during daily activities and airflow limitation or static hyperinflation in COPD. Methods We examined 167 consecutive outpatients with stable COPD. The Baseline Dyspnea Index (BDI was used to evaluate dyspnea with activities of daily living. The relationship between the BDI score and the clinical measurements of pulmonary function was then investigated. Results The Spearman rank correlation coefficients (Rs between the BDI score and the FEV1(L, FEV1(%pred and FEV1/FVC were 0.60, 0.56 and 0.56, respectively. On the other hand, the BDI score also correlated with the IC, IC/predicted total lung capacity (TLC and IC/TLC (Rs = 0.45, 0.46 and 0.47, respectively. Although all of the relationships studied were strongly correlated, the correlation coefficients were better between dyspnea and airflow limitation than between dyspnea and static hyperinflation. In stepwise multiple regression analyses, the BDI score was most significantly explained by the FEV1 (R2 = 26.2% and the diffusion capacity for carbon monoxide (R2 = 14.4% (Cumulative R2 = 40.6%. Static hyperinflation was not a significant factor for clinical dyspnea on the stepwise multiple regression analysis. Conclusion Both static hyperinflation and airflow limitation contributed greatly to dyspnea in COPD patients.

  15. Dual-induced multifractality of human online activity

    CERN Document Server

    Qin, Yuhao; Cai, Shimin; Gao, Liang

    2014-01-01

    Recent discoveries of human activity reveal the existence of long-term correlation and its relation with the fat-tailed distribution of inter-event times, which imply that there exists the fractality of human activity. However, works further analyzing the type of fractality and its origin still lack. Herein, DFA and MFDFA methods are applied in the analysis of time series of online reviewing activity from Movielens and Netflix. Results show the long-term correlation at individual and whole community level, while the strength of such correlation at individual level is restricted to activity level. Such long-term correlation reveals the fractality of online reviewing activity. In our further investigation of this fractality, we \\emph{first} demonstrate it is multifractality, which results from the dual effect of broad probability density function and long-term correlation of time series in online reviewing activity. This result is also verified by three synthesized series. Therefore, we conclude that the combin...

  16. ATP-sensitive K/sup +/ channels that are blocked by hypoglycemia-inducing sulfonylureas in insulin-secreting cells are activated by galanin, a hyperglycemia-inducing hormone

    Energy Technology Data Exchange (ETDEWEB)

    de Weille, J.; Schmid-Antomarchi, H.; Fosset, M.; Lazdunski, M.

    1988-02-01

    The action of the hyperglycemia-inducing hormone galanin, a 29-amino acid peptide names from its N-terminal glycine and C-terminal amidated alanine, was studied in rat insulinoma (RINm5F) cells using electrophysiological and /sup 86/Rb/sup +/ flux techniques. Galanin hyperpolarizes and reduces spontaneous electrical activity by activating a population of APT-sensitive K/sup +/ channels with a single-channel conductance of 30 pS (at -60 mV). Galanin-induced hyperpolarization and reduction of spike activity are reversed by the hypoglycemia-inducing sulfonylurea glibenclamine. Glibenclamide blocks the galanin-activated ATP-sensitive K/sup +/ channel. /sup 86/Rb/sup +/ efflux from insulinoma cells is stimulated by galanin in a dose-dependent manner. The half-maximum value of activation is found at 1.6 nM. Galanin-induced /sup 86/Rb/sup +/ efflux is abolished by glibenclamide. The half-maximum value of inhibition is found at 0.3 nM, which is close to the half-maximum value of inhibition of the ATP-dependent K/sup +/ channel reported earlier. /sup 86/Rb/sup +/ efflux studies confirm the electrophysiological demonstration that galanin activates and ATP-dependent K/sup +/ channel.

  17. Molecular mechanisms of cold-induced CYP1A activation in rat liver microsomes.

    Science.gov (United States)

    Perepechaeva, Maria; Kolosova, Natalia; Grishanova, Alevtina

    2011-12-01

    Cytochrome P4501A (the CYP1A1 and CYP1A2 enzymes) is known to metabolize anthropogenic xenobiotics to carcinogenic and mutagenic compounds. CYP1A1 transcriptional activation is regulated via the aryl hydrocarbon receptor (AhR)-dependent signal transduction pathway. CYP1A2 activation may occur through the AhR-dependent or AhR-independent signal transduction pathways. We used male Wistar rats to explore possible mechanisms of CYP1A activation induced by exposure to cold and the effects of the protein-tyrosine kinase inhibitors genistein, herbimycin A, and geldanamycin on the properties of hepatic CYP1A1 and CYP1A2 proteins following exposure to cold and to classic CYP1A inducers. The molecular mechanisms of cold-induced CYP1A1 and CYP1A2 activation are different. The CYP1A2 activation apparently occurs at the post-transcriptional level. The CYP1A1 activation, whether caused by exposure to cold or by classic CYP1A inducers, is AhR-dependent and occurs at the transcriptional level. Protein tyrosine kinase inhibitors have no effect on benzo(a)pyrene-induced CYP1A expression but alter cold-induced CYP1A1 activity and the CYP1A1 mRNA level. Thus, treatment with herbimycin A or geldanamycin leads to an increase in CYP1A1 activity, while treatment with genistein increases CYP1A1 mRNA expression and decreases CYP1A2 activity. These data elucidate the molecular mechanisms of cold-induced CYP1A activation and the role of protein kinases in the regulation of CYP1A during exposure to cold. Our results can also help identify the differences between the molecular mechanisms underlying the effects of the classic CYP1A inducers and the effects of cooling.

  18. BTZO-15, an ARE-activator, ameliorates DSS- and TNBS-induced colitis in rats.

    Science.gov (United States)

    Yukitake, Hiroshi; Kimura, Haruhide; Suzuki, Hirobumi; Tajima, Yasukazu; Sato, Yoshimi; Imaeda, Toshihiro; Kajino, Masahiro; Takizawa, Masayuki

    2011-01-01

    Inflammatory bowel disease (IBD) is a group of chronic inflammatory disorders that are primarily represented by ulcerative colitis and Crohn's disease. The etiology of IBD is not well understood; however, oxidative stress is considered a potential etiological and/or triggering factor for IBD. We have recently reported the identification of BTZO-1, an activator of antioxidant response element (ARE)-mediated gene expression, which protects cardiomyocytes from oxidative stress-induced insults. Here we describe the potential of BTZO-15, an active BTZO-1 derivative for ARE-activation with a favorable ADME-Tox profile, for the treatment of IBD. BTZO-15 induced expression of heme oxygenase-1 (HO-1), an ARE-regulated cytoprotective protein, and inhibited NO-induced cell death in IEC-18 cells. Large intestine shortening, rectum weight gain, diarrhea, intestinal bleeding, and an increase in rectal myeloperoxidase (MPO) activity were observed in a dextran sulfate sodium (DSS)-induced colitis rat model. Oral administration of BTZO-15 induced HO-1 expression in the rectum and attenuated DSS-induced changes. Furthermore BTZO-15 reduced the ulcerated area and rectal MPO activity in 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis rats without affecting rectal TNF-α levels. These results suggest that BTZO-15 is a promising compound for a novel IBD therapeutic drug with ARE activation properties.

  19. BTZO-15, an ARE-activator, ameliorates DSS- and TNBS-induced colitis in rats.

    Directory of Open Access Journals (Sweden)

    Hiroshi Yukitake

    Full Text Available Inflammatory bowel disease (IBD is a group of chronic inflammatory disorders that are primarily represented by ulcerative colitis and Crohn's disease. The etiology of IBD is not well understood; however, oxidative stress is considered a potential etiological and/or triggering factor for IBD. We have recently reported the identification of BTZO-1, an activator of antioxidant response element (ARE-mediated gene expression, which protects cardiomyocytes from oxidative stress-induced insults. Here we describe the potential of BTZO-15, an active BTZO-1 derivative for ARE-activation with a favorable ADME-Tox profile, for the treatment of IBD. BTZO-15 induced expression of heme oxygenase-1 (HO-1, an ARE-regulated cytoprotective protein, and inhibited NO-induced cell death in IEC-18 cells. Large intestine shortening, rectum weight gain, diarrhea, intestinal bleeding, and an increase in rectal myeloperoxidase (MPO activity were observed in a dextran sulfate sodium (DSS-induced colitis rat model. Oral administration of BTZO-15 induced HO-1 expression in the rectum and attenuated DSS-induced changes. Furthermore BTZO-15 reduced the ulcerated area and rectal MPO activity in 2,4,6-trinitrobenzene sulfonic acid (TNBS-induced colitis rats without affecting rectal TNF-α levels. These results suggest that BTZO-15 is a promising compound for a novel IBD therapeutic drug with ARE activation properties.

  20. Pollen Killer Gene S35 Function Requires Interaction with an Activator That Maps Close to S24, Another Pollen Killer Gene in Rice

    Directory of Open Access Journals (Sweden)

    Takahiko Kubo

    2016-05-01

    Full Text Available Pollen killer genes disable noncarrier pollens, and are responsible for male sterility and segregation distortion in hybrid populations of distantly related plant species. The genetic networks and the molecular mechanisms underlying the pollen killer system remain largely unknown. Two pollen killer genes, S24 and S35, have been found in an intersubspecific cross of Oryza sativa ssp. indica and japonica. The effect of S24 is counteracted by an unlinked locus EFS. Additionally, S35 has been proposed to interact with S24 to induce pollen sterility. These genetic interactions are suggestive of a single S24-centric genetic pathway (EFS–S24–S35 for the pollen killer system. To examine this hypothetical genetic pathway, the S35 and the S24 regions were further characterized and genetically dissected in this study. Our results indicated that S35 causes pollen sterility independently of both the EFS and S24 genes, but is dependent on a novel gene close to the S24 locus, named incentive for killing pollen (INK. We confirmed the phenotypic effect of the INK gene separately from the S24 gene, and identified the INK locus within an interval of less than 0.6 Mb on rice chromosome 5. This study characterized the genetic effect of the two independent genetic pathways of INK–S35 and EFS–S24 in indica–japonica hybrid progeny. Our results provide clear evidence that hybrid male sterility in rice is caused by several pollen killer networks with multiple factors positively and negatively regulating pollen killer genes.

  1. Cholesterol-mediated activation of P-glycoprotein: distinct effects on basal and drug-induced ATPase activities.

    Science.gov (United States)

    Belli, Sara; Elsener, Priska M; Wunderli-Allenspach, Heidi; Krämer, Stefanie D

    2009-05-01

    Cholesterol promotes basal and verapamil-induced ATPase activity of P-glycoprotein (P-gp). We investigated whether these effects are related to each other and to the impact of the sterol on bilayer fluidity and verapamil membrane affinity. P-gp was reconstituted in egg-phosphatidylcholine (PhC) liposomes with or without cholesterol, 1,2-dipalmitoyl-phosphatidylcholine (DPPC), alpha-tocopherol (alpha-Toc) or 2,2,5,7,8-pentamethyl-6-chromanol (PMC). Basal and verapamil-induced ATPase activities were studied with an enzymatic assay. Membrane fluidity was characterized with diphenyl-hexatriene anisotropy measurements and membrane affinity by equilibrium dialysis. DPPC (70% mol/mol) decreased the fluidity of PhC bilayers to the same level as 20% cholesterol. PMC (20%) and alpha-Toc (20%) decreased the fluidity to lesser extents. alpha-Toc and PMC, but not DPPC increased the verapamil membrane affinity. While 20% cholesterol strikingly enhanced the basal ATPase activity, none of the other constituents had a similar effect. In contrast, verapamil stimulation of P-gp ATPase activity was not only enabled by cholesterol but also by alpha-Toc and DPPC. PMC had no effect. In conclusion, cholesterol exerts distinct effects on basal and verapamil-induced ATPase activity. The influence on basal ATPase activity is sterol-specific while its effect on verapamil-induced ATPase activity is unspecific and not related to its influence on membrane fluidity and on verapamil membrane affinity.

  2. Exercise induces transient transcriptional activation of the PGC-1a gene in human skeletal muscle

    DEFF Research Database (Denmark)

    Pilegaard, Henriette; Saltin, Bengt; Neufer, P. Darrell

    2003-01-01

    Endurance exercise training induces mitochondrial biogenesis in skeletal muscle. The peroxisome proliferator activated receptor co-activator 1a (PGC-1a) has recently been identified as a nuclear factor critical for coordinating the activation of genes required for mitochondrial biogenesis in cell...

  3. Effect of montelukast on platelet activating factor- and tachykinin induced mucus secretion in the rat

    Directory of Open Access Journals (Sweden)

    Groneberg David A

    2008-02-01

    Full Text Available Abstract Background Platelet activating factor and tachykinins (substance P, neurokinin A, neurokinin B are important mediators contributing to increased airway secretion in the context of different types of respiratory diseases including acute and chronic asthma. Leukotriene receptor antagonists are recommended as add-on therapy for this disease. The cys-leukotriene-1 receptor antagonist montelukast has been used in clinical asthma therapy during the last years. Besides its inhibitory action on bronchoconstriction, only little is known about its effects on airway secretions. Therefore, the aim of this study was to evaluate the effects of montelukast on platelet activating factor- and tachykinin induced tracheal secretory activity. Methods The effects of montelukast on platelet activating factor- and tachykinin induced tracheal secretory activity in the rat were assessed by quantification of secreted 35SO4 labelled mucus macromolecules using the modified Ussing chamber technique. Results Platelet activating factor potently stimulated airway secretion, which was completely inhibited by the platelet activating factor receptor antagonist WEB 2086 and montelukast. In contrast, montelukast had no effect on tachykinin induced tracheal secretory activity. Conclusion Cys-leukotriene-1 receptor antagonism by montelukast reverses the secretagogue properties of platelet activating factor to the same degree as the specific platelet activating factor antagonist WEB 2086 but has no influence on treacheal secretion elicited by tachykinins. These results suggest a role of montelukast in the signal transduction pathway of platelet activating factor induced secretory activity of the airways and may further explain the beneficial properties of cys-leukotriene-1 receptor antagonists.

  4. Cold Suppresses Agonist-induced Activation of TRPV1

    OpenAIRE

    2011-01-01

    Cold therapy is frequently used to reduce pain and edema following acute injury or surgery such as tooth extraction. However, the neurobiological mechanisms of cold therapy are not completely understood. Transient receptor potential vanilloid 1 (TRPV1) is a capsaicin- and heat-gated nociceptive ion channel implicated in thermosensation and pathological pain under conditions of inflammation or injury. Although capsaicin-induced nociception, neuropeptide release, and ionic currents are suppress...

  5. {open_quotes}The effects of diabetes on the activity of the enzyme glutamine: fructose-6-phosphate amindotransferase{close_quotes}

    Energy Technology Data Exchange (ETDEWEB)

    Nelson, S.P.

    1994-12-31

    Hexsoamine synthetic pathway (HexNSP) controls the supply of essential substrates for glycoprotein synthesis. In vitro studies suggest that increased flux of glucose via the hexsoamine synthetic pathway may play a role in glucose induced insulin resistance of glucose transport. Glutamine: fructose-6-phosphate amindotransferase (GFAT) controls flux into the hexsoamine synthetic pathway; the major products are UDPN-acetylhexosamines (UDP.HexNac=UDP.GlcNAc= UDP.GalNac). I examined whether diabetes ({approximately} 7 days post intravenous streptozotocin, and genetically linked) affects the activity of glutamine: fructose-6-phosphate in rat and mouse skeletal muscle in vivo. Nucleotide linked HexNAc were analyzed by high pressure liquid chromatography(HPLC) in deproteinized hind limb muscle extracts.

  6. Oligomerization of Vibrio cholerae Hemolysin Induces CXCR3 Upregulation and Activation of B-1a Cell

    Institute of Scientific and Technical Information of China (English)

    Gayatri Mukherjee; Kalyan K Banerjee; Tapas Biswas

    2008-01-01

    The hemolysin oligomer promotes the proliferation of B-1a cells and the expression of CD25, which is indicative of cell activation, on B-1a cells. The upregulation of CD86 induced by the oligomer showed its selective bias for the B7-2 member of B7 family while the monomer failed to induce these effects. The oligomer induced the expression of CXCR3, associated with B cell activation, while the monomer induced the expression of CXCL4, a powerful angiostatic chemokine. In conclusion, we found that B-1a cells responded to the apoptogenic monomer by expressing CXCL4, whereas oligomerization of the immunogen induced CXCR3 to shift the response towards activation. Cellular & Molecular Immunology. 2008;5(3):231-234.

  7. Activation of Signal Transducer and Activator of Transcription 5 (STAT5) in Splenocyte Proliferation of Asthma Mice Induced by Ovalbumin

    Institute of Scientific and Technical Information of China (English)

    Guoping Li; Zhigang Liu; Peixing Ran; Jing Qiu; Nanshan Zhong

    2004-01-01

    To investigate the role of signal transducer and transcriptional activator 5 (STAT5) activated in ovalbumin (OVA)-induced splenocyte proliferation of asthma mice, an asthma mouse model was set up by intraperitoneal injection and aspiration of OVA with nebulizer. The proliferation of splenocytes isolated from the asthma mice was detected by [3H] thymidine incorporation. The phosphorytation of STAT5 was examined by Western blotting and STAT5-DNA binding was measured by electrophoretic mobility shift assay (EMSA). OVA could pronouncedly induce the splenocyte proliferation of asthma mice in a dose-dependent manner compared with control groups. Phosphorylation of STAT5 and STAT5-DNA binding were observed in splenocytes from asthma mice induced by OVA at 1 h and 3 h. These results indicated that STAT5 signal pathway played an important role in lymphocyte proliferation of asthma mice induced by OVA. Cellular & Molecular Immunology.2004;1(6):471-474.

  8. STAT5 activation induced by diabetic LDL depends on LDL glycation and occurs via src kinase activity.

    Science.gov (United States)

    Brizzi, Maria Felice; Dentelli, Patrizia; Gambino, Roberto; Cabodi, Sara; Cassader, Maurizio; Castelli, Ada; Defilippi, Paola; Pegoraro, Luigi; Pagano, Gianfranco

    2002-11-01

    Advanced glycation end products (AGEs) have been implicated in the accelerated vascular injury occurring in diabetes. We recently reported that LDL prepared from type 2 diabetic patients (dm-LDL), but not normal LDL (n-LDL) triggered signal transducers and activators of transcription STAT5 activation and p21(waf) expression in endothelial cells (ECs). The aims of the present study were to investigate the role of LDL glycation in dm-LDL- mediated signals and to analyze the molecular mechanisms leading to STAT5 activation. We found that glycated LDL (gly-LDL) triggered STAT5 activation, the formation of a prolactin inducible element (PIE)-binding complex containing STAT5, and increased p21(waf) expression through the activation of the receptor for AGE (RAGE). We also demonstrated that dm-LDL and gly-LDL, but not n-LDL treatment induced the formation of a stable complex containing the activated STAT5 and RAGE. Moreover, gly-LDL triggered src but not JAK2 kinase activity. Pretreatment with the src kinase inhibitor PP1 abrogated both STAT5 activation and the expression of p21(waf) induced by gly-LDL. Consistently, gly-LDL failed to activate STAT5 in src(-/-) fibroblasts. Collectively, our results provide evidence for the role of glycation in dm-LDL-mediated effects and for a specific role of src kinase in STAT5-dependent p21(waf) expression.

  9. Mechanisms of Ca2+-dependent calcineurin activation in mechanical stretch-induced hypertrophy.

    Science.gov (United States)

    Zobel, Carsten; Rana, Obaida R; Saygili, Erol; Bölck, Birgit; Saygili, Esra; Diedrichs, Holger; Reuter, Hannes; Frank, Konrad; Müller-Ehmsen, Jochen; Pfitzer, Gabriele; Schwinger, Robert H G

    2007-01-01

    Pressure overload is the major stimulus for cardiac hypertrophy. Accumulating evidence suggests an important role for calcium-induced activation of calcineurin in mediating hypertrophic signaling. Hypertrophy is an important risk factor for cardiovascular morbidity and mortality. We therefore employed an in vitro mechanical stretch model of cultured neonatal cardiomyocytes to evaluate proposed mechanisms of calcium-induced calcineurin activation in terms of inhibition of calcineurin activity and hypertrophy. The protein/DNA ratio and ANP gene expression were used as markers for stretch-induced hypertrophy. Stretch increased the calcineurin activity, MCIP1 gene expression and DNA binding of NFATc as well as the protein/DNA ratio and ANP mRNA in a significant manner. The specific inhibitor of calcineurin, cyclosporin A, inhibited the stretch-induced increase in calcineurin activity, MCIP1 gene expression and hypertrophy. The L-type Ca2+ channel blocker nifedipine and a blocker of the Na+/H+ exchanger (cariporide) both suppressed stretch-dependent enhanced calcineurin activity and hypertrophy. Also application of a blocker of the Na+/Ca2+ exchanger (KB-R7943) was effective in preventing calcineurin activation and increases in the protein/DNA ratio. Inhibition of capacitative Ca2+ entry with SKF 96365 was also sufficient to abrogate calcineurin activation and hypertrophy. The blocker of stretch-activated ion channels, streptomycin, was without effect on stretch-induced hypertrophy and calcineurin activity. The present work suggests that of the proposed mechanisms for the calcium-induced activation of calcineurin (L-type Ca2+ channels, capacitative Ca2+ entry, Na+/H+ exchanger, Na+/Ca2+ exchanger and stretch-activated channels) all but stretch-activated channels are possible targets for the inhibition of hypertrophy. 2007 S. Karger AG, Basel

  10. Effects of Parecoxib and Fentanyl on nociception-induced cortical activity

    Directory of Open Access Journals (Sweden)

    Wang Ying-Wei

    2010-01-01

    Full Text Available Abstract Background Analgesics, including opioids and non-steroid anti-inflammatory drugs reduce postoperative pain. However, little is known about the quantitative effects of these drugs on cortical activity induced by nociceptive stimulation. The aim of the present study was to determine the neural activity in response to a nociceptive stimulus and to investigate the effects of fentanyl (an opioid agonist and parecoxib (a selective cyclooxygenase-2 inhibitor on this nociception-induced cortical activity evoked by tail pinch. Extracellular recordings (electroencephalogram and multi-unit signals were performed in the area of the anterior cingulate cortex while intracellular recordings were made in the primary somatosensory cortex. The effects of parecoxib and fentanyl on induced cortical activity were compared. Results Peripheral nociceptive stimulation in anesthetized rats produced an immediate electroencephalogram (EEG desynchronization resembling the cortical arousal (low-amplitude, fast-wave activity, while the membrane potential switched into a persistent depolarization state. The induced cortical activity was abolished by fentanyl, and the fentanyl's effect was reversed by the opioid receptor antagonist, naloxone. Parecoxib, on the other hand, did not significantly affect the neural activity. Conclusion Cortical activity was modulated by nociceptive stimulation in anesthetized rats. Fentanyl showed a strong inhibitory effect on the nociceptive-stimulus induced cortical activity while parecoxib had no significant effect.

  11. cAMP Modulates Macrophage Development by Suppressing M-CSF-Induced MAPKs Activation

    Institute of Scientific and Technical Information of China (English)

    Ning Zhu; Jian Cui; Chunxia Qiao; Yan Li; Yuanfang Ma; Jiyan Zhang; Beifen Shen

    2008-01-01

    M-CSF is a key cytokine in macrophage development by inducing MAPKs activation, and cAMP can inhibit MAPKs activation induced by inflammatory stimuli. To explore the effects of cAMP on M-CSF-induced MAPKs activation and on macrophage development, the model of bone marrow-derived murine macrophages (BMMs) was used. The effects of cAMP on M-CSF-induced MAPKs activation were analyzed by Western blotting assay, and the effects of cAMP on CD14 and F4/80 expression during macrophage development were examined by FACS analysis.Macrophage morphology showed the successful establishment of the model of macrophage development. Western blotting assay revealed that M-CSF activated ERK, JNK and p38 in both mature and immature macrophages, and cAMP inhibited M-CSF-induced ERK, JNK and p38 activation in a time-dependent manner. FACS analysis revealed that macrophage development was impaired with cAMP pretreatment. In conclusion, cAMP modulates macrophage development by suppressing M-CSF-induced MAPKs activation.

  12. Haloalkalitolerant Actinobacteria with capacity for anthracene degradation isolated from soils close to areas with oil activity in the State of Veracruz, Mexico.

    Science.gov (United States)

    Lara-Severino, Reyna Del C; Camacho-López, Miguel A; Casanova-González, Edgar; Gómez-Oliván, Leobardo M; Sandoval-Trujillo, Ángel H; Isaac-Olivé, Keila; Ramírez-Durán, Ninfa

    2016-03-01

    The use of native strains of microorganisms from soils is an excellent option for bioremediation. To our knowledge, until now there has been no other group working on the isolation of Actinobacteria from contaminated soils in Mexico. In this study, samples of soils close to areas with oil activity in the State of Veracruz, Mexico, were inoculated for the isolation of Actinobacteria. The strains isolated were characterized morphologically, and the concentrations of NaCl and pH were determined for optimal growth. Strain selection was performed by the detection of a phylogenetic marker for Actinobacteria located at the 23S rRNA gene, followed by species identification by sequencing the 16S rRNA gene. Several haloalkalitolerant Actinobacteria were isolated and identified as: Kocuria rosea, K. palustris, Microbacterium testaceum, Nocardia farcinica and Cellulomonas denverensis. Except for C. denverensis, the biomass of all strains increased in the presence of anthracene. The strains capacity to metabolize anthracene (at 48 h), determined by fluorescence emission, was in the range of 46-54%. During this time, dihydroxy aromatic compounds formed, characterized by attenuated total reflectance Fourier transform infrared spectroscopy bands of 1205 cm-1 and 1217 cm-1. Those Actinobacteria are potentially useful for the bioremediation of saline and alkaline environments contaminated with polycyclic aromatic hydrocarbon compounds. [Int Microbiol 2016; 19(1):15-26].

  13. Human retinal pigment epithelial cell-induced apoptosis in activated T cells

    DEFF Research Database (Denmark)

    Jørgensen, A; Wiencke, A K; la Cour, M;

    1998-01-01

    induced apoptosis in several activated T-cell populations and T-cell lines, including T-cell antigen receptor (TCR)-CD3-negative T-cell lines. In contrast, RPE cells induced little or no apoptosis in resting peripheral T cells. Major histocompatibility complex (MHC) class II monoclonal antibodies, which...

  14. Complement activation contributes to ventilator-induced lung injury in rats

    NARCIS (Netherlands)

    B. Petersen; T. Busch; J. Gaertner; J.J. Haitsma (Jack); S.C. Krabbendam (Stefan); M. Ebsen (Michael); B.F. Lachmann (Burkhard); U.X. Kaisers

    2016-01-01

    textabstractThe complement system contributes to ventilator induced lung injury (VILI). We hypothesized that pretreatment with the C1 esterase inhibitor (C1INH) Berinert® constrains complement activation consecutively inducing improvements in arterial oxygenation and histological pulmonary damage. A

  15. Exercise-induced AMPK activity in skeletal muscle

    DEFF Research Database (Denmark)

    Friedrichsen, Martin; Mortensen, Brynjulf; Pehmøller, Christian

    2013-01-01

    The energy/fuel sensor 5'-AMP-activated protein kinase (AMPK) is viewed as a master regulator of cellular energy balance due to its many roles in glucose, lipid, and protein metabolism. In this review we focus on the regulation of AMPK activity in skeletal muscle and its involvement in glucose me...... metabolism, including glucose transport and glycogen synthesis. In addition, we discuss the plausible interplay between AMPK and insulin signaling regulating these processes.......The energy/fuel sensor 5'-AMP-activated protein kinase (AMPK) is viewed as a master regulator of cellular energy balance due to its many roles in glucose, lipid, and protein metabolism. In this review we focus on the regulation of AMPK activity in skeletal muscle and its involvement in glucose...

  16. Apigenin induces apoptosis in human leukemia cells and exhibits anti-leukemic activity in vivo

    National Research Council Canada - National Science Library

    Budhraja, Amit; Gao, Ning; Zhang, Zhuo; Son, Young-Ok; Cheng, Senping; Wang, Xin; Ding, Songze; Hitron, Andrew; Chen, Gang; Luo, Jia; Shi, Xianglin

    2012-01-01

    In this study, we investigated the functional role of Akt and c-jun-NH(2)-kinase (JNK) signaling cascades in apigenin-induced apoptosis in U937 human leukemia cells and anti-leukemic activity of apigenin in vivo...

  17. Catalase activity as a biomarker for mild-stress-induced robustness in Bacillus weihenstephanensis

    NARCIS (Netherlands)

    Besten, den H.M.W.; Effraimidou, S.; Abee, T.

    2013-01-01

    Microorganisms are able to survive and grow in changing environments by activating stress adaptation mechanisms which may enhance bacterial robustness. Stress-induced enhanced robustness complicates the predictability of microbial inactivation. Using psychrotolerant Bacillus weihenstephanensis strai

  18. Study of antihyperglycaemic activity of medicinal plant extracts in alloxan induced diabetic rats

    Directory of Open Access Journals (Sweden)

    Anoja P Attanayake

    2013-01-01

    C onclusion: The aqueous extract of G. arborea, S. pinnata, K. zeylanica, S. caryophyllatum, S. dulcis, S. alnifolia, L. galanga and C. grandis possess potent acute antihyperglycaemic activity in alloxan induced diabetic rats.

  19. Etoposide Induces ATM-Dependent Mitochondrial Biogenesis through AMPK Activation

    OpenAIRE

    Xuan Fu; Shan Wan; Yi Lisa Lyu; Liu, Leroy F.; Haiyan Qi

    2008-01-01

    BACKGROUND: DNA damage such as double-stranded DNA breaks (DSBs) has been reported to stimulate mitochondrial biogenesis. However, the underlying mechanism is poorly understood. The major player in response to DSBs is ATM (ataxia telangiectasia mutated). Upon sensing DSBs, ATM is activated through autophosphorylation and phosphorylates a number of substrates for DNA repair, cell cycle regulation and apoptosis. ATM has been reported to phosphorylate the alpha subunit of AMP-activated protein k...

  20. Microwave-induced thermogenetic activation of single cells

    Energy Technology Data Exchange (ETDEWEB)

    Safronov, N. A. [Physics Department, International Laser Center, M.V. Lomonosov Moscow State University, Moscow 119992 (Russian Federation); Fedotov, I. V. [Physics Department, International Laser Center, M.V. Lomonosov Moscow State University, Moscow 119992 (Russian Federation); Department of Physics and Astronomy, Texas A and M University, College Station, Texas 77843 (United States); Russian Quantum Center, ul. Novaya 100, Skolkovo, Moscow Region 143025 (Russian Federation); Ermakova, Yu. G.; Matlashov, M. E.; Belousov, V. V. [M.M. Shemyakin and Yu.A. Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117997 (Russian Federation); Sidorov-Biryukov, D. A.; Fedotov, A. B. [Physics Department, International Laser Center, M.V. Lomonosov Moscow State University, Moscow 119992 (Russian Federation); Russian Quantum Center, ul. Novaya 100, Skolkovo, Moscow Region 143025 (Russian Federation); Zheltikov, A. M. [Physics Department, International Laser Center, M.V. Lomonosov Moscow State University, Moscow 119992 (Russian Federation); Department of Physics and Astronomy, Texas A and M University, College Station, Texas 77843 (United States); Russian Quantum Center, ul. Novaya 100, Skolkovo, Moscow Region 143025 (Russian Federation); Kurchatov Institute National Research Center, Moscow 123182 (Russian Federation)

    2015-04-20

    Exposure to a microwave field is shown to enable thermogenetic activation of individual cells in a culture of cell expressing thermosensitive ion channels. Integration of a microwave transmission line with an optical fiber and a diamond quantum thermometer has been shown to allow thermogenetic single-cell activation to be combined with accurate local online temperature measurements based on an optical detection of electron spin resonance in nitrogen–vacancy centers in diamond.

  1. Mangiferin induces apoptosis in multiple myeloma cell lines by suppressing the activation of nuclear factor kappa B-inducing kinase.

    Science.gov (United States)

    Takeda, Tomoya; Tsubaki, Masanobu; Kino, Toshiki; Yamagishi, Misa; Iida, Megumi; Itoh, Tatsuki; Imano, Motohiro; Tanabe, Genzoh; Muraoka, Osamu; Satou, Takao; Nishida, Shozo

    2016-05-05

    Mangiferin is a naturally occurring glucosyl xanthone, which induces apoptosis in various cancer cells. However, the molecular mechanism underlying mangiferin-induced apoptosis has not been clarified thus far. Therefore, we examined the molecular mechanism underlying mangiferin-induced apoptosis in multiple myeloma (MM) cell lines. We found that mangiferin decreased the viability of MM cell lines in a concentration-dependent manner. We also observed an increased number of apoptotic cells, caspase-3 activation, and a decrease in the mitochondrial membrane potential. In addition, mangiferin inhibited the nuclear translocation of nuclear factor kappa B (NF-κB) and expression of phosphorylated inhibitor kappa B (IκB) and increased the expression of IκB protein, whereas no changes were observed in the phosphorylation levels of extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal protein kinase 1/2 (JNK1/2), and mammalian target of rapamycin (mTOR). The molecular mechanism responsible for mangiferin-induced inhibition of nuclear translocation of NF-κB was a decrease in the expression of phosphorylated NF-κB-inducing kinase (NIK). Moreover, mangiferin decreased the expression of X-linked inhibitor of apoptosis protein (XIAP), survivin, and Bcl-xL proteins. Knockdown of NIK expression showed results similar to those observed with mangiferin treatment. Our results suggest that mangiferin induces apoptosis through the inhibition of nuclear translocation of NF-κB by suppressing NIK activation in MM cell lines. Our results provide a new insight into the molecular mechanism of mangiferin-induced apoptosis. Importantly, since the number of reported NIK inhibitors is limited, mangiferin, which targets NIK, may be a potential anticancer agent for the treatment of MM.

  2. Piperine ameliorates the severity of cerulein-induced acute pancreatitis by inhibiting the activation of mitogen activated protein kinases.

    Science.gov (United States)

    Bae, Gi-Sang; Kim, Min-Sun; Jeong, Jinsu; Lee, Hye-Youn; Park, Kyoung-Chel; Koo, Bon Soon; Kim, Byung-Jin; Kim, Tae-Hyeon; Lee, Seung Ho; Hwang, Sung-Yeon; Shin, Yong Kook; Song, Ho-Joon; Park, Sung-Joo

    2011-07-01

    Piperine is a phenolic component of black pepper (Piper nigrum) and long pepper (Piper longum), fruits used in traditional Asian medicine. Our previous study showed that piperine inhibits lipopolysaccharide-induced inflammatory responses. In this study, we investigated whether piperine reduces the severity of cerulein-induced acute pancreatitis (AP). Administration of piperine reduced histologic damage and myeloperoxidase (MPO) activity in the pancreas and ameliorated many of the examined laboratory parameters, including the pancreatic weight (PW) to body weight (BW) ratio, as well as serum levels of amylase and lipase and trypsin activity. Furthermore, piperine pretreatment reduced the production of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 during cerulein-induced AP. In accordance with in vivo results, piperine reduced cell death, amylase and lipase activity, and cytokine production in isolated cerulein-treated pancreatic acinar cells. In addition, piperine inhibited the activation of mitogen-activated protein kinases (MAPKs). These findings suggest that the anti-inflammatory effect of piperine in cerulein-induced AP is mediated by inhibiting the activation of MAPKs. Thus, piperine may have a protective effect against AP.

  3. Force-Induced H2S by PDLSCs Modifies Osteoclastic Activity during Tooth Movement.

    Science.gov (United States)

    Liu, F; Wen, F; He, D; Liu, D; Yang, R; Wang, X; Yan, Y; Liu, Y; Kou, X; Zhou, Y

    2017-06-01

    Hydrogen sulfide (H2S), a gasotransmitter, has been recently linked to mesenchymal stem cell (MSC) function and bone homeostasis. Periodontal ligament stem cells (PDLSCs) are the main MSCs in PDL, which respond to mechanical force to induce physiological activities during orthodontic tooth movement (OTM). However, it is unknown whether mechanical force might induce endogenous H2S production by PDLSCs to regulate alveolar bone homeostasis. Here, we used a mouse OTM model to demonstrate that orthodontic force-induced endogenous H2S production in PDL tissue was associated with macrophage accumulation and osteoclastic activity in alveolar bone. Then, we showed that mechanical force application induced cystathionine β-synthase (CBS) expression and endogenous H2S production by PDLSCs. Moreover, blocking endogenous H2S or systemically increasing H2S levels could decrease or enhance force-induced osteoclastic activities to control tooth movement. We further revealed how force-induced H2S production by PDLSCs contributed to the secretion of monocyte chemoattractant protein-1 (MCP-1) and the expression of receptor activator of nuclear factor-κB ligand/osteoprotegerin (RANKL/OPG) system by PDLSCs. The secretion and expression of these factors controlled macrophage migration and osteoclast differentiation. This study demonstrated that PDLSCs produced H2S to respond to and transduce force signals. Force-induced gasotransmitter H2S production in PDLSCs therefore regulated osteoclastic activities in alveolar bone and controlled the OTM process through the MCP-1 secretion and RANKL/OPG system.

  4. Apigenin induces apoptosis in human leukemia cells and exhibits anti-leukemic activity in vivo via inactivation of Akt and activation of JNK

    OpenAIRE

    Budhraja, Amit; Gao, Ning; Zhang, Zhuo; Son, Young-Ok; Cheng, Senping; Wang, Xin; Ding, Songze; Hitron, Andrew; Chen, Gang; Luo, Jia; Shi, Xianglin

    2011-01-01

    In this study, we investigated the functional role of Akt and JNK signaling cascades in apigenin-induced apoptosis in U937 human leukemia cells and anti-leukemic activity of apigenin in vivo. Apigenin-induced apoptosis by inactivation of Akt with a concomitant activation of JNK, Mcl-1 and Bcl-2 down-regulation, cytochrome c release from mitochondria and activation of caspases. Constitutively active myristolated Akt prevented apigenin-induced JNK, caspases activation, and apoptosis. Conversely...

  5. Resveratrol Induces Hepatic Mitochondrial Biogenesis Through the Sequential Activation of Nitric Oxide and Carbon Monoxide Production

    OpenAIRE

    Kim, Seul-Ki; Joe, Yeonsoo; Min ZHENG; Kim, Hyo Jeong; Yu, Jae-Kyoung; Cho, Gyeong Jae; Chang, Ki Churl; Kim, Hyoung Kyu; Han, Jin; Ryter, Stefan W.; Chung, Hun Taeg

    2014-01-01

    Aims: Nitric oxide (NO) can induce mitochondrial biogenesis in cultured cells, through increased guanosine 3′,5′-monophosphate (cGMP), and activation of peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α). We sought to determine the role of NO, heme oxygenase-1 (HO-1), and its reaction product (carbon monoxide [CO]) in the induction of mitochondrial biogenesis by the natural antioxidant resveratrol. Results: S-nitroso-N-acetylpenicillamine (SNAP), an NO donor, induced ...

  6. ANTIDIABETIC AND HYPOLIPIDEMIC ACTIVITY OF GYMNEMA SYLVESTRE IN DEXAMETHASONE INDUCED INSULIN RESISTANCE IN ALBINO RATS

    OpenAIRE

    Hemanth Kumar V, Nagendra Nayak IM , Shobha V Huilgol, Saeed M Yendigeri , Narendar K

    2015-01-01

    Background: Gymnema sylvestre plant was widely used for medicinal purpose. The plant leaves were traditionally used to treat diabetes. Aim: To determine the antidiabetic and hypolipidemic activity of Gymnema sylvestre in dexamethasone induced insulin resistance in Albino rats. Objectives: The present study was undertaken to evaluate antidiabetic and hypolipidemic activity of Gymnema sylvestre leaf aqueous extract against dexamethasone induced insulin resistance in Albino rats. Materials and M...

  7. Apoptosis-inducing activity of a driselase digest fraction of green tea residue.

    Science.gov (United States)

    Katsuno, Y; Koyama, Y; Saeki, K; Sazuka, M; Ookawa, K; Isemura, M

    2001-01-01

    We enzymatically digested green tea residue with Driselase, a crude preparation containing cellulase, pectinase and proteases, in order to examine the potential usefulness of the residue. A fraction of the digest soluble in 70% ethanol was found to induce the death of U937 human histiocytic lymphoma cells by apoptosis. Other enzyme preparations gave similar products with cell death-inducing activity of varing potency. The green tea residue may therefore be a useful source of potential agents with anti-cancer activity.

  8. The marine toxin, Yessotoxin, induces apoptosis and increases mitochondrial activity

    Directory of Open Access Journals (Sweden)

    Andrea Fernandez-Araujo

    2014-06-01

    Discussion: Colorimetric MTT assay is widely used as a viability measurement method (McHale and L., 1988;Chiba et al., 1998. But after YTX treatment, MTT assay had shown problems to detect a cell viability decrease. In this sense, in primary cardiac cell cultures, a false increment of the proliferation rate opposite to Sulforhodamine B assay (SRB results was reported after YTX treatment (Dell'Ovo et al., 2008. Also the same effect was obtained in different cancer cell lines after assaying anticancer therapies (Ulukaya et al., 2004. In our study, an increase in cell viability using MTT was observed when the number of cells was high, while by using the LDH assay a significant viability decrease was measured. In these conditions, YTX is activating extrinsic apoptosis cell death by increasing caspase 8 activity and caspase 3 levels. The explanation for this increase was found when the mitochondrial activity was quantified cell by cell in a cytometer. In these conditions a significant increment of mitochondrial activity was detected. Since the cell population is too high, the increase in mitochondrial activity that detects the MTT test disguised the decrease of signal due to the cell death and point to a false proliferation increase. In this sense, a mitochondrial activity decrease was observed after 48 hours YTX treatment in BE(2-M17 neuroblastoma cell line (Leira et al., 2002. However, this study was done in a microplate reader with a small number of cells (Leira et al., 2002. Therefore, to measure the viability by MTT assay is very important to take into account the number of cells per condition when the experiment is designed. Alternative assays, such as LDH test, independently of the direct mitochondrial activity, can be used.

  9. Active tuning of stroke-induced vibrations by tennis players.

    Science.gov (United States)

    Chadefaux, Delphine; Rao, Guillaume; Androuet, Philippe; Berton, Eric; Vigouroux, Laurent

    2017-08-01

    This paper investigates how tennis players control stroke-induced vibration. Its aim is to characterise how a tennis player deals with entering vibration waves or how he/she has the ability to finely adjust them. A specific experimental procedure was designed, based on simultaneously collecting sets of kinematic, vibration and electromyographic data during forehand strokes using various commercial rackets and stroke intensities. Using 14 expert players, a wide range of excitations at spectral and temporal levels were investigated. Energetic and spectral descriptors of stroke-induced vibration occurring at the racket handle and at the player's wrist and elbow were computed. Results indicated that vibrational characteristics are strongly governed by grip force and to a lower extent by the racket properties. Grip force management drives the amount of energy, as well as its distribution, into the forearm. Furthermore, hand-grip can be assimilated to an adaptive filter which can significantly modify the spectral parameters propagating into the player's upper limb. A significant outcome is that these spectral characteristics are as much dependent on the player as on the racket. This contribution opens up new perspectives in equipment manufacture by underlining the need to account for player/racket interaction in the design process.

  10. Temperature-induced activation of freshwater Cyanophage AS-1 prophage.

    Science.gov (United States)

    Chu, Tin-Chun; Murray, Sean R; Hsu, Shi-Fang; Vega, Quinn; Lee, Lee H

    2011-05-01

    Synechococcus sp. IU 625 is one of the freshwater cyanobacteria responsible for harmful algal blooms (HAB). Cyanophages can serve as natural control agents and may be responsible for algal bloom prevention and disappearance. Cyanophage AS-1, which infects Synechococcus sp. IU 625 (Anacystis nidulans) and Synechococcus cedrorum, plays an important role in the environment, significantly altering the numbers of its hosts. Since seasonal (temperature-dependent) lytic induction of cyanobacterial prophage has been proposed to affect seawater algal blooms, we investigated if the AS-1 lytic cycle could be induced by a shift to high temperature. Our hypothesis was confirmed, as more phages were released at 35°C than at 24°C, with maximal induction observed with a shift from 24 to 35°C. Furthermore, transmission electron microscopy (TEM) images provide direct evidence of lysogenic to lytic conversion with temperature shift. Thus, temperature is an important inducer for AS-1 conversion from lysogenic to lytic cycle and could have applications in terms of modulating cyanobacterial populations in freshwater aquatic environments. The study gives insight into the effect of climate change on the interaction between cyanophage and cyanobacteria in freshwater ecosystems.

  11. Practice induces function-specific changes in brain activity.

    Directory of Open Access Journals (Sweden)

    Tamar R van Raalten

    Full Text Available BACKGROUND: Practice can have a profound effect on performance and brain activity, especially if a task can be automated. Tasks that allow for automatization typically involve repeated encoding of information that is paired with a constant response. Much remains unknown about the effects of practice on encoding and response selection in an automated task. METHODOLOGY: To investigate function-specific effects of automatization we employed a variant of a Sternberg task with optimized separation of activity associated with encoding and response selection by means of m-sequences. This optimized randomized event-related design allows for model free measurement of BOLD signals over the course of practice. Brain activity was measured at six consecutive runs of practice and compared to brain activity in a novel task. PRINCIPAL FINDINGS: Prompt reductions were found in the entire cortical network involved in encoding after a single run of practice. Changes in the network associated with response selection were less robust and were present only after the third run of practice. CONCLUSIONS/SIGNIFICANCE: This study shows that automatization causes heterogeneous decreases in brain activity across functional regions that do not strictly track performance improvement. This suggests that cognitive performance is supported by a dynamic allocation of multiple resources in a distributed network. Our findings may bear importance in understanding the role of automatization in complex cognitive performance, as increased encoding efficiency in early stages of practice possibly increases the capacity to otherwise interfering information.

  12. Reduced PKC α Activity Induces Senescent Phenotype in Erythrocytes

    Directory of Open Access Journals (Sweden)

    Rukmini B. Govekar

    2012-01-01

    Full Text Available The molecular mechanism mediating expression of senescent cell antigen-aggregated or cleaved band 3 and externalized phosphatidylserine (PS on the surface of aged erythrocytes and their premature expression in certain anemias is not completely elucidated. The erythrocytes with these surface modifications undergo macrophage-mediated phagocytosis. In this study, the role of protein kinase C (PKC isoforms in the expression of these surface modifications was investigated. Inhibition of PKC α by 30 μM rottlerin (R30 and 2.3 nM Gö 6976 caused expression of both the senescent cell marker-externalized PS measured by FACS analysis and aggregated band 3 detected by western blotting. In contrast to this observation, but in keeping with literature, PKC activation by phorbol-12-myristate-13-acetate (PMA also led to the expression of senescence markers. We explain this antithesis by demonstrating that PMA-treated cells show reduction in the activity of PKC α, thereby simulating inhibition. The reduction in PKC α activity may be attributed to the known downregulation of PMA-activated PKC α, caused by its membrane translocation and proteolysis. We demonstrate membrane translocation of PKC α in PMA-treated cells to substantiate this inference. Thus loss of PKC α activity either by inhibition or downregulation can cause surface modifications which can trigger erythrophagocytosis.

  13. Expression and activities of three inducible enzymes in the healing of gastric ulcers in rats

    Institute of Scientific and Technical Information of China (English)

    Jin-Sheng Guo; Chi-Hin Cho; Wei-Ping Wang; Xi-Zhong Shen; Chuen-Lung Cheng; Marcel Wing Leung Koo

    2003-01-01

    AIM: To explore the roles of nitric oxide synthase (NOS),heme oxygenase (HO) and cyclooxygenase (COX) in gastric ulceration and to investigate the relationships of the expression and activities of these enzymes at different stages of gastric ulceration.METHODS: Gastric ulcers (kissing ulcers) were induced by luminal application of acetic acid. Gastric tissue samples were obtained from the ulcer base, ulcer margin, and nonulcerated area around the ulcer margin at different time intervals after ulcer induction. The mRNA expression and protein levels of inducible and constitutive isoforms of NOS,HO and COX were analyzed with RT-PCR and Western blotting methods. The activities of the total NOS, inducible NOS (iNOS), HO, and COX were also determined.RESULTS: Differential expression of inducible iNOS, HO-1and COX-2 and enzyme activities of NOS, HO and COX were found in the gastric ulcer base. High iNOS expression and activity were observed on day 1 to day 3 in severely inflamed ulcer tissues. Maximum expressions of HO-1 and COX-2 and enzyme activities of HO and COX lagged behind that of iNOS,and remained at high levels during the healing phase.CONCLUSION: The expression and activities of inducible NOS, HO-1 and COX-2 are found to be correlated to different stages of gastric ulceration. Inducible NOS may contribute to ulcer formation while HO-1 and COX-2 may promote ulcer healing.

  14. Inhibition of Hydrogen Peroxide-Induced Human Umbilical Vein Endothelial Cells Aging by Allicin Depends on Sirtuin1 Activation

    Science.gov (United States)

    Lin, Xiao-Long; Liu, Yuanbo; Liu, Mihua; Hu, Huijun; Pan, Yongquan; Fan, Xiao-Juan; Hu, Xue-Mei; Zou, Wei-Wen

    2017-01-01

    Background The abnormal activity of Sirtuin 1 (Sirt1) is closely related to the aging of vascular endothelial cells. As a bioactive molecule, allicin has antioxidant, anti-inflammatory, and lipid-regulating mechanisms. However, few reports about the relationship of allicin and Sirt1 have been published. In this study, we aimed to elucidate the effect of allicin on Human Umbilical Vein Endothelial Cells (HUVECs) aging induced by hydrogen peroxide (H2O2) and the role of Sirt1 in this phenomenon. Material/Methods HUVEC were exposed to H2O2 to establish the aging model. The expression of protein and RNA were detected by Western blot and Reverse transcription-quantitative polymerase chain reaction. The 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to assess cell viability. Sirt1 enzyme activity assay was used to analyze enzymatic activity. Reactive oxygen species was detected by dichlorofluorescein diacetate (DCFH-DA). Cell aging was detected by Senescence β-Galactosidase (SA-β-gal) staining. Results Results of this study revealed that pretreating HUVECs with 5 ng/mL allicin before exposure to H2O2 resulted in increased cell viability and reduced reactive oxygen species generation. Western blot and quantitative real-time polymerase chain reaction (qRT-PCR) analysis showed that H2O2 attenuated the phosphorylation and activation of Sirt1 and increased the expression of plasminogen activator inhibitor-1(PAI-1) protein. Moreover, H2O2 also promoted HUVEC aging. These effects were significantly alleviated by 5 ng/mL allicin co-treatment. Furthermore, the anti-aging effects of allicin were abolished by the Sirt1 inhibitor nicotinamide (NAM). Conclusions Overall, the results demonstrated that allicin protects HUVECs from H2O2-induced oxidative stress and aging via the activation of Sirt1. PMID:28139552

  15. T-cell receptor-induced JNK activation requires proteolytic inactivation of CYLD by MALT1.

    Science.gov (United States)

    Staal, Jens; Driege, Yasmine; Bekaert, Tine; Demeyer, Annelies; Muyllaert, David; Van Damme, Petra; Gevaert, Kris; Beyaert, Rudi

    2011-05-04

    The paracaspase mucosa-associated lymphoid tissue 1 (MALT1) is central to lymphocyte activation and lymphomagenesis. MALT1 mediates antigen receptor signalling to NF-κB by acting as a scaffold protein. Furthermore, MALT1 has proteolytic activity that contributes to optimal NF-κB activation by cleaving the NF-κB inhibitor A20. Whether MALT1 protease activity is involved in other signalling pathways, and the identity of the relevant substrates, is unknown. Here, we show that T-cell receptors (TCR) activation, as well as overexpression of the oncogenic API2-MALT1 fusion protein, results in proteolytic inactivation of CYLD by MALT1, which is specifically required for c-jun N-terminal kinase (JNK) activation and the inducible expression of a subset of genes. These results indicate a novel role for MALT1 proteolytic activity in TCR-induced JNK activation and reveal CYLD cleavage as the underlying mechanism.

  16. Anticonvulsive effects of nimodipine on penicillin-induced epileptiform activity.

    Science.gov (United States)

    Bağirici, Faruk; Bostanci, M Omer

    2006-01-01

    The common features of all types of epilepsy are synchronized and uncontrolled discharges of nerve cell assemblies. It is believed that calcium ions play an important role in the generation of epileptic activity. Excessive calcium influx into neurons is the first step toward a seizure. The aim of the present study is to investigate whether the calcium channel blocker nimodipine has anticonvulsive effects. The left cerebral cortex was exposed by craniotomy in anaesthetized rats. An epileptic focus was produced by injection of penicillin G potassium (500 units) into the somatomotor cortex. After the epileptiform activity reached maximum frequency and amplitude; nimodipine was injected into the same area. Application of nimodipine caused an inhibition in the electrocorticograms (ECoG). Solvent alone did not affect the epileptiform activity. The results of this study indicate that nimodipine may have anticonvulsant effects.

  17. Closed-loop, open-source electrophysiology

    Directory of Open Access Journals (Sweden)

    John D Rolston

    2010-09-01

    Full Text Available Multiple extracellular microelectrodes (multi-electrode arrays, or MEAs effectively record rapidly varying neural signals, and can also be used for electrical stimulation. Multi-electrode recording can serve as artificial output (efferents from a neural system, while complex spatially and temporally targeted stimulation can serve as artificial input (afferents to the neuronal network. Multi-unit or local field potential recordings can not only be used to control real world artifacts, such as prostheses, computers or robots, but can also trigger or alter subsequent stimulation. Real-time feedback stimulation may serve to modulate or normalize aberrant neural activity, to induce plasticity, or to serve as artificial sensory input. Despite promising closed-loop applications, commercial electrophysiology systems do not yet take advantage of the bidirectional capabilities of multi-electrodes, especially for use in freely moving animals. We addressed this lack of tools for closing the loop with NeuroRighter, an open-source system including recording hardware, stimulation hardware, and control software with a graphical user interface. The integrated system is capable of multi-electrode recording and simultaneous patterned microstimulation triggered by recordings with minimal stimulation artifact. The potential applications of closed-loop systems as research tools and clinical treatments are broad; we provide one example where epileptic activity recorded by a multi-electrode probe is used to trigger targeted stimulation, via that probe, to freely moving rodents.

  18. Physical activity moderates stressor-induced rumination on cortisol reactivity

    Science.gov (United States)

    Puterman, Eli; O’Donovan, Aoife; Adler, Nancy E.; Tomiyama, A. Janet; Kemeny, Margaret; Wolkowitz, Owen M.; Epel, Elissa

    2011-01-01

    Objective Physically active individuals have lower rates of morbidity and mortality, and recent evidence indicates that physical activity may be particularly beneficial to those experiencing chronic stress. The tendency to ruminate increases and prolongs physiological stress responses, including hypothalamic-pituitary adrenal (HPA) axis responses as indexed by cortisol reactivity to stressful experiences. We examined the association between ruminating in response to a laboratory stressor task and HPA axis reactivity and recovery, and whether a physically active lifestyle moderates the associations between rumination and cortisol output trajectories. Methods Forty-six post-menopausal women underwent the Trier Social Stress Test while salivary cortisol was repeatedly measured. Twenty-five minutes after the end of the stressor, participants reported level of rumination in response to the stress. Results Findings indicate that physical activity moderated the initial rate (B = −.10, SE = .04, p < .05) and curvature (B = −.03, SE = .01, p = .06) of the relationship between rumination and log-transformed cortisol trajectory. Among sedentary participants, those who responded to the stressor with higher levels of rumination had a more rapid initial increase in cortisol (0.26 vs 0.21, p < .001), a later peak (56 vs. 39 minutes), and a delayed recovery (curvature −0.07 vs. −0.08, p < .001) compared to those with lower levels of rumination. In active participants, cortisol trajectories were equivalent, regardless of level of rumination. Conclusions In sum, individuals who maintain a physically active lifestyle may be protected against the effects of rumination on HPA axis reactivity to and recovery from acute stress. PMID:21873586

  19. Arctigenin Inhibits Adipogenesis by Inducing AMPK Activation and Reduces Weight Gain in High-Fat Diet-Induced Obese Mice.

    Science.gov (United States)

    Han, Yo-Han; Kee, Ji-Ye; Park, Jinbong; Kim, Hye-Lin; Jeong, Mi-Young; Kim, Dae-Seung; Jeon, Yong-Deok; Jung, Yunu; Youn, Dong-Hyun; Kang, JongWook; So, Hong-Seob; Park, Raekil; Lee, Jong-Hyun; Shin, Soyoung; Kim, Su-Jin; Um, Jae-Young; Hong, Seung-Heon

    2016-09-01

    Although arctigenin (ARC) has been reported to have some pharmacological effects such as anti-inflammation, anti-cancer, and antioxidant, there have been no reports on the anti-obesity effect of ARC. The aim of this study is to investigate whether ARC has an anti-obesity effect and mediates the AMP-activated protein kinase (AMPK) pathway. We investigated the anti-adipogenic effect of ARC using 3T3-L1 pre-adipocytes and human adipose tissue-derived mesenchymal stem cells (hAMSCs). In high-fat diet (HFD)-induced obese mice, whether ARC can inhibit weight gain was investigated. We found that ARC reduced weight gain, fat pad weight, and triglycerides in HFD-induced obese mice. ARC also inhibited the expression of peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT/enhancer-binding protein alpha (C/EBPα) in in vitro and in vivo. Furthermore, ARC induced the AMPK activation resulting in down-modulation of adipogenesis-related factors including PPARγ, C/EBPα, fatty acid synthase, adipocyte fatty acid-binding protein, and lipoprotein lipase. This study demonstrates that ARC can reduce key adipogenic factors by activating the AMPK in vitro and in vivo and suggests a therapeutic implication of ARC for obesity treatment. J. Cell. Biochem. 117: 2067-2077, 2016. © 2016 Wiley Periodicals, Inc.

  20. Differences in the mannose oligomer specificities of the closely related lectins from Galanthus nivalis and Zea mays strongly determine their eventual anti-HIV activity

    Directory of Open Access Journals (Sweden)

    Fouquaert Elke

    2011-02-01

    Full Text Available Abstract Background In a recent report, the carbohydrate-binding specificities of the plant lectins Galanthus nivalis (GNA and the closely related lectin from Zea mays (GNAmaize were determined by glycan array analysis and indicated that GNAmaize recognizes complex-type N-glycans whereas GNA has specificity towards high-mannose-type glycans. Both lectins are tetrameric proteins sharing 64% sequence similarity. Results GNAmaize appeared to be ~20- to 100-fold less inhibitory than GNA against HIV infection, syncytia formation between persistently HIV-1-infected HuT-78 cells and uninfected CD4+ T-lymphocyte SupT1 cells, HIV-1 capture by DC-SIGN and subsequent transmission of DC-SIGN-captured virions to uninfected CD4+ T-lymphocyte cells. In contrast to GNA, which preferentially selects for virus strains with deleted high-mannose-type glycans on gp120, prolonged exposure of HIV-1 to dose-escalating concentrations of GNAmaize selected for mutant virus strains in which one complex-type glycan of gp120 was deleted. Surface Plasmon Resonance (SPR analysis revealed that GNA and GNAmaize interact with HIV IIIB gp120 with affinity constants (KD of 0.33 nM and 34 nM, respectively. Whereas immobilized GNA specifically binds mannose oligomers, GNAmaize selectively binds complex-type GlcNAcβ1,2Man oligomers. Also, epitope mapping experiments revealed that GNA and the mannose-specific mAb 2G12 can independently bind from GNAmaize to gp120, whereas GNAmaize cannot efficiently bind to gp120 that contained prebound PHA-E (GlcNAcβ1,2man specific or SNA (NeuAcα2,6X specific. Conclusion The markedly reduced anti-HIV activity of GNAmaize compared to GNA can be explained by the profound shift in glycan recognition and the disappearance of carbohydrate-binding sites in GNAmaize that have high affinity for mannose oligomers. These findings underscore the need for mannose oligomer recognition of therapeutics to be endowed with anti-HIV activity and that mannose, but

  1. The hypoxia-inducible factor-1α activates ectopic production of fibroblast growth factor 23 in tumor-induced osteomalacia

    Science.gov (United States)

    Zhang, Qian; Doucet, Michele; Tomlinson, Ryan E; Han, Xiaobin; Quarles, L Darryl; Collins, Michael T; Clemens, Thomas L

    2016-01-01

    Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome in which ectopic production of fibroblast growth factor 23 (FGF23) by non-malignant mesenchymal tumors causes phosphate wasting and bone fractures. Recent studies have implicated the hypoxia-inducible factor-1α (HIF-1α) in other phosphate wasting disorders caused by elevated FGF23, including X-linked hypophosphatemic rickets and autosomal dominant hypophosphatemia. Here we provide evidence that HIF-1α mediates aberrant FGF23 in TIO by transcriptionally activating its promoter. Immunohistochemical studies in phosphaturic mesenchymal tumors resected from patients with documented TIO showed that HIF-1α and FGF23 were co-localized in spindle-shaped cells adjacent to blood vessels. Cultured tumor tissue produced high levels of intact FGF23 and demonstrated increased expression of HIF-1α protein. Transfection of MC3T3-E1 and Saos-2 cells with a HIF-1α expression construct induced the activity of a FGF23 reporter construct. Prior treatment of tumor organ cultures with HIF-1α inhibitors decreased HIF-1α and FGF23 protein accumulation and inhibited HIF-1α-induced luciferase reporter activity in transfected cells. Chromatin immunoprecipitation assays confirmed binding to a HIF-1α consensus sequence within the proximal FGF23 promoter, which was eliminated by treatment with a HIF-1α inhibitor. These results show for the first time that HIF-1α is a direct transcriptional activator of FGF23 and suggest that upregulation of HIF-1α activity in TIO contributes to the aberrant FGF23 production in these patients. PMID:27468359

  2. Mitogen-Activated Protein Kinase–Activated Protein Kinase 2 in Angiotensin II–Induced Inflammation and Hypertension

    Science.gov (United States)

    Ebrahimian, Talin; Li, Melissa Wei; Lemarié, Catherine A.; Simeone, Stefania M.C.; Pagano, Patrick J.; Gaestel, Matthias; Paradis, Pierre; Wassmann, Sven; Schiffrin, Ernesto L.

    2015-01-01

    Vascular oxidative stress and inflammation play an important role in angiotensin II–induced hypertension, and mitogen-activated protein kinases participate in these processes. We questioned whether mitogen-activated protein kinase–activated protein kinase 2 (MK2), a downstream target of p38 mitogen–activated protein kinase, is involved in angiotensin II–induced vascular responses. In vivo experiments were performed in wild-type and Mk2 knockout mice infused intravenously with angiotensin II. Angiotensin II induced a 30 mm Hg increase in mean blood pressure in wild-type that was delayed in Mk2 knockout mice. Angiotensin II increased superoxide production and vascular cell adhesion molecule-1 in blood vessels of wild-type but not in Mk2 knockout mice. Mk2 knockdown by small interfering RNA in mouse mesenteric vascular smooth muscle cells caused a 42% reduction in MK2 protein and blunted the angiotensin II–induced 40% increase of MK2 expression. Mk2 knockdown blunted angiotensin II–induced doubling of intracellular adhesion molecule-1 expression, 2.4-fold increase of nuclear p65, and 1.4-fold increase in Ets-1. Mk2 knockdown abrogated the angiotensin II–induced 4.7-fold and 1.3-fold increase of monocyte chemoattractant protein-1 mRNA and protein. Angiotensin II enhanced reactive oxygen species levels (by 29%) and nicotinamide adenine dinucleotide phosphate oxidase activity (by 48%), both abolished by Mk2 knockdown. Reduction of MK2 blocked angiotensin II–induced p47phox translocation to the membrane, associated with a 53% enhanced catalase expression. Angiotensin II–induced increase of MK2 was prevented by the nicotinamide adenine dinucleotide phosphate oxidase inhibitor Nox2ds-tat. Mk2 small interfering RNA prevented the angiotensin II–induced 30% increase of proliferation. In conclusion, MK2 plays a critical role in angiotensin II signaling, leading to hypertension, oxidative stress via activation of p47phox and inhibition of antioxidants, and

  3. Activation of JNK/Bim/Bax pathway in UV-induced apoptosis

    Science.gov (United States)

    Liu, Lei; Hui, Li; Zhang, Zhen-zhen

    2011-03-01

    Cell apoptosis induced by UV irradiation is a highly complex process in which different molecular signaling pathways are involved. JNK has been proposed as an important regulator in UV irradiation-induced apoptosis. However, the molecular mechanism through which JNK regulates apoptosis, especially how JNK activates Bax in response to UV irradiation is still controversial. In this study, using real-time single-cell analysis, we studied the machinery of Bax activation during UV-induced apoptosis. UV treatment resulted in a series of events: phosphorylation of JNK, mitochondrial translocation of Bim, and subsequent activation of Bax. The activation of Bim and Bax could be inhibited in the presence of SP600125 (a specific inhibitor of JNK), suggesting that UV irradiation activated the JNK/Bim/Bax pathway.

  4. TELOMERASE ACTIVITY DURING 7, 12-DIMETHYLBENZ [a] ANTHRACENE-INDUCED HAMSTER BUCCAL POUCH CARCINOGENESIS

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    Objective: To investigate the roles of telomerase activity (TA) in relation to hamster buccal pouch tumor progression. Methods: male hamster were treated three times weekly with 0.5% of 7, 12-dimethyl- benzanthracene (DMBA) over a 15 weeks experimental period. Hamsters were sacrificed at 3, 6, 9, 12 and 15 weeks after treatment. Telomerase activity of hamster buccal pouch tissue were measured along with the analyses of the formation of DMBA-induced hamster buccal pouch tumors. Results: DMBA-induced squamous cell carcinomas were found at the 6th week after dosing. Telomerase activity elevation began at the 3rd week and was increasing to a plateau at the 12th week. Conclusion: Our results show that telomerase activity in the target tissue may be detected at the early stage of the DMBA-induced hamster buccal pouch tumor formation and suggests that telomerase activity may be used as a biomarker for an early clinical detection of buccal pouch cancer.

  5. High hydrostatic pressure treatment of porcine oocytes induces parthenogenetic activation

    DEFF Research Database (Denmark)

    Lin, Lin; Pribenszky, Csaba; Molnár, Miklós

    2010-01-01

    An innovative technique called high hydrostatic pressure (HHP) treatment has recently been reported to improve the cryosurvival of gametes and embryos in certain mammalian species, including the mouse, pig, and cattle. In the present study the parthenogenetic activation (PA) of pig oocytes caused...

  6. Activation of endothelial β-catenin signaling induces heart failure

    Science.gov (United States)

    Nakagawa, Akito; Naito, Atsuhiko T.; Sumida, Tomokazu; Nomura, Seitaro; Shibamoto, Masato; Higo, Tomoaki; Okada, Katsuki; Sakai, Taku; Hashimoto, Akihito; Kuramoto, Yuki; Oka, Toru; Lee, Jong-Kook; Harada, Mutsuo; Ueda, Kazutaka; Shiojima, Ichiro; Limbourg, Florian P.; Adams, Ralf H.; Noda, Tetsuo; Sakata, Yasushi; Akazawa, Hiroshi; Komuro, Issei

    2016-01-01

    Activation of β-catenin-dependent canonical Wnt signaling in endothelial cells plays a key role in angiogenesis during development and ischemic diseases, however, other roles of Wnt/β-catenin signaling in endothelial cells remain poorly understood. Here, we report that sustained activation of β-catenin signaling in endothelial cells causes cardiac dysfunction through suppressing neuregulin-ErbB pathway in the heart. Conditional gain-of-function mutation of β-catenin, which activates Wnt/β-catenin signaling in Bmx-positive arterial endothelial cells (Bmx/CA mice) led to progressive cardiac dysfunction and 100% mortality at 40 weeks after tamoxifen treatment. Electron microscopic analysis revealed dilatation of T-tubules and degeneration of mitochondria in cardiomyocytes of Bmx/CA mice, which are similar to the changes observed in mice with decreased neuregulin-ErbB signaling. Endothelial expression of Nrg1 and cardiac ErbB signaling were suppressed in Bmx/CA mice. The cardiac dysfunction of Bmx/CA mice was ameliorated by administration of recombinant neuregulin protein. These results collectively suggest that sustained activation of Wnt/β-catenin signaling in endothelial cells might be a cause of heart failure through suppressing neuregulin-ErbB signaling, and that the Wnt/β-catenin/NRG axis in cardiac endothelial cells might become a therapeutic target for heart failure. PMID:27146149

  7. AMP-activated protein kinase (AMPK) regulates the insulin-induced activation of the nitric oxide synthase in human platelets.

    Science.gov (United States)

    Fleming, Ingrid; Schulz, Christian; Fichtlscherer, Birgit; Kemp, Bruce E; Fisslthaler, Beate; Busse, Rudi

    2003-11-01

    Little is known about the signaling cascades that eventually regulate the activity of the endothelial nitric oxide synthase (eNOS) in platelets. Here, we investigated the effects of insulin on the phosphorylation and activation of eNOS in washed human platelets and in endothelial cells. Insulin activated the protein kinase Akt in cultured endothelial cells and increased the phosphorylation of eNOS on Ser(1177) but failed to increase endothelial cyclic GMP levels or to elicit the relaxation of endothelium-intact porcine coronary arteries. In platelets, insulin also elicited the activation of Akt as well as the phosphorylation of eNOS and initiated NO production which was associated with increased cyclic GMP levels and the inhibition of thrombin-induced aggregation. The insulin-induced inhibition of aggregation was accompanied by a decreased Ca(2+) response to thrombin and was also prevented by N(omega) nitro-L-arginine. In platelets, but not in endothelial cells, insulin induced the activation of the AMP-activated protein kinase (AMPK), a metabolic stress-sensing kinase which was sensitive to the phosphatidylinositol 3-kinase (PI3-K) inhibitor wortmannin and the AMPK inhibitor iodotubercidin. Moreover, the insulin-mediated inhibition of thrombin-induced aggregation was prevented by iodotubercidin. Insulin-independent activation of the AMPK using 5-aminoimidazole-4-carboxamide ribonucleoside, increased platelet eNOS phosphorylation, increased cyclic GMP levels and attenuated platelet aggregation. These results highlight the differences in the signal transduction cascade activated by insulin in endothelial cells and platelets, and demonstrate that insulin stimulates the formation of NO in human platelets, in the absence of an increase in Ca(2+), by acti-vating PI3-K and AMPK which phosphorylates eNOS on Ser(1177).

  8. Staphylococcus aureus - induced tumor necrosis factor - related apoptosis - inducing ligand expression mediates apoptosis and caspase-8 activation in infected osteoblasts

    Directory of Open Access Journals (Sweden)

    Bost Kenneth L

    2003-04-01

    Full Text Available Abstract Background Staphylococcus aureus infection of normal osteoblasts induces expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL. Results Normal osteoblasts were incubated in the presence of purified bacterial products over a range of concentrations. Results demonstrate that purified surface structures and a selected superantigen present in the extracellular environment are not capable of inducing TRAIL expression by osteoblasts. Osteoblasts were co-cultured with S. aureus at various multiplicities of infection utilizing cell culture chamber inserts. Results of those experiments suggest that direct contact between bacteria and osteoblasts is necessary for optimal TRAIL induction. Finally, S. aureus infection of osteoblasts in the presence of anti-TRAIL antibody demonstrates that TRAIL mediates caspase-8 activation and apoptosis of infected cells. Conclusions Collectively, these findings suggest a mechanism whereby S. aureus mediates bone destruction via induction of osteoblast apoptosis.

  9. Satellites of Xe transitions induced by infrared active vibrational modes of CF4 and C2F6 molecules.

    Science.gov (United States)

    Alekseev, Vadim A; Schwentner, Nikolaus

    2011-07-28

    Absorption and luminescence excitation spectra of Xe/CF(4) mixtures were studied in the vacuum UV region at high resolution using tunable synchrotron radiation. Pressure-broadened resonance bands and bands associated with dipole-forbidden states of the Xe atom due to collision-induced breakdown of the optical selection rules are reported. The spectra display in addition numerous satellite bands corresponding to transitions to vibrationally excited states of a Xe-CF(4) collisional complex. These satellites are located at energies of Xe atom transition increased by one quantum energy in the IR active v(3) vibrational mode of CF(4) (v(3) = 1281 cm(-1)). Satellites of both resonance and dipole-forbidden transitions were observed. Satellites of low lying resonance states are spectrally broad bands closely resembling in shape their parent pressure-broadened resonance bands. In contrast, satellites of dipole-forbidden states and of high lying resonance states are spectrally narrow bands (FWHM ∼10 cm(-1)). The satellites of dipole-forbidden states are orders of magnitude stronger than transitions to their parent states due to collision-induced breakdown of the optical selection rules. These satellites are attributed to a coupling of dipole-forbidden and resonance states induced by the electric field of the transient CF(4) (v(3) = 0 ↔ v(3) = 1) dipole. Similar satellites are present in spectra of Xe/C(2)F(6) mixtures where these bands are induced by the IR active v(10) mode of C(2)F(6). Transitions to vibrationally excited states of Xe-CF(4)(C(2)F(6)) collision pairs were also observed in two-photon LIF spectra.

  10. P38 activation is more important than ERK activation in lung injury induced by prolonged hyperbaric oxygen.

    Science.gov (United States)

    Ma, Jun; Fang, Yi-Qun; Gu, Ai-Mei; Wang, Fang-Fang; Zhang, Shi; Li, Kai-Cheng

    2013-01-01

    Prolonged exposure to hyperbaric oxygen can cause pulmonary and nerve system toxicity. Although hyperbaric oxygen treatment has been used for a broad spectrum of ailments, the mechanisms of prolonged hyperbaric oxygen-induced lung injury are not fully understood. The purpose of the present work was to investigate the roles of ERK, p38, and caspase-3 in rat lung tissue exposed to hyperbaric oxygen at 2.3 atmospheres absolute (atm abs) for two, six and 10 hours. The results showed that the ERK and p38 were phosphorylated at two hours and reached a peak at six hours into exposure to hyperbaric oxygen. While the phosphorylation level of ERK decreased, p38 remained at a high level of activation at 10 hours. The activation of ERK and p38 was down-regulated when rats were exposed to normoxic hyperbaric nitrogen for 10 hours. However, caspase-3 was activated at six hours and 10 hours into exposure to hyperbaric oxygen. These results demonstrated different changes of activation of ERK and p38 during lung injury induced by prolonged exposure to hyperbaric oxygen. The time course changes of activated caspase-3 were similar to the process of p38 activation upon exposure to hyperbaric oxygen. In this way, activation of p38, not ERK, seems to be a mechanism associated with prolonged hyperbaric oxygen-induced lung injury.

  11. High-power, photofission-inducing bremsstrahlung source for intense pulsed active detection of fissile material

    Directory of Open Access Journals (Sweden)

    J. C. Zier

    2014-06-01

    Full Text Available Intense pulsed active detection (IPAD is a promising technique for detecting fissile material to prevent the proliferation of special nuclear materials. With IPAD, fissions are induced in a brief, intense radiation burst and the resulting gamma ray or neutron signals are acquired during a short period of elevated signal-to-noise ratio. The 8 MV, 200 kA Mercury pulsed-power generator at the Naval Research Laboratory coupled to a high-power vacuum diode produces an intense 30 ns bremsstrahlung beam to study this approach. The work presented here reports on Mercury experiments designed to maximize the photofission yield in a depleted-uranium (DU object in the bremsstrahlung far field by varying the anode-cathode (AK diode gap spacing and by adding an inner-diameter-reducing insert in the outer conductor wall. An extensive suite of diagnostics was fielded to measure the bremsstrahlung beam and DU fission yield as functions of diode geometry. Delayed fission neutrons from the DU proved to be a valuable diagnostic for measuring bremsstrahlung photons above 5 MeV. The measurements are in broad agreement with particle-in-cell and Monte Carlo simulations of electron dynamics and radiation transport. These show that with increasing AK gap, electron losses to the insert and outer conductor wall increase and that the electron angles impacting the bremsstrahlung converter approach normal incidence. The diode conditions for maximum fission yield occur when the gap is large enough to produce electron angles close to normal, yet small enough to limit electron losses.

  12. Apigenin induces apoptosis in human leukemia cells and exhibits anti-leukemic activity in vivo.

    Science.gov (United States)

    Budhraja, Amit; Gao, Ning; Zhang, Zhuo; Son, Young-Ok; Cheng, Senping; Wang, Xin; Ding, Songze; Hitron, Andrew; Chen, Gang; Luo, Jia; Shi, Xianglin

    2012-01-01

    In this study, we investigated the functional role of Akt and c-jun-NH(2)-kinase (JNK) signaling cascades in apigenin-induced apoptosis in U937 human leukemia cells and anti-leukemic activity of apigenin in vivo. Apigenin induced apoptosis by inactivation of Akt with a concomitant activation of JNK, Mcl-1 and Bcl-2 downregulation, cytochrome c release from mitochondria, and activation of caspases. Constitutively active myristolated Akt prevented apigenin-induced JNK, caspase activation, and apoptosis. Conversely, LY294002 and a dominant-negative construct of Akt potentiated apigenin-induced apoptosis in leukemia cells. Interruption of the JNK pathway showed marked reduction in apigenin-induced caspase activation and apoptosis in leukemia cells. Furthermore, in vivo administration of apigenin resulted in attenuation of tumor growth in U937 xenografts accompanied by inactivation of Akt and activation of JNK. Attenuation of tumor growth in U937 xenografts by apigenin raises the possibility that apigenin may have clinical implications and can be further tested for incorporating in leukemia treatment regimens. ©2011 AACR.

  13. Ethanol-Induced Neurodegeneration and Glial Activation in the Developing Brain

    Directory of Open Access Journals (Sweden)

    Mariko Saito

    2016-08-01

    Full Text Available Ethanol induces neurodegeneration in the developing brain, which may partially explain the long-lasting adverse effects of prenatal ethanol exposure in fetal alcohol spectrum disorders (FASD. While animal models of FASD show that ethanol-induced neurodegeneration is associated with glial activation, the relationship between glial activation and neurodegeneration has not been clarified. This review focuses on the roles of activated microglia and astrocytes in neurodegeneration triggered by ethanol in rodents during the early postnatal period (equivalent to the third trimester of human pregnancy. Previous literature indicates that acute binge-like ethanol exposure in postnatal day 7 (P7 mice induces apoptotic neurodegeneration, transient activation of microglia resulting in phagocytosis of degenerating neurons, and a prolonged increase in glial fibrillary acidic protein-positive astrocytes. In our present study, systemic administration of a moderate dose of lipopolysaccharides, which causes glial activation, attenuates ethanol-induced neurodegeneration. These studies suggest that activation of microglia and astrocytes by acute ethanol in the neonatal brain may provide neuroprotection. However, repeated or chronic ethanol can induce significant proinflammatory glial reaction and neurotoxicity. Further studies are necessary to elucidate whether acute or sustained glial activation caused by ethanol exposure in the developing brain can affect long-lasting cellular and behavioral abnormalities observed in the adult brain.

  14. Interleukin-1-induced neurotoxicity is mediated by glia and requires caspase activation and free radical release.

    Science.gov (United States)

    Thornton, Peter; Pinteaux, Emmanuel; Gibson, Rosemary M; Allan, Stuart M; Rothwell, Nancy J

    2006-07-01

    Interleukin (IL)-1 expression is induced rapidly in response to diverse CNS insults and is a key mediator of experimentally induced neuronal injury. However, the mechanisms of IL-1-induced neurotoxicity are unknown. The aim of the present study was to examine the toxic effects of IL-1 on rat cortical cell cultures. Treatment with IL-1beta did not affect the viability of pure cortical neurones. However, IL-1 treatment of cocultures of neurones with glia or purified astrocytes induced caspase activation resulting in neuronal death. Neuronal cell death induced by IL-1 was prevented by pre-treatment with the IL-1 receptor antagonist, the broad spectrum caspase inhibitor Boc-Asp-(OMe)-CH(2)F or the antioxidant alpha-tocopherol. The NMDA receptor antagonist dizolcipine (MK-801) attenuated cell death induced by low doses of IL-1beta but the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBQX) had no effect. Inhibition of inducible nitric oxide synthase with N(omega)-nitro-l-arginine methyl ester had no effect on neuronal cell death induced by IL-1beta. Thus, IL-1 activates the IL-1 type 1 receptor in astrocytes to induce caspase-dependent neuronal death, which is dependent on the release of free radicals and may contribute to neuronal cell death in CNS diseases.

  15. Cucurbitacin E Induces Autophagy via Downregulating mTORC1 Signaling and Upregulating AMPK Activity.

    Directory of Open Access Journals (Sweden)

    Qing-Bing Zha

    Full Text Available Cucurbitacins, the natural triterpenoids possessing many biological activities, have been reported to suppress the mTORC1/p70S6K pathway and to induce autophagy. However, the correlation between such activities is largely unknown. In this study, we addressed this issue in human cancer cells in response to cucurbitacin E (CuE treatment. Our results showed that CuE induced autophagy as evidenced by the formation of LC3-II and colocalization of punctate LC3 with the lysosomal marker LAMP2 in HeLa and MCF7 cells. However, CuE induced much lower levels of autophagy in ATG5-knocked down cells and failed to induce autophagy in DU145 cells lacking functional ATG5 expression, suggesting the dependence of CuE-induced autophagy on ATG5. Consistent with autophagy induction, mTORC1 activity (as reflected by p70S6K and ULK1S758 phosphorylation was inhibited by CuE treatment. The suppression of mTORC1 activity was further confirmed by reduced recruitment of mTOR to the lysosome, which is the activation site of mTORC1. In contrast, CuE rapidly activated AMPK leading to increased phosphorylation of its substrates. AMPK activation contributed to CuE-induced suppression of mTORC1/p70S6K signaling and autophagy induction, since AMPK knockdown diminished these effects. Collectively, our data suggested that CuE induced autophagy in human cancer cells at least partly via downregulation of mTORC1 signaling and upregulation of AMPK activity.

  16. Rosiglitazone enhances fluorouracil-induced apoptosis of HT-29 cells by activating peroxisome proliferator-activated receptor γ

    Institute of Scientific and Technical Information of China (English)

    Yan-Qin Zhang; Xiao-Qing Tang; Li Sun; Lin Dong; Yong Qin; Hua-Qing Liu; Hong Xia; Jian-Guo Cao

    2007-01-01

    AIM: To examine whether and how rosiglitazone enhances apoptosis induced by fluorouracil in human colon cancer (HT-29) cells.METHODS: Human colon cancer HT-29 cells were cultured in vitro and treated with fluorouracil and/or rosiglitazone. Proliferation and growth of HT-29 cells were evaluated by MTT assay and trypan blue exclusion methods, respectively. The apoptosis of HT-29 cells was determined by acridine orange/ethidium bromide staining and flow cytometry using PI fluorescence staining. The expressions of peroxisome proliferator-activated receptor y (PPARy), Bcl-2 and Bax in HT-29 cells were analyzed by Western blot.RESULTS: Although rosiglitazone at the concentration below 30 umol/L for 72 h exerted almost no inhibitory effect on proliferation and growth of HT-29 cells, it could significantly enhance fluorouracil-induced HT-29 cell proliferation and growth inhibition. Furthermore, 10 umol/L rosilitazone did not induce apoptosis of HT-29 cells but dramatically enhanced fluorouracil-induced apoptosis of HT-29 cells. However, rosiglitazone did not improve apoptosis induced by fluorouracil in HT-29 cells pretreated with GW9662, a PPARy antagonist. Meanwhile, the expression of Bax and PPARy was up-regulated, while the expression of Bcl-2 was down regulated in HT-29 cells treated with rosiglitazone in a time-dependent manner. However, the effect of rosiglitazone on Bcl-2 and Bax was blocked or diminished in the presence of GW9662.CONCLUSION: Rosiglitazone enhances fluorouracil-induced apoptosis of HT-29 cells by activating PPARγ.

  17. Human retinal pigment epithelial cell-induced apoptosis in activated T cells

    DEFF Research Database (Denmark)

    Jørgensen, A; Wiencke, A K; la Cour, M

    1998-01-01

    human retinal pigment epithelial (RPE) cells can induce apoptosis in activated T cells. METHODS: Fas ligand (FasL) expression was detected by flow cytometry and immunohistochemistry. Cultured RPE cells were cocultured with T-cell lines and peripheral blood lymphocytes for 6 hours to 2 days. Induction...... of apoptosis was detected by 7-amino-actinomycin D and annexin V staining. RESULTS: Retinal pigment epithelial cells expressed FasL and induced apoptosis in activated Fas+ T cells. Blocking of Fas-FasL interaction with antibody strongly inhibited RPE-mediated T-cell apoptosis. Retinal pigment epithelial cells...... induced apoptosis in several activated T-cell populations and T-cell lines, including T-cell antigen receptor (TCR)-CD3-negative T-cell lines. In contrast, RPE cells induced little or no apoptosis in resting peripheral T cells. Major histocompatibility complex (MHC) class II monoclonal antibodies, which...

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2010-10-15

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

  19. Stress-induced traveltime variations at SAFOD revealed by continuous cross-well active source monitoring

    Science.gov (United States)

    Yang, C.; Niu, F.; Daley, T. M.; Taira, T.

    2016-12-01

    The time-varying stress/strain field at seismogenic depths is arguable the single most important property controlling the sequencing and nucleation of seismic events. The measurement of stress, however, is notoriously difficult, particularly at seismogenic depths. Seismic imaging, in principle, has the capability to provide this critical depth component. Numerous laboratory studies over the last few decades have shown that the elastic properties of crustal rocks clearly exhibit stress dependence. Such dependence is attributed to the opening/closing of fluid-filled cracks in response to changes in the stress normal to the crack surface. Temporal changes in stress are thus, in principle, measurable through seismic imaging of changes in elastic properties, such as seismic velocity field. We have been conducting continuous cross-well active source experiments utilizing the SAFOD (San Andreas Fault Observatory at Depth) pilot and main holes to develop a seismic stress meter to monitor the subsurface stress field by exploring the velocity-stress sensitivity. In a two-month period in 2005-2006, we found a 0.3% change in the average S-wave velocity, which shows a good correlation with barometric pressure, corresponding to a stress sensitivity of 2.4x10-7Pa-1. We also observed two large excursions in the delay time measurement, corresponding to 0.55% and 0.15% decreases of seismic velocity, that are coincident with two earthquakes that are among those predicted to produce the largest coseismic stress changes. The two excursions started approximately 10 and 2 hours before the events, respectively, suggesting that they may be related to pre-rupture stress induced changes in crack properties, as observed in early laboratory studies. We repeated the experiment in early 2010 with a slightly different experiment configuration, and collected 40-days data. The new data confirmed the negative correlation between traveltime and barometric pressure. The estimated stress sensitivity is

  20. TRPM2 contributes to LPC-induced intracellular Ca(2+) influx and microglial activation.

    Science.gov (United States)

    Jeong, Heejin; Kim, Yong Ho; Lee, Yunsin; Jung, Sung Jun; Oh, Seog Bae

    2017-02-20

    Microglia are the resident immune cells which become activated in some pathological conditions in central nervous system (CNS). Lysophosphatidylcholine (LPC), an endogenous inflammatory phospholipid, is implicated in immunomodulatory function of glial cells in the CNS. Although several studies uncovered that LPC induces intracellular Ca(2+) influx and morphologic change in microglia, there is still no direct evidence showing change of phosphorylation of mitogen-activated protein kinase (MAPK) p38 (p-p38), a widely used microglia activation marker, by LPC. Furthermore, the cellular mechanism of LPC-induced microglia activation remains unknown. In this study, we found that LPC induced intracellular Ca(2+) increase in primary cultured microglia, which was blocked in the presence of Gd(3+), non-selective transient receptor potential (TRP) channel blocker. RT-PCR and whole cell patch clamp recordings revealed molecular and functional expression of TRP melastatin 2 (TRPM2) in microglia. Using western blotting, we also observed that LPC increased phosphorylation of p38 MAPK, and the increase of p-p38 expression is also reversed in TRPM2-knockout (KO) microglia. Moreover, LPC induced membrane trafficking of TRPM2 and intrathecal injection of LPC increased Iba-1 immunoreactivity in the spinal cord, which were significantly reduced in KO mice. In addition, LPC-induced intracellular Ca(2+) increase and inward currents were abolished in TRPM2-KO microglia. Taken together, our results suggest that LPC induces intracellular Ca(2+) influx and increases phosphorylation of p38 MAPK via TRPM2, which in turn activates microglia.

  1. Parallel activation of Ca(2+)-induced survival and death pathways in cardiomyocytes by sorbitol-induced hyperosmotic stress.

    Science.gov (United States)

    Chiong, M; Parra, V; Eisner, V; Ibarra, C; Maldonado, C; Criollo, A; Bravo, R; Quiroga, C; Contreras, A; Vicencio, J M; Cea, P; Bucarey, J L; Molgó, J; Jaimovich, E; Hidalgo, C; Kroemer, G; Lavandero, S

    2010-08-01

    Hyperosmotic stress promotes rapid and pronounced apoptosis in cultured cardiomyocytes. Here, we investigated if Ca(2+) signals contribute to this response. Exposure of cardiomyocytes to sorbitol [600 mosmol (kg water)(-1)] elicited large and oscillatory intracellular Ca(2+) concentration increases. These Ca(2+) signals were inhibited by nifedipine, Cd(2+), U73122, xestospongin C and ryanodine, suggesting contributions from both Ca(2+) influx through voltage dependent L-type Ca(2+) channels plus Ca(2+) release from intracellular stores mediated by IP(3) receptors and ryanodine receptors. Hyperosmotic stress also increased mitochondrial Ca(2+) levels, promoted mitochondrial depolarization, reduced intracellular ATP content, and activated the transcriptional factor cyclic AMP responsive element binding protein (CREB), determined by increased CREB phosphorylation and electrophoretic mobility shift assays. Incubation with 1 mM EGTA to decrease extracellular [Ca(2+)] prevented cardiomyocyte apoptosis induced by hyperosmotic stress, while overexpression of an adenoviral dominant negative form of CREB abolished the cardioprotection provided by 1 mM EGTA. These results suggest that hyperosmotic stress induced by sorbitol, by increasing Ca(2+) influx and raising intracellular Ca(2+) concentration, activates Ca(2+) release from stores and causes cell death through mitochondrial function collapse. In addition, the present results suggest that the Ca(2+) increase induced by hyperosmotic stress promotes cell survival by recruiting CREB-mediated signaling. Thus, the fate of cardiomyocytes under hyperosmotic stress will depend on the balance between Ca(2+)-induced survival and death pathways.

  2. The structure of Doppler peaks induced by active perturbations

    CERN Document Server

    Magueijo, J; Ferreira, P; Coulson, D; Magueijo, Joao; Albrecht, Andreas; Ferreira, Pedro; Coulson, David

    1996-01-01

    We investigate how the qualitative structure of Doppler peaks in the angular power spectrum of the cosmic microwave anisotropy is affected by basic assumptions going into theories of structure formation. We define the concepts of ``coherent'' and ``incoherent'' fluctuations, and also of ``active'' and ``passive'' fluctuations. In these terms inflationary fluctuations are passive and coherent while topological defects are active incoherent fluctuations. Causality and scale invariance are shown to have different implementations in theories differing in the above senses. We then extend the formalism of Hu and Sugiyama to treat models with cosmic defects. Using this formalism we show that the existence or absence of secondary Doppler peaks and the rough placing of the primary peak are very sensitive to the fundamental properties defined. We claim therefore that even a rough measurement of the angular power spectrum C_l shape at 100

  3. Knockdown of FOXO3 induces primordial oocyte activation in pigs.

    Science.gov (United States)

    Moniruzzaman, Mohammad; Lee, Jibak; Zengyo, Mai; Miyano, Takashi

    2010-02-01

    Mammalian ovaries are endowed with a large number of primordial follicles, each containing a nongrowing oocyte. Only a small population of primordial oocytes (oocytes in primordial follicles) is activated to enter the growth phase throughout a female's reproductive life. Little is known about the mechanism regulating the activation of primordial oocytes. Here, we found that the primordial oocytes from infant pigs (10- to 20-day-old) grew to full size at 2 months after xenografting to immunodeficient mice, whereas those from prepubertal pigs (6-month-old) survived without initiation of their growth even after 4 months; thereafter, they started to grow and reached full size after 6 months. These results suggest that the mechanism regulating the activation of primordial oocytes in prepubertal pigs is different from that in infant pigs. In this regard, the involvement of FOXO3, a forkhead transcription factor, was studied. In prepubertal pigs, FOXO3 was detected in almost all (94+/-2%) primordial oocyte nuclei, and in infant pigs, 42+/-7% primordial oocytes were FOXO3 positive. At 4 months after xenografting, the percentage of FOXO3-positive primordial oocytes from prepubertal pigs had decreased to the infant level. Further, siRNA was designed to knock down porcine FOXO3. FOXO3-knockdown primordial follicles from prepubertal pigs developed to the antral stage accompanied by oocyte growth at 2 months after xenografting. These results suggest that primordial oocytes are dormant in prepubertal pigs by a FOXO3-related mechanism to establish a nongrowing oocyte pool in the ovary, and that a transient knockdown of the FOXO3 activates the primordial oocytes to enter the growth phase.

  4. HIV-induced immune activation - pathogenesis and clinical relevance

    Directory of Open Access Journals (Sweden)

    Stellbrink HJ

    2010-01-01

    Full Text Available Abstract This manuscript is communicated by the German AIDS Society (DAIG http://www.daignet.de. It summarizes a series of presentations and discussions during a workshop on immune activation due to HIV infection. The workshop was held on November 22nd 2008 in Hamburg, Germany. It was organized by the ICH Hamburg under the auspices of the German AIDS Society (DAIG e.V..

  5. Hypolipidemic activity of Semecarpus anacardium in Streptozotocin induced diabetic rats.

    Science.gov (United States)

    Jaya, Aseervatham; Shanthi, Palanivelu; Sachdanandam, Panchanatham

    2010-08-01

    Alterations in lipid metabolism and lipoprotein disturbances have played an important role in increasing the risk of cardiovascular mortality and morbidity in diabetes. A drug that has hypoglycemic activity can be used for the treatment of hyperlipidemia also. The present study was carried out to evaluate the hypolipidemic activity of Semecarpus anacardium. Male Wister rats weighing 250-270 g were injected with Streptozotocin at a dose of 50 mg/kg body weight and administered with S. anacardium (300 mg/kg body weight) and Metformin (500 mg/kg body weight) for 21 days. Control and drug control groups were also included in the study. After the experimental duration, serum was collected, liver and kidney were excised and used for the analysis of lipid and lipid metabolizing enzymes. The results of the study revealed that S. anacardium administration was able to decrease the levels of LDL, cholesterol, VLDL, TG, phospholipid and free fatty acid and increase the HDL levels and favorably modulate the lipid metabolizing enzymes in the liver and kidney. These results show that S. anacardium exerts hypolipidemic activity in diabetic rats.

  6. Disappearance of a coronal hole induced by a filament activation

    CERN Document Server

    Lin, Ma; Xiao-Li, Yan; Zhi-Ke, Xue

    2014-01-01

    We present a rare observation of direct magnetic interaction between an activating filament and a coronal hole (CH). The filament was a quiescent one located at the northwest of the CH. It underwent a nonradial activation, during which filament material constantly fell and intruded into the CH. As a result, the CH was clearly destroyed by the intrusion. Brightenings appeared at the boundaries and in the interior of the CH, meanwhile, its west boundaries began to retreat and the area gradually shrank. It is noted that the CH went on shrinking after the end of the intrusion and finally disappeared entirely. Following the filament activation, three coronal dimmings (D1-D3) were formed, among which D1 and D2 persisted throughout the complete disappearance of the CH. The derived coronal magnetic configuration shows that the filament was located below an extended loop system which obviously linked D1 to D2. By comparison with this result of extrapolation, our observations imply that the interaction between the fila...

  7. Smoking-Cue Induced Brain Activation In Adolescent Light Smokers

    Science.gov (United States)

    Rubinstein, Mark L.; Luks, Tracy L.; Moscicki, Anna-Barbara; Dryden, Wendy; Rait, Michelle A.; Simpson, Gregory V.

    2010-01-01

    Purpose Using fMRI, we examined whether or not adolescents with low levels of nicotine exposure (light smokers) display neural activation in areas shown to be involved with addiction in response to smoking-related stimuli. Design/Setting/Participants Twelve adolescent light smokers (aged 13 to17, smoked 1 to 5 cigarettes per day) and 12 non-smokers (ages 13 to 17, never smoked a cigarette) from the San Francisco Bay Area underwent fMRI scanning. During scanning they viewed blocks of photographic smoking and control cues. Smoking cues consisted of pictures of people smoking cigarettes and smoking-related objects such as lighters and ashtrays. Neutral cues consisted of everyday objects and people engaged in everyday activities. Findings For smokers, smoking cues elicited greater activation than neutral cues in the mesolimbic reward circuit (left anterior cingulate (T=7.88, pbrain regions seen in adult and heavy teen smokers suggests that even at low levels of smoking, adolescents exhibit heightened reactivity to smoking cues. This paper adds to the existing literature suggesting that nicotine dependence may begin with exposure to low levels of nicotine, underscoring the need for early intervention among adolescent smokers. PMID:21185518

  8. Bactericidal activity of titanium dioxide ultraviolet-induced films

    Energy Technology Data Exchange (ETDEWEB)

    Pleskova, S.N., E-mail: pleskova@mail.ru [Laboratory of Biochemistry and Molecular Biology, Tomsk State University, ave. Lenina 36, Tomsk 634050 (Russian Federation); Golubeva, I.S., E-mail: golubmay@mail.ru [Institute of applied biotechnology of Nizhny Novgorod, Yablonevaya Street 22, Nizhny Novgorod 603093 (Russian Federation); Verevkin, Y.K., E-mail: verevkin@appl.sci-nnov.ru [Institute of applied physics of the Russian Academy of Science, Ul' yanov Street, 46, Nizhny Novgorod 603950 (Russian Federation)

    2016-02-01

    TiO{sub 2} films are used as a self-sterilization surface due to their property to form reactive oxygen species (ROS) when irradiated with ultraviolet light. These ROS attack bacteria and kill them. We present a new way to enhance the bactericidal activity of TiO{sub 2}-films: formation of nanopores on the surface by four-beam high-power laser irradiation. Such surfaces have significantly higher antibacterial activity as compared to conventional TiO{sub 2} surfaces after 15 and 60 min of UV irradiation. Study of the bacterial cell morphology by atomic force microscopy after 60 min irradiation showed that Staphylococcus aureus 956 and Escherichia coli 321–5 undergo significant morphological changes. S. aureus assume atypical elongated shapes after UV treatment alone and swollen forms with protrusions after UV treatment on TiO{sub 2} surface. E. coli exhibit oval or round forms after UV treatment alone, and round forms with small protrusions, and destroyed cells after incubation under UV on the TiO{sub 2} film. - Highlights: • Nanopores on the TiO{sub 2} surface enhance the bactericidal activity of films. • The bactericidal effect of TiO{sub 2} is strain-specific. • The bacterial morphology significantly changes after UV/TiO{sub 2} treatment.

  9. Aucubin, a naturally occurring iridoid glycoside inhibits TNF-α-induced inflammatory responses through suppression of NF-κB activation in 3T3-L1 adipocytes.

    Science.gov (United States)

    Park, Kyoung Sik

    2013-06-01

    Obesity is closely associated with a state of chronic, low-grade inflammation characterized by abnormal cytokine production and activation of inflammatory signaling pathways in adipose tissue. Tumor necrosis factor (TNF)-α is chronically elevated in adipose tissues of obese rodents and humans. Increased levels of TNF-α are implicated in the induction of atherogenic adipokines, such as plasminogen activator inhibitor (PAI)-1, adipose-tissue-derived monocyte chemoattractant protein (MCP)-1, and interleukin (IL)-6. Aucubin, an iridoid glycoside existing in medicinal plants, has been reported to show an anti-inflammatory activity by suppression of TNF-α production in murine macrophages. The present study is aimed to investigate the effects of aucubin on TNF-α-induced atherogenic changes of the adipokines in differentiated 3T3-L1 cells. Aucubin significantly inhibited TNF-α-induced secretion and mRNA synthesis of the atherogenic adipokines including PAI-1, MCP-1, and IL-6. Further investigation of the molecular mechanism revealed that pretreatment with aucubin suppressed extracellular signal-regulated kinase (ERK) activation, inhibitory kappa Bα (IκBα) degradation, and subsequent nuclear factor kappa B (NF-κB) activation. These findings suggest that aucubin may improve obesity-induced atherosclerosis by attenuating TNF-α-induced inflammatory responses.

  10. L1 cell adhesion molecule induces melanoma cell motility by activation of mitogen-activated protein kinase pathways.

    Science.gov (United States)

    Yi, Young-Su; Baek, Kwang-Soo; Cho, Jae Youl

    2014-06-01

    L1 cell adhesion molecule (L1CAM) is highly expressed in various types of cancer cells and has been implicated in the control of cell proliferation and motility. Recently, L1CAM was reported to induce the motility of melanoma cells, but the mechanism of this induction remains poorly understood. In this study, we investigated the molecular mechanisms by which L1CAM induces the motility of melanoma cells. Unlike other types of cancer cells, B16F10 melanoma cells highly expressed L1CAM at both the RNA and protein levels, and the expression of L1CAM induced AP-1 activity. In accordance to AP-1 activation, MAPK signaling pathways were activated by L1CAM. Inhibition of L1CAM expression by L1CAM-specific siRNA suppressed the activation of MAPKs such as ERK and p38. However, no significant change was observed in JNK activation. As expected, upstream MAP2K, MKK3/6, MAP3K, and TAK1 were also deactivated by the inhibition of L1CAM expression. L1CAM induced the motility of B16F10 cells. Inhibition of L1CAM expression suppressed migration and invasion of B16F10 cells, but no suppressive effect was observed on their proliferation and anti-apoptotic resistance. Treatment of B16F10 cells with U0126, an ERK inhibitor, or SB203580, a p38 inhibitor, suppressed the migration and invasion abilities of B16F10 cells. Taken together, our results suggest that L1CAM induces the motility of B16F10 melanoma cells via the activation of MAPK pathways. This finding provides a more detailed molecular mechanism of L1CAM-mediated induction of melanoma cell motility.

  11. Sphingosine-1-phosphate mediates epidermal growth factor-induced muscle satellite cell activation

    Energy Technology Data Exchange (ETDEWEB)

    Nagata, Yosuke, E-mail: cynagata@mail.ecc.u-tokyo.ac.jp; Ohashi, Kazuya; Wada, Eiji; Yuasa, Yuki; Shiozuka, Masataka; Nonomura, Yoshiaki; Matsuda, Ryoichi

    2014-08-01

    Skeletal muscle can regenerate repeatedly due to the presence of resident stem cells, called satellite cells. Because satellite cells are usually quiescent, they must be activated before participating in muscle regeneration in response to stimuli such as injury, overloading, and stretch. Although satellite cell activation is a crucial step in muscle regeneration, little is known of the molecular mechanisms controlling this process. Recent work showed that the bioactive lipid sphingosine-1-phosphate (S1P) plays crucial roles in the activation, proliferation, and differentiation of muscle satellite cells. We investigated the role of growth factors in S1P-mediated satellite cell activation. We found that epidermal growth factor (EGF) in combination with insulin induced proliferation of quiescent undifferentiated mouse myoblast C2C12 cells, which are also known as reserve cells, in serum-free conditions. Sphingosine kinase activity increased when reserve cells were stimulated with EGF. Treatment of reserve cells with the D-erythro-N,N-dimethylsphingosine, Sphingosine Kinase Inhibitor, or siRNA duplexes specific for sphingosine kinase 1, suppressed EGF-induced C2C12 activation. We also present the evidence showing the S1P receptor S1P2 is involved in EGF-induced reserve cell activation. Moreover, we demonstrated a combination of insulin and EGF promoted activation of satellite cells on single myofibers in a manner dependent on SPHK and S1P2. Taken together, our observations show that EGF-induced satellite cell activation is mediated by S1P and its receptor. - Highlights: • EGF in combination with insulin induces proliferation of quiescent C2C12 cells. • Sphingosine kinase activity increases when reserve cells are stimulated with EGF. • EGF-induced activation of reserve cells is dependent on sphingosine kinase and ERK. • The S1P receptor S1P2 is involved in EGF-induced reserve cell activation. • EGF-induced reserve cell activation is mediated by S1P and its

  12. Functional coupling of Cys-226 and Cys-296 in the glucagon-like peptide-1 (GLP-1) receptor indicates a disulfide bond that is close to the activation pocket.

    Science.gov (United States)

    Mann, Rosalind J; Al-Sabah, Suleiman; de Maturana, Rakel López; Sinfield, John K; Donnelly, Dan

    2010-12-01

    G protein-coupled receptors (GPCRs) are seven transmembrane α-helical (7TM) integral membrane proteins that play a central role in both cell signaling and in the action of many pharmaceuticals. The crystal structures of several Family A GPCRs have shown the presence of a disulfide bond linking transmembrane helix 3 (TM3) to the second extracellular loop (ECL2), enabling ECL2 to stabilize and contribute to the ligand binding pocket. Family B GPCRs share no significant sequence identity with those in Family A but nevertheless share two conserved cysteines in topologically equivalent positions. Since there are no available crystal structures for the 7TM domain of any Family B GPCR, we used mutagenesis alongside pharmacological analysis to investigate the role of ECL2 and the conserved cysteine residues. We mutated Cys-226, at the extracellular end of TM3 of the glucagon-like peptide-1 (GLP-1) receptor, to alanine and observed a 38-fold reduction in GLP-1 potency. Interestingly, this potency loss was restored by the additional substitution of Cys-296 in ECL2 to alanine. Alongside the complete conservation of these cysteine residues in Family B GPCRs, this functional coupling suggested the presence of a disulfide bond. Further mutagenesis demonstrated that the low potency observed at the C226A mutant, compared with the C226A-C296A double mutant, was the result of the bulky nature of the released Cys-296 side chain. Since this suggested that ECL2 was in close proximity to the agonist activation pocket, an alanine scan of ECL2 was carried out which confirmed the important role of this loop in agonist-induced receptor activation.

  13. RIG-I and dsRNA-induced IFNbeta activation.

    Directory of Open Access Journals (Sweden)

    Stéphane Hausmann

    Full Text Available Except for viruses that initiate RNA synthesis with a protein primer (e.g., picornaviruses, most RNA viruses initiate RNA synthesis with an NTP, and at least some of their viral (pppRNAs remain unblocked during the infection. Consistent with this, most viruses require RIG-I to mount an innate immune response, whereas picornaviruses require mda-5. We have examined a SeV infection whose ability to induce interferon depends on the generation of capped dsRNA (without free 5' tri-phosphate ends, and found that this infection as well requires RIG-I and not mda-5. We also provide evidence that RIG-I interacts with poly-I/C in vivo, and that heteropolymeric dsRNA and poly-I/C interact directly with RIG-I in vitro, but in different ways; i.e., poly-I/C has the unique ability to stimulate the helicase ATPase of RIG-I variants which lack the C-terminal regulatory domain.

  14. Mutations induced by dacarbazine activated with cytochrome P-450.

    Science.gov (United States)

    Mudipalli, A; Nadadur, S S; Maccubbin, A E; Gurtoo, H L

    1995-03-01

    The mutagenicity of the antitumor drug dacarbazine (DTIC) is due to alkylation of cellular DNA by metabolites resulting from the metabolism of this drug by the mixed function oxidase system. In the present study, we used an in vitro shuttle vector assay to study the base and sequence specificity of mutagenesis by DTIC. The shuttle vector plasmid pSP189 was treated with DTIC (1-2.5 mM) in vitro in a reconstituted cytochrome P-450 system at 37 degrees C for either 30 or 60 min. SupF tRNA gene insert contained in the plasmid was sequenced after replication of the drug-treated plasmid in human Ad 293 cells followed by amplification in indicator bacteria. Mutagenesis of DTIC in this system was dependent upon the presence of the cytochrome P-450 reconstituted system and NADPH. Mutations induced by DTIC included single base substitutions (35%), single base deletions (30.5%), single base insertions (19.4%) and large deletions (13.8%). Among the substitutions, transversions and transitions were in the ratio of 1:0.7. Base pairs 108 and 127 in the SupF tRNA of the pSP189 were identified as mutational hot spots.

  15. In vivo antioxidant activity of bark extract of Bixa orellana L. against acetaminophen- induced oxidative stress

    Institute of Scientific and Technical Information of China (English)

    Smilin Bell Aseervatham G; Shamna R; Sangeetha B; Sasikumar JM

    2012-01-01

    Objective: To evaluate the in vivo activity of bark extract of Bixa orellana L. (B. orellana) against acetaminophen induced oxidative stress. Methods: In the present study, antioxidant activity ofB. orellana was evaluated by using normal and acetaminophen induced oxidative stressed rats at the dose of 100 mg/kg and 200 mg/kg p.o. oraly daily for 20 days. The animal's body weight was checked before and after treatment. Different biochemical parameters such as serum glutamate pyruvate transaminases, serum glutamate oxalo transaminases, alkaline phosphatase, total bilirubin, cholesterol, protein, lactate dehydrogenase, superoxide dismutase, catalase, ascorbic acid, lipid peroxide was performed. Histopathological analysis of the control and the hepatotoxicity induced rats were performed. Results: It was observed that the B. orellana bark extract showed significant protective activity against acetaminophen induced damage at 200 mg/kg dose level, while the 100 mg/kg dose showed moderate activity. Conclusions: From the result obtained in the present study suggest that B. orellana bark extract elicit protective activity through antioxidant activity on acetaminophen induced hepatic damage in rats.

  16. Cardiac hypertrophy induced by active Raf depends on Yorkie-mediated transcription.

    Science.gov (United States)

    Yu, Lin; Daniels, Joseph P; Wu, Huihui; Wolf, Matthew J

    2015-02-03

    Organ hypertrophy can result from enlargement of individual cells or from cell proliferation or both. Activating mutations in the serine-threonine kinase Raf cause cardiac hypertrophy and contribute to Noonan syndrome in humans. Cardiac-specific expression of activated Raf also causes hypertrophy in Drosophila melanogaster. We found that Yorkie (Yki), a transcriptional coactivator in the Hippo pathway that regulates organ size, is required for Raf-induced cardiac hypertrophy in flies. Although aberrant activation of Yki orthologs stimulates cardiac hyperplasia in mice, cardiac-specific expression of an activated mutant form of Yki in fruit flies caused cardiac hypertrophy without hyperplasia. Knockdown of Yki caused cardiac dilation without loss of cardiomyocytes and prevented Raf-induced cardiac hypertrophy. In flies, Yki-induced cardiac hypertrophy required the TEA domain-containing transcription factor Scalloped, and, in mammalian cells, expression of mouse Raf(L613V), an activated form of Raf with a Noonan syndrome mutation, increased Yki-induced Scalloped activity. Furthermore, overexpression of Tgi (a Tondu domain-containing Scalloped-binding corepressor) in the fly heart abrogated Yki- or Raf-induced cardiac hypertrophy. Thus, crosstalk between Raf and Yki occurs in the heart and can influence Raf-mediated cardiac hypertrophy.

  17. Effects of alpha-AMPK knockout on exercise-induced gene activation in mouse skeletal muscle

    DEFF Research Database (Denmark)

    Jørgensen, Sebastian Beck; Wojtaszewski, Jørgen; Viollet, Benoit

    2005-01-01

    We tested the hypothesis that 5'AMP-activated protein kinase (AMPK) plays an important role in regulating the acute, exercise-induced activation of metabolic genes in skeletal muscle, which were dissected from whole-body a2- and a1-AMPK knockout (KO) and wild-type (WT) mice at rest, after treadmi...

  18. Effect of high-pressure helium on latex-induced activated chemiluminescence of human blood leucocytes.

    Science.gov (United States)

    Tyurin-Kuz'min, A Yu; Vdovin, A V

    2003-09-01

    High-pressure helium reduces the latex-induced activated chemiluminescence of diluted human blood. This effect is more noticeable, when lucigenin rather than luminol is used as the activator of chemiluminescence. The effect lessens in the presence of Mg2+ but not Ca2+. The data suggest the association of this effect with actin polymerization in leucocytes phagocytosing the latex particles.

  19. Measurement and simulation of proton induced activation of LaBr3 : Ce

    NARCIS (Netherlands)

    Buis, E. J.; Beijers, H.; Brandenburg, S.; Bos, A. J. J.; Dathy, C.; Dorenbos, P.; Drozdowski, W.; Kraft, S.; Maddox, E.; Ostendorf, R. W.; Owens, A.; Quarati, F.

    2007-01-01

    To assess the suitability of LaBr3:Ce scintillators for space mission applications, proton induced activation of LaBr3 has been investigated. The crystals were irradiated using proton beams at several different energies to mimic the spectrum of a solar flare. We have measured the activation both int

  20. PPARβ/δ regulates glucocorticoid- and sepsis-induced FOXO1 activation and muscle wasting.

    Directory of Open Access Journals (Sweden)

    Estibaliz Castillero

    Full Text Available FOXO1 is involved in glucocorticoid- and sepsis-induced muscle wasting, in part reflecting regulation of atrogin-1 and MuRF1. Mechanisms influencing FOXO1 expression in muscle wasting are poorly understood. We hypothesized that the transcription factor peroxisome proliferator-activated receptor β/δ (PPARβ/δ upregulates muscle FOXO1 expression and activity with a downstream upregulation of atrogin-1 and MuRF1 expression during sepsis and glucocorticoid treatment and that inhibition of PPARβ/δ activity can prevent muscle wasting. We found that activation of PPARβ/δ in cultured myotubes increased FOXO1 activity, atrogin-1 and MuRF1 expression, protein degradation and myotube atrophy. Treatment of myotubes with dexamethasone increased PPARβ/δ expression and activity. Dexamethasone-induced FOXO1 activation and atrogin-1 and MuRF1 expression, protein degradation, and myotube atrophy were inhibited by PPARβ/δ blocker or siRNA. Importantly, muscle wasting induced in rats by dexamethasone or sepsis was prevented by treatment with a PPARβ/δ inhibitor. The present results suggest that PPARβ/δ regulates FOXO1 activation in glucocorticoid- and sepsis-induced muscle wasting and that treatment with a PPARβ/δ inhibitor may ameliorate loss of muscle mass in these conditions.

  1. Mitogen-activated protein kinases mediate Mycobacterium tuberculosis–induced CD44 surface expression in monocytes

    Indian Academy of Sciences (India)

    Natarajan Palaniappan; S Anbalagan; Sujatha Narayanan

    2012-03-01

    CD44, an adhesion molecule, has been reported to be a binding site for Mycobacterium tuberculosis (M. tuberculosis) in macrophages and it also mediates mycobacterial phagocytosis, macrophage recruitment and protective immunity against pulmonary tuberculosis in vivo. However, the signalling pathways that are involved in M. tuberculosis–induced CD44 surface expression in monocytic cells are currently unknown. Exposure of THP-1 human monocytes to M. tuberculosis H37Rv and H37Ra induced distinct, time-dependent, phosphorylation of mitogen-activated protein kinase kinase-1, extracellular signal regulated kinase 1/2, mitogen-activated protein kinase kinase 3/6, p38 mitogen-activated protein kinase and c-jun N-terminal kinases. The strains also differed in their usage of CD14 and human leukocyte antigen-DR (HLA-DR) receptors in mediating mitogen-activated protein kinase activation. M. tuberculosis H37Rv strain induced lower CD44 surface expression and tumour necrosis factor-alpha levels, whereas H37Ra the reverse. Using highly specific inhibitors of mitogen-activated protein kinase kinase-1, p38 mitogen-activated protein kinase and c-jun N-terminal kinase, we report that inhibition of extracellular signal regulated kinase 1/2 and c-jun N-terminal kinases increases, but that inhibition of p38 mitogen-activated protein kinase decreases M. tuberculosis–induced CD44 surface expression in THP-1 human monocytes.

  2. Lipopolysaccharide (LPS-Induced Biliary Epithelial Cell NRas Activation Requires Epidermal Growth Factor Receptor (EGFR.

    Directory of Open Access Journals (Sweden)

    Christy E Trussoni

    Full Text Available Cholangiocytes (biliary epithelial cells actively participate in microbe-induced proinflammatory responses in the liver and contribute to inflammatory and infectious cholangiopathies. We previously demonstrated that cholangiocyte TLR-dependent NRas activation contributes to proinflammatory/ proliferative responses. We test the hypothesis that LPS-induced activation of NRas requires the EGFR. SV40-transformed human cholangiocytes (H69 cells, or low passage normal human cholangiocytes (NHC, were treated with LPS in the presence or absence of EGFR or ADAM metallopeptidase domain 17 (TACE inhibitors. Ras activation assays, quantitative RT-PCR, and proliferation assays were performed in cells cultured with or without inhibitors or an siRNA to Grb2. Immunofluorescence for phospho-EGFR was performed on LPS-treated mouse samples and specimens from patients with primary sclerosing cholangitis, primary biliary cirrhosis, hepatitis C, and normal livers. LPS-treatment induced an association between the TLR/MyD88 and EGFR/Grb2 signaling apparatus, NRas activation, and EGFR phosphorylation. NRas activation was sensitive to EGFR and TACE inhibitors and correlated with EGFR phosphorylation. The TACE inhibitor and Grb2 depletion prevented LPS-induced IL6 expression (p<0.05 and proliferation (p<0.01. Additionally, cholangiocytes from LPS-treated mouse livers and human primary sclerosing cholangitis (PSC livers exhibited increased phospho-EGFR (p<0.01. Moreover, LPS-induced mouse cholangiocyte proliferation was inhibited by concurrent treatment with the EGFR inhibitor, Erlotinib. Our results suggest that EGFR is essential for LPS-induced, TLR4/MyD88-mediated NRas activation and induction of a robust proinflammatory cholangiocyte response. These findings have implications not only for revealing the signaling potential of TLRs, but also implicate EGFR as an integral component of cholangiocyte TLR-induced proinflammatory processes.

  3. Lipopolysaccharide (LPS)-Induced Biliary Epithelial Cell NRas Activation Requires Epidermal Growth Factor Receptor (EGFR).

    Science.gov (United States)

    Trussoni, Christy E; Tabibian, James H; Splinter, Patrick L; O'Hara, Steven P

    2015-01-01

    Cholangiocytes (biliary epithelial cells) actively participate in microbe-induced proinflammatory responses in the liver and contribute to inflammatory and infectious cholangiopathies. We previously demonstrated that cholangiocyte TLR-dependent NRas activation contributes to proinflammatory/ proliferative responses. We test the hypothesis that LPS-induced activation of NRas requires the EGFR. SV40-transformed human cholangiocytes (H69 cells), or low passage normal human cholangiocytes (NHC), were treated with LPS in the presence or absence of EGFR or ADAM metallopeptidase domain 17 (TACE) inhibitors. Ras activation assays, quantitative RT-PCR, and proliferation assays were performed in cells cultured with or without inhibitors or an siRNA to Grb2. Immunofluorescence for phospho-EGFR was performed on LPS-treated mouse samples and specimens from patients with primary sclerosing cholangitis, primary biliary cirrhosis, hepatitis C, and normal livers. LPS-treatment induced an association between the TLR/MyD88 and EGFR/Grb2 signaling apparatus, NRas activation, and EGFR phosphorylation. NRas activation was sensitive to EGFR and TACE inhibitors and correlated with EGFR phosphorylation. The TACE inhibitor and Grb2 depletion prevented LPS-induced IL6 expression (pphospho-EGFR (p<0.01). Moreover, LPS-induced mouse cholangiocyte proliferation was inhibited by concurrent treatment with the EGFR inhibitor, Erlotinib. Our results suggest that EGFR is essential for LPS-induced, TLR4/MyD88-mediated NRas activation and induction of a robust proinflammatory cholangiocyte response. These findings have implications not only for revealing the signaling potential of TLRs, but also implicate EGFR as an integral component of cholangiocyte TLR-induced proinflammatory processes.

  4. Electroless Plating on Plastic Induced by Selective Laser Activation

    DEFF Research Database (Denmark)

    Zhang, Yang; Tang, Peter Torben; Hansen, Hans Nørgaard

    2009-01-01

    This paper presents a new method for selective micro metallization of polymers. A Nd:YAG laser is employed to draw patterns on polymer surfaces that are submerged in a liquid (usually water). After subsequent activation with palladium chloride and followed by auto-catalytic electroless plating...... in width with 50μm between two tracks, but further optimization is expected in this field. Due to the porous and rough structure of the laser track, excellent adhesion between metallization and substrate is obtained. On top of the first copper layer, additional metal such as nickel, gold, palladium or tin...

  5. Resonant Activation Induced by Four-Value Noise

    Institute of Scientific and Technical Information of China (English)

    LIU Hui; HAN Yin-Xia; HOU De-Fu; LI Jing-Hui; LI Jia-Rong

    2008-01-01

    The phenomenon of the resonant activation (RA) of a particle over a fluctuating potential barrier with a four-value noise is investigated. It is shown that the mean first passage time (MFPT) displays six minima as the function of the transition rates γ1, γ2, γ3, γ4,γ5, and γ6 of the four-value noise, respectively. In addition, the effect of other parameters of the system, such as the noise strength D of the additive Gaussian white noise and the parameter value a,b, c, and d of the four-value noise, on the RAs is also investigated.

  6. Chitosan-induced antiviral activity and innate immunity in plants.

    Science.gov (United States)

    Iriti, Marcello; Varoni, Elena Maria

    2015-02-01

    Immunity represents a trait common to all living organisms, and animals and plants share some similarities. Therefore, in susceptible host plants, complex defence machinery may be stimulated by elicitors. Among these, chitosan deserves particular attention because of its proved efficacy. This survey deals with the antiviral activity of chitosan, focusing on its perception by the plant cell and mechanism of action. Emphasis has been paid to benefits and limitations of this strategy in crop protection, as well as to the potential of chitosan as a promising agent in virus disease control.

  7. Hepatitis B virus x protein induces autophagy via activating death-associated protein kinase.

    Science.gov (United States)

    Zhang, H-T; Chen, G G; Hu, B-G; Zhang, Z-Y; Yun, J-P; He, M-L; Lai, P B S

    2014-01-01

    Hepatitis B virus x protein (HBX), a product of hepatitis B virus (HBV), is a multifunctional protein that regulates viral replication and various cellular functions. Recently, HBX has been shown to induce autophagy; however, the responsible mechanism is not fully known. In this study, we established stable HBX-expressing epithelial Chang cells as the platform to study how HBX induced autophagy. The results showed that the overexpression of HBX resulted in starvation-induced autophagy. HBX-induced autophagy was related to its ability to dephosphorylate/activate death-associated protein kinase (DAPK). The block of DAPK by its siRNA significantly counteracted HBX-mediated autophagy, confirming the positive role of DAPK in this process. HBX also induced Beclin 1, which functions at the downstream of the DAPK-mediated autophagy pathway. Although HBX could activate JNK, a kinase known to participate in autophagy in certain conditions, the change in JNK failed to influence HBX-induced autophagy. In conclusion, HBX induces autophagy via activating DAPK in a pathway related to Beclin 1, but not JNK. This new finding should help us to understand the role of autophagy in HBX-mediated pathogenesis and thus may provide targets for intervening HBX-related disorders.

  8. Excitotoxin-induced neuronal degeneration and seizure are mediated by tissue plasminogen activator.

    Science.gov (United States)

    Tsirka, S E; Gualandris, A; Amaral, D G; Strickland, S

    1995-09-28

    Neuronal degeneration in the hippocampus, a region of the brain important for acquisition of memory in humans, occurs in various pathological conditions, including Alzheimer's disease, brain ischaemia and epilepsy. When neuronal activity is stimulated in the adult rat and mouse hippocampus, tissue plasminogen activator (tPA), a serine protease that converts inactive plasminogen to the active protease plasmin, is transcriptionally induced. The activity of tPA in neural tissue is correlated with neurite outgrowth, regeneration and migration, suggesting that it might be involved in neuronal plasticity. Here we show that tPA is produced primarily by microglia in the hippocampus. Using excitotoxins to induce neuronal cell loss, we demonstrate that tPA-deficient mice are resistant to neuronal degeneration. These mice are also less susceptible to pharmacologically induced seizures than wild-type mice. These findings identify a role for tPA in neuronal degeneration and seizure.

  9. Thrombin-induced apoptosis in neurons through activation of c-Jun-N-terminal kinase.

    Science.gov (United States)

    Bao, Lei; Zu, Jie; He, Qianqian; Zhao, Hui; Zhou, Su; Ye, Xinchun; Yang, Xinxin; Zan, Kun; Zhang, Zuohui; Shi, Hongjuan; Cui, Guiyun

    2017-01-01

    Studies have shown that thrombin activation played a central role in cell injuries associated with intracerebral hemorrhage (ICH). Here, our study investigated the cytotoxicity of thrombin on neurons, and determined the involvement of JNK pathways in thrombin-induced neuronal apoptosis. Primary cultured neurons were treated with different doses of thrombin. Some neurons were given either SP600125 or vehicle. LDH release assay and flow cytometry were used to measure neuronal apoptosis caused by thrombin. The activation of JNK and capases-3 were measured by Western blot. Our results showed large doses of thrombin that increased the LDH release, the level of cleaved caspase-3 and apoptosis rate of neurons. JNK was activated by thrombin in a time-dependent manner. Administration of SP600125 protects neurons from thrombin-induced apoptosis. These data indicate that the activation of JNK is crucial for thrombin-induced neuronal apoptosis, and inhibition of JNK may be a potential therapeutic target for ICH.

  10. Is Allelopathic Activity of Ipomoea murucoides Induced by Xylophage Damage?

    Science.gov (United States)

    Flores-Palacios, Alejandro; Corona-López, Angélica María; Rios, María Yolanda; Aguilar-Guadarrama, Berenice; Toledo-Hernández, Víctor Hugo; Rodríguez-López, Verónica; Valencia-Díaz, Susana

    2015-01-01

    Herbivory activates the synthesis of allelochemicals that can mediate plant-plant interactions. There is an inverse relationship between the activity of xylophages and the abundance of epiphytes on Ipomoea murucoides. Xylophagy may modify the branch chemical constitution, which also affects the liberation of allelochemicals with defense and allelopathic properties. We evaluated the bark chemical content and the effect of extracts from branches subjected to treatments of exclusion, mechanical damage and the presence/absence of epiphytes, on the seed germination of the epiphyte Tillandsia recurvata. Principal component analysis showed that branches without any treatment separate from branches subjected to treatments; damaged and excluded branches had similar chemical content but we found no evidence to relate intentional damage with allelopathy; however 1-hexadecanol, a defense volatile compound correlated positively with principal component (PC) 1. The chemical constitution of branches subject to exclusion plus damage or plus epiphytes was similar among them. PC2 indicated that palmitic acid (allelopathic compound) and squalene, a triterpene that attracts herbivore enemies, correlated positively with the inhibition of seed germination of T. recurvata. Inhibition of seed germination of T. recurvata was mainly correlated with the increment of palmitic acid and this compound reached higher concentrations in excluded branches treatments. Then, it is likely that the allelopathic response of I. murucoides would increase to the damage (shade, load) that may be caused by a high load of epiphytes than to damage caused by the xylophages. PMID:26625350

  11. Is Allelopathic Activity of Ipomoea murucoides Induced by Xylophage Damage?

    Directory of Open Access Journals (Sweden)

    Alejandro Flores-Palacios

    Full Text Available Herbivory activates the synthesis of allelochemicals that can mediate plant-plant interactions. There is an inverse relationship between the activity of xylophages and the abundance of epiphytes on Ipomoea murucoides. Xylophagy may modify the branch chemical constitution, which also affects the liberation of allelochemicals with defense and allelopathic properties. We evaluated the bark chemical content and the effect of extracts from branches subjected to treatments of exclusion, mechanical damage and the presence/absence of epiphytes, on the seed germination of the epiphyte Tillandsia recurvata. Principal component analysis showed that branches without any treatment separate from branches subjected to treatments; damaged and excluded branches had similar chemical content but we found no evidence to relate intentional damage with allelopathy; however 1-hexadecanol, a defense volatile compound correlated positively with principal component (PC 1. The chemical constitution of branches subject to exclusion plus damage or plus epiphytes was similar among them. PC2 indicated that palmitic acid (allelopathic compound and squalene, a triterpene that attracts herbivore enemies, correlated positively with the inhibition of seed germination of T. recurvata. Inhibition of seed germination of T. recurvata was mainly correlated with the increment of palmitic acid and this compound reached higher concentrations in excluded branches treatments. Then, it is likely that the allelopathic response of I. murucoides would increase to the damage (shade, load that may be caused by a high load of epiphytes than to damage caused by the xylophages.

  12. Hemolysis-induced lethality involves inflammasome activation by heme.

    Science.gov (United States)

    Dutra, Fabianno F; Alves, Letícia S; Rodrigues, Danielle; Fernandez, Patricia L; de Oliveira, Rosane B; Golenbock, Douglas T; Zamboni, Dario S; Bozza, Marcelo T

    2014-09-30

    The increase of extracellular heme is a hallmark of hemolysis or extensive cell damage. Heme has prooxidant, cytotoxic, and inflammatory effects, playing a central role in the pathogenesis of malaria, sepsis, and sickle cell disease. However, the mechanisms by which heme is sensed by innate immune cells contributing to these diseases are not fully characterized. We found that heme, but not porphyrins without iron, activated LPS-primed macrophages promoting the processing of IL-1β dependent on nucleotide-binding domain and leucine rich repeat containing family, pyrin domain containing 3 (NLRP3). The activation of NLRP3 by heme required spleen tyrosine kinase, NADPH oxidase-2, mitochondrial reactive oxygen species, and K(+) efflux, whereas it was independent of heme internalization, lysosomal damage, ATP release, the purinergic receptor P2X7, and cell death. Importantly, our results indicated the participation of macrophages, NLRP3 inflammasome components, and IL-1R in the lethality caused by sterile hemolysis. Thus, understanding the molecular pathways affected by heme in innate immune cells might prove useful to identify new therapeutic targets for diseases that have heme release.

  13. Is Allelopathic Activity of Ipomoea murucoides Induced by Xylophage Damage?

    Science.gov (United States)

    Flores-Palacios, Alejandro; Corona-López, Angélica María; Rios, María Yolanda; Aguilar-Guadarrama, Berenice; Toledo-Hernández, Víctor Hugo; Rodríguez-López, Verónica; Valencia-Díaz, Susana

    2015-01-01

    Herbivory activates the synthesis of allelochemicals that can mediate plant-plant interactions. There is an inverse relationship between the activity of xylophages and the abundance of epiphytes on Ipomoea murucoides. Xylophagy may modify the branch chemical constitution, which also affects the liberation of allelochemicals with defense and allelopathic properties. We evaluated the bark chemical content and the effect of extracts from branches subjected to treatments of exclusion, mechanical damage and the presence/absence of epiphytes, on the seed germination of the epiphyte Tillandsia recurvata. Principal component analysis showed that branches without any treatment separate from branches subjected to treatments; damaged and excluded branches had similar chemical content but we found no evidence to relate intentional damage with allelopathy; however 1-hexadecanol, a defense volatile compound correlated positively with principal component (PC) 1. The chemical constitution of branches subject to exclusion plus damage or plus epiphytes was similar among them. PC2 indicated that palmitic acid (allelopathic compound) and squalene, a triterpene that attracts herbivore enemies, correlated positively with the inhibition of seed germination of T. recurvata. Inhibition of seed germination of T. recurvata was mainly correlated with the increment of palmitic acid and this compound reached higher concentrations in excluded branches treatments. Then, it is likely that the allelopathic response of I. murucoides would increase to the damage (shade, load) that may be caused by a high load of epiphytes than to damage caused by the xylophages.

  14. Roscovitine in combination with calcium ionophore induces oocyte activation through reduction of M-phase promoting factor activity in mice.

    Science.gov (United States)

    Iba, Tomomi; Yano, Yuya; Umeno, Mayumi; Hinokio, Kenji; Kuwahara, Akira; Irahara, Minoru; Yamano, Shuji; Yasui, Toshiyuki

    2012-11-01

    The aim of the present study was to determine oocyte activation and change in M-phase promoting factor (MPF) activity induced by treatment with calcium ionophore and roscovitine in comparison with those induced by treatment with roscovitine alone and treatment with calcium ionophore and puromycin in mice. Freshly ovulated oocytes obtained from 6-8-week-old mice were divided into five groups (no activation treatment; 5 μM calcium ionophore A23187; 50 μM roscovitine; 5 μM calcium ionophore and 10 μg/ml puromycin; and 5 μM calcium ionophore and 50 μM roscovitine) and were incubated for 6 h. Oocyte activation, assessed by morphological changes, and changes in MPF activity in the five groups at 0, 2, 4 and 6 h of incubation were examined. Activated oocytes were defined as oocytes with at least one pronucleus. Oocytes treated with roscovitine alone were not activated during the 6-h incubation period. All of the oocytes in the calcium ionophore with puromycin group and in the calcium ionophore with roscovitine group were activated. The percentage activity of MPF in oocytes treated with roscovitine alone was decreased after 2 h and increased after 4 h of incubation. The percentage activity of MPF in oocytes treated with calcium ionophore and roscovitine was significantly decreased with suppression of MPF activity being maintained for 6 h, and this change was similar to that in oocytes treated with calcium ionophore and puromycin. Roscovitine with calcium ionophore is effective for induction of oocyte activation through suppression of MPF activity in mice.

  15. Gibberellins negatively regulate light-induced nitrate reductase activity in Arabidopsis seedlings.

    Science.gov (United States)

    Zhang, Yongqiang; Liu, Zhongjuan; Liu, Rongzhi; Wang, Liguang; Bi, Yurong

    2011-12-15

    In the present study, the role of phytohormone gibberellins (GAs) on regulating the nitrate reductase (NR) activity was tested in Arabidopsis seedlings. The NR activity in light-grown Col-0 seedlings was reduced by exogenous GA₃ (an active form of GAs), but enhanced by exogenous paclobutrazol (PAC, a gibberellin biosynthesis inhibitor), suggesting that GAs negatively regulate the NR activity in light-grown seedlings. Light is known to influence the NR activity through both photosynthesis and phytochromes. When etiolated seedlings were transferred to white or red light, both exogenously applied GA₃ and PAC were found to function on the NR activity only in the presence of sucrose, implying that GAs are not involved in light signaling-induced but negatively regulate photoproducts-induced NR activity. NR is regulated by light mainly at two levels: transcript level and post-translational level. Our reverse transcription (RT)-PCR assays showed that GAs did not affect the transcript levels of NIA1 and NIA2, two genes that encode NR proteins. But the divalent cations (especially Mg²⁺) were required for GAs negative regulation of NR activity, in view of the importance of divalent cations during the process of post-translational regulation of NR activity, which indicates that GAs very likely regulate the NR activity at the post-translational level. In the following dark-light shift analyses, GAs were found to accelerate dark-induced decrease, but retard light-induced increase of the NR activity. Furthermore, it was observed that application of G₃ or PAC could impair diurnal variation of the NR activity. These results collectively indicate that GAs play a negative role during light regulation of NR activity in nature.

  16. Propofol and magnesium attenuate isoflurane-induced caspase-3 activation via inhibiting mitochondrial permeability transition pore

    Directory of Open Access Journals (Sweden)

    Zhang Yiying

    2012-08-01

    Full Text Available Abstract Background The inhalation anesthetic isoflurane has been shown to open the mitochondrial permeability transition pore (mPTP and induce caspase activation and apoptosis, which may lead to learning and memory impairment. Cyclosporine A, a blocker of mPTP opening might attenuate the isoflurane-induced mPTP opening, lessening its ripple effects. Magnesium and anesthetic propofol are also mPTP blockers. We therefore set out to determine whether propofol and magnesium can attenuate the isoflurane-induced caspase activation and mPTP opening. Methods We investigated the effects of magnesium sulfate (Mg2+, propofol, and isoflurane on the opening of mPTP and caspase activation in H4 human neuroglioma cells stably transfected to express full-length human amyloid precursor protein (APP (H4 APP cells and in six day-old wild-type mice, employing Western blot analysis and flowcytometry. Results Here we show that Mg2+ and propofol attenuated the isoflurane-induced caspase-3 activation in H4-APP cells and mouse brain tissue. Moreover, Mg2+ and propofol, the blockers of mPTP opening, mitigated the isoflurane-induced mPTP opening in the H4-APP cells. Conclusion These data illustrate that Mg2+ and propofol may ameliorate the isoflurane-induced neurotoxicity by inhibiting its mitochondrial dysfunction. Pending further studies, these findings may suggest the use of Mg2+ and propofol in preventing and treating anesthesia neurotoxicity.

  17. Salidroside Suppresses HUVECs Cell Injury Induced by Oxidative Stress through Activating the Nrf2 Signaling Pathway.

    Science.gov (United States)

    Zhu, Yao; Zhang, Ya-Jie; Liu, Wei-Wei; Shi, Ai-Wu; Gu, Ning

    2016-08-09

    Oxidative stress plays an important role in the pathogenesis of cardiovascular diseases. Salidroside (SAL), one of the main effective constituents of Rhodiola rosea, has been reported to suppress oxidative stress-induced cardiomyocyte injury and necrosis by promoting transcription of nuclear factor E2-related factor 2 (Nrf2)-regulated genes such as heme oxygenase-1 (HO-1) and NAD(P)H dehydrogenase (quinone1) (NQO1). However, it has not been indicated whether SAL might ameliorate endothelial injury induced by oxidative stress. Here, our study demonstrated that SAL might suppress HUVEC cell injury induced by oxidative stress through activating the Nrf2 signaling pathway. The results of our study indicated that SAL decreased the levels of intercellular reactive oxygen species (ROS) and malondialdehyde (MDA), and improved the activities of superoxide dismutase (SOD) and catalase (CAT), resulting in protective effects against oxidative stress-induced cell damage in HUVECs. It suppressed oxidative stress damage by inducing Nrf2 nuclear translocation and activating the expression of Nrf2-regulated antioxidant enzyme genes such as HO-1 and NQO1 in HUVECs. Knockdown of Nrf2 with siRNA abolished the cytoprotective effects against oxidative stress, decreased the expression of Nrf2, HO-1, and NQO1, and inhibited the nucleus translocation of Nrf2 in HUVECs. This study is the first to demonstrate that SAL suppresses HUVECs cell injury induced by oxidative stress through activating the Nrf2 signaling pathway.

  18. Resveratrol inhibits the hydrogen dioxide-induced apoptosis via Sirt 1 activation in osteoblast cells.

    Science.gov (United States)

    He, Na; Zhu, Xuewei; He, Wei; Zhao, Shiwei; Zhao, Weiyan; Zhu, Chunlei

    2015-01-01

    Sirt 1 plays a critical role in stress responses. We determined the deregulation of Sirt 1 activity, p53 acetylation, Bcl-2 expression, and mitochondria-dependent apoptosis in mouse osteoblast MC3T3-E1 cells which were exposed to H2O2. And then we investigated the protective role of Sirt 1 activator, Resveratrol (RSV), against the H2O2-induced apoptosis. Results demonstrated that Sirt 1 and Bcl-2 were inhibited, whereas p53 acetylation, Bax, and caspase 9 were promoted by H2O2, as was aggravated by the Sirt 1 inhibitor, EX-527. Instead, RSV inhibited the H2O2-induced both p53 acetylation and the caspase 9 activation, whereas ameliorated the H2O2-induced Bcl-2 inhibition and apoptosis. In conclusion, Sirt 1 was downregulated during the H2O2-induced apoptosis in MC3T3-E1 cells. And the chemical activation of Sirt 1 inhibited the H2O2-induced apoptosis via the downregulation of p53 acetylation. Our results suggest that Sirt 1 upregulation appears to be an important strategy to inhibit the oxidative stress-induced apoptosis.

  19. Salidroside Suppresses HUVECs Cell Injury Induced by Oxidative Stress through Activating the Nrf2 Signaling Pathway

    Directory of Open Access Journals (Sweden)

    Yao Zhu

    2016-08-01

    Full Text Available Oxidative stress plays an important role in the pathogenesis of cardiovascular diseases. Salidroside (SAL, one of the main effective constituents of Rhodiola rosea, has been reported to suppress oxidative stress-induced cardiomyocyte injury and necrosis by promoting transcription of nuclear factor E2-related factor 2 (Nrf2-regulated genes such as heme oxygenase-1 (HO-1 and NAD(PH dehydrogenase (quinone1 (NQO1. However, it has not been indicated whether SAL might ameliorate endothelial injury induced by oxidative stress. Here, our study demonstrated that SAL might suppress HUVEC cell injury induced by oxidative stress through activating the Nrf2 signaling pathway. The results of our study indicated that SAL decreased the levels of intercellular reactive oxygen species (ROS and malondialdehyde (MDA, and improved the activities of superoxide dismutase (SOD and catalase (CAT, resulting in protective effects against oxidative stress-induced cell damage in HUVECs. It suppressed oxidative stress damage by inducing Nrf2 nuclear translocation and activating the expression of Nrf2-regulated antioxidant enzyme genes such as HO-1 and NQO1 in HUVECs. Knockdown of Nrf2 with siRNA abolished the cytoprotective effects against oxidative stress, decreased the expression of Nrf2, HO-1, and NQO1, and inhibited the nucleus translocation of Nrf2 in HUVECs. This study is the first to demonstrate that SAL suppresses HUVECs cell injury induced by oxidative stress through activating the Nrf2 signaling pathway.

  20. Matrix metalloproteinase-9 and urokinase plasminogen activator mediate interleukin-1-induced neurotoxicity.

    Science.gov (United States)

    Thornton, Peter; Pinteaux, Emmanuel; Allan, Stuart M; Rothwell, Nancy J

    2008-01-01

    Matrix metalloproteinases (MMPs) are endopeptidases known to mediate acute neuronal injury, but it is unclear whether these proteases are induced by the primary insult or by inflammation associated with injury. We have reported recently that interleukin-1 (IL-1) induces neurotoxicity by an astrocyte-dependent mechanism. The aim of the present study was to test the hypothesis that MMPs mediate IL-1 neurotoxicity in rat, glial-neuronal cocultures. IL-1beta induced the release of astrocytic MMP-9 in cocultures, whilst an antagonist of MMP-9 inhibited IL-1beta-induced neuronal death. Urokinase plasminogen activator (uPA) was constitutively expressed on neuronal membrane fractions, and amiloride (an antagonist of uPA) or plasminogen activator inhibitor (PAI)-1 significantly reduced IL-1beta-induced neurotoxicity. Thus, neuronal uPA contributes to IL-1 neurotoxicity, and may be responsible for activating MMP-9 released from IL-1-primed astrocytes. In summary, IL-1-induced neurotoxicity is dependent on extracellular protease activity, and these mechanisms may contribute to neuronal cell death in CNS diseases.

  1. Bone-inducing Activity of Biological Piezoelectric Ceramic

    Institute of Scientific and Technical Information of China (English)

    2005-01-01

    To simulate the piezoelectric effect of nature bone, two kinds of biological piezoelectric composite ceramics consisted of hydroxyapatite ( HA ) and lithium sodium potassium riobate (LNK) ceramic of which the ratio of HA/ LNK was 1: 10 and 5:5( wt/ wt ) were prepared. Their piezoelectric property and growth of apatite crystal in the ceramics surface were investigated. With the increase of LNK amount, piezoelectric activity increased correspondingly. By immersing the poled piezoelectric ceramics in simulated body fluid (SBF) at 36.5 ℃ for 7,14, and 21 days, apatite crystal was formed on negatively charged surfaces. After 21 days immersion in SBF,the thickest apatite crystal on the negatively charged surfaces increased to 3.337μm. The novel biological piezoelectric ceramics show an excellent piezoelectric property and superior potential bioactivity.

  2. Does roflumilast induce phagocytic activity in COPD patients?

    Directory of Open Access Journals (Sweden)

    Ghosh B

    2015-09-01

    Full Text Available Baishakhi Ghosh,1,2 Nitin V Vanjare1 1Chest Research Foundation (CRF, Pune, Maharashtra, India; 2Faculty of Health and Biomedical Science (FOHBS, Symbiosis International University, Pune, Maharashtra, IndiaWe read the article by Porpodis et al1 with great interest. In this study, the authors have evaluated the effect of roflumilast on the phagocytic activity of systemic phagocytes in severe and very severe COPD patients by measuring the oxidative burst post-bacterial stimulation. The study group for this study involved 21 severe or very severe COPD patients who were administered roflumilast in addition to other COPD treatments such as long-acting beta-adrenoceptor agonists (LABA + inhaled corticosteroids (ICS + long-acting anti-muscarinic agent (LAMA or ICS + LABA.View original paper by Porpodis and colleagues.

  3. Telmisartan prevention of LPS-induced microglia activation involves M2 microglia polarization via CaMKKβ-dependent AMPK activation.

    Science.gov (United States)

    Xu, Yuan; Xu, Yazhou; Wang, Yurong; Wang, Yunjie; He, Ling; Jiang, Zhenzhou; Huang, Zhangjian; Liao, Hong; Li, Jia; Saavedra, Juan M; Zhang, Luyong; Pang, Tao

    2015-11-01

    Brain inflammation plays an important role in the pathophysiology of many psychiatric and neurological diseases. During brain inflammation, microglia cells are activated, producing neurotoxic molecules and neurotrophic factors depending on their pro-inflammatory M1 and anti-inflammatory M2 phenotypes. It has been demonstrated that Angiotensin II type 1 receptor blockers (ARBs) ameliorate brain inflammation and reduce M1 microglia activation. The ARB telmisartan suppresses glutamate-induced upregulation of inflammatory genes in cultured primary neurons. We wished to clarify whether telmisartan, in addition, prevents microglia activation through polarization to an anti-inflammatory M2 phenotype. We found that telmisartan promoted M2 polarization and reduced M1 polarization in LPS-stimulated BV2 and primary microglia cells, effects partially dependent on PPARγ activation. The promoting effects of telmisartan on M2 polarization, were attenuated by an AMP-activated protein kinase (AMPK) inhibitor or AMPK knockdown, indicating that AMPK activation participates on telmisartan effects. Moreover, in LPS-stimulated BV2 cells, telmisartan enhancement of M2 gene expression was prevented by the inhibitor STO-609 and siRNA of calmodulin-dependent protein kinase kinase β (CaMKKβ), an upstream kinase of AMPK. Furthermore, telmisartan enhanced brain AMPK activation and M2 gene expression in a mouse model of LPS-induced neuroinflammation. In addition, telmisartan reduced the LPS-induced sickness behavior in this in vivo model, and this effect was prevented by prior administration of an AMPK inhibitor. Our results indicate that telmisartan can be considered as a novel AMPK activator, suppressing microglia activation by promoting M2 polarization. Telmisartan may provide a novel, safe therapeutic approach to treat brain disorders associated with enhanced inflammation.

  4. Brain activity correlates with emotional perception induced by dynamic avatars.

    Science.gov (United States)

    Goldberg, Hagar; Christensen, Andrea; Flash, Tamar; Giese, Martin A; Malach, Rafael

    2015-11-15

    An accurate judgment of the emotional state of others is a prerequisite for successful social interaction and hence survival. Thus, it is not surprising that we are highly skilled at recognizing the emotions of others. Here we aimed to examine the neuronal correlates of emotion recognition from gait. To this end we created highly controlled dynamic body-movement stimuli based on real human motion-capture data (Roether et al., 2009). These animated avatars displayed gait in four emotional (happy, angry, fearful, and sad) and speed-matched neutral styles. For each emotional gait and its equivalent neutral gait, avatars were displayed at five morphing levels between the two. Subjects underwent fMRI scanning while classifying the emotions and the emotional intensity levels expressed by the avatars. Our results revealed robust brain selectivity to emotional compared to neutral gait stimuli in brain regions which are involved in emotion and biological motion processing, such as the extrastriate body area (EBA), fusiform body area (FBA), superior temporal sulcus (STS), and the amygdala (AMG). Brain activity in the amygdala reflected emotional awareness: for visually identical stimuli it showed amplified stronger response when the stimulus was perceived as emotional. Notably, in avatars gradually morphed along an emotional expression axis there was a parametric correlation between amygdala activity and emotional intensity. This study extends the mapping of emotional decoding in the human brain to the domain of highly controlled dynamic biological motion. Our results highlight an extensive level of brain processing of emotional information related to body language, which relies mostly on body kinematics.

  5. Ginsenoside Rg1 Attenuates Isoflurane-induced Caspase-3 Activation via Inhibiting Mitochondrial Dysfunction

    Institute of Scientific and Technical Information of China (English)

    MIAO Hui Hui; ZHEN Yu; DING Guan Nan; HONG Fang Xiao; XIE Zhong Cong; TIAN Ming

    2015-01-01

    Objective The inhalation anesthetic isoflurane has been shown to induce mitochondrial dysfunction and caspase activation, which may lead to learning and memory impairment. Ginsenoside Rg1 is reported to be neuroprotective. We therefore set out to determine whether ginsenoside Rg1 can attenuate isoflurane-induced caspase activation via inhibiting mitochondrial dysfunction. Methods We investigated the effects of ginsenoside Rg1 at concentrations of 12.5, 25, and 50 µmol/L and pretreatment times of 12 h and 24 h on isoflurane-induced caspase-3 activation in H4 naïve and stably transfected H4 human neuroglioma cells that express full-length human amyloid precursor protein (APP) (H4-APP cells). For mitochondrial dysfunction, we assessed mitochondrial permeability transition pore (mPTP) and adenosine-5’-triphosphate (ATP) levels. We employed Western blot analysis, chemiluminescence, and flowcytometry. Results Here we show that pretreatment with 50 µmol/L ginsenoside Rg1 for 12 h attenuated isoflurane-induced caspase-3 activation and mitochondrial dysfunction in H4-APP cells, while pretreatment with 25 and 50 µmol/L ginsenoside Rg1 for 24 h attenuated isoflurane-induced caspase-3 activation and mitochondrial dysfunction in both H4 naïve and H4-APP cells. Conclusion These data suggest that ginsenoside Rg1 may ameliorate isoflurane-induced caspase-3 activation by inhibiting mitochondrial dysfunction. Pending further studies, these findings might recommend the use of ginsenoside Rg1 in preventing and treating isoflurane-induced neurotoxicity.

  6. Radix Scrophulariae extracts (harpagoside) suppresses hypoxia-induced microglial activation and neurotoxicity

    OpenAIRE

    Sheu, Shiow-Yunn; Hong, Yi-Wen; Sun, Jui-Sheng; Liu, Man-Hai; Chen, Ching-Yun; Ke, Cherng-Jyh

    2015-01-01

    Background Hypoxia could lead to microglia activation and inflammatory mediators’ overproduction. These inflammatory molecules could amplify the neuroinflammatory process and exacerbate neuronal injury. The aim of this study is to find out whether harpagoside could reduce hypoxia-induced microglia activation. Methods In this study, primary microglia cells harvested from neonatal ICR mice were activated by exposure to hypoxia (1 % O2 for 3 h). Harpagoside had been shown to be no cytotoxicity o...

  7. Critical role of p38 MAPK in IL-4-induced alternative activation of peritoneal macrophages.

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    Jiménez-Garcia, Lidia; Herránz, Sandra; Luque, Alfonso; Hortelano, Sonsoles

    2015-01-01

    Alternative activation of macrophages plays an important role in a range of physiological and pathological processes. This alternative phenotype, also known as M2 macrophages, is induced by type 2 cytokines such as IL-4. The binding of IL-4 to its receptor leads to activation of two major signaling pathways: STAT-6 and PI3K. However, recent studies have described that p38 MAPK might play a role in IL-4-dependent signaling in some cells, although its role in macrophages is still controversial. In this study, we investigated whether p38 MAPK plays a role in the polarization of macrophages in mice. Our results reveal that IL-4 induces phosphorylation of p38 MAPK in thioglycollate-elicited murine peritoneal macrophages, in addition to STAT-6 and PI3K activation. Furthermore, p38 MAPK inactivation, by gene silencing or pharmacological inhibition, suppressed IL-4-induced typical M2 markers, indicating the involvement of p38 MAPK in the signaling of IL-4 leading to M2-macrophage polarization. Moreover, p38 MAPK inhibition blocked phosphorylation of STAT-6 and Akt, suggesting that p38 MAPK is upstream of these signaling pathways. Finally, we show that in an in vivo model of chitin-induced M2 polarization, p38 MAPK inhibition also diminished activation of M2 markers. Taken together, our data establish a new role for p38 MAPK during IL-4-induced alternative activation of macrophages. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  8. Bisdemethoxycurcumin Induces Apoptosis in Activated Hepatic Stellate Cells via Cannabinoid Receptor 2

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    Phil Jun Lee

    2015-01-01

    Full Text Available Activated Hepatic Stellate Cells (HSCs, major fibrogenic cells in the liver, undergo apoptosis when liver injuries cease, which may contribute to the resolution of fibrosis. Bisdemethoxycurcumin (BDMC is a natural derivative of curcumin with anti-inflammatory and anti-cancer activities. The therapeutic potential of BDMC in hepatic fibrosis has not been studied thus far in the context of the apoptosis in activated HSCs. In the current study, we compared the activities of BDMC and curcumin in the HSC-T6 cell line and demonstrated that BDMC relatively induced a potent apoptosis. BDMC-induced apoptosis was mediated by a combinatory inhibition of cytoprotective proteins, such as Bcl2 and heme oxygenase-1 and increased generation of reactive oxygen species. Intriguingly, BDMC-induced apoptosis was reversed with co-treatment of sr144528, a cannabinoid receptor (CBR 2 antagonist, which was confirmed with genetic downregulation of the receptor using siCBR2. Additionally, incubation with BDMC increased the formation of death-induced signaling complex in HSC-T6 cells. Treatment with BDMC significantly diminished total intracellular ATP levels and upregulated ATP inhibitory factor-1. Collectively, the results demonstrate that BDMC induces apoptosis in activated HSCs, but not in hepatocytes, by impairing cellular energetics and causing a downregulation of cytoprotective proteins, likely through a mechanism that involves CBR2.

  9. Hepatoprotective and antioxidant activity of pentagamavunon-0 against carbon tetrachloride-induced hepatic injury in rats

    Institute of Scientific and Technical Information of China (English)

    Arief Nurrochmad; Supardjan Amir Margono; Sardjiman; Arief Rahman Hakim; Ernawati; Erna Kurniawati; Erva Fatmawati

    2013-01-01

    Objective: To investigate the hepatoprotective and antioxidant activity of pentagamavunon-0(PGV-0) against CCl4-induced hepatic injury in rats. Methods: The groups of animals were administered with PGV-0 at the doses 2.5, 5, 10, and 20 mg/kg b.w., p.o. once in a day for 6 days and at day 7 the animals were administrated with carbon tetrachloride (CCl4) (20%, 2 mL/kg b.w. in liquid paraffin (i.p.). The effect of PGV-0 on serum transaminase (SGPT), alkaline phosphates (ALP) and total bilirubin were determined in CCl4-induced hepatotoxicity in rats. Further, the effects of PGV-0 on glutathione (GSH) content, catalase (CAT) and NO free radical scavenging activity also were investigated. Results: The results demonstrated that PGV-0 significantly reduced the activity of SGPT, serum ALP and total bilirubin in CCl4 induced rat hepatotoxicity. PGV-0 has effect on the antioxidant and free radical defense system. It prevented the depletion level of GSH and decrease activity of CAT in CCl4-induced liver injury in rats. PGV-0 also demonstrated the free radical scavenger effects on NO free radical scavenging activity with ES value of 32.32 μM. Conculsion: All of our findings suggests that PGV-0 could protect the liver cells from CCl4-induced liver damages and the mechanism may through the antioxidative effect of PGV-0 to prevent the accumulation of free radicals and protect the liver damage.

  10. Role of CD59 in T cell activation induced by non-lethal complement attack

    Institute of Scientific and Technical Information of China (English)

    HAN Gen-cheng; BAI Yun; JIANG Man; LI Wan-ling; ZHU Xi-hua

    2001-01-01

    To study the mechanism ofT-cell activation induced by non-lethal complement attack and the role of CD59 in this process. Methods: Human CD59 and its transmembrane counterpart CD59TM cDNA were transfected into murine thymoma EL-4 cells. Activation and proliferation of EL-4 transfectants were observed with MTT assay.Results: Both CD59 and CD59 TM cDNA expressed on EL-4 cells effectively inhibited complement-mediated membrane damage. Cross-linking of CD59 with antibody induced activation of CD59/EL-4 cells but not CD59TM/EL-4cells. This effect was inhibited by Herbimycin A, a special protein tyrosine kinase (PTK) inhibitor. Non-lethal complement attack induced CD59/EL-4 but not CD59TM/EL-4 cell to proliferate, and this reaction was not blocked by Herbimycin A. Conclusion: CD59 takes part in T cell activation induced by non-lethal complement attack. The mechanisms of T cell activation induced by non-lethal complement attack are different from those by cross-linking of CD59.

  11. Paraptosis and NF-κB activation are associated with protopanaxadiol-induced cancer chemoprevention

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    Wang Chong-Zhi

    2013-01-01

    Full Text Available Abstract Background Protopanaxadiol (PPD is a triterpenoid that can be prepared from steamed ginseng. PPD possesses anticancer potential via caspase-dependent apoptosis. Whether paraptosis, a type of the caspase-independent cell death, is also induced by PPD has not been evaluated. Methods Cell death, the cell cycle and intracellular reactive oxygen species (ROS were analyzed by flow cytometry after staining with annexin V/PI, PI/RNase or H2DCFDA. We observed morphological changes by crystal violet staining assay. Mitochondrial swelling was measured by ultraviolet–visible spectrophotometry. The activation of NF-κB was measured by luciferase reporter assay. Results At comparable concentrations of 5-fluorouracil, PPD induced more cell death in human colorectal cancer cell lines HCT-116 and SW-480. We demonstrated that PPD induced paraptosis in these cancer cells. PPD treatment significantly increased the percentage of cancer cells with cytoplasmic vacuoles. After the cells were treated with PPD and cycloheximides, cytoplasmic vacuole generation was inhibited. The paraptotic induction effect of PPD was also supported by the results of the mitochondrial swelling assay. PPD induced ROS production in cancer cells, which activated the NF-κB pathway. Blockage of ROS by NAC or PS-1145 inhibited the activation of NF-κB signaling. Conclusions PPD induces colorectal cancer cell death in part by induction of paraptosis. The anticancer activity of PPD may be enhanced by antioxidants such as green tea, which also inhibit the activation of NF-κB signaling.

  12. Melatonin Attenuates Manganese and Lipopolysaccharide-Induced Inflammatory Activation of BV2 Microglia.

    Science.gov (United States)

    Park, Euteum; Chun, Hong Sung

    2017-02-01

    Melatonin, a naturally occurring neurohormone in the pineal gland, has been shown to exert antioxidant and anti-inflammatory effects. This study examined the effects of melatonin on manganese (Mn) and/or lipopolysaccharide (LPS)-induced microglial activation. Melatonin (10 μM) inhibited Mn (100 μM) and/or LPS (0.5 μg/ml)-induced phagocytotic activity of activated BV2 microglia. It also inhibited the lipid peroxidation and intracellular reduced glutathione (GSH) depletion induced by Mn and/or LPS. Melatonin effectively suppressed the upregulation of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) at both mRNA and protein levels in Mn and/or LPS-stimulated BV2 microglia. In addition, melatonin pretreatment attenuated Mn and/or LPS-induced degradation of IκB-α, nuclear translocation of nuclear factor-κB (NF-κB) and its activation, and the expressions of inducible nitric oxide synthase (iNOS) and nitric oxide (NO) in BV2 microglial cells. These results suggest that melatonin can effectively modulate phagocytosis and expression of proinflammatory mediators, and can prevent neuroinflammatory disorders accompanied by microglial activation.

  13. 5-ALA mediated photodynamic therapy induces autophagic cell death via AMP-activated protein kinase

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    Lin Yu-Hsin

    2010-04-01

    Full Text Available Abstract Photodynamic therapy (PDT has been developed as an anticancer treatment, which is based on the tumor-specific accumulation of a photosensitizer that induces cell death after irradiation of light with a specific wavelength. Depending on the subcellular localization of the photosensitizer, PDT could trigger various signal transduction cascades and induce cell death such as apoptosis, autophagy, and necrosis. In this study, we report that both AMP-activated protein kinase (AMPK and mitogen-activated protein kinase (MAPK signaling cascades are activated following 5-aminolevulinic acid (ALA-mediated PDT in both PC12 and CL1-0 cells. Although the activities of caspase-9 and -3 are elevated, the caspase inhibitor zVAD-fmk did not protect cells against ALA-PDT-induced cell death. Instead, autophagic cell death was found in PC12 and CL1-0 cells treated with ALA-PDT. Most importantly, we report here for the first time that it is the activation of AMPK, but not MAPKs that plays a crucial role in mediating autophagic cell death induced by ALA-PDT. This novel observation indicates that the AMPK pathway play an important role in ALA-PDT-induced autophagy.

  14. Leptin induces CREB-dependent aromatase activation through COX-2 expression in breast cancer cells.

    Science.gov (United States)

    Kim, Hyung Gyun; Jin, Sun Woo; Kim, Yong An; Khanal, Tilak; Lee, Gi Ho; Kim, Se Jong; Rhee, Sang Dal; Chung, Young Chul; Hwang, Young Jung; Jeong, Tae Cheon; Jeong, Hye Gwang

    2017-08-01

    Leptin plays a key role in the control of adipocyte formation, as well as in the associated regulation of energy intake and expenditure. The goal of this study was to determine if leptin-induced aromatase enhances estrogen production and induces tumor cell growth stimulation. To this end, breast cancer cells were incubated with leptin in the absence or presence of inhibitor pretreatment, and changes in aromatase and cyclooxygenase-2 (COX-2) expression were evaluated at the mRNA and protein levels. Transient transfection assays were performed to examine the aromatase and COX-2 gene promoter activities and immunoblot analysis was used to examine protein expression. Leptin induced aromatase expression, estradiol production, and promoter activity in breast cancer cells. Protein levels of phospho-STAT3, PKA, Akt, ERK, and JNK were increased by leptin. Leptin also significantly increased cAMP levels, cAMP response element (CRE) activation, and CREB phosphorylation. In addition, leptin induced COX-2 expression, promoter activity, and increased the production of prostaglandin E2. Finally, a COX-2 inhibitor and aromatase inhibitor suppressed leptin-induced cell proliferation in MCF-7 breast cancer cells. Together, our data show that leptin increased aromatase expression in breast cancer cells, which was correlated with COX-2 upregulation, mediated through CRE activation and cooperation among multiple signaling pathways. Copyright © 2017 Elsevier Ltd. All rights reserved.

  15. The psychedelic state induced by ayahuasca modulates the activity and connectivity of the default mode network.

    Science.gov (United States)

    Palhano-Fontes, Fernanda; Andrade, Katia C; Tofoli, Luis F; Santos, Antonio C; Crippa, Jose Alexandre S; Hallak, Jaime E C; Ribeiro, Sidarta; de Araujo, Draulio B

    2015-01-01

    The experiences induced by psychedelics share a wide variety of subjective features, related to the complex changes in perception and cognition induced by this class of drugs. A remarkable increase in introspection is at the core of these altered states of consciousness. Self-oriented mental activity has been consistently linked to the Default Mode Network (DMN), a set of brain regions more active during rest than during the execution of a goal-directed task. Here we used fMRI technique to inspect the DMN during the psychedelic state induced by Ayahuasca in ten experienced subjects. Ayahuasca is a potion traditionally used by Amazonian Amerindians composed by a mixture of compounds that increase monoaminergic transmission. In particular, we examined whether Ayahuasca changes the activity and connectivity of the DMN and the connection between the DMN and the task-positive network (TPN). Ayahuasca caused a significant decrease in activity through most parts of the DMN, including its most consistent hubs: the Posterior Cingulate Cortex (PCC)/Precuneus and the medial Prefrontal Cortex (mPFC). Functional connectivity within the PCC/Precuneus decreased after Ayahuasca intake. No significant change was observed in the DMN-TPN orthogonality. Altogether, our results support the notion that the altered state of consciousness induced by Ayahuasca, like those induced by psilocybin (another serotonergic psychedelic), meditation and sleep, is linked to the modulation of the activity and the connectivity of the DMN.

  16. The psychedelic state induced by ayahuasca modulates the activity and connectivity of the default mode network.

    Directory of Open Access Journals (Sweden)

    Fernanda Palhano-Fontes

    Full Text Available The experiences induced by psychedelics share a wide variety of subjective features, related to the complex changes in perception and cognition induced by this class of drugs. A remarkable increase in introspection is at the core of these altered states of consciousness. Self-oriented mental activity has been consistently linked to the Default Mode Network (DMN, a set of brain regions more active during rest than during the execution of a goal-directed task. Here we used fMRI technique to inspect the DMN during the psychedelic state induced by Ayahuasca in ten experienced subjects. Ayahuasca is a potion traditionally used by Amazonian Amerindians composed by a mixture of compounds that increase monoaminergic transmission. In particular, we examined whether Ayahuasca changes the activity and connectivity of the DMN and the connection between the DMN and the task-positive network (TPN. Ayahuasca caused a significant decrease in activity through most parts of the DMN, including its most consistent hubs: the Posterior Cingulate Cortex (PCC/Precuneus and the medial Prefrontal Cortex (mPFC. Functional connectivity within the PCC/Precuneus decreased after Ayahuasca intake. No significant change was observed in the DMN-TPN orthogonality. Altogether, our results support the notion that the altered state of consciousness induced by Ayahuasca, like those induced by psilocybin (another serotonergic psychedelic, meditation and sleep, is linked to the modulation of the activity and the connectivity of the DMN.

  17. Activation of nicotinic cholinergic receptors prevents ventilator-induced lung injury in rats.

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    Fabienne Brégeon

    Full Text Available Respiratory distress syndrome is responsible for 40 to 60 percent mortality. An over mortality of about 10 percent could result from additional lung injury and inflammation due to the life-support mechanical ventilation, which stretches the lung. It has been recently demonstrated, in vitro, that pharmacological activation of the alpha 7 nicotinic receptors (α7-nAChR could down regulate intracellular mediators involved in lung cell inflammatory response to stretch. Our aim was to test in vivo the protective effect of the pharmacological activation of the α7-nAChR against ventilator-induced lung injury (VILI. Anesthetized rats were ventilated for two hours with a high stretch ventilation mode delivering a stroke volume large enough to generate 25-cmH(2O airway pressure, and randomly assigned to four groups: pretreated with parenteral injection of saline or specific agonist of the α7-nAChR (PNU-282987, or submitted to bilateral vagus nerve electrostimulation while pre-treated or not with the α7-nAChR antagonist methyllycaconitine (MLA. Controls ventilated with a conventional stroke volume of 10 mL/kg gave reference data. Physiological indices (compliance of the respiratory system, lung weight, blood oxygenation, arterial blood pressure and lung contents of inflammatory mediators (IL-6 measured by ELISA, substance P assessed using HPLC were severely impaired after two hours of high stretch ventilation (sham group. Vagal stimulation was able to maintain the respiratory parameters close to those obtained in Controls and reduced lung inflammation except when associated to nicotinic receptor blockade (MLA, suggesting the involvement of α7-nAChR in vagally-mediated protection against VILI. Pharmacological pre-treatment with PNU-282987 strongly decreased lung injury and lung IL-6 and substance P contents, and nearly abolished the increase in plasmatic IL-6 levels. Pathological examination of the lungs confirmed the physiological differences observed

  18. Structural insights into ligand-induced activation of the insulin receptor

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    Ward, C.; Lawrence, M.; Streltsov, V.; Garrett, T.; McKern, N.; Lou, M.-Z.; Lovrecz, G.; Adams, T. (CSIRO); (WEHIMR)

    2008-04-29

    The current model for insulin binding to the insulin receptor proposes that there are two binding sites, referred to as sites 1 and 2, on each monomer in the receptor homodimer and two binding surfaces on insulin, one involving residues predominantly from the dimerization face of insulin (the classical binding surface) and the other residues from the hexamerization face. High-affinity binding involves one insulin molecule using its two surfaces to make bridging contacts with site 1 from one receptor monomer and site 2 from the other. Whilst the receptor dimer has two identical site 1-site 2 pairs, insulin molecules cannot bridge both pairs simultaneously. Our structures of the insulin receptor (IR) ectodomain dimer and the L1-CR-L2 fragments of IR and insulin-like growth factor receptor (IGF-1R) explain many of the features of ligand-receptor binding and allow the two binding sites on the receptor to be described. The IR dimer has an unexpected folded-over conformation which places the C-terminal surface of the first fibronectin-III domain in close juxtaposition to the known L1 domain ligand-binding surface suggesting that the C-terminal surface of FnIII-1 is the second binding site involved in high-affinity binding. This is very different from previous models based on three-dimensional reconstruction from scanning transmission electron micrographs. Our single-molecule images indicate that IGF-1R has a morphology similar to that of IR. In addition, the structures of the first three domains (L1-CR-L2) of the IR and IGF-1R show that there are major differences in the two regions governing ligand specificity. The implications of these findings for ligand-induced receptor activation will be discussed. This review summarizes the key findings regarding the discovery and characterization of the insulin receptor, the identification and arrangement of its structural domains in the sequence and the key features associated with ligand binding. The remainder of the review

  19. Resveratrol induces growth arrest and apoptosis through activation of FOXO transcription factors in prostate cancer cells.

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    Qinghe Chen

    Full Text Available BACKGROUND: Resveratrol, a naturally occurring phytopolyphenol compound, has attracted extensive interest in recent years because of its diverse pharmacological characteristics. Although resveratrol possesses chemopreventive properties against several cancers, the molecular mechanisms by which it inhibits cell growth and induces apoptosis have not been clearly understood. The present study was carried out to examine whether PI3K/AKT/FOXO pathway mediates the biological effects of resveratrol. METHODOLOGY/PRINCIPAL FINDINGS: Resveratrol inhibited the phosphorylation of PI3K, AKT and mTOR. Resveratrol, PI3K inhibitors (LY294002 and Wortmannin and AKT inhibitor alone slightly induced apoptosis in LNCaP cells. These inhibitors further enhanced the apoptosis-inducing potential of resveratrol. Overexpression of wild-type PTEN slightly induced apoptosis. Wild type PTEN and PTEN-G129E enhanced resveratrol-induced apoptosis, whereas PTEN-G129R had no effect on proapoptotic effects of resveratrol. Furthermore, apoptosis-inducing potential of resveratrol was enhanced by dominant negative AKT, and inhibited by wild-type AKT and constitutively active AKT. Resveratrol has no effect on the expression of FKHR, FKHRL1 and AFX genes. The inhibition of FOXO phosphorylation by resveratrol resulted in its nuclear translocation, DNA binding and transcriptional activity. The inhibition of PI3K/AKT pathway induced FOXO transcriptional activity resulting in induction of Bim, TRAIL, p27/KIP1, DR4 and DR5, and inhibition of cyclin D1. Similarly, resveratrol-induced FOXO transcriptional activity was further enhanced when activation of PI3K/AKT pathway was blocked. Over-expression of phosphorylation deficient mutants of FOXO proteins (FOXO1-TM, FOXO3A-TM and FOXO4-TM induced FOXO transcriptional activity, which was further enhanced by resveratrol. Inhibition of FOXO transcription factors by shRNA blocked resveratrol-induced upregulation of Bim, TRAIL, DR4, DR5, p27/KIP1 and

  20. Acquisition of Genetic Aberrations by Activation-Induced Cytidine Deaminase (AID during Inflammation-Associated Carcinogenesis

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    Tsutomu Chiba

    2011-06-01

    Full Text Available Genetic abnormalities such as nucleotide alterations and chromosomal disorders that accumulate in various tumor-related genes have an important role in cancer development. The precise mechanism of the acquisition of genetic aberrations, however, remains unclear. Activation-induced cytidine deaminase (AID, a nucleotide editing enzyme, is essential for the diversification of antibody production. AID is expressed only in activated B lymphocytes under physiologic conditions and induces somatic hypermutation and class switch recombination in immunoglobulin genes. Inflammation leads to aberrant AID expression in various gastrointestinal organs and increased AID expression contributes to cancer development by inducing genetic alterations in epithelial cells. Studies of how AID induces genetic disorders are expected to elucidate the mechanism of inflammation-associated carcinogenesis.

  1. Acquisition of Genetic Aberrations by Activation-Induced Cytidine Deaminase (AID) during Inflammation-Associated Carcinogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Takai, Atsushi; Marusawa, Hiroyuki, E-mail: maru@kuhp.kyoto-u.ac.jp; Chiba, Tsutomu [Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507 (Japan)

    2011-06-22

    Genetic abnormalities such as nucleotide alterations and chromosomal disorders that accumulate in various tumor-related genes have an important role in cancer development. The precise mechanism of the acquisition of genetic aberrations, however, remains unclear. Activation-induced cytidine deaminase (AID), a nucleotide editing enzyme, is essential for the diversification of antibody production. AID is expressed only in activated B lymphocytes under physiologic conditions and induces somatic hypermutation and class switch recombination in immunoglobulin genes. Inflammation leads to aberrant AID expression in various gastrointestinal organs and increased AID expression contributes to cancer development by inducing genetic alterations in epithelial cells. Studies of how AID induces genetic disorders are expected to elucidate the mechanism of inflammation-associated carcinogenesis.

  2. Tetrandrine suppresses lipopolysaccharide-induced microglial activation by inhibiting NF-κB pathway

    Institute of Scientific and Technical Information of China (English)

    Yang XUE; Ying WANG; De-chun FENG; Bao-guo XIAO; Ling-yun XU

    2008-01-01

    Aim: Microglial activation has been implicated in many neurological diseases. In this study, we examined the effects of tetrandrine (TET), a major pharmacologi-cally-active compound of Chinese herb Stephania tetrandra S Moore on micro-glial activation. Methods: The microglia pretreated with or without TET were activated by lipoopolysaccharide (LPS) in vitro. Nitric oxide (NO) release, superox-ide anion (O2-) generation, as well as TNF-α and intedeukin-6 (IL-6) production by microglia were measured afterwards. Electrophoretic mobility shift assay was performed to determine whether NF-κB activity in microglia was affected by TET treatment. Results: We found that TET inhibited the LPS-induced activation of microglia by decreasing the production of NO and O2-, consequently affecting the release of TNF-α and IL-6 in LPS-induced microglial activation. Such suppressive effect was accompanied by inhibiting transcription factor NF-κB activation. Conclusion: Our results suggest that TET might modulate LPS-induced microglial activation by inhibiting the NF-κB-mediated release of inflammatory factors.

  3. Nerve Injury-Induced c-Jun Activation in Schwann Cells Is JNK Independent

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    Charlotta Lindwall Blom

    2014-01-01

    Full Text Available We investigated (a if activation of the mitogen activated protein kinase (MAPK pathway was linked to the stress activated protein kinase (SAPK pathway and (b if JNK was required for activation of c-Jun in Schwann cells of rat sciatic nerve following injury. To this aim, ERK1/2 and the transcription factors c-Jun and ATF-3 were studied by immunohistochemistry in segments of transected nerves. We utilized pharmacological inhibitors of both signal transduction pathways in vitro to determine the effects on downstream signalling events, such as c-Jun activation, and on Schwann cell survival and proliferation. A transection induces c-Jun and ATF-3 transcription in Schwann cells. These events are followed by Schwann cell activation of c-Jun in the injured nerve. The MAPK inhibitor U0126 blocked ERK1/2 activation and reduced Schwann cell proliferation as well as induction of c-Jun transcription. The JNK inhibitor SP600125 reduced Schwann cell proliferation, but did not affect the expression of ERK1/2 or injury-induced increases in c-Jun or ATF-3 levels. Importantly, nerve injury induces Schwann cell activation of c-Jun by phosphorylation, which, in contrast to in sensory neurons, is JNK independent. MAP kinases, other than JNK, can potentially activate c-Jun in Schwann cells following injury; information that is crucial to create new nerve reconstruction strategies.

  4. Inhibitory effects of harpagoside on TNF-α-induced pro-inflammatory adipokine expression through PPAR-γ activation in 3T3-L1 adipocytes.

    Science.gov (United States)

    Kim, Tae Kon; Park, Kyoung Sik

    2015-12-01

    Obesity is closely associated with increased production of pro-inflammatory adipokines, including interleukin (IL)-6, plasminogen activator inhibitor (PAI)-1, and adipose-tissue-derived monocyte chemoattractant protein (MCP)-1, which contribute to chronic and low-grade inflammation in adipose tissue. Harpagoside, a major iridoid glycoside present in devil's claw, has been reported to show anti-inflammatory activities by suppression of lipopolysaccharide (LPS)-induced production of inflammatory cytokines in murine macrophages. The present study is aimed to investigate the effects of harpagoside on both tumor necrosis factor (TNF)-α-induced inflammatory adipokine expression and its underlying signaling pathways in differentiated 3T3-L1 cells. Harpagoside significantly inhibited TNF-α-induced mRNA synthesis and protein production of the atherogenic adipokines including IL-6, PAI-1, and MCP-1. Further investigation of the molecular mechanism revealed that pretreatment with harpagoside activated peroxisome proliferator-activated receptor (PPAR)-γ. These findings suggest that the clinical application of medicinal plants which contain harpagoside may lead to a partial prevention of obesity-induced atherosclerosis by attenuating inflammatory responses.

  5. The exonuclease ISG20 is directly induced by synthetic dsRNA via NF-kappaB and IRF1 activation.

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    Espert, Lucile; Rey, Clémence; Gonzalez, Laure; Degols, Geneviève; Chelbi-Alix, Mounira Kmar; Mechti, Nadir; Gongora, Céline

    2004-06-03

    Many interferon (IFN)-stimulated genes are also induced by double-stranded RNA (dsRNA), a component closely associated with the IFN system in the context of virus-host interactions. Recently, we demonstrated that the IFN-induced 3' --> 5' exonuclease ISG20 possesses antiviral activities against RNA viruses. Here we show that ISG20 induction by synthetic dsRNA (pIpC) is stronger and faster than its induction by IFN. Two families of transcription factors are implicated in the transcriptional activation of ISG20 by dsRNA. Initially, the NF-kappaB factors p50 and p65 bind and activate the kappaB element of the Isg20 promoter. This is followed by IRF1 binding to the ISRE. As pIpC often induces protein movements in the cells, we questioned whether it could influence ISG20 localization. Interestingly and contrary to IFN, dsRNA induces a nuclear matrix enrichment of the ISG20 protein. dsRNA induction of ISG20 via NF-kappaB and its antiviral activity led us to suggest that ISG20 could participate in the cellular response to virus infection.

  6. Does Infection-Induced Immune Activation Contribute to Dementia?

    Science.gov (United States)

    Barichello, Tatiana; Generoso, Jaqueline S; Goularte, Jessica A; Collodel, Allan; Pitcher, Meagan R; Simões, Lutiana R; Quevedo, João; Dal-Pizzol, Felipe

    2015-09-01

    The central nervous system (CNS) is protected by a complex blood-brain barrier system; however, a broad diversity of virus, bacteria, fungi, and protozoa can gain access and cause illness. As pathogens replicate, they release molecules that can be recognized by innate immune cells. These molecules are pathogen-associated molecular patterns (PAMP) and they are identified by pattern-recognition receptors (PRR) expressed on antigen-presenting cells. Examples of PRR include toll-like receptors (TLR), receptors for advanced glycation endproducts (RAGE), nucleotide binding oligomerisation domain (NOD)-like receptors (NLR), c-type lectin receptors (CLR), RIG-I-like receptors (RLR), and intra-cytosolic DNA sensors. The reciprocal action between PAMP and PRR triggers the release of inflammatory mediators that regulate the elimination of invasive pathogens. Damage-associated molecular patterns (DAMP) are endogenous constituents released from damaged cells that also have the ability to activate the innate immune response. An increase of RAGE expression levels on neurons, astrocytes, microglia, and endothelial cells could be responsible for the accumulation of αβ-amyloid in dementia and related to the chronic inflammatory state that is found in neurodegenerative disorders.

  7. Stress-Induced Out-of-Context Activation of Memory

    Science.gov (United States)

    Ježek, Karel; Lee, Benjamin B.; Kelemen, Eduard; McCarthy, Katharine M.; McEwen, Bruce S.; Fenton, André A.

    2010-01-01

    Inappropriate recollections and responses in stressful conditions are hallmarks of post-traumatic stress disorder and other anxiety and mood disorders, but how stress contributes to the disorders is unclear. Here we show that stress itself reactivates memories even if the memory is unrelated to the stressful experience. Forced-swim stress one day after learning enhanced memory recall. One-day post-learning amnestic treatments were ineffective unless administered soon after the swim, indicating that a stressful experience itself can reactivate unrelated consolidated memories. The swim also triggered inter-hemispheric transfer of a lateralized memory, confirming stress reactivates stable memories. These novel effects of stress on memory required the hippocampus although the memories themselves did not, indicating hippocampus-dependent modulation of extrahippocampal memories. These findings that a stressful experience itself can activate memory suggest the novel hypothesis that traumatic stress reactivates pre-trauma memories, linking them to memory for the trauma and pathological facilitation of post-traumatic recall. PMID:21203585

  8. Stat1 activation attenuates IL-6 induced Stat3 activity but does not alter apoptosis sensitivity in multiple myeloma

    Directory of Open Access Journals (Sweden)

    Dimberg Lina Y

    2012-07-01

    Full Text Available Abstract Background Multiple myeloma (MM is at present an incurable malignancy, characterized by apoptosis-resistant tumor cells. Interferon (IFN treatment sensitizes MM cells to Fas-induced apoptosis and is associated with an increased activation of Signal transducer and activator of transcription (Stat1. The role of Stat1 in MM has not been elucidated, but Stat1 has in several studies been ascribed a pro-apoptotic role. Conversely, IL-6 induction of Stat3 is known to confer resistance to apoptosis in MM. Methods To delineate the role of Stat1 in IFN mediated sensitization to apoptosis, sub-lines of the U-266-1970 MM cell line with a stable expression of the active mutant Stat1C were utilized. The influence of Stat1C constitutive transcriptional activation on endogenous Stat3 expression and activation, and the expression of apoptosis-related genes were analyzed. To determine whether Stat1 alone would be an important determinant in sensitizing MM cells to apoptosis, the U-266-1970-Stat1C cell line and control cells were exposed to high throughput compound screening (HTS. Results To explore the role of Stat1 in IFN mediated apoptosis sensitization of MM, we established sublines of the MM cell line U-266-1970 constitutively expressing the active mutant Stat1C. We found that constitutive nuclear localization and transcriptional activity of Stat1 was associated with an attenuation of IL-6-induced Stat3 activation and up-regulation of mRNA for the pro-apoptotic Bcl-2 protein family genes Harakiri, the short form of Mcl-1 and Noxa. However, Stat1 activation alone was not sufficient to sensitize cells to Fas-induced apoptosis. In a screening of > 3000 compounds including bortezomib, dexamethasone, etoposide, suberoylanilide hydroxamic acid (SAHA, geldanamycin (17-AAG, doxorubicin and thalidomide, we found that the drug response and IC50 in cells constitutively expressing active Stat1 was mainly unaltered. Conclusion We conclude that Stat1 alters IL-6

  9. Activation barrier scaling and crossover for noise-induced switching in micromechanical parametric oscillators.

    Science.gov (United States)

    Chan, H B; Stambaugh, C

    2007-08-10

    We explore fluctuation-induced switching in parametrically driven micromechanical torsional oscillators. The oscillators possess one, two, or three stable attractors depending on the modulation frequency. Noise induces transitions between the coexisting attractors. Near the bifurcation points, the activation barriers are found to have a power law dependence on frequency detuning with critical exponents that are in agreement with predicted universal scaling relationships. At large detuning, we observe a crossover to a different power law dependence with an exponent that is device specific.

  10. Serum thymic factor, FTS, attenuates cisplatin nephrotoxicity by suppressing cisplatin-induced ERK activation.

    Science.gov (United States)

    Kohda, Yuka; Kawai, Yoshiko; Iwamoto, Noriaki; Matsunaga, Yoshiko; Aiga, Hiromi; Awaya, Akira; Gemba, Munekazu

    2005-11-01

    Serum thymic factor (FTS), a thymic peptide hormone, has been reported to attenuate the bleomycin-induced pulmonary injury and also experimental pancreatitis and diabetes. In the present study, we investigated the effect of FTS on cis-diamminedichloroplatinum II (cisplatin)-induced nephrotoxicity. We have already demonstrated that cephaloridine, a nephrotoxic antibiotic, leads to extracellular signal-regulated protein kinase (ERK) activation in the rat kidney, which probably contributes to cephaloridine-induced renal dysfunction. The aim of this study was to examine the effect of cisplatin on ERK activation in the rat kidney and also the effect of FTS on cisplatin-induced nephrotoxicity in rats. In vitro treatment of LLC-PK1 cells with FTS significantly ameliorated cisplatin-induced cell injury. Treatment of rats with intravenous cisplatin for 3 days markedly induced renal dysfunction and increased platinum contents in the kidney cortex. An increase in pERK was detected in the nuclear fraction prepared from the rat kidney cortex from days 1 to 3 after injection of cisplatin. FTS suppressed cisplatin-induced renal dysfunction and ERK activation in the kidney. FTS did not influence any Pt contents in the kidney after cisplatin administration. FTS has been shown to enhance the in vivo expression of heat shock protein (HSP) 70 in the kidney cortex. The beneficial role of FTS against cisplatin nephrotoxicity may be mediated in part by HSP70, as suggested by its up-regulation in the kidney cortex treated with FTS alone. Our results suggest that FTS participates in protection from cisplatin-induced nephrotoxicity by suppressing ERK activation caused by cisplatin.

  11. Salinomycin induces activation of autophagy, mitophagy and affects mitochondrial polarity : Differences between primary and cancer cells

    OpenAIRE

    Jangamreddy, Jaganmohan; Ghavami, Saeid; Grabarek, Jerzy; Kratz, Gunnar; Wiechec, Emilia; Fredriksson, Bengt-Arne; Rao, Rama K.; Cieślar-Pobuda, Artur; Panigrahi, Soumya; Łos, Marek

    2013-01-01

    The molecular mechanism of Salinomycin's toxicity is not fully understood. Various studies reported that Ca2 +, cytochrome c, and caspase activation play a role in Salinomycin-induced cytotoxicity. Furthermore, Salinomycin may target Wnt/β-catenin signaling pathway to promote differentiation and thus elimination of cancer stem cells. In this study, we show a massive autophagic response to Salinomycin (substantially stronger than to commonly used autophagic inducer Rapamycin) in prostrate-, br...

  12. 4-Hydroxy-2-nonenal induces endothelial cell injury via PKCdelta and biphasic JNK activation

    OpenAIRE

    Goya, Sho; Hirata, Haruhiko; Hoshino, Shigenori; Inoue, Koji; Kashiwa, Yozo; Kawase, Ichiro; Kijima, Takashi; Kumagai, Toru; Mayumi, Masahiko; Osaki, Tadashi; Suzuki, Mayumi; Tachibana, Isao; Takeda, Yoshito; Takimoto, Takayuki; Yano, Yukihiro

    2008-01-01

    4-Hydroxy-2-nonenal (4-HNE), a major product generated during oxidative stress, exhibits cytotoxic effects; however, the mechanisms of 4-HNE-induced endothelial cell injury are not well defined. To explore this issue, we examined how 4-HNE damages human umbilical vein endothelial cells (HUVECs) and found that 4-HNE induced biphasic activation of c-Jun N-terminal kinase (JNK). Both pre- and post-treatment of HUVECs with SP600125, a specific JNK inhibitor, significantly suppresse...

  13. Learning about hydrothermal volcanic activity by modeling induced geophysical changes

    Science.gov (United States)

    Currenti, Gilda M.; Napoli, Rosalba

    2017-05-01

    Motivated by ongoing efforts to understand the nature and the energy potential of geothermal resources, we devise a coupled numerical model (hydrological, thermal, mechanical), which may help in the characterization and monitoring of hydrothermal systems through computational experiments. Hydrothermal areas in volcanic regions arise from a unique combination of geological and hydrological features which regulate the movement of fluids in the vicinity of magmatic sources capable of generating large quantities of steam and hot water. Numerical simulations help in understanding and characterizing rock-fluid interaction processes and the geophysical observations associated with them. Our aim is the quantification of the response of different geophysical observables (i.e. deformation, gravity and magnetic field) to hydrothermal activity on the basis of a sound geological framework (e.g. distribution and pathways of the flows, the presence of fractured zones, caprock). A detailed comprehension and quantification of the evolution and dynamics of the geothermal systems and the definition of their internal state through a geophysical modeling approach are essential to identify the key parameters for which the geothermal system may fulfill the requirements to be exploited as a source of energy. For the sake of illustration only, the numerical computations are focused on a conceptual model of the hydrothermal system of Vulcano Island by simulating a generic 1-year unrest and estimating different geophysical changes. We solved (i) the mass and energy balance equations of flow in porous media for temperature, pressure and density changes, (ii) the elastostatic equation for the deformation field and (iii) the Poisson’s equations for gravity and magnetic potential fields. Under the model assumptions, a generic unrest of 1-year engenders on the ground surface low amplitude changes in the investigated geophysical observables, that are, however, above the accuracies of the modern

  14. ETHANOL-INDUCED LOCOMOTOR ACTIVITY IN ADOLESCENT RATS AND THE RELATIONSHIP WITH ETHANOL-INDUCED CONDITIONED PLACE PREFERENCE AND CONDITIONED TASTE AVERSION

    OpenAIRE

    Acevedo, María Belén; Nizhnikov, Michael E.; Spear, Norman E.; Molina, Juan C.; Pautassi, Ricardo Marcos

    2012-01-01

    Adolescent rats exhibit ethanol-induced locomotor activity (LMA), which is considered an index of ethanol’s motivational properties likely to predict ethanol self-administration, but few studies have reported or correlated ethanol-induced LMA with conditioned place preference by ethanol at this age. The present study assessed age-related differences in ethanol’s motor stimulating effects and analysed the association between ethanol-induced LMA and conventional measures of ethanol-induced rein...

  15. Mitogen-activated protein kinases regulate susceptibility to ventilator-induced lung injury.

    Directory of Open Access Journals (Sweden)

    Tamás Dolinay

    Full Text Available BACKGROUND: Mechanical ventilation causes ventilator-induced lung injury in animals and humans. Mitogen-activated protein kinases have been implicated in ventilator-induced lung injury though their functional significance remains incomplete. We characterize the role of p38 mitogen-activated protein kinase/mitogen activated protein kinase kinase-3 and c-Jun-NH(2-terminal kinase-1 in ventilator-induced lung injury and investigate novel independent mechanisms contributing to lung injury during mechanical ventilation. METHODOLOGY AND PRINCIPLE FINDINGS: C57/BL6 wild-type mice and mice genetically deleted for mitogen-activated protein kinase kinase-3 (mkk-3(-/- or c-Jun-NH(2-terminal kinase-1 (jnk1(-/- were ventilated, and lung injury parameters were assessed. We demonstrate that mkk3(-/- or jnk1(-/- mice displayed significantly reduced inflammatory lung injury and apoptosis relative to wild-type mice. Since jnk1(-/- mice were highly resistant to ventilator-induced lung injury, we performed comprehensive gene expression profiling of ventilated wild-type or jnk1(-/- mice to identify novel candidate genes which may play critical roles in the pathogenesis of ventilator-induced lung injury. Microarray analysis revealed many novel genes differentially expressed by ventilation including matrix metalloproteinase-8 (MMP8 and GADD45alpha. Functional characterization of MMP8 revealed that mmp8(-/- mice were sensitized to ventilator-induced lung injury with increased lung vascular permeability. CONCLUSIONS: We demonstrate that mitogen-activated protein kinase pathways mediate inflammatory lung injury during ventilator-induced lung injury. C-Jun-NH(2-terminal kinase was also involved in alveolo-capillary leakage and edema formation, whereas MMP8 inhibited alveolo-capillary protein leakage.

  16. Lactobacillus acidophilus alleviates platelet-activating factor-induced inflammatory responses in human intestinal epithelial cells.

    Directory of Open Access Journals (Sweden)

    Alip Borthakur

    Full Text Available Probiotics have been used as alternative prevention and therapy modalities in intestinal inflammatory disorders including inflammatory bowel diseases (IBD and necrotizing enterocolitis (NEC. Pathophysiology of IBD and NEC includes the production of diverse lipid mediators, including platelet-activating factor (PAF that mediate inflammatory responses in the disease. PAF is known to activate NF-κB, however, the mechanisms of PAF-induced inflammation are not fully defined. We have recently described a novel PAF-triggered pathway of NF-κB activation and IL-8 production in intestinal epithelial cells (IECs, requiring the pivotal role of the adaptor protein Bcl10 and its interactions with CARMA3 and MALT1. The current studies examined the potential role of the probiotic Lactobacillus acidophilus in reversing the PAF-induced, Bcl10-dependent NF-κB activation and IL-8 production in IECs. PAF treatment (5 µM×24 h of NCM460 and Caco-2 cells significantly increased nuclear p65 NF-κB levels and IL-8 secretion (2-3-fold, P<0.05, compared to control, which were blocked by pretreatment of the cells for 6 h with L. acidophilus (LA or its culture supernatant (CS, followed by continued treatments with PAF for 24 h. LA-CS also attenuated PAF-induced increase in Bcl10 mRNA and protein levels and Bcl10 promoter activity. LA-CS did not alter PAF-induced interaction of Bcl10 with CARMA3, but attenuated Bcl10 interaction with MALT1 and also PAF-induced ubiquitination of IKKγ. Efficacy of bacteria-free CS of LA in counteracting PAF-induced inflammatory cascade suggests that soluble factor(s in the CS of LA mediate these effects. These results define a novel mechanism by which probiotics counteract PAF-induced inflammation in IECs.

  17. Vitamin C Attenuates Isoflurane-Induced Caspase-3 Activation and Cognitive Impairment.

    Science.gov (United States)

    Cheng, Baiqi; Zhang, Yiying; Wang, Arthur; Dong, Yuanlin; Xie, Zhongcong

    2015-12-01

    Anesthetic isoflurane has been reported to induce caspase-3 activation. The underlying mechanism(s) and targeted intervention(s), however, remain largely to be determined. Vitamin C (VitC) inhibits oxidative stress and apoptosis. We therefore employed VitC to further determine the up-stream mechanisms and the down-stream consequences of the isoflurane-induced caspase-3 activation. H4 human neuroglioma cells overexpressed human amyloid precursor protein (H4-APP cells) and rat neuroblastoma cells were treated either with (1) 2% isoflurane or (2) with the control condition, plus saline or 400 μM VitC for 3 or 6 h. Western blot analysis and fluorescence assay were utilized at the end of the experiments to determine caspase-3 activation, levels of reactive oxygen species and ATP, and mitochondrial function. The interaction of isoflurane (1.4% for 2 h) and VitC (100 mg/kg) on cognitive function in mice was also assessed in the fear conditioning system. Here, we show for the first time that the VitC treatment attenuated the isoflurane-induced caspase-3 activation. Moreover, VitC mitigated the isoflurane-induced increases in the levels of reactive oxygen species, opening of mitochondrial permeability transition pore, reduction in mitochondrial membrane potential, and the reduction in ATP levels in the cells. Finally, VitC ameliorated the isoflurane-induced cognitive impairment in the mice. Pending confirmation from future studies, these results suggested that VitC attenuated the isoflurane-induced caspase-3 activation and cognitive impairment by inhibiting the isoflurane-induced oxidative stress, mitochondrial dysfunction, and reduction in ATP levels. These findings would promote further research into the underlying mechanisms and targeted interventions of anesthesia neurotoxicity.

  18. Acute Ethanol Intake Induces NAD(P)H Oxidase Activation and Rhoa Translocation in Resistance Arteries

    Science.gov (United States)

    Simplicio, Janaina A.; Hipólito, Ulisses Vilela; do Vale, Gabriel Tavares; Callera, Glaucia Elena; Pereira, Camila André; Touyz, Rhian M; Tostes, Rita de Cássia; Tirapelli, Carlos R.

    2016-01-01

    Background The mechanism underlying the vascular dysfunction induced by ethanol is not totally understood. Identification of biochemical/molecular mechanisms that could explain such effects is warranted. Objective To investigate whether acute ethanol intake activates the vascular RhoA/Rho kinase pathway in resistance arteries and the role of NAD(P)H oxidase-derived reactive oxygen species (ROS) on such response. We also evaluated the requirement of p47phox translocation for ethanol-induced NAD(P)H oxidase activation. Methods Male Wistar rats were orally treated with ethanol (1g/kg, p.o. gavage) or water (control). Some rats were treated with vitamin C (250 mg/kg, p.o. gavage, 5 days) before administration of water or ethanol. The mesenteric arterial bed (MAB) was collected 30 min after ethanol administration. Results Vitamin C prevented ethanol-induced increase in superoxide anion (O2-) generation and lipoperoxidation in the MAB. Catalase and superoxide dismutase activities and the reduced glutathione, nitrate and hydrogen peroxide (H2O2) levels were not affected by ethanol. Vitamin C and 4-methylpyrazole prevented the increase on O2- generation induced by ethanol in cultured MAB vascular smooth muscle cells. Ethanol had no effect on phosphorylation levels of protein kinase B (Akt) and eNOS (Ser1177 or Thr495 residues) or MAB vascular reactivity. Vitamin C prevented ethanol-induced increase in the membrane: cytosol fraction ratio of p47phox and RhoA expression in the rat MAB. Conclusion Acute ethanol intake induces activation of the RhoA/Rho kinase pathway by a mechanism that involves ROS generation. In resistance arteries, ethanol activates NAD(P)H oxidase by inducing p47phox translocation by a redox-sensitive mechanism. PMID:27812679

  19. Eicosanoid signaling and vascular dysfunction: methylmercury-induced phospholipase D activation in vascular endothelial cells.

    Science.gov (United States)

    Sherwani, Shariq I; Pabon, Sheila; Patel, Rishi B; Sayyid, Muzzammil M; Hagele, Thomas; Kotha, Sainath R; Magalang, Ulysses J; Maddipati, Krishna R; Parinandi, Narasimham L

    2013-11-01

    Mercury, especially methylmercury (MeHg), is implicated in the etiology of cardiovascular diseases. Earlier, we have reported that MeHg induces phospholipase D (PLD) activation through oxidative stress and thiol-redox alteration. Hence, we investigated the mechanism of the MeHg-induced PLD activation through the upstream regulation by phospholipase A2 (PLA2) and lipid oxygenases such as cyclooxygenase (COX) and lipoxygenase (LOX) in the bovine pulmonary artery endothelial cells (BPAECs). Our results showed that MeHg significantly activated both PLA2 (release of [(3)H]arachidonic acid, AA) and PLD (formation of [(32)P]phosphatidylbutanol) in BPAECs in dose- (0-10 μM) and time-dependent (0-60 min) fashion. The cPLA2-specific inhibitor, arachidonyl trifluoromethyl ketone (AACOCF3), significantly attenuated the MeHg-induced [(3)H]AA release in ECs. MeHg-induced PLD activation was also inhibited by AACOCF3 and the COX- and LOX-specific inhibitors. MeHg also induced the formation of COX- and LOX-catalyzed eicosanoids in ECs. MeHg-induced cytotoxicity (based on lactate dehydrogenase release) was protected by PLA2-, COX-, and LOX-specific inhibitors and 1-butanol, the PLD-generated PA quencher. For the first time, our studies showed that MeHg activated PLD in vascular ECs through the upstream action of cPLA2 and the COX- and LOX-generated eicosanoids. These results offered insights into the mechanism(s) of the MeHg-mediated vascular endothelial cell lipid signaling as an underlying cause of mercury-induced cardiovascular diseases.

  20. AG490 inhibits NFATc1 expression and STAT3 activation during RANKL induced osteoclastogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Li, Chang-hong; Zhao, Jin-xia; Sun, Lin; Yao, Zhong-qiang; Deng, Xiao-li; Liu, Rui; Liu, Xiang-yuan, E-mail: liu-xiangyuan@263.net

    2013-06-14

    Highlights: •AG490 inhibits RANKL-induced osteoclastogenesis in RAW264.7 cells. •AG490 affects cell proliferation and cell cycle distribution. •AG490 reduces NFATc1 expression during RANKL-induced osteoclastogenesis. •AG490 disrupts the activation of RANKL-mediated JAK2/STAT3 signaling pathway. •STAT3 depletion partly mimics the effect of AG490 on RANKL-induced osteoclastogenesis. -- Abstract: Commonly, JAK/STAT relays cytokine signals for cell activation and proliferation, and recent studies have shown that the elevated expression of JAK/STAT is associated with the immune rejection of allografts and the inflammatory processes of autoimmune disease. However, the role which JAK2/STAT3 signaling plays in the receptor activator of nuclear factor-κB ligand (RANKL)-mediated osteoclastogenesis is unknown. In this study, we investigated the effects of AG490, specific JAK2 inhibitor, on osteoclast differentiation in vitro. AG490 significantly inhibited osteoclastogenesis in murine osteoclast precursor cell line RAW264.7 induced by RANKL. AG490 suppressed cell proliferation and delayed the G1 to S cell cycle transition. Furthermore, AG490 also suppressed the expression of nuclear factor of activated T cells (NFAT) c1 but not c-Fos in RAW264.7. Subsequently, we investigated various intracellular signaling components associated with osteoclastogenesis. AG490 had no effects on RANKL-induced activation of Akt, ERK1/2. Interestingly, AG490 partly inhibited RANKL-induced phosphorylation of Ser{sup 727} in STAT3. Additionally, down-regulation of STAT3 using siRNA resulted in suppression of TRAP, RANK and NFATc1 expression. In conclusion, we demonstrated that AG490 inhibited RANKL-induced osteoclastogenesis by suppressing NFATc1 production and cell proliferation via the STAT3 pathway. These results suggest that inhibition of JAK2 may be useful for the treatment of bone diseases characterized by excessive osteoclastogenesis.

  1. Bifidobacterium bifidum Actively Changes the Gene Expression Profile Induced by Lactobacillus acidophilus in Murine Dendritic Cells

    DEFF Research Database (Denmark)

    Weiss, Gudrun Margarethe; Rasmussen, Simon; Fink, Lisbeth Nielsen;

    2010-01-01

    Dendritic cells (DC) play a pivotal regulatory role in activation of both the innate as well as the adaptive immune system by responding to environmental microorganisms. We have previously shown that Lactobacillus acidophilus induces a strong production of the pro-inflammatory and Th1 polarizing...... cytokine IL-12 in DC, whereas bifidobacteria do not induce IL-12 but inhibit the IL-12 production induced by lactobacilli. In the present study, genome-wide microarrays were used to investigate the gene expression pattern of murine DC stimulated with Lactobacillus acidophilus NCFM and Bifidobacterium...

  2. Music-induced emotions can be predicted from a combination of brain activity and acoustic features.

    Science.gov (United States)

    Daly, Ian; Williams, Duncan; Hallowell, James; Hwang, Faustina; Kirke, Alexis; Malik, Asad; Weaver, James; Miranda, Eduardo; Nasuto, Slawomir J

    2015-12-01

    It is widely acknowledged that music can communicate and induce a wide range of emotions in the listener. However, music is a highly-complex audio signal composed of a wide range of complex time- and frequency-varying components. Additionally, music-induced emotions are known to differ greatly between listeners. Therefore, it is not immediately clear what emotions will be induced in a given individual by a piece of music. We attempt to predict the music-induced emotional response in a listener by measuring the activity in the listeners electroencephalogram (EEG). We combine these measures with acoustic descriptors of the music, an approach that allows us to consider music as a complex set of time-varying acoustic features, independently of any specific music theory. Regression models are found which allow us to predict the music-induced emotions of our participants with a correlation between the actual and predicted responses of up to r=0.234,pemotions can be predicted by their neural activity and the properties of the music. Given the large amount of noise, non-stationarity, and non-linearity in both EEG and music, this is an encouraging result. Additionally, the combination of measures of brain activity and acoustic features describing the music played to our participants allows us to predict music-induced emotions with significantly higher accuracies than either feature type alone (p<0.01).

  3. Progranulin promotes activation of microglia/macrophage after pilocarpine-induced status epilepticus.

    Science.gov (United States)

    Zhu, Shanshan; Tai, Chao; Petkau, Terri L; Zhang, Si; Liao, Chengyong; Dong, Zhifang; Wen, Wendy; Chang, Qing; Tian Wang, Yu; MacVicar, Brian A; Leavitt, Blair R; Jia, William; Cynader, Max S

    2013-09-12

    Progranulin (PGRN) haploinsufficiency accounts for up to 10% of frontotemporal lobe dementia. PGRN has also been implicated in neuroinflammation in acute and chronic neurological disorders. Here we report that both protein and mRNA levels of cortical and hippocampal PGRN are significantly enhanced following pilocarpine-induced status epilepticus. We also identify intense PGRN immunoreactivity that colocalizes with CD11b in seizure-induced animals, suggesting that PGRN elevation occurs primarily in activated microglia and macrophages. To test the role of PGRN in activation of microglia/macrophages, we apply recombinant PGRN protein directly into the hippocampal formation, and observe no change in the number of CD11b(+) microglia/macrophages in the dentate gyrus. However, with pilocarpine-induced status epilepticus, PGRN application significantly increases the number of CD11b(+) microglia/macrophages in the dentate gyrus, without affecting the extent of hilar cell death. In addition, the number of CD11b(+) microglia/macrophages induced by status epilepticus is not significantly different between PGRN knockout mice and wildtype. Our findings suggest that status epilepticus induces PGRN expression, and that PGRN potentiates but is not required for seizure-induced microglia/macrophage activation.

  4. Snow-mold-induced apoplastic proteins in winter rye leaves lack antifreeze activity

    Science.gov (United States)

    Hiilovaara-Teijo; Hannukkala; Griffith; Yu; Pihakaski-Maunsbach

    1999-10-01

    During cold acclimation, winter rye (Secale cereale L.) plants secrete antifreeze proteins that are similar to pathogenesis-related (PR) proteins. In this experiment, the secretion of PR proteins was induced at warm temperatures by infection with pink snow mold (Microdochium nivale), a pathogen of overwintering cereals. A comparison of cold-induced and pathogen-induced proteins showed that PR proteins accumulated in the leaf apoplast to a greater level in response to cold. The PR proteins induced by cold and by snow mold were similar when separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and examined by immunoblotting. Both groups of PR proteins contained glucanase-like, chitinase-like, and thaumatin-like proteins, and both groups exhibited similar levels of glucanase and chitinase activities. However, only the PR proteins induced by cold exhibited antifreeze activity. Our findings suggest that the cold-induced PR proteins may be isoforms that function as antifreeze proteins to modify the growth of ice during freezing while also providing resistance to the growth of low-temperature pathogens in advance of infection. Both functions of the cold-induced PR proteins may improve the survival of overwintering cereals.

  5. Activation of NR2A receptors induces ischemic tolerance through CREB signaling.

    Science.gov (United States)

    Terasaki, Yasukazu; Sasaki, Tsutomu; Yagita, Yoshiki; Okazaki, Shuhei; Sugiyama, Yukio; Oyama, Naoki; Omura-Matsuoka, Emi; Sakoda, Saburo; Kitagawa, Kazuo

    2010-08-01

    Previous exposure to a nonlethal ischemic insult protects the brain against subsequent harmful ischemia. N-methyl-D-aspartate (NMDA) receptors are a highly studied target of neuroprotection after ischemia. Recently, NMDA receptor subtypes were implicated in neuronal survival and death. We focused on the contribution of NR2A and cyclic-AMP response element (CRE)-binding protein (CREB) signaling to ischemic tolerance using primary cortical neurons. Ischemia in vitro was modeled by oxygen-glucose deprivation (OGD). Ischemic tolerance was induced by applying 45-mins OGD 24 h before 180-mins OGD. Sublethal OGD also induced cross-tolerance against lethal glutamate and hydrogen peroxide. After sublethal OGD, expression of phosphorylated CREB and CRE transcriptional activity were significantly increased. When CRE activity was inhibited by CREB-S133A, a mutant CREB, ischemic tolerance was abolished. Inhibiting NR2A using NVP-AAM077 attenuated preconditioning-induced neuroprotection and correlated with decreased CRE activity levels. Activating NR2A using bicuculline and 4-aminopiridine induced resistance to lethal ischemia accompanied by elevated CRE activity levels, and this effect was abolished by NVP-AAM077. Elevated brain-derived neurotrophic factor (BDNF) transcriptional activities were observed after sublethal OGD and administration of bicuculline and 4-aminopiridine. NR2A-containing NMDA receptors and CREB signaling have important functions in the induction of ischemic tolerance. This may provide potential novel therapeutic strategies to treat ischemic stroke.

  6. Involvement of endoplasmic reticulum stress in albuminuria induced inflammasome activation in renal proximal tubular cells.

    Directory of Open Access Journals (Sweden)

    Li Fang

    Full Text Available Albuminuria contributes to the progression of tubulointerstitial fibrosis. Although it has been demonstrated that ongoing albuminuria leads to tubular injury manifested by the overexpression of numerous proinflammatory cytokines, the mechanism remains largely unknown. In this study, we found that the inflammasome activation which has been recognized as one of the cornerstones of intracellular surveillance system was associated with the severity of albuminuria in the renal biopsies specimens. In vitro, bovine serum albumin (BSA could also induce the activation of NLRP3 inflammasome in the cultured kidney epithelial cells (NRK-52E. Since there was a significant overlap of NLRP3 with the ER marker calreticulin, the ER stress provoked by BSA seemed to play a crucial role in the activation of inflammasome. Here, we demonstrated that the chemical chaperone taurine-conjugated ursodeoxycholic acid (TUDCA which was proved to be an enhancer for the adaptive capacity of ER could attenuate the inflammasome activation induced by albuminuria not only in vitro but also in diabetic nephropathy. Taken together, these data suggested that ER stress seemed to play an important role in albuminuria-induced inflammasome activation, elimination of ER stress via TUDCA might hold promise as a novel avenue for preventing inflammasome activation ameliorating kidney epithelial cells injury induced by albuminuria.

  7. Protease-activated receptor-2 activation contributes to house dust mite-induced IgE responses in mice.

    Directory of Open Access Journals (Sweden)

    Sijranke Post

    Full Text Available Aeroallergens such as house dust mite (HDM, cockroach, and grass or tree pollen are innocuous substances that can induce allergic sensitization upon inhalation. The serine proteases present in these allergens are thought to activate the protease-activated receptor (PAR-2, on the airway epithelium, thereby potentially inducing allergic sensitization at the expense of inhalation tolerance. We hypothesized that the proteolytic activity of allergens may play an important factor in the allergenicity to house dust mite and is essential to overcome airway tolerance. Here, we aimed to investigate the role of PAR-2 activation in allergic sensitization and HDM-induced allergic airway inflammation. In our study, Par-2 deficient mice were treated with two different HDM extracts containing high and low serine protease activities twice a week for a period of 5 weeks. We determined airway inflammation through quantification of percentages of mononuclear cells, eosinophils and neutrophils in the bronchial alveolar lavage fluid and measured total IgE and HDM-specific IgE and IgG1 levels in serum. Furthermore, Th2 and pro-inflammatory cytokines including IL-5, IL-13, Eotaxin-1, IL-17, KC, Chemokine (C-C motif ligand 17 (CCL17 and thymic stromal lymphopoietin (TSLP, were measured in lung tissue homogenates. We observed that independent of the serine protease content, HDM was able to induce elevated levels of eosinophils and neutrophils in the airways of both wild-type (WT and Par-2 deficient mice. Furthermore, we show that induction of pro-inflammatory cytokines by HDM exposure is independent of Par-2 activation. In contrast, serine protease activity of HDM does contribute to enhanced levels of total IgE, but not HDM-specific IgE. We conclude that, while Par-2 activation contributes to the development of IgE responses, it is largely dispensable for the HDM-induced induction of pro-inflammatory cytokines and airway inflammation in an experimental mouse model of HDM

  8. Roscovitine inhibits ERK1/2 activation induced by angiotensin II in vascular smooth muscle cells.

    Science.gov (United States)

    Li, Ai-Ying; Han, Mei; Zheng, Bin; Wen, Jin-Kun

    2008-01-23

    Roscovitine is a potent CDK inhibitor often used as a biological tool in cell-cycle studies, but its working mechanism and real targets in vascular smooth muscle cells (VSMCs) remain unclear. In this study, we observed that ERK1/2 phosphorylation induced by Ang II was abrogated by pretreating VSMCs with roscovitine for 15h. Pretreating VSMCs with roscovitine also inhibited Ang II-induced c-Jun expression and phosphorylation. We further demonstrated that roscovitine could suppress the DNA binding activity of c-Jun and activation of angiotensinogen promoter by Ang II. These results suggest that roscovitine represses Ang II-induced angiotensinogen expression by inhibiting activation of ERK1/2 and c-Jun.

  9. Cognitive-enhancing activity of loganin isolated from Cornus officinalis in scopolamine-induced amnesic mice.

    Science.gov (United States)

    Lee, Ki Yong; Sung, Sang Hyun; Kim, Seung Hyun; Jang, Young Pyo; Oh, Tae Hwan; Kim, Young Choong

    2009-05-01

    We examined anti-amnesic activity of the methanolic extract of Cornus officinalis fruits (COT) and a major constituent, loganin using scopolamine-induced (1 mg/kg body weight, s.c.) amnesic mice with both passive avoidance and the Morris water maze tests. Oral treatment of mice with COT (100 mg/kg body weight) and loganin (1 and 2 mg/kg body weight) significantly mitigated scopolamine-induced memory deficits in passive avoidance test. In the Morris water maze test, oral treatment of loganin significantly ameliorated scopolamine-induced memory deficits showing the formation of long-term and/or short-term spatial memory. Moreover, loganin (2 mg/kg body weight) significantly inhibited acetylcholinesterase activity by as much as 45% of control in the mouse hippocampus. These results indicate that loganin may exert antiamnesic activity in in vivo through acetylcholinesterase inhibition.

  10. Activated Rho kinase mediates diabetes-induced elevation of vascular arginase activation and contributes to impaired corpora cavernosa relaxation: possible involvement of p38 MAPK activation.

    Science.gov (United States)

    Toque, Haroldo A; Nunes, Kenia P; Yao, Lin; Liao, James K; Webb, R Clinton; Caldwell, Ruth B; Caldwell, R William

    2013-06-01

    Activated RhoA/Rho kinase (ROCK) has been implicated in diabetes-induced erectile dysfunction. Earlier studies have demonstrated involvement of ROCK pathway in the activation of arginase in endothelial cells. However, signaling pathways activated by ROCK in the penis remain unclear. We tested whether ROCK and p38 MAPK are involved in the elevation of arginase activity and subsequent impairment of corpora cavernosal (CC) relaxation in diabetes. Eight weeks after streptozotocin-induced diabetes, vascular functional studies, arginase activity assay, and protein expression of RhoA, ROCK, phospho-p38 MAPK, p38 MAPK, phospho-MYPT-1(Thr850), MYPT-1 and arginase levels were assessed in CC tissues from nondiabetic wild type (WT), diabetic (D) WT (WT + D), partial ROCK 2(+/-) knockout (KO), and ROCK 2(+/-) KO + D mice. The expression of RhoA, ROCK 1 and 2, phosphorylation of MYPT-1(Thr850) and p38 MAPK, arginase activity/expression, endothelial- and nitrergic-dependent relaxation of CC was assayed. Diabetes significantly reduced maximum relaxation (Emax ) to both endothelium-dependent acetylcholine (WT + D: Emax; 61 ± 4% vs. WT: Emax; 75 ± 2%) and nitrergic nerve stimulation. These effects were associated with increased expression of active RhoA, ROCK 2, phospho-MYPT-1(Thr850), phospho-p38 MAPK, arginase II, and activity of corporal arginase (1.6-fold) in WT diabetic CC. However, this impairment in CC of WT + D mice was absent in heterozygous ROCK 2(+/-) KO + D mice for acetylcholine (Emax : 80 ± 5%) and attenuated for nitrergic nerve-induced relaxation. CC of ROCK 2(+/-) KO + D mice showed much less ROCK activity, did not exhibit p38 MAPK activation, and had reduced arginase activity and arginase II expression. These findings indicate that ROCK 2 mediates diabetes-induced elevation of arginase activity. Additionally, pretreatment of WT diabetic CC with inhibitors of arginase (ABH) or p38 MAPK (SB203580) partially prevented impairment of ACh- and nitrergic nerve-induced

  11. Caspase Inhibitors may Attenuate Opioid-induced Hyperalgesia and Tolerance via Inhibiting Microglial Activation and Neuroinflammation

    Directory of Open Access Journals (Sweden)

    Jiancheng Zhang

    2013-07-01

    Full Text Available Prolonged exposure to an opioid induces hyperalgesia and tolerance, which negatively affect pain management in turn and significantly hamper the application of opioids. A growing body of evidence has demonstrated that glial activation contributes to the development of these two side effects. Recent studies have demonstrated that morphine, binding to an accessory protein of Toll-like receptor 4 (TLR4, activates microglia and produces neuroinflammation in amanner parallel to lipopolysaccharide. Meanwhile, lipopolysaccharide activates microglia through TLR4/caspase signalling. Therefore, we hypothesise that morphine may activate microglia throughTLR4/caspase signalling and that caspase inhibitors may attenuate opioid-induced hyperalgesia and tolerance via inhibiting microglial activation and neuroinflammation

  12. NADPH oxidase mediates β-amyloid peptide-induced activation of ERK in hippocampal organotypic cultures

    Science.gov (United States)

    Serrano, Faridis; Chang, Angela; Hernandez, Caterina; Pautler, Robia G; Sweatt, J David; Klann, Eric

    2009-01-01

    Background Previous studies have shown that beta amyloid (Aβ) peptide triggers the activation of several signal transduction cascades in the hippocampus, including the extracellular signal-regulated kinase (ERK) cascade. In this study we sought to characterize the cellular localization of phosphorylated, active ERK in organotypic hippocampal cultures after acute exposure to either Aβ (1-42) or nicotine. Results We observed that Aβ and nicotine increased the levels of active ERK in distinct cellular localizations. We also examined whether phospho-ERK was regulated by redox signaling mechanisms and found that increases in active ERK induced by Aβ and nicotine were blocked by inhibitors of NADPH oxidase. Conclusion Our findings indicate that NADPH oxidase-dependent redox signaling is required for Aβ-induced activation of ERK, and suggest a similar mechanism may occur during early stages of Alzheimer's disease. PMID:19804648

  13. Light-induced Notch activity controls neurogenic and gliogenic potential of neural progenitors.

    Science.gov (United States)

    Kim, Kyung-Tai; Song, Mi-Ryoung

    2016-10-28

    Oscillations in Notch signaling are essential for reserving neural progenitors for cellular diversity in developing brains. Thus, steady and prolonged overactivation of Notch signaling is not suitable for generating neurons. To acquire greater temporal control of Notch activity and mimic endogenous oscillating signals, here we adopted a light-inducible transgene system to induce active form of Notch NICD in neural progenitors. Alternating Notch activity saved more progenitors that are prone to produce neurons creating larger number of mixed clones with neurons and progenitors in vitro, compared to groups with no light or continuous light stimulus. Furthermore, more upper layer neurons and astrocytes arose upon intermittent Notch activity, indicating that dynamic Notch activity maintains neural progeny and fine-tune neuron-glia diversity.

  14. Crafting Creative Nonfiction: From Close Reading to Close Writing

    Science.gov (United States)

    Dollins, Cynthia A.

    2016-01-01

    A process writing project in a third-grade classroom explored the idea of using nonfiction mentor texts to assist students in writing their own creative informational texts about animals. By looking at author craft and structure during close reading activities with nonfiction Twin Texts, students were taught how to emulate these techniques in…

  15. PKCε ACTIVATION PROMOTES FGF-2 EXOCYTOSIS AND INDUCES ENDOTHELIAL CELL PROLIFERATION AND SPROUTING

    Science.gov (United States)

    Monti, Martina; Donnini, Sandra; Morbidelli, Lucia; Giachetti, Antonio; Mochly-Rosen, Daria; Mignatti, Paolo; Ziche, Marina

    2013-01-01

    Protein kinase C epsilon (PKCε) activation controls fibroblast growth factor-2 (FGF-2) angiogenic signaling. Here, we examined the effect of activating PKCε on FGF-2 dependent vascular growth and endothelial activation. ψεRACK, a selective PKCε agonist induces pro-angiogenic responses in endothelial cells, including formation of capillary like structures and cell growth. These effects are mediated by FGF-2 export to the cell membrane, as documented by biotinylation and immunofluorescence, and FGF-2/FGFR1 signaling activation, as attested by ERK1/2-STAT-3 phosphorylation and de novo FGF-2 synthesis. Similarly, vascular endothelial growth factor (VEGF) activates PKCε in endothelial cells, and promotes FGF-2 export and FGF-2/FGFR1 signaling activation. ψεRACK fails to elicit responses in FGF-2−/− endothelial cells, and in cells pretreated with methylamine (MeNH2), an exocytosis inhibitor, indicating that both intracellular FGF-2 and its export toward the membrane are required for the ψεRACK activity. In vivo ψεRACK does not induce angiogenesis in the rabbit cornea. However, ψεRACK promotes VEGF angiogenic responses, an effect sustained by endothelial FGF-2 release and synthesis, since anti-FGF-2 antibody strongly attenuates VEGF responses. The results demonstrate that PKCε stimulation promotes angiogenesis and modulates VEGF activity, by inducing FGF-2 release and autocrine signaling. PMID:23880610

  16. Carnosine: effect on aging-induced increase in brain regional monoamine oxidase-A activity.

    Science.gov (United States)

    Banerjee, Soumyabrata; Poddar, Mrinal K

    2015-03-01

    Aging is a natural biological process associated with several neurological disorders along with the biochemical changes in brain. Aim of the present investigation is to study the effect of carnosine (0.5-2.5μg/kg/day, i.t. for 21 consecutive days) on aging-induced changes in brain regional (cerebral cortex, hippocampus, hypothalamus and pons-medulla) mitochondrial monoamine oxidase-A (MAO-A) activity with its kinetic parameters. The results of the present study are: (1) The brain regional mitochondrial MAO-A activity and their kinetic parameters (except in Km of pons-medulla) were significantly increased with the increase of age (4-24 months), (2) Aging-induced increase of brain regional MAO-A activity including its Vmax were attenuated with higher dosages of carnosine (1.0-2.5μg/kg/day) and restored toward the activity that observed in young, though its lower dosage (0.5μg/kg/day) were ineffective in these brain regional MAO-A activity, (3) Carnosine at higher dosage in young rats, unlike aged rats significantly inhibited all the brain regional MAO-A activity by reducing their only Vmax excepting cerebral cortex, where Km was also significantly enhanced. These results suggest that carnosine attenuated the aging-induced increase of brain regional MAO-A activity by attenuating its kinetic parameters and restored toward the results of MAO-A activity that observed in corresponding brain regions of young rats.

  17. Palm kernel cake extract exerts hepatoprotective activity in heat-induced oxidative stress in chicken hepatocytes.

    Science.gov (United States)

    Oskoueian, Ehsan; Abdullah, Norhani; Idrus, Zulkifli; Ebrahimi, Mahdi; Goh, Yong Meng; Shakeri, Majid; Oskoueian, Armin

    2014-10-02

    Palm kernel cake (PKC), the most abundant by-product of oil palm industry is believed to contain bioactive compounds with hepatoprotective potential. These compounds may serve as hepatoprotective agents which could help the poultry industry to alleviate adverse effects of heat stress on liver function in chickens. This study was performed to evaluate the hepatoprotective potential of PKC extract in heat-induced oxidative stress in chicken hepatocytes. The nature of the active metabolites and elucidation of the possible mechanism involved were also investigated. The PKC extract possessed free radical scavenging activity with values significantly (p Heat-induced oxidative stress in chicken hepatocyte impaired the total protein, lipid peroxidation and antioxidant enzymes activity significantly (p heat-induced hepatocytes with PKC extract (125 μg/ml) and silymarin as positive control increased these values significantly (p stress biomarkers including TNF-like, IFN-γ and IL-1β genes; NF-κB, COX-2, iNOS and Hsp70 proteins expression upon heat stress in chicken hepatocytes. The PKC extract and silymarin were able to alleviate the expression of all of these biomarkers in heat-induced chicken hepatocytes. The gas chromatography-mass spectrometry analysis of PKC extract showed the presence of fatty acids, phenolic compounds, sugar derivatives and other organic compounds such as furfural which could be responsible for the observed hepatoprotective activity. Palm kernel cake extract could be a potential agent to protect hepatocytes function under heat induced oxidative stress.

  18. Natural Product Vibsanin A Induces Differentiation of Myeloid Leukemia Cells through PKC Activation.

    Science.gov (United States)

    Yu, Zu-Yin; Xiao, He; Wang, Li-Mei; Shen, Xing; Jing, Yu; Wang, Lin; Sun, Wen-Feng; Zhang, Yan-Feng; Cui, Yu; Shan, Ya-Jun; Zhou, Wen-Bing; Xing, Shuang; Xiong, Guo-Lin; Liu, Xiao-Lan; Dong, Bo; Feng, Jian-Nan; Wang, Li-Sheng; Luo, Qing-Liang; Zhao, Qin-Shi; Cong, Yu-Wen

    2016-05-01

    All-trans retinoic acid (ATRA)-based cell differentiation therapy has been successful in treating acute promyelocytic leukemia, a unique subtype of acute myeloid leukemia (AML). However, other subtypes of AML display resistance to ATRA-based treatment. In this study, we screened natural, plant-derived vibsane-type diterpenoids for their ability to induce differentiation of myeloid leukemia cells, discovering that vibsanin A potently induced differentiation of AML cell lines and primary blasts. The differentiation-inducing activity of vibsanin A was mediated through direct interaction with and activation of protein kinase C (PKC). Consistent with these findings, pharmacological blockade of PKC activity suppressed vibsanin A-induced differentiation. Mechanistically, vibsanin A-mediated activation of PKC led to induction of the ERK pathway and decreased c-Myc expression. In mouse xenograft models of AML, vibsanin A administration prolonged host survival and inhibited PKC-mediated inflammatory responses correlated with promotion of skin tumors in mice. Collectively, our results offer a preclinical proof of concept for vibsanin A as a myeloid differentiation-inducing compound, with potential application as an antileukemic agent. Cancer Res; 76(9); 2698-709. ©2016 AACR.

  19. MUC1 contributes to BPDE-induced human bronchial epithelial cell transformation through facilitating EGFR activation.

    Directory of Open Access Journals (Sweden)

    Xiuling Xu

    Full Text Available Although it is well known that epidermal growth factor receptor (EGFR is involved in lung cancer progression, whether EGFR contributes to lung epithelial cell transformation is less clear. Mucin 1 (MUC1 in human and Muc1 in animals, a glycoprotein component of airway mucus, is overexpressed in lung tumors; however, its role and underlying mechanisms in early stage lung carcinogenesis is still elusive. This study provides strong evidence demonstrating that EGFR and MUC1 are involved in bronchial epithelial cell transformation. Knockdown of MUC1 expression significantly reduced transformation of immortalized human bronchial epithelial cells induced by benzo[a]pyrene diol epoxide (BPDE, the active form of the cigarette smoke (CS carcinogen benzo(apyrene (BaPs. BPDE exposure robustly activated a pathway consisting of EGFR, Akt and ERK, and blocking this pathway significantly increased BPDE-induced cell death and inhibited cell transformation. Suppression of MUC1 expression resulted in EGFR destabilization and inhibition of the BPDE-induced activation of Akt and ERK and increase of cytotoxicity. These results strongly suggest an important role for EGFR in BPDE-induced transformation, and substantiate that MUC1 is involved in lung cancer development, at least partly through mediating carcinogen-induced activation of the EGFR-mediated cell survival pathway that facilitates cell transformation.

  20. Prevention of Paclitaxel-Induced Neuropathy Through Activation of the Central Cannabinoid Type 2 Receptor System

    Science.gov (United States)

    Naguib, Mohamed; Xu, Jijun J.; Diaz, Philippe; Brown, David L.; Cogdell, David; Bie, Bihua; Hu, Jianhua; Craig, Suzanne; Hittelman, Walter N.

    2012-01-01

    Background Peripheral neuropathy is a major dose-limiting toxicity of chemotherapy, especially after multiple courses of paclitaxel. The development of paclitaxel-induced neuropathy is associated with the activation of microglia followed by the activation and proliferation of astrocytes, and the expression and release of proinflammatory cytokines in the spinal dorsal horn. Cannabinoid type 2 (CB2) receptors are expressed in the microglia in neurodegenerative disease models. Methods To explore the potential of CB2 agonists for preventing paclitaxel-induced neuropathy, we designed and synthesized a novel CB2-selective agonist, namely MDA7. The effect of MDA7 in preventing paclitaxel-induced allodynia was assessed in rats and in CB2+/+ and CB2–/– mice. We hypothesize that the CB2 receptor functions in a negative-feedback loop and that early MDA7 administration can blunt the neuroinflammatory response to paclitaxel and prevent mechanical allodynia through interference with specific signaling pathways. Results We found that MDA7 prevents paclitaxel-induced mechanical allodynia in rats and mice in a dose- and time-dependent manner without compromising paclitaxel's antineoplastic effect. MDA7's neuroprotective effect was absent in CB2-/- mice and was blocked by CB2 antagonists, suggesting that MDA7's action directly involves CB2 receptor activation. MDA7 treatment was found to interfere with early events in the paclitaxel-induced neuroinflammatory response as evidenced by relatively reduced Toll-like receptor and CB2 expression in the lumbar spinal cord, reduced levels of extracellular signal regulated kinase 1/2 activity, reduced numbers of activated microglia and astrocytes, and reduced secretion of proinflammatory mediators in vivo and in in vitro models. Conclusions Our findings suggest an innovative therapeutic approach to prevent chemotherapy-induced neuropathy and may permit more aggressive use of active chemotherapeutic regimens with reduced long-term sequelae

  1. Stress and radiation-induced activation of multiple intracellular signaling pathways.

    Science.gov (United States)

    Dent, Paul; Yacoub, Adly; Contessa, Joseph; Caron, Ruben; Amorino, George; Valerie, Kristoffer; Hagan, Michael P; Grant, Steven; Schmidt-Ullrich, Rupert

    2003-03-01

    Exposure of cells to a variety of stresses induces compensatory activations of multiple intracellular signaling pathways. These activations can play critical roles in controlling cell survival and repopulation effects in a stress-specific and cell type-dependent manner. Some stress-induced signaling pathways are those normally activated by mitogens such as the EGFR/RAS/PI3K-MAPK pathway. Other pathways activated by stresses such as ionizing radiation include those downstream of death receptors, including pro-caspases and the transcription factor NFKB. This review will attempt to describe some of the complex network of signals induced by ionizing radiation and other cellular stresses in animal cells, with particular attention to signaling by growth factor and death receptors. This includes radiation-induced signaling via the EGFR and IGFI-R to the PI3K, MAPK, JNK, and p38 pathways as well as FAS-R and TNF-R signaling to pro-caspases and NFKB. The roles of autocrine ligands in the responses of cells and bystander cells to radiation and cellular stresses will also be discussed. Based on the data currently available, it appears that radiation can simultaneously activate multiple signaling pathways in cells. Reactive oxygen and nitrogen species may play an important role in this process by inhibiting protein tyrosine phosphatase activity. The ability of radiation to activate signaling pathways may depend on the expression of growth factor receptors, autocrine factors, RAS mutation, and PTEN expression. In other words, just because pathway X is activated by radiation in one cell type does not mean that pathway X will be activated in a different cell type. Radiation-induced signaling through growth factor receptors such as the EGFR may provide radioprotective signals through multiple downstream pathways. In some cell types, enhanced basal signaling by proto-oncogenes such as RAS may provide a radioprotective signal. In many cell types, this may be through PI3K, in others

  2. Inducible removal of UV-induced pyrimidine dimers from transcriptionally active and inactive genes of Saccharomyces cerevisiae.

    Science.gov (United States)

    Waters, R; Zhang, R; Jones, N J

    1993-05-01

    The prior UV irradiation of alpha haploid Saccharomyces cerevisiae with a UV dose of 25 J/m2 substantially increases the repairability of damage subsequently induced by a UV dose of 70 J/m2 given 1 h after the first irradiation. This enhancement of repair is seen at both the MAT alpha and HML alpha loci, which are, respectively, transcriptionally active and inactive in alpha haploid cells. The presence in the medium of the protein synthesis inhibitor, cycloheximide in the period between the two irradiations eliminated this effect. Enhanced repair still occurred if cycloheximide was present only after the final UV irradiation. This indicated that the first result is not due to cycloheximide merely blocking the synthesis of repair enzymes associated with a hypothetical rapid turnover of such molecules. The enhanced repairability is not the result of changes in chromatin accessibility without protein synthesis, merely caused by the repair of the damage induced by the prior irradiation. The data clearly show that a UV-inducible removal of pyrimidine dimers has occurred which involves the synthesis of new proteins. The genes known to possess inducible promoters, and which are involved in excision are RAD2, RAD7, RAD16 and RAD23. Studies with the rad7 and rad16 mutants which are defective in the ability to repair HML alpha and proficient in the repair of MAT alpha showed that in rad7, preirradiation enhanced the repair at MAT alpha, whereas in rad16 this increased repair of MAT alpha was absent. The preirradiation did not modify the inability to repair HML alpha in either strain. Thus RAD16 has a role in this inducible repair.(ABSTRACT TRUNCATED AT 250 WORDS)

  3. Silver(I)-catalyzed dual activation of propargylic alcohol and aziridine/azetidine: triggering ring-opening and endo-selective ring-closing in a cascade.

    Science.gov (United States)

    Bera, Milan; Roy, Sujit

    2009-11-20

    [Ag(COD)(2)]PF(6) catalyzes the reaction between propargyl alcohols and N-tosylaziridines/azetidines leading to a diverse range of N,O-heterocycles, namely, oxazines, oxazepines, and oxazocines via ring-opening and ring-closing in a cascade.

  4. A new type of self-supported, polymeric Ru-carbene complex for homogeneous catalysis and heterogeneous recovery: synthesis and catalytic activities for ring-closing metathesis.

    Science.gov (United States)

    Chen, Shu-Wei; Kim, Ju Hyun; Shin, Hyunik; Lee, Sang-Gi

    2008-08-01

    A novel 2nd generation Grubbs-type catalyst tethering an isopropoxystyrene has been synthesized and automatically polymerized in solution to form a self-supported polymeric Ru-carbene complex, which catalyzed ring-closing metathesis homogeneously, but was recovered heterogeneously.

  5. Rotationally Induced Surface Slope-Instabilities and the Activation of CO2 Activity on Comet 103P/Hartley 2

    CERN Document Server

    Steckloff, Jordan K; Hirabayashi, Toshi; Melosh, H Jay; Richardson, James

    2016-01-01

    Comet 103P/Hartley 2 has diurnally controlled, CO2-driven activity on the tip of the small lobe of its bilobate nucleus. Such activity is unique among the comet nuclei visited by spacecraft, and suggests that CO2 ice is very near the surface, which is inconsistent with our expectations of an object that thermophysically evolved for ~45 million years prior to entering the Jupiter Family of comets. Here we explain this pattern of activity by showing that a very plausible recent episode of rapid rotation (rotation period of ~11 [10-13] hours) would have induced avalanches in Hartley 2's currently active regions that excavated down to CO2-rich ices and activated the small lobe of the nucleus. At Hartley 2's current rate of spindown about its principal axis, the nucleus would have been spinning fast enough to induce avalanches ~3-4 orbits prior to the DIXI flyby (~1984-1991). This coincides with Hartley 2's discovery in 1986, and implies that the initiation of CO2 activity facilitated the comet's discovery. During...