Science.gov

Sample records for helium 6 target

  1. Calculation of hydrogen and helium concentrations for CSNS target

    NASA Astrophysics Data System (ADS)

    Pan, Dong-Dong; Liang, Tai-Ran; Yin, Wen; Yao, Ze-En

    2016-03-01

    The China Spallation Neutron Source (CSNS) is driven by protons whose energies are about 1.6 GeV. At such high energies, the spallation neutrons lead to the formation of large amounts of helium, hydrogen and new heavier species in the form of transmutation products. These hydrogen, helium and transmutation products have a critical effect on the mechanical properties on the one hand and exacerbate the displacement radiation damage on the other hand. In this paper, the background hydrogen/helium concentrations and the maximum hydrogen/helium concentrations near cracks in a tungsten target for CSNS have been calculated at temperatures of 100°C and 300°C by applying a theoretical model. For the CSNS tungsten target plate, we find the maximum hydrogen concentration near the tips of cracks ranges from 3.0 × 10-2-2 × 10-1, which exceeds the hydrogen background concentration by 1.2-1.8 times; the maximum helium concentration near the tips of cracks ranges from 3.0 × 10-4 -1.2 × 10-3, which exceeds the helium background concentration by 2-4 times; the maximum hydrogen/helium concentration increases with the increase of the transfer length across the surfaces of the target and it decreases with the increase of temperature. Supported by National Science Foundation of China (51371195, 11174358)

  2. THERMAL OSCILLATIONS IN LIQUID HELIUM TARGETS.

    SciTech Connect

    WANG,L.; JIA,L.X.

    2001-07-16

    A liquid helium target for the high-energy physics was built and installed in the proton beam line at the Alternate Gradient Synchrotron of Brookhaven National Laboratory in 2001. The target flask has a liquid volume of 8.25 liters and is made of thin Mylar film. A G-M/J-T cryocooler of five-watts at 4.2K was used to produce liquid helium and refrigerate the target. A thermosyphon circuit for the target was connected to the J-T circuit by a liquid/gas separator. Because of the large heat load to the target and its long transfer lines, thermal oscillations were observed during the system tests. To eliminate the oscillation, a series of tests and analyses were carried out. This paper describes the phenomena and provides the understanding of the thermal oscillations in the target system.

  3. Active helium target: Neutron scalar polarizability extraction via Compton scattering

    SciTech Connect

    Morris, Meg Hornidge, David; Annand, John; Strandberg, Bruno

    2015-12-31

    Precise measurement of the neutron scalar polarizabilities has been a lasting challenge because of the lack of a free-neutron target. Led by the University of Glasgow and the Mount Allison University groups of the A2 collaboration in Mainz, Germany, preparations have begun to test a recent theoretical model with an active helium target with the hope of determining these elusive quantities with small statistical, systematic, and model-dependent errors. Apparatus testing and background-event simulations have been carried out, with the full experiment projected to run in 2015. Once determined, these values can be applied to help understand quantum chromodynamics in the nonperturbative region.

  4. Active helium target: Neutron scalar polarizability extraction via Compton scattering

    NASA Astrophysics Data System (ADS)

    Morris, Meg; Annand, John; Hornidge, David; Strandberg, Bruno

    2015-12-01

    Precise measurement of the neutron scalar polarizabilities has been a lasting challenge because of the lack of a free-neutron target. Led by the University of Glasgow and the Mount Allison University groups of the A2 collaboration in Mainz, Germany, preparations have begun to test a recent theoretical model with an active helium target with the hope of determining these elusive quantities with small statistical, systematic, and model-dependent errors. Apparatus testing and background-event simulations have been carried out, with the full experiment projected to run in 2015. Once determined, these values can be applied to help understand quantum chromodynamics in the nonperturbative region.

  5. Optimization of Spin-Polarization of Helium-3 Target Cell by Thermal Convection Processes

    NASA Astrophysics Data System (ADS)

    Karthas, Stacy

    2013-10-01

    Polarized Helium-3 (3He) is an effective polarized neutron target that has been used in particle accelerators like the Thomas Jefferson National Accelerator Facility (TJNAF) for the past three decades to study properties of the neutron. Due to the spin structure of its nucleons, the nucleus of 3He can be approximated as a single polarized neutron. The previous generations of 3He targets have reached their limit in polarization and are not ideal for use as targets with the 12 GeV update at TJNAF due to large polarization gradients. The new target cell uses thermal convection to transfer polarized gas to the target chamber quickly. The focus of this project was to study the effects of the new convection system, at various gas velocities, on Adiabatic Fast Passage (AFP) polarization loss that results from measuring the polarization of 3He with Nuclear Magnetic Resonance (NMR). Gas velocities were varied by using a Kapton flexible heater to induce thermal convection. This target cell loses less than one percent of its polarization by measurement when convection is induced at a gas velocity under 6 cm/min thereby verifying the possible use of convection induction for the future experiments. Research conducted at Thomas Jefferson National Accelerator Facility funded through a grant from NSF by the Old Dominion University Research Experience for Undergraduates Program.

  6. A helium gas scintillator active target for photoreaction measurements

    NASA Astrophysics Data System (ADS)

    Al Jebali, Ramsey; Annand, John R. M.; Adler, Jan-Olof; Akkurt, Iskender; Buchanan, Emma; Brudvik, Jason; Fissum, Kevin; Gardner, Simon; Hamilton, David J.; Hansen, Kurt; Isaksson, Lennart; Livingston, Kenneth; Lundin, Magnus; McGeorge, John C.; MacGregor, Ian J. D.; MacRae, Roderick; Middleton, Duncan G.; Reiter, Andreas J. H.; Rosner, Günther; Schröder, Bent; Sjögren, Johan; Sokhan, Daria; Strandberg, Bruno

    2015-10-01

    A multi-cell He gas scintillator active target, designed for the measurement of photoreaction cross sections, is described. The target has four main chambers, giving an overall thickness of 0.103 g/cm3 at an operating pressure of 2 MPa. Scintillations are read out by photomultiplier tubes and the addition of small amounts of N2 to the He, to shift the scintillation emission from UV to visible, is discussed. First results of measurements at the MAX IV Laboratory tagged-photon facility show that the target has a timing resolution of around 1 ns and can cope well with a high-flux photon beam. The determination of reaction cross sections from target yields relies on a Monte Carlo simulation, which considers scintillation light transport, photodisintegration processes in 4He, background photon interactions in target windows and interactions of the reaction-product particles in the gas and target container. The predictions of this simulation are compared to the measured target response.

  7. Performance characterization of a 6-K multiple JT helium adsorption cryocooler

    NASA Technical Reports Server (NTRS)

    Elliot, S.; Johnson, D. L.; Lindersmith, C. A.; Sirbi, A.

    2002-01-01

    We present the work done at the Jet Propulsion Laboratory for a Helium Adsorption Cooler to produce continuous cooling power at a temperature around 6 K. The goal of this development is to be able to propose for future space mission a long lifetime, vibration free cooler, which can cover the temperature range 18 K to 5 K.

  8. Study of the New Pulse NMR System for the Jefferson Lab Helium-3 Polarized Target

    NASA Astrophysics Data System (ADS)

    Newton, Joseph

    2013-10-01

    At Jefferson Lab, a polarized Helium-3 target is used to study the neutron. The Helium-3 target is undergoing an upgrade to improve its polarization. Measuring it involved a new technique known as pulse Nuclear Magnetic Resonance (NMR). The focus of this project was to find noise in the Pulse NMR signal and to compute the calibration constant to make the polarization easier to deduce. Pulse NMR calibration tests were performed by doing AFP NMR measurements followed by Pulse NMR measurements while varying certain conditions. These included the convection heater, the operation of the oven, and the operation of the laser. Data analysis was done by fitting the pulse NMR signal from the oscilloscope and utilizing the Fourier Transform. Noise was analyzed in the fitting and the Fourier Transform. The calibration constants were affected by the convection heater. The values deviated between the pumping and target chambers of the cell when there was no convection but the values were closer when convection was induced. As far as the noise, it was found to be significant. These results will enable the calculation of the polarization with pulse NMR. In addition, the signal analysis provided insight into the influence of background noise on the pulse NMR measurement. This research was done though the SULI program of the Department of Energy.

  9. Heat transfer design and performance of a helium cryostat operating at 6.5 K

    SciTech Connect

    Gasteyer, T.H.; Krempetz, K.J.; Lee, A.; Rucinski, R.A.; Stefanik, A.M.

    1994-12-31

    A liquid helium cryostat has been designed and operated for the purpose of testing visible light photon counter (VLPC) chips at 6.5 K. To achieve the desired operational characteristics for the VLPC devices their operating temperature is restricted to 6.5 K +/{minus} 0.1 K. They will be used in a scintillating fiber tracker being proposed as part of an upgrade of the D(0) detector at Fermilab. The final version of the scintillating fiber tracker will contain roughly 100,000 VLPC channels. Two cryostats with identical thermal design (a 128 channel and a 3072 channel design) have been built to perform the initial VLPC testing. The heat transfer needed to maintain the VLPC at its operating temperature occurs by conduction across an annular helium gas gap to a liquid helium reservoir. Helium boiloff is used to intercept conduction heat leak to the liquid reservoir. ANSYS finite element heat transfer analysis was utilized in the thermal design of the cryostat. The cryostat design and thermal performance (predicted and measured) are presented.

  10. Polarization of the light from the 3P(1)-2S(1) transition in proton beam excited helium. Ph.D. Thesis; [target gas pressure effects

    NASA Technical Reports Server (NTRS)

    Weinhous, M. S.

    1973-01-01

    Measurements of the polarization of the light from the 3 1p-2 1s transition in proton beam excited Helium have shown both a proton beam energy and Helium target gas pressure dependence. Results for the linear polarization fraction range from +2.6% at 100 keV proton energy to -5.5% at 450 keV. The zero crossover occurs at approximately 225 keV. This is in good agreement with other experimental work in the field, but in poor agreement with theoretical predictions. Measurements at He target gas pressures as low as .01 mtorr show that the linear polarization fraction is still pressure dependent at .01 mtorr.

  11. Active Helium 3/4 Target for Use in MAMI Crystal Ball

    NASA Astrophysics Data System (ADS)

    Demell, Jennifer; A2 Collaboration

    2014-09-01

    By using a Helium 3 Active target (AT) with the A2 photon beam in MAMI, the polarizability of the neutron, a value that has not yet been well defined, can be determined. In order to be used in the MAMI Crystal Ball, the size of the 3He Active Target needed to be decreased. For our experiment we tested new, compact photomultiplier tubes (PMTs) by comparing their response to changes in nitrogen admixture concentration to those of the original, larger PMTs. We also examined the contribution of NINO discriminators, to be attached to the new PMTs to decrease noise effects. We found that the new PMTs and NINO discriminator functioned well and will be used in the future experiment, though a decrease in voltage detection was experienced. Additionally, using AT Geant4, simulations of the upcoming experiment were performed and background and resolution studies conducted. We specifically examined mass loss due to quasi free Compton Scattering, π0 production and the breakup of the 3He nucleus. By using a Helium 3 Active target (AT) with the A2 photon beam in MAMI, the polarizability of the neutron, a value that has not yet been well defined, can be determined. In order to be used in the MAMI Crystal Ball, the size of the 3He Active Target needed to be decreased. For our experiment we tested new, compact photomultiplier tubes (PMTs) by comparing their response to changes in nitrogen admixture concentration to those of the original, larger PMTs. We also examined the contribution of NINO discriminators, to be attached to the new PMTs to decrease noise effects. We found that the new PMTs and NINO discriminator functioned well and will be used in the future experiment, though a decrease in voltage detection was experienced. Additionally, using AT Geant4, simulations of the upcoming experiment were performed and background and resolution studies conducted. We specifically examined mass loss due to quasi free Compton Scattering, π0 production and the breakup of the 3He nucleus

  12. Characteristics of interstellar helium observed with Prognoz 6 58.4-nm photometers

    NASA Astrophysics Data System (ADS)

    Dalaudier, F.; Bertaux, J. L.; Kurt, V. G.; Mironova, E. N.

    1984-05-01

    The whole set of Prognoz 6 data on He 58.4 nm obtained during September 1977 to January 1978 and collected from various positions of the earth relative to the helium cone of gravitational focusing. The whole set of parameters describing the characteristics of the helium component of LISM and its interaction with the solar environment were calculated by modeling the phenomenon and by using a quantitative estimate of quality fit. The ionization lifetime of one He atom at 1 AU was determined as 8 + or - 1.5 megaseconds, and the solar line width was found to be equal to or greater than 90 mA. The sensitivity of the He I emission pattern to the solar line width and shape is indicated. The temperature of the interstellar helium was found to lie between 11,000 and 24,000 K with a favored value of 16,000 K. Several possible explanations for the difference in temperature in the interstellar medium between He and H are considered.

  13. Targeting interleukin-6 for noninfectious uveitis

    PubMed Central

    Lin, Phoebe

    2015-01-01

    Interleukin-6 (IL-6) is a pleiotropic cytokine implicated in the pathogenesis of many immune-mediated disorders including several types of non-infectious uveitis. These uveitic conditions include Vogt-Koyanagi-Harada syndrome, uveitis associated with Behçet disease, and sarcoidosis. This review summarizes the role of IL-6 in immunity, highlighting its effect on Th17, Th1, and plasmablast differentiation. It reviews the downstream mediators activated in the process of IL-6 binding to its receptor complex. This review also summarizes the biologics targeting either IL-6 or the IL-6 receptor, including tocilizumab, sarilumab, sirukumab, olokizumab, clazakizumab, and siltuximab. The target, dosage, potential side effects, and potential uses of these biologics are summarized in this article based on the existing literature. In summary, anti-IL-6 therapy for non-infectious uveitis shows promise in terms of efficacy and side effect profile. PMID:26392750

  14. Planar Rayleigh Scattering Results in Helium/Air Mixing Experiments in a Mach 6 Wind Tunnel

    NASA Technical Reports Server (NTRS)

    Shirinzadeh, B.; Balla, R. Jeffrey; Hillard, M. E.; Anders, J. B.; Exton, R. J.; Waitz, I. A.

    1991-01-01

    Planar Rayleigh scattering measurements using an ArF-excimer laser have been performed to investigate helium mixing into air at supersonic speeds. The capability of the Rayleigh scattering technique for flow visualization of a turbulent environment is demonstrated in a large-scale, Mach 6facility. The detection limit obtained with the present setup indicates that planar, quantitative measurements of density can be made over a large cross sectional area (5 cm by 10 cm) of the flow field in the absence of clusters.

  15. Properties of V-(8-9)Cr-(5-6)Ti alloys irradiated in the dynamic helium charging experiment

    SciTech Connect

    Chung, H.M.; Nowicki, L.; Smith, D.L.

    1996-10-01

    In the Dynamic Helium Charging Experiment (DHCE), helium was produced uniformly in vanadium alloy specimens by the decay of tritium during irradiation to 18-31 dpa at 425-600{degrees}C in lithium-filled capsules in the Fast Flux Test Facility. This report presents results of postirradiation tests of tensile properties and density change in V-8Cr-6Ti and V-9Cr-5Ti. Compared to tensile properties of the alloys irradiated in the non-DHCE (helium generation negligible), the effect of helium on tensile strength and ductility of V-8Cr-6Ti and V-9Cr-5Ti was insignificant after irradiation and testing at 420, 500, and 600{degrees}C. Both alloys retained a total elongation of >11 % at these temperatures. Density change was <0.48% for both alloys.

  16. The Effects of Helium Bubble Microstructure on Ductility in Annealed and HERF 21Cr-6Ni-9Mn Stainless Steel

    SciTech Connect

    Tosten, M.H.; Morgan, M.J.

    1998-01-01

    This study examined the effects of microstructure on the ambient temperature embrittlement from hydrogen isotopes and decay helium in 21Cr-6Ni-9Mn stainless steel. Hydrogen and tritium-exposed 21Cr-6Ni-9Mn stainless steel tensile samples were pulled to failure and then characterized by transmission electron microscopy (TEM) and optical microscopy. This study determined that ductility differences between annealed and high-energy-rate-forged (HERF) stainless steel containing tritium and its decay product, helium, could be related to differences in the helium bubble microstructures. The HERF microstructures were more resistant to tritium-induced embrittlement than annealed microstructures because the high number density of helium bubbles on dislocations trap tritium within the matrix and away from the grain boundaries.

  17. Interleukin-6 as a therapeutic target.

    PubMed

    Rossi, Jean-François; Lu, Zhao-Yang; Jourdan, Michel; Klein, Bernard

    2015-03-15

    Human IL6 is a cytokine produced by many cell types that has pleiotropic effects. In agreement, anti-IL6 therapy reduces inflammation, hepatic acute phase proteins, and anemia and has antiangiogenic effects. Blocking IL6 has demonstrated therapeutic efficacy with drug registration in Castleman disease and inflammatory diseases (rheumatoid arthritis) without major toxicity. Interestingly, the inhibition of C-reactive protein (CRP) production is a trustworthy surrogate marker of anti-IL6 therapy efficacy. Clinically registered IL6 inhibitors include siltuximab, an anti-IL6 mAb, and tocilizumab, an anti-IL6R mAb. In various cancers, in particular plasma cell cancers, large randomized trials showed no efficacy of IL6 inhibitors, despite a full inhibition of CRP production in treated patients in vivo, the numerous data showing an involvement of IL6 in these diseases, and initial short-term treatments demonstrating a dramatic inhibition of cancer cell proliferation in vivo. A likely explanation is the plasticity of cancer cells, with the presence of various subclones, making the outgrowth of cancer subclones possible using growth factors other than IL6. In addition, current therapeutic strategies used in these cancers already target IL6 activity. Thus, anti-IL6 therapeutics are able to neutralize IL6 production in vivo and are safe and useful in inflammatory diseases and Castleman disease. PMID:25589616

  18. Helium behavior in ferritic/martensitic steels irradiated in spallation target

    NASA Astrophysics Data System (ADS)

    Krsjak, Vladimir; Kuriplach, Jan; Shen, Tielong; Sabelova, Veronika; Sato, Koichi; Dai, Yong

    2015-01-01

    Two positron annihilation spectroscopy (PAS) techniques have been used for the investigation of helium behavior in STIP samples. Positron lifetime measurements and coincidence Doppler broadening spectroscopy have been employed together in a complex PAS characterization of RAFM steel irradiated in a mixed neutron-proton spectrum up to 20 dpa and 1800 appm He. Both techniques show an increase of the He-to-dpa ratio up to ∼10 dpa. At higher irradiation loads, the ratio is decreasing, which was attributed to the formation and growth of helium bubbles.

  19. Characterization of deuterium clusters mixed with helium gas for an application in beam-target-fusion experiments

    DOE PAGESBeta

    Bang, W.; Quevedo, H. J.; Bernstein, A. C.; Dyer, G.; Ihn, Y. S.; Cortez, J.; Aymond, F.; Gaul, E.; Donovan, M. E.; Barbui, M.; et al

    2014-12-10

    We measured the average deuterium cluster size within a mixture of deuterium clusters and helium gas by detecting Rayleigh scattering signals. The average cluster size from the gas mixture was comparable to that from a pure deuterium gas when the total backing pressure and temperature of the gas mixture were the same as those of the pure deuterium gas. According to these measurements, the average size of deuterium clusters depends on the total pressure and not the partial pressure of deuterium in the gas mixture. To characterize the cluster source size further, a Faraday cup was used to measure themore » average kinetic energy of the ions resulting from Coulomb explosion of deuterium clusters upon irradiation by an intense ultrashort pulse. The deuterium ions indeed acquired a similar amount of energy from the mixture target, corroborating our measurements of the average cluster size. As the addition of helium atoms did not reduce the resulting ion kinetic energies, the reported results confirm the utility of using a known cluster source for beam-target-fusion experiments by introducing a secondary target gas.« less

  20. Characterization of deuterium clusters mixed with helium gas for an application in beam-target-fusion experiments

    SciTech Connect

    Bang, W.; Quevedo, H. J.; Bernstein, A. C.; Dyer, G.; Ihn, Y. S.; Cortez, J.; Aymond, F.; Gaul, E.; Donovan, M. E.; Barbui, M.; Bonasera, A.; Natowitz, J. B.; Albright, B. J.; Fernández, J. C.; Ditmire, T.

    2014-12-10

    We measured the average deuterium cluster size within a mixture of deuterium clusters and helium gas by detecting Rayleigh scattering signals. The average cluster size from the gas mixture was comparable to that from a pure deuterium gas when the total backing pressure and temperature of the gas mixture were the same as those of the pure deuterium gas. According to these measurements, the average size of deuterium clusters depends on the total pressure and not the partial pressure of deuterium in the gas mixture. To characterize the cluster source size further, a Faraday cup was used to measure the average kinetic energy of the ions resulting from Coulomb explosion of deuterium clusters upon irradiation by an intense ultrashort pulse. The deuterium ions indeed acquired a similar amount of energy from the mixture target, corroborating our measurements of the average cluster size. As the addition of helium atoms did not reduce the resulting ion kinetic energies, the reported results confirm the utility of using a known cluster source for beam-target-fusion experiments by introducing a secondary target gas.

  1. Spent Nuclear Fuel (SNF) Project Cask and MCO Helium Purge System Design Review Completion Report Project A.5 and A.6

    SciTech Connect

    ARD, K.E.

    2000-04-19

    This report documents the results of the design verification performed on the Cask and Multiple Canister Over-pack (MCO) Helium Purge System. The helium purge system is part of the Spent Nuclear Fuel (SNF) Project Cask Loadout System (CLS) at 100K area. The design verification employed the ''Independent Review Method'' in accordance with Administrative Procedure (AP) EN-6-027-01.

  2. Description and initial operating performance of the Langley 6-inch expansion tube using heated helium driver gas

    NASA Technical Reports Server (NTRS)

    Moore, J. A.

    1975-01-01

    A general description of the Langley 6-inch expansion tube is presented along with discussion of the basic components, internal resistance heater, arc-discharge assemblies, instrumentation, and operating procedure. Preliminary results using unheated and resistance-heated helium as the driver gas are presented. The driver-gas pressure ranged from approximately 17 to 59 MPa and its temperature ranged from 300 to 510 K. Interface velocities of approximately 3.8 to 6.7 km/sec were generated between the test gas and the acceleration gas using air as the test gas and helium as the acceleration gas. Test flow quality and comparison of measured and predicted expansion-tube flow quantities are discussed.

  3. The effect of intergalactic helium on hydrogen reionization: implications for the sources of ionizing photons at z>6

    NASA Astrophysics Data System (ADS)

    Ciardi, B.; Bolton, J. S.; Maselli, A.; Graziani, L.

    2012-06-01

    We investigate the effect of primordial helium on hydrogen reionization using a hydrodynamical simulation combined with the cosmological radiative transfer code CRASH. The radiative transfer simulations are performed in a 35.12 h-1 comoving Mpc box using a variety of assumptions for the amplitude and power-law extreme-ultraviolet (EUV) spectral index of the ionizing emissivity at z > 6. We use an empirically motivated prescription for ionizing sources which, by design, ensures all of the models are consistent with constraints on the Thomson scattering optical depth and the metagalactic hydrogen photoionization rate at z˜ 6. The inclusion of helium slightly delays reionization due to the small number of ionizing photons which reionize neutral helium instead of hydrogen. However, helium has a significant impact on the thermal state of the intergalactic medium (IGM) during hydrogen reionization. Models with a soft EUV spectral index, α= 3, produce IGM temperatures at the mean density at z˜ 6, T0≃ 10 500 K, which are ˜20 per cent higher compared to models in which helium photoheating is excluded. Harder EUV indices produce even larger IGM temperature boosts by the end of hydrogen reionization. A comparison of these simulations to recent observational estimates of the IGM temperature at z˜ 5-6 suggests that hydrogen reionization was primarily driven by Population II stellar sources with a soft EUV index, ?. We also find that faint, as yet undetected galaxies, characterized by a luminosity function with a steepening faint-end slope (αLF≤-2) and an increasing Lyman continuum escape fraction (fesc˜ 0.5), are required to reproduce the ionizing emissivity used in our simulations at z > 6. Finally, we note there is some tension between recent observational constraints which indicate the IGM is >10 per cent neutral by volume z˜ 7, and estimates of the ionizing emissivity at z= 6 which indicate only 1-3 ionizing photons are emitted per hydrogen atom over a Hubble

  4. Helium and hydrogen measurements on pure materials irradiated in SINQ Target 4

    NASA Astrophysics Data System (ADS)

    Oliver, B. M.; Dai, Y.

    2009-04-01

    Several irradiations have been performed in the Swiss Spallation Neutron Source (SINQ) to establish a materials database for mixed proton and neutron fluxes for future spallation neutron and other accelerator sources. Pure metal dosimetry materials from the second irradiation (STIP-II) have been analyzed for their total helium and hydrogen contents and their release characteristics with temperature (TDS). Total helium results are similar to those observed earlier from the first irradiation experiment (STIP-I), with concentrations ranging from ˜500 to ˜1000 appm. Hydrogen contents varied over a larger range from ˜100 to ˜60 000. 3He/ 4He ratios were generally consistent with expectations, except for Ti, Nb, and Ta which showed lower values due to 3He from decay of irradiation-generated tritium. Some differences were observed in the hydrogen TDS data for the control and irradiated materials, including some evidence for additional lower-temperature release and for multiple release peaks. Additionally, differences were noted in the releases for irradiated material that been cleaned versus material that had no cleaning.

  5. Ordered helium trapping and bonding in compressed arsenolite: Synthesis of A s4O6.2 He

    NASA Astrophysics Data System (ADS)

    Sans, Juan A.; Manjón, Francisco J.; Popescu, Catalin; Cuenca-Gotor, Vanesa P.; Gomis, Oscar; Muñoz, Alfonso; Rodríguez-Hernández, Plácida; Contreras-García, Julia; Pellicer-Porres, Julio; Pereira, Andre L. J.; Santamaría-Pérez, David; Segura, Alfredo

    2016-02-01

    Compression of arsenolite has been studied from a joint experimental and theoretical point of view. Experiments on this molecular solid at high pressures with different pressure-transmitting media have been interpreted thanks to state-of-the-art ab initio calculations. Our results confirm arsenolite as one of the most compressible minerals and provide evidence for ordered helium trapping above 3 GPa between adamantane-type A s4O6 cages. Our calculations indicate that, at relatively small pressures, helium establishes rather localized structural bonds with arsenic forming a compound with stoichiometry A s4O6.2 He . All properties of A s4O6.2 He are different from those of parent A s4O6 . In particular, pressure-induced amorphization, which occurs in arsenolite above 15 GPa, is impeded in A s4O6.2 He , thus resulting in a mechanical stability of A s4O6.2 He beyond 30 GPa. Our work paves the way to explore the formation of alternative compounds by pressure-induced trapping and reaction of gases, small atomic or molecular species, in the voids of molecular solids containing active lone electron pairs.

  6. Nuclear Reaction Analysis of Helium Retention in 6H SiC as a function of irradiation and annealing

    NASA Astrophysics Data System (ADS)

    Bissell, L. J.; Smith, R. J.; Shutthanadan, V.; Adams, E. M.; Thevuthasan, S.; Jiang, W.; Weber, W. J.; Zhang, Y.

    2002-10-01

    Silicon carbide has been proposed as a coating material in nuclear fuel, and silicon carbide composites have been proposed as cladding material in advanced gas-cooled and light water reactors. As such, the effects of irradiation and fission gases on the performance of SiC in the reactor environment are critical in several ways. Since He serves as a fission gas, low-energy He (< 50 keV) will be colliding with coolant gas and outer surface cladding layers. As such, it is important to understand He retention in SiC under advanced reactor operating conditions. We investigated He retention in single crystal 6H SiC as a function of irradiation dose and annealing temperature using nuclear reaction analysis (NRA) via the 3He(D,alpha)1H reaction. Helium ions with 40 keV energy were implanted in the SiC to a depth of ˜360 nm at room temperature under high vacuum conditions. The samples were then transferred to another high vacuum chamber where the NRA was performed using a 1.0 MeV D+ beam. Helium retention was studied as a function of D+ irradiation dose from 5 x 10^(16) to 4 x 10^(18) D+ /cm2, and as a function of annealing temperature ranging from 300 1600 K. No significant helium loss was observed under this dosage range, and only annealing temperatures above 1400 K caused measurable loss of helium. These results will be discussed along with the details associated with the 3He(D,alpha)1H nuclear reaction.

  7. Effect of initial-state target polarization on the single ionization of helium by 1-keV electron impact

    NASA Astrophysics Data System (ADS)

    Sun, Shi-Yan; Ma, Xiao-Yan; Li, Xia; Miao, Xiang-Yang; Jia, Xiang-Fu

    2012-07-01

    We report new results of triple differential cross sections for the single ionization of helium by 1-KeV electron impact at the ejection energy of 10 eV. Investigations have been made for both the perpendicular plane and the plane perpendicular to the momentum transfer geometries. The present calculation is based on the three-Coulomb wave function. Here we have also incorporated the effect of target polarization in the initial state. A comparison is made between the present calculation with the results of other theoretical methods and a recent experiment [Dürr M, Dimopoulou C, Najjari B, Dorn A, Bartschat K, Bray I, Fursa D V, Chen Z, Madison D H and Ullrich J 2008 Phys. Rev. A 77 032717]. At an impact energy of 1 KeV, the target polarization is found to induce a substantial change of the cross section for the ionization process. We observe that the effect of target polarization plays a dominant role in deciding the shape of triple differential cross sections.

  8. Elastic recoil cross section determination of deuterium by helium-4 ions at 30° with the energy range of 2.6-7.4 MeV

    NASA Astrophysics Data System (ADS)

    Han, Zhibin; Hao, Wanli; Wang, Chunjie; Shi, Liqun

    2016-05-01

    The elastic recoil cross section for D(4He, D) 4He was determined at a recoil angle of 30° over an incident helium energy range from 2.6 to 7.4 MeV. A thin solid target Ta/TiDx/Si used for cross section measurement was prepared by direct current magnetron sputtering, and it was so stable to ion beam bombardment that nearly no deuterium loss (less than 0.2%) exists over the whole experiment. A relative determination method is adopted in this measurement. It can avoid the error from the beam dose and the solid angle of the detectors and it is also free to direct measurement of D content in the film. The total uncertainty in the cross section determination is less than 5%.

  9. Efficient charge-breeding of helium-6 in an EBIT for precision measurement of the beta-neutrino correlation

    SciTech Connect

    Schmidt, M.; Hass, M.; Rappaport, M. L.; Heber, O.; Prygarin, A.; Shachar, Y.; Vaintraub, S.; Zschornack, G.

    2015-01-09

    The precise determination of the beta-neutrino correlation in the decay of radioactive nuclei is an important tool in the effort to probe fundamental interactions for possible deviation from the Standard Model of particles and fields. In order to realize this, a novel scheme for precision measurement of such correlation in the decay of radioactive helium-6 (half-life 0.8 s) using an electrostatic ion beam trap (EIBT) is being constructed at the Weizmann Institute. Efficient ionization of the expected weak flux of helium-6, together with a bunching characteristic suitable for injection into the EIBT, is thereby essential. Both of these requirements are optimally met by an electron beam ion source/trap (EBIT). In this contribution we present the design of a modified DREEBIT (Dresden EBIT) featuring a direct, nearly closed gas intake into the drift tube assembly for maximum trapping and ionization efficiency for low flux rates, without diminishing the bunching phase space of the EBIT. First tests already indicate significant ion production at a minimal gas flow rate observable by a marginal pressure increase that is close to the detection limit of a Leybold extractor gauge located in close proximity to the drift tube assembly. This is a necessary precondition in order to exploit even tiny amounts of rare isotopes.

  10. 6. VIEW, LOOKING SOUTHEAST, SHOWING DETAIL OF RANGE 1 TARGET ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    6. VIEW, LOOKING SOUTHEAST, SHOWING DETAIL OF RANGE 1 TARGET END, Interior - Winchester Repeating Arms Company, Tract K Shooting Range, 125 Munson Street (rear section), New Haven, New Haven County, CT

  11. Targeting interleukin-6 in inflammatory autoimmune diseases and cancers.

    PubMed

    Yao, Xin; Huang, Jiaqi; Zhong, Haihong; Shen, Nan; Faggioni, Raffaella; Fung, Michael; Yao, Yihong

    2014-02-01

    Interleukin-6 (IL-6) is a pleiotropic cytokine with significant functions in the regulation of the immune system. As a potent pro-inflammatory cytokine, IL-6 plays a pivotal role in host defense against pathogens and acute stress. However, increased or deregulated expression of IL-6 significantly contributes to the pathogenesis of various human diseases. Numerous preclinical and clinical studies have revealed the pathological roles of the IL-6 pathway in inflammation, autoimmunity, and cancer. Based on the rich body of studies on biological activities of IL-6 and its pathological roles, therapeutic strategies targeting the IL-6 pathway are in development for cancers, inflammatory and autoimmune diseases. Several anti-IL-6/IL-6 receptor monoclonal antibodies developed for targeted therapy have demonstrated promising results in both preclinical studies and clinical trials. Tocilizumab, an anti-IL-6 receptor antibody, is effective in the treatment of various autoimmune and inflammatory conditions notably rheumatoid arthritis. It is the only IL-6 pathway targeting agent approved by the regulatory agencies for clinical use. Siltuximab, an anti-IL-6 antibody, has been shown to have potential benefits treating various human cancers either as a single agent or in combination with other chemotherapy drugs. Several other anti-IL-6-based therapies are also under clinical development for various diseases. IL-6 antagonism has been shown to be a potential therapy for these disorders refractory to conventional drugs. New strategies, such as combination of IL-6 blockade with inhibition of other signaling pathways, may further improve IL-6-targeted immunotherapy of human diseases. PMID:24076269

  12. Converged cross-section results for double photoionization of helium atoms in hyperspherical partial wave theory at 6 eV above threshold

    SciTech Connect

    Das, J.N.; Paul, S.; Chakrabarti, K.

    2004-04-01

    Here we report a set of converged cross-section results for double photoionization of helium atoms obtained in the hyperspherical partial wave theory for equal energy sharing kinematics at 6 eV energy above threshold. The calculated cross section results are generally in excellent agreement with the absolute measured results of Doerner et al. [Phys. Rev. 57, 1074 (1998)].

  13. Domain definition and target classification for CASP6.

    PubMed

    Tress, Michael; Tai, Chin-Hsien; Wang, Guoli; Ezkurdia, Iakes; López, Gonzalo; Valencia, Alfonso; Lee, Byungkook; Dunbrack, Roland L

    2005-01-01

    Assessment of structure predictions in CASP6 was based on single domains isolated from experimentally determined structures, which were categorized into comparative modeling, fold recognition, and new fold targets. Domain definitions were defined upon visual examination of the structures with the aid of automated domain-parsing programs. Domain categorization was determined by comparison of the target structures with those in the Protein Data Bank at the time each target expired and a variety of sequence and structure-based methods to determine potential homologous relationships. PMID:16187342

  14. Proton-helium correlation in 94 MeV/nucleon sup 16 O-induced reactions on Al, Ni, and Au targets

    SciTech Connect

    Badala, A.; Barbera, R.; Palmeri, A.; Pappalardo, G.S. ); Riggi, F. ); Bizard, G.; Durand, D.; Laville, J.L. )

    1992-04-01

    Azimuthal distributions of helium ions have been measured in coincidence with high-energy protons in reactions induced by {sup 16}O at 94 MeV/nucleon on {sup 27}Al, {sup 58}Ni, and {sup 197}Au. Helium ions have been detected in a large area multidetector. Protons have been observed at 90{degree}. Mean multiplicities of light charged particles (H and He) are found slightly dependent on the target mass. Strong azimuthal asymmetries whose intensity is larger for the Al target and vanishes with the increasing of the target mass are observed in the He distributions. Experimental data are discussed in the framework of the participant-spectator picture of a modified fireball model, taking into account intermediate energy corrections. In this framework the behavior of the azimuthal asymmetries, as a function of the target mass, indicates a strong final-state interaction between participant and spectator fragments. Such a result is found in agreement with interaction time predictions of a microscopical calculation based on the Boltzmann-Nordheim-Vlasov equation.

  15. Thrombospondin-1 is a transcriptional repression target of PRMT6.

    PubMed

    Michaud-Levesque, Jonathan; Richard, Stéphane

    2009-08-01

    Protein arginine methyltransferase 6 (PRMT6) is known to catalyze the generation of asymmetric dimethylarginine in polypeptides. Although the cellular role of PRMT6 is not well understood, it has been implicated in human immunodeficiency virus pathogenesis, DNA repair, and transcriptional regulation. PRMT6 is known to methylate histone H3 Arg-2 (H3R2), and this negatively regulates the lysine methylation of H3K4 resulting in gene repression. To identify in a nonbiased manner genes regulated by PRMT6 expression, we performed a microarray analysis on U2OS osteosarcoma cells transfected with control and PRMT6 small interfering RNAs. We identified thrombospondin-1 (TSP-1), a potent natural inhibitor of angiogenesis, as a transcriptional repression target of PRMT6. Moreover, we show that PRMT6-deficient U2OS cells exhibited cell migration defects that were rescued by blocking the secreted TSP-1 with a neutralizing peptide or blocking alpha-TSP-1 antibody. PRMT6 associates with the TSP-1 promoter and regulates the balance of methylation of H3R2 and H3K4, such that in PRMT6-deficient cells H3R2 was hypomethylated and H3K4 was trimethylated at the TSP-1 promoter. Using a TSP-1 promoter reporter gene, we further show that PRMT6 directly regulates the TSP-1 promoter activity. These findings show that TSP-1 is a transcriptional repression target of PRMT6 and suggest that neutralizing the activity of PRMT6 could inhibit tumor progression and therefore may be of cancer therapeutic significance. PMID:19509293

  16. Mouse Elovl-6 promoter is an SREBP target

    SciTech Connect

    Kumadaki, Shin; Matsuzaka, Takashi; Kato, Toyonori; Yahagi, Naoya; Yamamoto, Takashi; Okada, Sumiyo; Kobayashi, Kazuto; Takahashi, Akimitsu; Yatoh, Shigeru; Suzuki, Hiroaki; Yamada, Nobuhiro; Shimano, Hitoshi

    2008-04-04

    Elovl-6, a long fatty acid elongase, contributes to de novo synthesis of fatty acids and regulates hepatic insulin sensitivity. Hepatic regulation of Elovl-6 gene expression in various nutritional conditions suggested that, like other lipogenic enzyme genes, Elovl-6 is a target of SREBP-1, a transcription factor governing fatty acid synthesis. Supportively, adenoviral RNAi knockdown of SREBP-1 in mouse liver suppressed Elovl-6 mRNA and fatty acid synthase levels. Therefore, we analyzed mouse Elovl-6 gene promoter to determine its role as an SREBP-1 target. Luciferase reporter assays of 1.4-kb 5' flanking region of mouse Elovl-6 gene in HepG2 cells demonstrated that nuclear SREBPs activated the Elovl-6 promoter, highlighting two SREBP binding sites: proximal SRE-1 and distal SRE-2. EMSA indicated that SRE-1 had higher affinity than SRE-2 for SREBP. ChIP assays confirmed in vivo binding of hepatic nuclear SREBP-1c protein. These data demonstrated that Elovl-6 is regulated directly and primarily by SREBP-1c.

  17. Development of AN Active 238UF6 Gas Target

    NASA Astrophysics Data System (ADS)

    Eckardt, C.; Enders, J.; Freudenberger, M.; Göök, A.; von Neumann-Cosel, P.; Oberstedt, A.; Oberstedt, S.

    2014-09-01

    Detailed studies of the fission process, e.g., the search for parity nonconservation (PNC) effects, the energy dependence of fission modes or the population of fission isomers, depend on high quality data, therefore requiring high luminosities. An active gas target containing uranium may overcome the deterioration of energy and angular resolution caused by large solid target thicknesses. A single Frisch-grid ionization chamber has been built to test a mixture of standard counting gases (e.g., argon) with depleted uranium hexafluoride (238UF6), utilizing a triple alpha source to evaluate signal quality and drift velocity. For mass fractions of up to 4 percent of 238U the drift velocity increases with rising UF6 content, while a good signal quality and energy resolution is preserved.

  18. Nuclear and nucleolar targeting of human ribosomal protein S6.

    PubMed Central

    Schmidt, C; Lipsius, E; Kruppa, J

    1995-01-01

    Chimeric proteins were constructed to define the nuclear localization signals (NLSs) of human ribosomal protein S6. The complete cDNA sequence, different cDNA fragments and oligonucleotides of the human ribosomal proteins S6, respectively, were joined to the 5' end of the entire LacZ gene of Escherichia coli by using recombinant techniques. The hybrid genes were transfected into L cells, transiently expressed, and the intracellular location of the fusion proteins was determined by their beta-galactosidase activity. Three NLSs were identified in the C-terminal half of the S6 protein. Deletion mutagenesis demonstrated that a single NLS is sufficient for targeting the corresponding S6-beta-galactosidase chimera into the nucleus. Removal of all three putative NLSs completely blocked the nuclear import of the resulting S6-beta-galactosidase fusion protein, which instead became evenly distributed in the cytoplasm. Chimeras containing deletion mutants of S6 with at least one single NLS or unmodified S6 accumulated in the nucleolus. Analysis of several constructs reveals the existence of a specific domain that is essential but not sufficient for nucleolar accumulation of S6. Images PMID:8590812

  19. The Serotonin-6 Receptor as a Novel Therapeutic Target

    PubMed Central

    Yun, Hyung-Mun

    2011-01-01

    Serotonin (5-hydroxytryptamine, 5-HT) is an important neurotransmitter that is found in both the central and peripheral nervous systems. 5-HT mediates its diverse physiological responses through 7 different 5-HT receptor families: 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6, and 5-HT7 receptors. Among them, the 5-HT6 receptor (5-HT6R) is the most recently cloned serotonin receptor and plays important roles in the central nervous system (CNS) and in the etiology of neurological diseases. Compared to other 5-HT receptors, the 5-HT6R has been considered as an attractive CNS therapeutic target because it is expressed exclusively in the CNS and has no known isoforms. This review evaluates in detail the role of the 5-HT6R in the physiology and pathophysiology of the CNS and the potential usefulness of 5-HT6R ligands in the development of therapeutic strategies for the treatment of CNS disorders. Preclinical studies provide support for the use of 5-HT6R ligands as promising medications to treat the cognitive dysfunction associated with Alzheimer's disease, obesity, depression, and anxiety. PMID:22355260

  20. Targeting CDK4/6 in patients with cancer.

    PubMed

    Hamilton, Erika; Infante, Jeffrey R

    2016-04-01

    The cyclin D-cyclin dependent kinase (CDK) 4/6-inhibitor of CDK4 (INK4)-retinoblastoma (Rb) pathway controls cell cycle progression by regulating the G1-S checkpoint. Dysregulation of the cyclin D-CDK4/6-INK4-Rb pathway results in increased proliferation, and is frequently observed in many types of cancer. Pathway activation can occur through a variety of mechanisms, including gene amplification or rearrangement, loss of negative regulators, epigenetic alterations, and point mutations in key pathway components. Due to the importance of CDK4/6 activity in cancer cells, CDK4/6 inhibitors have emerged as promising candidates for cancer treatment. Moreover, combination of a CDK4/6 inhibitor with other targeted therapies may help overcome acquired or de novo treatment resistance. Ongoing studies include combinations of CDK4/6 inhibitors with endocrine therapy and phosphatidylinositol 3-kinase (PI3K) pathway inhibitors for hormone receptor-positive (HR+) breast cancers, and with selective RAF and MEK inhibitors for tumors with alterations in the mitogen activated protein kinase (MAPK) pathway such as melanoma. In particular, the combination of CDK4/6 inhibitors with endocrine therapy, such as palbociclib's recent first-line approval in combination with letrozole, is expected to transform the treatment of HR+ breast cancer. Currently, three selective CDK4/6 inhibitors have been approved or are in late-stage development: palbociclib (PD-0332991), ribociclib (LEE011), and abemaciclib (LY2835219). Here we describe the current preclinical and clinical data for these novel agents and discuss combination strategies with other agents for the treatment of cancer. PMID:27017286

  1. ABCC6 as a target in Pseudoxanthoma Elasticum

    PubMed Central

    Váradi, András; Szabó, Zalán; Pomozi, Viola; de Boussac, Hugues; Fülöp, Krisztina; Arányi, Tamás

    2012-01-01

    The ABCC6 gene encodes an organic anion transporter protein, ABCC6/MRP6. Mutations in the gene cause a rare, recessive genetic disease, pseudoxanthoma elasticum, while the loss of one ABCC6 allele is a genetic risk factor in coronary artery disease. We review here the information available on gene structure, evolution as well as the present knowledge on its transcriptional regulation. We give a detailed description of the characteristics of the protein, and analyze the relationship between the distributions of missense disease–causing mutations in the predicted three-dimensional structure of the transporter, which suggests functional importance of the domain-domain interactions. Though neither the physiological function of the protein nor its role in the pathobiology of the diseases are known, a current hypothesis that ABCC6 may be involved in the efflux of one form of Vitamin K from the liver is discussed. Finally, we analyze potential strategies how the gene can be targeted on the transcriptional level to increase protein expression in order to compensate for reduced activity. In addition, pharmacologic correction of trafficking-defect mutants or suppression of stop codon mutations as potential future therapeutic interventions are also reviewed. PMID:21039331

  2. Development of an Active 238UF6 Gas Target

    NASA Astrophysics Data System (ADS)

    Eckardt, C.; Enders, J.; Freudenberger, M.; Gook, A.; von Neumann-Cosel, P.; Oberstedt, A.; Oberstedt, S.

    At the superconducting 130 MeV Darmstadt electron linac S-DALINAC a new source of spin-polarized electrons using a GaAs cathode has been installed, opening the path for experiments with polarized electron and photon beams for nuclear structure studies at low momentum transfers, e.g., the search for forward-backward asymmetries originating from parity non-conservation (PNC) in the photon-induced fission process of 238U.Detailed studies of different properties, e.g., the energy dependence of fission modes, the population of fission isomers, or the search for (PNC) effects in the photon-induced fission process of 238U, depends on high quality data, therefore needing high luminosities. An active gas target containing uranium may overcome the problem that large solid target thicknesses cause poor energy and angular resolution.A single Frisch-grid ionization chamber has been built to test a mixture of standard counting gases (e.g., argon) with depleted uraniumhexafluoride (238UF6) using a triple alpha source, evaluating signal quality and drift velocity. For mass fractions up to 2 percent of 238U in the counting gas. The drift velocity increases with rising UF6 content, while a good signal quality and energy resolution is preserved.

  3. The Collection 6 'dark-target' MODIS Aerosol Products

    NASA Technical Reports Server (NTRS)

    Levy, Robert C.; Mattoo, Shana; Munchak, Leigh A.; Kleidman, Richard G.; Patadia, Falguni; Gupta, Pawan; Remer, Lorraine

    2013-01-01

    Aerosol retrieval algorithms are applied to Moderate resolution Imaging Spectroradiometer (MODIS) sensors on both Terra and Aqua, creating two streams of decade-plus aerosol information. Products of aerosol optical depth (AOD) and aerosol size are used for many applications, but the primary concern is that these global products are comprehensive and consistent enough for use in climate studies. One of our major customers is the international modeling comparison study known as AEROCOM, which relies on the MODIS data as a benchmark. In order to keep up with the needs of AEROCOM and other MODIS data users, while utilizing new science and tools, we have improved the algorithms and products. The code, and the associated products, will be known as Collection 6 (C6). While not a major overhaul from the previous Collection 5 (C5) version, there are enough changes that there are significant impacts to the products and their interpretation. In its entirety, the C6 algorithm is comprised of three sub-algorithms for retrieving aerosol properties over different surfaces: These include the dark-target DT algorithms to retrieve over (1) ocean and (2) vegetated-dark-soiled land, plus the (3) Deep Blue (DB) algorithm, originally developed to retrieve over desert-arid land. Focusing on the two DT algorithms, we have updated assumptions for central wavelengths, Rayleigh optical depths and gas (H2O, O3, CO2, etc.) absorption corrections, while relaxing the solar zenith angle limit (up to 84) to increase pole-ward coverage. For DT-land, we have updated the cloud mask to allow heavy smoke retrievals, fine-tuned the assignments for aerosol type as function of season location, corrected bugs in the Quality Assurance (QA) logic, and added diagnostic parameters such as topographic altitude. For DT-ocean, improvements include a revised cloud mask for thin-cirrus detection, inclusion of wind speed dependence in the retrieval, updates to logic of QA Confidence flag (QAC) assignment, and

  4. 21 CFR 582.1355 - Helium.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Helium. 582.1355 Section 582.1355 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS... Helium. (a) Product. Helium. (b) Conditions of use. This substance is generally recognized as safe...

  5. 21 CFR 582.1355 - Helium.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 6 2011-04-01 2011-04-01 false Helium. 582.1355 Section 582.1355 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS... Helium. (a) Product. Helium. (b) Conditions of use. This substance is generally recognized as safe...

  6. 21 CFR 582.1355 - Helium.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 6 2013-04-01 2013-04-01 false Helium. 582.1355 Section 582.1355 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS... Helium. (a) Product. Helium. (b) Conditions of use. This substance is generally recognized as safe...

  7. 21 CFR 582.1355 - Helium.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 6 2014-04-01 2014-04-01 false Helium. 582.1355 Section 582.1355 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS... Helium. (a) Product. Helium. (b) Conditions of use. This substance is generally recognized as safe...

  8. 21 CFR 582.1355 - Helium.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 6 2012-04-01 2012-04-01 false Helium. 582.1355 Section 582.1355 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS... Helium. (a) Product. Helium. (b) Conditions of use. This substance is generally recognized as safe...

  9. Helium Atom Scattering from C2H6, F2HCCH3, F3CCH2F and C2F6 in Crossed Molecular Beams

    NASA Astrophysics Data System (ADS)

    Hammer, Markus; Seidel, Wolfhart

    1997-10-01

    Rotationally unresolved differential cross sections were measured in crossed molecular beam experiments by scattering Helium atoms from Ethane, 1,1-Difluoroethane, 1,1,1,2-Tetrafluoroethane and Hexafluoroethane. The damping of observed diffraction oscillations was used to extract anisotropic interaction potentials for these scattering systems applying the infinite order sudden approximation (IOSA). Binary macroscopic parameters such as second heterogeneous virial coefficients and the coefficients of diffusion and viscosity were computed from these potentials and compared to results from macroscopic experiments.

  10. Plasmodium falciparum glucose-6-phosphate dehydrogenase 6-phosphogluconolactonase is a potential drug target.

    PubMed

    Allen, Stacey M; Lim, Erin E; Jortzik, Esther; Preuss, Janina; Chua, Hwa Huat; MacRae, James I; Rahlfs, Stefan; Haeussler, Kristina; Downton, Matthew T; McConville, Malcolm J; Becker, Katja; Ralph, Stuart A

    2015-10-01

    The malarial parasite Plasmodium falciparum is exposed to substantial redox challenges during its complex life cycle. In intraerythrocytic parasites, haemoglobin breakdown is a major source of reactive oxygen species. Deficiencies in human glucose-6-phosphate dehydrogenase, the initial enzyme in the pentose phosphate pathway (PPP), lead to a disturbed redox equilibrium in infected erythrocytes and partial protection against severe malaria. In P. falciparum, the first two reactions of the PPP are catalysed by the bifunctional enzyme glucose-6-phosphate dehydrogenase 6-phosphogluconolactonase (PfGluPho). This enzyme differs structurally from its human counterparts and represents a potential target for drugs. In the present study we used epitope tagging of endogenous PfGluPho to verify that the enzyme localises to the parasite cytosol. Furthermore, attempted double crossover disruption of the PfGluPho gene indicates that the enzyme is essential for the growth of blood stage parasites. As a further step towards targeting PfGluPho pharmacologically, ellagic acid was characterised as a potent PfGluPho inhibitor with an IC50 of 76 nM. Interestingly, pro-oxidative drugs or treatment of the parasites with H2O2 only slightly altered PfGluPho expression or activity under the conditions tested. Furthermore, metabolic profiling suggested that pro-oxidative drugs do not significantly perturb the abundance of PPP intermediates. These data indicate that PfGluPho is essential in asexual parasites, but that the oxidative arm of the PPP is not strongly regulated in response to oxidative challenge. PMID:26198663

  11. Description and operating performance of a parallel-rail electric-arc system with helium driver gas for the Langley 6-inch expansion tube

    NASA Technical Reports Server (NTRS)

    Moore, J. A.

    1976-01-01

    A parallel-rail arc-discharge system to heat and pressurize the initial helium driver gas of the Langley 6-inch expansion tube is described. This system was designed for a 2.44-m-long driver vessel rated at 138 MPa, with a distance between rails of 20.3 cm. Electric energy was obtained from a capacitor storage system rated at 12,000 V with a maximum energy of 5 MJ. Tests were performed over a range of energy from 1.74 MJ to the maximum value. The operating experience and system performance are discussed, along with results from a limited number of expansion-tube tests with air and carbon dioxide as test gases.

  12. Liquid helium cryostat with internal fluorescence detection for x-ray absorption studies in the 2-6 keV energy region

    NASA Astrophysics Data System (ADS)

    McFarlane Holman, Karen L.; Latimer, Matthew J.; Yachandra, Vittal K.

    2004-06-01

    X-ray absorption spectroscopy (XAS) in the intermediate x-ray region (2-6 keV) for dilute biological samples has been limited because of detector/flux limitations and inadequate cryogenic instrumentation. We have designed and constructed a new tailpiece/sample chamber for a commercially available liquid helium cooled cryostat which overcomes difficulties related to low fluorescence signals by using thin window materials and incorporating an internal photodiode detector. With the apparatus, XAS data at the Cl, S, and Ca K edges have been collected on frozen solutions and biological samples at temperatures down to 60 K. A separate chamber has been incorporated for collecting room-temperature spectra of standard compounds (for energy calibration purposes) which prevents contamination of the cryostat chamber and allows the sample to remain undisturbed, both important concerns for studying dilute and radiation-sensitive samples.

  13. Shock shapes on blunt bodies in hypersonic-hypervelocity helium, air, and CO2 flows, and calibration results in Langley 6-inch expansion tube

    NASA Technical Reports Server (NTRS)

    Miller, C. G., III

    1975-01-01

    Shock shape results for flat-faced cylinders, spheres, and spherically blunted cones in various test gases, along with preliminary results from a calibration study performed in the Langley 6-inch expansion tube are presented. Free-stream velocities from 5 to 7 km/sec are generated at hypersonic conditions with helium, air, and CO2, resulting in normal shock density ratios from 4 to 19. Ideal-gas shock shape predictions, in which an effective ratio of specific heats is used as input, are compared with the measured results. The effect of model diameter is examined to provide insight to the thermochemical state of the flow in the shock layer. The regime for which equilibrium exists in the shock layer for the present air and CO2 test conditions is defined. Test core flow quality, test repeatability, and comparison of measured and predicted expansion-tube flow quantities are discussed.

  14. Design of oil-free simple turbo type 65 K/6 KW helium and neon mixture gas refrigerator for high temperature superconducting power cable cooling

    NASA Astrophysics Data System (ADS)

    Saji, N.; Asakura, H.; Yoshinaga, S.; Ishizawa, T.; Miyake, A.; Obata, M.; Nagaya, S.

    2002-05-01

    For the requirement of HTS facility cooling, we propose oil-free simple turbo-type refrigerator. The working gas is a helium and neon mixture. Two single-stage turbo compressors and two expansion turbines are applied to the cycle. The rotor consists of the compressor impeller, turbine impeller and driving motor, and is supported by foil type gas bearing. The refrigerator requires two rotating machines with excellent reliability and compactness, and the motor power required is 72.5 kW for a refrigeration load of 6 kW. For the cooling of power cable, sub-cooled pressurized liquid nitrogen and a circulation pump must be provided. If the estimated distance between inter-cooling stations is quite long, for example 5 km, plural refrigerators may be set up on one cooling station.

  15. Interleukin-6: a multifunctional targetable cytokine in human prostate cancer.

    PubMed

    Culig, Zoran; Puhr, Martin

    2012-09-01

    Several cytokines are involved in regulation of cellular events in prostate cancer. Interleukin-6 (IL-6) was frequently investigated in prostate cancer models because of its increased expression in cancer tissue at early stages of the disease. In patients with metastatic prostate cancer, it is well-known that IL-6 levels increase in serum. High levels of IL-6 were measured in the supernatants of cells which do not respond to androgenic stimulation. IL-6 expression in prostate cancer increases due to enhanced expression of transforming growth factor-beta, and members of the activating protein-1 complex, and loss of the retinoblastoma tumour suppressor. IL-6 activation of androgen receptor (AR) may contribute to progression of a subgroup of prostate cancers. Results obtained with two prostate cancer cell lines, LNCaP and MDA PCa 2b, indicate that IL-6 activation of AR may cause either stimulatory or inhibitory responses on proliferation. Interestingly, prolonged treatment with IL-6 led to establishment of an IL-6 autocrine loop, suppressed signal transducer and activator of transcription (STAT)3 activation, and increased mitogen-activated protein kinase phosphorylation. In several cell lines IL-6 acts as a survival molecule through activation of the signalling pathway of phosphotidylinositol 3-kinase. Expression of suppressors of cytokine signalling (SOCS) has been studied in prostate cancer. SOCS-3 prevents phosphorylation of STAT3 and is an important anti-apoptotic factor in AR-negative prostate cancer cells. Experimental therapy against IL-6 in prostate cancer is based on the use of the monoclonal antibody siltuximab which may be used for personalised therapy coming in the future. PMID:21664423

  16. Helium-3 emission related to volcanic activity

    SciTech Connect

    Sano, Y.; Nakamura, Y.; Wakita, H.; Urabe, A.; Tominaga, T.

    1984-04-13

    The helium-3/helium-4 ratio in bubbling gases from ten hot springs located around Mount Ontake, an active volcano in central Japan, ranges from 1.71 R/sub atm/ (1.71 times the atmospheric ratio of 1.40 x 10/sup -6/) to 6.15 R/sub atm/. The value of the ratio decreases with distance from the central cone of the volcano. Such a tendency may be a characteristic of helium-3 emission in volcanic areas and suggests more primitive helium-3 is carried with fluid flowing through a conduit during volcanic activity. 6 references, 1 figure, 1 table.

  17. Estimate of interstellar helium parameters from Prognoz 6 and Voyager 1/2 - EUV resonance glow measurements taking into account a possible redshift in the solar line profile

    NASA Astrophysics Data System (ADS)

    Chassefiere, E.; Dalaudier, F.; Bertaux, J. L.

    1988-07-01

    Voyager 1 and 2 observations at 58.4 nm are used to reanalyze the He I 58.4 nm interplanetary resonance glow measurements made by two EUV photometers aboard Prognoz 6. It is shown that model fitting using a low temperature (7000 + or - 2000 K) and velocity (21.5 + or - 2.5 km/s) resolves several contradictions concerning the physics of the coupling between neutrals and protons at the heliopause and the comparison with independent measurements of the solar line width. New solar parameter values of 36 + or - 6 km/s for the solar line half width at 1/e, 9 + or - 3 km/s for the redshift of the solar line, and 1.4 (+ 0.6 - 0.3) x 10 to the 7th for the lifetime are proposed. It is pointed out that if the redshift assumption is valid, a weak differentiation between helium and hydrogen at the heliospheric interface is implied.

  18. The BIRC6 gene as a novel target for therapy of prostate cancer: dual targeting of inhibitors of apoptosis

    PubMed Central

    Iris Luk, Sze Ue; Xue, Hui; Cheng, Hongwei; Lin, Dong; Gout, Peter W.; Fazli, Ladan; Collins, Colin C.; Gleave, Martin E.; Wang, Yuzhuo

    2014-01-01

    Treatment resistance, the major challenge in the management of advanced prostate cancer, is in part based on resistance to apoptosis. The Inhibitor of Apoptosis (IAP) protein family is thought to play key roles in survival and drug resistance of cancer via inhibition of apoptosis. Of the IAP family members, cIAP1, cIAP2, XIAP and survivin are known to be up-regulated in prostate cancer. BIRC6, a much less studied IAP member, was recently shown to be elevated in castration-resistant prostate cancer (CRPC). In the present study, we showed a correlation between elevated BIRC6 expression in clinical prostate cancer specimens and poor patient prognostic factors, as well as co-upregulation of certain IAP members. In view of this, we designed antisense oligonucleotides that simultaneously target BIRC6 and another co-upregulated IAP member (dASOs). Two dASOs, targeting BIRC6+cIAP1 and BIRC6+survivin, showed substantial inhibition of CRPC cell proliferation, exceeding that obtained with single BIRC6 targeting. The growth inhibition was associated with increased apoptosis, cell cycle arrest and suppression of NFkB activation. Moreover, treatment with either dASO led to significantly lower viable tumor volume in vivo, without major host toxicity. This study shows that BIRC6-based dual IAP-targeting ASOs represent potential novel therapeutic agents against advanced prostate cancer. PMID:25071009

  19. Deactivation of xenon atoms in the 6s resonant state in collisions with xenon and helium atoms

    SciTech Connect

    Zayarnyi, D A; Semenova, Ludmila V; Ustinovskii, N N; Kholin, I V; Chugunov, A Yu

    1999-02-28

    The absorption probing method was used to investigate collisional deactivation of the 6s[3/2]{sub 1}{sup 0}({sup 3}P{sub 1}) state of the xenon atom in high-pressure He - Xe mixtures with a low xenon concentration. Measurements were made of the rate constants of the following plasma-chemical reactions: Xe* + Xe + He {yields} Xe{sub 2}* + He [(2.1 {+-} 0.2) x 10{sup -32} cm{sup 6}s{sup -1}], Xe* + 2He {yields} HeXe* + He (less than 10{sup -35} cm{sup 6}s{sup -1}), and Xe* + He {yields} products + He (less than 3 x 10{sup -15} cm{sup 3}s{sup -1}). (active media)

  20. Single-electron-capture processes in collisions of He{sup 2+}, Li{sup q+} (q=1,2,3), C{sup 6+}, and O{sup 8+} ions with helium

    SciTech Connect

    Samanta, R.; Purkait, M.; Mandal, C. R.

    2011-03-15

    Cross sections for single-electron capture in collisions of He{sup 2+}, Li{sup q+} (q = 1,2,3), C{sup 6+}, and O{sup 8+} ions with helium atoms at incident energy ranging from 50 to 5000 keV/amu have been calculated in the framework of four-body boundary-corrected continuum intermediate state (BCCIS-4B) approximation in both prior and post forms. In this formalism, distortion in the final channel related to the Coulomb continuum states of the projectile ion and the active electron in the field of residual target ion are included. In all cases, total single-electron-capture cross sections have been calculated by summing over all contributions up to n = 3 shells and subshells, respectively. It has been observed that the contribution of the capture cross section into the excited states is significant for asymmetric collision (Z{sub P}>Z{sub T}) and is insignificant for symmetric collision. Numerical results for the total cross sections show good agreement with the available experimental findings, particularly in the post form. Post-prior discrepancy has been found to be within 30% except for Li{sup +} + He interactions below 150 keV/amu.

  1. Emerging Role and Targeting of Carcinoembryonic Antigen-related Cell Adhesion Molecule 6 (CEACAM6) in Human Malignancies

    PubMed Central

    Johnson, Benny; Mahadevan, Daruka

    2015-01-01

    Background: Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) is a member of the CEA family of cell adhesion proteins that belong to the immunoglobulin superfamily. CEACAM6 is normally expressed on the surface of myeloid (CD66c) and epithelial surfaces. Stiochiomertic expression of members of the CEA family (CEACAM1, 5, 6, 7) on epithelia maintains normal tissue architecture through homo-and hetero-philic interactions. Dysregulated over-expression of CEACAM6 is oncogenic, is associated with anoikis resistance and an invasive phenotype mediated by excessive TGFβ, AKT, FAK and SRC signaling in human malignancies. Methods: Extensive literature review through PubMed was conducted to identify relevant preclinical and clinical research publications regarding CEACAM6 over the last decade and was summarized in this manuscript. Results: CEACAM5 and 6 are over-expressed in nearly 70% of epithelial malignancies including colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDA), hepatobiliary, gastric, breast, non-small cell lung and head/neck cancers. Importantly, CEACAM6 is a poor prognostic marker in CRC, while its expression correlates with tumor stage, metastasis and post-operative survival in PDA. CEACAM6 appears to be an immune checkpoint suppressor in hematologic malignancies including acute lymphoblastic leukemia and multiple myeloma. Several therapeutic monoclonal antibodies or antibody fragments targeting CEACAM6 have been designed and developed as a targeted therapy for human malignancies. A Llama antibody targeting CEACAM6 is being evaluated in early phase clinical trials. Conclusion: This review focuses on the role of CEACAM6 in the pathogenesis and signaling of the malignant phenotype in solid and hematologic malignancies and highlights its potential as a therapeutic target for anti-cancer therapy.

  2. Experimental location of helium atoms in 6H-SiC crystal lattice after implantation and after annealing at 400 °C

    NASA Astrophysics Data System (ADS)

    Linez, F.; Garrido, F.; Erramli, H.; Sauvage, T.; Courtois, B.; Desgardin, P.; Barthe, M.-F.

    2015-04-01

    The question of the helium behavior in silicon carbide has been studied at the atomic scale by numerical simulations, but no experiment has been carried out to assess the results hitherto. This paper describes the first experiments allowing this comparison. 6H-SiC single crystals were implanted with 50-keV He ions at a fluence of 1015 He/cm2 at room temperature. The as-received and as-implanted samples were analyzed by RBS and NRA in channeling mode along the main crystallographic planes and across three main axes. The measurements have shown that a portion of the He is located in the interstitial tetrahedral sites as predicted by the numerical simulations. The same measurements were performed on an implanted sample subsequently annealed at 400 °C under Ar atmosphere. They have shown that the quantity of He detected in interstitial tetrahedral sites TSi and TC has not significantly changed whereas that of He detected in the main crystallographic plane and in the main axis has increased. This increase is likely caused by He atoms migration at 400 °C toward interstitial positions located inside vacancies such as VSi and VSiVC. In parallel a partial recovery of the Si and C sublattices has been observed.

  3. Ultra-Narrow Negative Flare Front Observed in Helium-10830 Å Using the1.6m New Solar Telescope

    NASA Astrophysics Data System (ADS)

    Xu, Yan; Cao, Wenda; Ding, Mingde; Kleint, Lucia; Su, Jiangtao; Liu, Chang; Ji, Haisheng; Chae, Jongchul; Jing, Ju; Cho, Kyuhyoun; Cho, Kyung-Suk; Gary, Dale E.; Wang, Haimin

    2016-05-01

    Solar flares are sudden flashes of brightness on the Sun and are often associated with coronal mass ejections and solar energetic particles that have adverse effects on the near-Earth environment. By definition, flares are usually referred to as bright features resulting from excess emission. Using the newly commissioned 1.6-m New Solar Telescope at Big Bear Solar Observatory, we show a striking “negative” flare with a narrow but unambiguous “dark” moving front observed in He I 10830 Å, which is as narrow as 340 km and is associated with distinct spectral characteristics in Hα and Mg II lines. Theoretically, such negative contrast in He I 10830 Å can be produced under special circumstances by nonthermal electron collisions or photoionization followed by recombination. Our discovery, made possible due to unprecedented spatial resolution, confirms the presence of the required plasma conditions and provides unique information in understanding the energy release and radiative transfer in solar flares.

  4. Ultra-narrow Negative Flare Front Observed in Helium-10830 Å Using the 1.6 m New Solar Telescope

    NASA Astrophysics Data System (ADS)

    Xu, Yan; Cao, Wenda; Ding, Mingde; Kleint, Lucia; Su, Jiangtao; Liu, Chang; Ji, Haisheng; Chae, Jongchul; Jing, Ju; Cho, Kyuhyoun; Cho, Kyungsuk; Gary, Dale; Wang, Haimin

    2016-03-01

    Solar flares are sudden flashes of brightness on the Sun and are often associated with coronal mass ejections and solar energetic particles that have adverse effects on the near-Earth environment. By definition, flares are usually referred to as bright features resulting from excess emission. Using the newly commissioned 1.6 m New Solar Telescope at Big Bear Solar Observatory, we show a striking “negative” flare with a narrow but unambiguous “dark” moving front observed in He i 10830 Å, which is as narrow as 340 km and is associated with distinct spectral characteristics in Hα and Mg ii lines. Theoretically, such negative contrast in He i 10830 Å can be produced under special circumstances by nonthermal electron collisions or photoionization followed by recombination. Our discovery, made possible due to unprecedented spatial resolution, confirms the presence of the required plasma conditions and provides unique information in understanding the energy release and radiative transfer in astronomical objects.

  5. Electron-impact ionization mass-spectrometry of molecules and clusters in a pulsed helium droplet source

    NASA Astrophysics Data System (ADS)

    Yang, Shengfu; Brereton, Scott; Ellis, Andrew M.

    2006-03-01

    A pulsed helium droplet source has been developed and characterized. The nozzle geometry was found to be critical in allowing controlled tuning of helium nanodroplet size by variation of the stagnation pressure and temperature. The average droplet size scales according to a simple p,T scaling law, placing pulsed helium nanodroplet sources on a par with cw sources for the first time. Using this pulsed source, the ability of helium nanodroplets to impede ion fragmentation in electron impact mass spectrometry has been explored. A number of haloalkanes and C1--C6 alcohols were selected as the target species. The presence of helium alters the fragmentation patterns when compared with the gas phase, with some ion product channels being more strongly affected than others. Parent ion intensities are also enhanced by the helium for alcohols, but only for the two cyclic alcohols studied, cyclopentanol and cyclohexanol, is this effect large enough to transform the parent ion from a minor product (in the gas phase) into the most abundant ion in the helium droplet experiments. The results obtained are difficult to explain solely by rapid cooling of the excited parent ions by the surrounding superfluid helium, although this undoubtedly takes place. A second factor also seems to be involved, a cage effect which favors hydrogen atom loss over other fragmentation channels.

  6. Approximating the Helium Wavefunction in Positronium-Helium Scattering

    NASA Technical Reports Server (NTRS)

    DiRienzi, Joseph; Drachman, Richard J.

    2003-01-01

    In the Kohn variational treatment of the positronium- hydrogen scattering problem the scattering wave function is approximated by an expansion in some appropriate basis set, but the target and projectile wave functions are known exactly. In the positronium-helium case, however, a difficulty immediately arises in that the wave function of the helium target atom is not known exactly, and there are several ways to deal with the associated eigenvalue in formulating the variational scattering equations to be solved. In this work we will use the Kohn variational principle in the static exchange approximation to d e t e e the zero-energy scattering length for the Ps-He system, using a suite of approximate target functions. The results we obtain will be compared with each other and with corresponding values found by other approximation techniques.

  7. Growth arrest specific protein 6 participates in DOCA-induced target-organ damage.

    PubMed

    Park, Joon-Keun; Theuer, Stefanie; Kirsch, Torsten; Lindschau, Carsten; Klinge, Uwe; Heuser, Arnd; Plehm, Ralph; Todiras, Mihai; Carmeliet, Peter; Haller, Hermann; Luft, Friedrich C; Muller, Dominik N; Fiebeler, Anette

    2009-08-01

    Growth arrest-specific protein 6 (Gas 6) is involved in inflammatory kidney diseases, vascular remodeling, cell adhesion, and thrombus formation. We explored a role for Gas 6 in aldosterone-induced target organ damage. We observed that Gas 6 was upregulated in rats with high aldosterone levels. Mineralocorticoid receptor blockade prevented target organ damage and decreased the elevated Gas 6 expression. Vascular smooth muscle cells given aldosterone increased their Gas 6 expression in vitro. To test the pathophysiological relevance, we investigated the effects of deoxycorticosterone acetate (DOCA) on Gas 6 gene-deleted ((-/-)) mice. After 6 weeks DOCA, Gas 6(-/-) mice developed similar telemetric blood pressure elevations compared to wild-type mice but were protected from cardiac hypertrophy. Cardiac expression of interleukin 6 and collagen IV was blunted in Gas 6(-/-) mice, indicating reduced inflammation and fibrosis. Gas 6(-/-) mice also had an improved renal function with reduced albuminuria, compared to wild-type mice. Renal fibrosis and fibronectin deposition in the kidney were also reduced. Gas 6 deficiency reduces the detrimental effects of aldosterone on cardiac and renal remodeling independent of blood pressure reduction. Gas 6 appears to play a role in mineralocorticoid receptor-mediated target organ damage. Furthermore, because warfarin interferes with Gas 6 protein expression, the findings could be of clinical relevance for anticoagulant choices. PMID:19564549

  8. A Novel Small-Molecule Inhibitor Targeting the IL-6 Receptor β Subunit, Glycoprotein 130.

    PubMed

    Hong, Soon-Sun; Choi, Jung Ho; Lee, Sung Yoon; Park, Yeon-Hwa; Park, Kyung-Yeon; Lee, Joo Young; Kim, Juyoung; Gajulapati, Veeraswamy; Goo, Ja-Il; Singh, Sarbjit; Lee, Kyeong; Kim, Young-Kook; Im, So Hee; Ahn, Sung-Hoon; Rose-John, Stefan; Heo, Tae-Hwe; Choi, Yongseok

    2015-07-01

    IL-6 is a major causative factor of inflammatory disease. Although IL-6 and its signaling pathways are promising targets, orally available small-molecule drugs specific for IL-6 have not been developed. To discover IL-6 antagonists, we screened our in-house chemical library and identified LMT-28, a novel synthetic compound, as a candidate IL-6 blocker. The activity, mechanism of action, and direct molecular target of LMT-28 were investigated. A reporter gene assay showed that LMT-28 suppressed activation of STAT3 induced by IL-6, but not activation induced by leukemia inhibitory factor. In addition, LMT-28 downregulated IL-6-stimulated phosphorylation of STAT3, gp130, and JAK2 protein and substantially inhibited IL-6-dependent TF-1 cell proliferation. LMT-28 antagonized IL-6-induced TNF-α production in vivo. In pathologic models, oral administration of LMT-28 alleviated collagen-induced arthritis and acute pancreatitis in mice. Based on the observation of upstream IL-6 signal inhibition by LMT-28, we hypothesized IL-6, IL-6Rα, or gp130 to be putative molecular targets. We subsequently demonstrated direct interaction of LMT-28 with gp130 and specific reduction of IL-6/IL-6Rα complex binding to gp130 in the presence of LMT-28, which was measured by surface plasmon resonance analysis. Taken together, our data suggest that LMT-28 is a novel synthetic IL-6 inhibitor that functions through direct binding to gp130. PMID:26026064

  9. Federal helium program: The reaction over an inert gas. Final report

    SciTech Connect

    Mielke, J.E.

    1996-10-09

    Helium, present in relatively high concentrations in only a few natural gas fields, is released to the atmosphere and wasted when the natural gas is burned as fuel. Government involvement in helium conservation dates to the Helium Act of 1925 which authorized the Bureau of Mines to build and operate a large-scale helium extraction and purification plant. From 1929 until 1960 the federal government was the only domestic helium producer. In 1960, Congress amended the Helium Act to provide incentives to natural gas producers for stripping natural gas of its helium, for purchase of the separated helium by the government, and for its long-term storage. With over 960 million cubic meters (34.6 billion cubic feet) of helium in government storage and a large private helium recovery industry, questions arise as to the need for either the federal helium extraction program or the federally maintained helium stockpile.

  10. Deactivation of the 6s and 6s' states of a xenon atom in collisions with helium, argon, and xenon atoms

    SciTech Connect

    Semenova, Ludmila V; Ustinovskii, N N; Kholin, I V

    2004-03-31

    A series of publications devoted to the study of collisional deactivation of Xe atoms in the 6s and 6s' states in high-pressure Ar - He and He - Xe mixtures with a low content of Xe is summarised. The processes of quenching of the *P{sub 1}, *P{sub 0}, *P{sub 1}, and *P{sub 2} levels are studied in two-particle Xe*+Ar(He) {yields} products+Ar(He), three-particle Xe*+ 2Ar(2He) {yields} ArXe*(HeXe*+Ar(He), and three-particle Xe*+Xe+Ar(He) {yields} Xe*{sub 2}+Ar(He) collisions. The gases were excited by a fast-electron beam. The measurements were performed by the method of absorption probing by analysing the time dependence of the concentration of the excited states in the afterglow of the electron beam. The rate constants of 24 plasma-chemical reactions were measured, 17 of which - for the first time. (invited paper)

  11. COSMIC-RAY HELIUM HARDENING

    SciTech Connect

    Ohira, Yutaka; Ioka, Kunihito

    2011-03-01

    Recent observations by the CREAM and ATIC-2 experiments suggest that (1) the spectrum of cosmic-ray (CR) helium is harder than that of CR protons below the knee energy, 10{sup 15}eV, and (2) all CR spectra become hard at {approx}>10{sup 11}eV nucleon{sup -1}. We propose a new idea, that higher energy CRs are generated in a more helium-rich region, to explain the hardening without introducing different sources for CR helium. The helium-to-proton ratio at {approx}100 TeV exceeds the Big Bang abundance Y = 0.25 by several times, and the different spectrum is not reproduced within the diffusive shock acceleration theory. We argue that CRs are produced in a chemically enriched region, such as a superbubble, and the outward-decreasing abundance naturally leads to the hard spectrum of CR helium if CRs escape from the supernova remnant shock in an energy-dependent way. We provide a simple analytical spectrum that also fits well the hardening due to the decreasing Mach number in the hot superbubble with {approx}10{sup 6} K. Our model predicts hard and concave spectra for heavier CR elements.

  12. Helium-Recycling Plant

    NASA Technical Reports Server (NTRS)

    Cook, Joseph

    1996-01-01

    Proposed system recovers and stores helium gas for reuse. Maintains helium at 99.99-percent purity, preventing water vapor from atmosphere or lubricating oil from pumps from contaminating gas. System takes in gas at nearly constant low back pressure near atmospheric pressure; introduces little or no back pressure into source of helium. Concept also extended to recycling of other gases.

  13. Mannose-6-phosphate receptor: a target for theranostics of prostate cancer.

    PubMed

    Vaillant, Ophélie; El Cheikh, Khaled; Warther, David; Brevet, David; Maynadier, Marie; Bouffard, Elise; Salgues, Frédéric; Jeanjean, Audrey; Puche, Pierre; Mazerolles, Catherine; Maillard, Philippe; Mongin, Olivier; Blanchard-Desce, Mireille; Raehm, Laurence; Rébillard, Xavier; Durand, Jean-Olivier; Gary-Bobo, Magali; Morère, Alain; Garcia, Marcel

    2015-05-11

    The development of personalized and non-invasive cancer therapies based on new targets combined with nanodevices is a major challenge in nanomedicine. In this work, the over-expression of a membrane lectin, the cation-independent mannose 6-phosphate receptor (M6PR), was specifically demonstrated in prostate cancer cell lines and tissues. To efficiently target this lectin a mannose-6-phosphate analogue was synthesized in six steps and grafted onto the surface of functionalized mesoporous silica nanoparticles (MSNs). These MSNs were used for in vitro and ex vivo photodynamic therapy to treat prostate cancer cell lines and primary cell cultures prepared from patient biopsies. The results demonstrated the efficiency of M6PR targeting for prostate cancer theranostic. PMID:25802144

  14. Particle Detection in Superfluid Helium: R&D for Low Energy Solar Neutrinos

    SciTech Connect

    Lanou, Robert E., Jr.

    2006-03-31

    This report presents a summary of the results from R&D conducted as a feasibility study in the Department of Physics of Brown University for detection of low energy solar neutrinos utilizing a superfluid helium target. The report outlines the results in several areas: 1) development of experimental facilities, 2) energy deposition by electrons and alphas in superfluid helium, 3) development of wafer and metallic magnetic calorimeters, 4) background studies, 5) coded apertures and conceptual design, 6) Detection of single electrons and 7) a simulation of expected performance of a full scale device. Recommendations for possible future work are also presented. A bibliography of published papers and unpublished doctoral theses is included.

  15. Preclinical validation of interleukin 6 as a therapeutic target in multiple myeloma

    PubMed Central

    Rosean, Timothy R.; Tompkins, Van S.; Tricot, Guido; Holman, Carol J.; Olivier, Alicia K.; Zhan, Fenghuang; Janz, Siegfried

    2014-01-01

    Studies on the biologic and molecular genetic underpinnings of multiple myeloma (MM) have identified the pleiotropic, pro-inflammatory cytokine, interleukin-6 (IL-6), as a factor crucial to the growth, proliferation and survival of myeloma cells. IL-6 is also a potent stimulator of osteoclastogenesis and a sculptor of the tumor microenvironment in the bone marrow of patients with myeloma. This knowledge has engendered considerable interest in targeting IL-6 for therapeutic purposes, using a variety of antibody- and small-molecule-based therapies. However, despite the early recognition of the importance of IL-6 for myeloma and the steady progress in our knowledge of IL-6 in normal and malignant development of plasma cells, additional efforts will be required to translate the promise of IL-6 as a target for new myeloma therapies into significant clinical benefits for patients with myeloma. This review summarizes published research on the role of IL-6 in myeloma development and describes ongoing efforts by the University of Iowa Myeloma Multidisciplinary Oncology Group to develop new approaches to the design and testing of IL-6-targeted therapies and preventions of MM. PMID:24845460

  16. A helium regenerative compressor

    SciTech Connect

    Swift, W.L.; Nutt, W.E.; Sixsmith, H.

    1994-12-31

    This paper discusses the design and performance of a regenerative compressor that was developed primarily for use in cryogenic helium systems. The objectives for the development were to achieve acceptable efficiency in the machine using conventional motor and bearing technology while reducing the complexity of the system required to control contamination from the lubricants. A single stage compressor was built and tested. The compressor incorporates aerodynamically shaped blades on a 218 mm (8.6 inches) diameter impeller to achieve high efficiency. A gas-buffered non-contact shaft seal is used to oppose the diffusion of lubricant from the motor bearings into the cryogenic circuit. Since it is a rotating machine, the flow is continuous and steady, and the machine is very quiet. During performance testing with helium, the single stage machine has demonstrated a pressure ratio of 1.5 at a flow rate of 12 g/s with measured isothermal efficiencies in excess of 30%. This performance compares favorably with efficiencies generally achieved in oil flooded screw compressors.

  17. Asymptotic and near-target direct breakup of 6Li and 7Li

    NASA Astrophysics Data System (ADS)

    Kalkal, Sunil; Simpson, E. C.; Luong, D. H.; Cook, K. J.; Dasgupta, M.; Hinde, D. J.; Carter, I. P.; Jeung, D. Y.; Mohanto, G.; Palshetkar, C. S.; Prasad, E.; Rafferty, D. C.; Simenel, C.; Vo-Phuoc, K.; Williams, E.; Gasques, L. R.; Gomes, P. R. S.; Linares, R.

    2016-04-01

    Background: Li,76 and 9Be are weakly bound against breakup into their cluster constituents. Breakup location is important for determining the role of breakup in above-barrier complete fusion suppression. Recent works have pointed out that experimental observables can be used to separate near-target and asymptotic breakup. Purpose: Our purpose is to distinguish near-target and asymptotic direct breakup of Li,76 in reactions with nuclei in different mass regions. Method: Charged particle coincidence measurements are carried out with pulsed Li,76 beams on 58Ni and 64Zn targets at sub-barrier energies and compared with previous measurements using 208Pb and 209Bi targets. A detector array providing a large angular coverage is used, along with time-of-flight information to give definitive particle identification of the direct breakup fragments. Results: In interactions of 6Li with 58Ni and 64Zn, direct breakup occurs only asymptotically far away from the target. However, in interactions with 208Pb and 209Bi, near-target breakup occurs in addition to asymptotic breakup. Direct breakup of 7Li into α -t is not observed in interactions with 58Ni and 64Zn. However, near-target dominated direct breakup was observed in measurements with 208Pb and 209Bi. A modified version of the Monte Carlo classical trajectory model code platypus, which explicitly takes into account lifetimes associated with unbound states, is used to simulate sub-barrier breakup reactions. Conclusions: Near-target breakup in interactions with Li,76 is an important mechanism only for the heavy targets 208Pb and 209Bi. There is insignificant near-target direct breakup of 6Li and no direct breakup of 7Li in reactions with 58Ni and 64Zn. Therefore, direct breakup is unlikely to suppress the above-barrier fusion cross section in reactions of Li,76 with 58Ni and 64Zn nuclei.

  18. High-level transient expression of ER-targeted human interleukin 6 in Nicotiana benthamiana.

    PubMed

    Nausch, Henrik; Mikschofsky, Heike; Koslowski, Roswitha; Meyer, Udo; Broer, Inge; Huckauf, Jana

    2012-01-01

    Tobacco plants can be used to express recombinant proteins that cannot be produced in a soluble and active form using traditional platforms such as Escherichia coli. We therefore expressed the human glycoprotein interleukin 6 (IL6) in two commercial tobacco cultivars (Nicotiana tabacum cv. Virginia and cv. Geudertheimer) as well as the model host N. benthamiana to compare different transformation strategies (stable vs. transient expression) and subcellular targeting (apoplast, endoplasmic reticulum (ER) and vacuole). In T(0) transgenic plants, the highest expression levels were achieved by ER targeting but the overall yields of IL6 were still low in the leaves (0.005% TSP in the ER, 0.0008% in the vacuole and 0.0005% in the apoplast). The apoplast variant accumulated to similar levels in leaves and seeds, whereas the ER-targeted variant was 1.2-fold more abundant in seeds and the vacuolar variant was 6-fold more abundant in seeds. The yields improved in subsequent generations, with the best-performing T(2) plants producing the ER-targeted IL6 at 0.14% TSP in both leaves and seeds. Transient expression of ER-targeted IL6 in leaves using the MagnICON system resulted in yields of up to 7% TSP in N. benthamiana, but only 1% in N. tabacum cv. Virginia and 0.5% in cv. Geudertheimer. Although the commercial tobacco cultivars produced up to threefold more biomass than N. benthamiana, this was not enough to compensate for the lower overall yields. The recombinant IL6 produced by transient and stable expression in plants was biologically active and presented as two alternative bands matching the corresponding native protein. PMID:23152824

  19. MicroRNA-183 suppresses retinoblastoma cell growth, invasion and migration by targeting LRP6.

    PubMed

    Wang, Jianwen; Wang, Xiaochun; Li, Zhongji; Liu, Hongtao; Teng, Yan

    2014-03-01

    Our study demonstrates the downregulation of microRNA-183 (miR-183) in retinoblastoma (RB) tissues and RB cell lines compared with normal retinal tissues. The ectopic expression of miR-183 in the RB cell lines Y79, SO-RB50 and WERI-RB1 suppresses cell viability, migration and invasion. Furthermore, the Wnt co-receptor low-density lipoprotein receptor-related protein 6 (LRP6) was identified as a new target of miR-183, and restoration of the expression of LRP6 rescues the effects induced by miR-183 in RB cells. These results indicate that miR-183 targets and downregulates LRP6 in the growth, migration and invasion of RB cells. PMID:24289859

  20. Recent developments for an active UF6 gas target for photon-induced fission experiments

    NASA Astrophysics Data System (ADS)

    Freudenberger, M.; Eckardt, C.; Enders, J.; Göök, A.; von Neumann-Cosel, P.; Oberstedt, A.; Oberstedt, S.

    2013-12-01

    Recent developments for an active uranium-hexafluoride-loaded gas target as well as results on the detector gas properties are presented. The gas of choice is a mixture of argon with small amounts of UF6. This contribution presents the experimental setup and focusses on the electron drift velocity with increasing UF6 content. A time-dependent decrease in electron drift velocity is observed in our setup.

  1. Teens on Target Violence Prevention Curriculum for Grades 6-12.

    ERIC Educational Resources Information Center

    Becker, Marla G.; Calhoun, Deane

    This curriculum is designed to help schools implement programs to prevent violence among students in grades 6-12. It is a six-session, school based curriculum intended for adolescents who are living in communities experiencing high rates of violence. It is facilitated by trained Teens on Target (TNT) members/peer educators, young people who are…

  2. Superfluid Helium Heat Pipe

    NASA Astrophysics Data System (ADS)

    Gully, P.

    This paper reports on the development and the thermal tests of three superfluid helium heat pipes. Two of them are designed to provide a large transport capacity (4 mW at 1.7 K). They feature a copper braid located inside a 6 mm outer diameter stainless tube fitted with copper ends for mechanical anchoring. The other heat pipe has no copper braid and is designed to get much smaller heat transport capacity (0.5 mW) and to explore lower temperature (0.7 - 1 K). The copper braid and the tube wall is the support of the Rollin superfluid helium film in which the heat is transferred. The low filling pressure makes the technology very simple with the possibility to easily bend the tube. We present the design and discuss the thermal performance of the heat pipes tested in the 0.7 to 2.0 K temperature range. The long heat pipe (1.2 m with copper braid) and the short one (0.25 m with copper braid) have similar thermal performance in the range 0.7 - 2.0 K. At 1.7 K the long heat pipe, 120 g in weight, reaches a heat transfer capacity of 6.2 mW and a thermal conductance of 600 mW/K for 4 mW transferred power. Due to the pressure drop of the vapor flow and Kapitza thermal resistance, the conductance of the third heat pipe dramatically decreases when the temperature decreases. A 3.8 mW/K is obtained at 0.7 K for 0.5 mW transferred power.

  3. The transcriptional modulator BCL6 as a molecular target for breast cancer therapy

    PubMed Central

    Walker, Sarah R.; Liu, Suhu; Xiang, Michael; Nicolais, Maria; Hatzi, Katerina; Giannopoulou, Eugenia; Elemento, Olivier; Cerchietti, Leandro; Melnick, Ari; Frank, David A.

    2014-01-01

    Inappropriate expression or activation of transcription factors can drive patterns of gene expression leading to the malignant behavior of breast cancer cells. We have found that the transcriptional repressor BCL6 is highly expressed in breast cancer cell lines, and its locus is amplified in about half of primary breast cancers. To understand how BCL6 regulates gene expression in breast cancer cells, we utilized ChIP-seq to identify the BCL6 binding sites on a genomic scale. This revealed that BCL6 regulates a unique cohort of genes in breast cancer cell lines compared to B cell lymphomas. Furthermore, BCL6 expression promotes the survival of breast cancer cells, and targeting BCL6 with a peptidomimetic inhibitor leads to apoptosis of these cells. Finally, combining a BCL6 inhibitor and a STAT3 inhibitor provided enhanced cell killing in triple negative breast cancer cell lines, suggesting that combination therapy may be particularly useful. Thus, targeting BCL6 alone or in conjunction with other signaling pathways may be a useful therapeutic strategy for treating breast cancer. PMID:24662818

  4. Discovery and assessment of conserved Pax6 target genes and enhancers

    PubMed Central

    Coutinho, Pedro; Pavlou, Sofia; Bhatia, Shipra; Chalmers, Kevin J.; Kleinjan, Dirk A.; van Heyningen, Veronica

    2011-01-01

    The characterization of transcriptional networks (TNs) is essential for understanding complex biological phenomena such as development, disease, and evolution. In this study, we have designed and implemented a procedure that combines in silico target screens with zebrafish and mouse validation, in order to identify cis-elements and genes directly regulated by Pax6. We chose Pax6 as the paradigm because of its crucial roles in organogenesis and human disease. We identified over 600 putative Pax6 binding sites and more than 200 predicted direct target genes, conserved in evolution from zebrafish to human and to mouse. This was accomplished using hidden Markov models (HMMs) generated from experimentally validated Pax6 binding sites. A small sample of genes, expressed in the neural lineage, was chosen from the predictions for RNA in situ validation using zebrafish and mouse models. Validation of DNA binding to some predicted cis-elements was also carried out using chromatin immunoprecipitation (ChIP) and zebrafish reporter transgenic studies. The results show that this combined procedure is a highly efficient tool to investigate the architecture of TNs and constitutes a useful complementary resource to ChIP and expression data sets because of its inherent spatiotemporal independence. We have identified several novel direct targets, including some putative disease genes, among them Foxp2; these will allow further dissection of Pax6 function in development and disease. PMID:21617155

  5. miR-5100 promotes tumor growth in lung cancer by targeting Rab6.

    PubMed

    Huang, Haili; Jiang, Yun; Wang, Yahong; Chen, Ting; Yang, Lawei; He, Huijuan; Lin, Ziying; Liu, Tie; Yang, Teng; Kamp, David W; Wu, Bin; Liu, Gang

    2015-06-28

    Our previous study demonstrated that microRNA 5100 (miR-5100) is overexpressed in lung cancer tissues; however, the function of miR-5100 remained elusive. In this study, we demonstrate that miR-5100 is highly expressed in a wide variety of lung cancer tissues and lung cancer cell lines. Exogenous expression of miR-5100 in A549 and H1299 lung cancer cells enhanced proliferation and colony formation, and conversely, suppression of miR-5100 exhibited inhibitory effects. Furthermore, we demonstrate that miR-5100 promotes tumor growth in nude mice. These effects may result from the ability of miR-5100 to promote G1/S transition and downregulate cyclin D1 and cyclin-dependent kinases 2 (CDK2) expressions in lung cancer stable cells. Using a bioinformatics target prediction tool, we identified Rab6 as a potential target of miR-5100. Consistently, overexpression of miR-5100 specifically reduced the expression of a luciferase reporter containing the predicted binding site from the 3'untranslated region (3'UTR) of Rab6 and decreased the accumulation of endogenous Rab6 in A549 and H1299 cells. Moreover, exogenous expression of Rab6 compromised the effects of miR-5100 on cell proliferation and colony formation. Our data suggest that miR-5100 promotes tumor growth by facilitating the G1/S transition and targeting Rab6. PMID:25754817

  6. The Cell Cycle Regulator CCDC6 Is a Key Target of RNA-Binding Protein EWS

    PubMed Central

    Duggimpudi, Sujitha; Larsson, Erik; Nabhani, Schafiq; Borkhardt, Arndt; Hoell, Jessica I

    2015-01-01

    Genetic translocation of EWSR1 to ETS transcription factor coding region is considered as primary cause for Ewing sarcoma. Previous studies focused on the biology of chimeric transcription factors formed due to this translocation. However, the physiological consequences of heterozygous EWSR1 loss in these tumors have largely remained elusive. Previously, we have identified various mRNAs bound to EWS using PAR-CLIP. In this study, we demonstrate CCDC6, a known cell cycle regulator protein, as a novel target regulated by EWS. siRNA mediated down regulation of EWS caused an elevated apoptosis in cells in a CCDC6-dependant manner. This effect was rescued upon re-expression of CCDC6. This study provides evidence for a novel functional link through which wild-type EWS operates in a target-dependant manner in Ewing sarcoma. PMID:25751255

  7. The integrin αvβ6: a novel target for CAR T-cell immunotherapy?

    PubMed

    Whilding, Lynsey M; Vallath, Sabari; Maher, John

    2016-04-15

    Immunotherapy of cancer using chimeric antigen receptor (CAR) T-cells is a rapidly expanding field. CARs are fusion molecules that couple the binding of a tumour-associated cell surface target to the delivery of a tailored T-cell activating signal. Re-infusion of such genetically engineered T-cells to patients with haematological disease has demonstrated unprecedented response rates in Phase I clinical trials. However, such successes have not yet been observed using CAR T-cells against solid malignancies and this is, in part, due to a lack of safe tumour-specific targets. The αvβ6 integrin is strongly up-regulated in multiple solid tumours including those derived from colon, lung, breast, cervix, ovaries/fallopian tube, pancreas and head and neck. It is associated with poorer prognosis in several cancers and exerts pro-tumorigenic activities including promotion of tumour growth, migration and invasion. By contrast, physiologic expression of αvβ6 is largely restricted to wound healing. These attributes render this epithelial-specific integrin a highly attractive candidate for targeting using immunotherapeutic strategies such as CAR T-cell adoptive immunotherapy. This mini-review will discuss the role and expression of αvβ6 in cancer, as well as its potential as a therapeutic target. PMID:27068939

  8. THPP target assignment reveals EchA6 as an essential fatty acid shuttle in mycobacteria.

    PubMed

    Cox, Jonathan A G; Abrahams, Katherine A; Alemparte, Carlos; Ghidelli-Disse, Sonja; Rullas, Joaquín; Angulo-Barturen, Iñigo; Singh, Albel; Gurcha, Sudagar S; Nataraj, Vijayashankar; Bethell, Stephen; Remuiñán, Modesto J; Encinas, Lourdes; Jervis, Peter J; Cammack, Nicholas C; Bhatt, Apoorva; Kruse, Ulrich; Bantscheff, Marcus; Fütterer, Klaus; Barros, David; Ballell, Lluis; Drewes, Gerard; Besra, Gurdyal S

    2016-01-01

    Phenotypic screens for bactericidal compounds against drug-resistant tuberculosis are beginning to yield novel inhibitors. However, reliable target identification remains challenging. Here, we show that tetrahydropyrazo[1,5-a]pyrimidine-3-carboxamide (THPP) selectively pulls down EchA6 in a stereospecific manner, instead of the previously assigned target Mycobacterium tuberculosis MmpL3. While homologous to mammalian enoyl-coenzyme A (CoA) hydratases, EchA6 is non-catalytic yet essential and binds long-chain acyl-CoAs. THPP inhibitors compete with CoA-binding, suppress mycolic acid synthesis, and are bactericidal in a mouse model of chronic tuberculosis infection. A point mutation, W133A, abrogated THPP-binding and increased both the in vitro minimum inhibitory concentration and the in vivo effective dose 99 in mice. Surprisingly, EchA6 interacts with selected enzymes of fatty acid synthase II (FAS-II) in bacterial two-hybrid assays, suggesting essentiality may be linked to feeding long-chain fatty acids to FAS-II. Finally, our data show that spontaneous resistance-conferring mutations can potentially obscure the actual target or alternative targets of small molecule inhibitors. PMID:27571973

  9. System Review of Safety Function Components for the Design of the Cask MCO Helium Purge System Project A.5 and A.6

    SciTech Connect

    LEW, B.S.

    2000-03-27

    The design of the Cask/Multiple Canister Overpack (MCO) Helium Purge System (HPS) is assessed for the appropriate designated safety function classification of its components. The purpose of this review is to determine appropriate safety function classifications for the system's components or to identify actions to be taken to reasonably assure that the system/component safety function(s) will be performed as intended. This review also includes consideration that the HPS would perform consistent with its analytical assumptions and basis in HNF-2833, Rev. 0.

  10. Targeted Ablation of the Abcc6 Gene Results in Ectopic Mineralization of Connective Tissues

    PubMed Central

    Klement, John F.; Matsuzaki, Yasushi; Jiang, Qiu-Jie; Terlizzi, Joseph; Choi, Hae Young; Fujimoto, Norihiro; Li, Kehua; Pulkkinen, Leena; Birk, David E.; Sundberg, John P.; Uitto, Jouni

    2005-01-01

    Pseudoxanthoma elasticum (PXE), characterized by connective tissue mineralization of the skin, eyes, and cardiovascular system, is caused by mutations in the ABCC6 gene. ABCC6 encodes multidrug resistance-associated protein 6 (MRP6), which is expressed primarily in the liver and kidneys. Mechanisms producing ectopic mineralization as a result of these mutations remain unclear. To elucidate this complex disease, a transgenic mouse was generated by targeted ablation of the mouse Abcc6 gene. Abcc6 null mice were negative for Mrp6 expression in the liver, and complete necropsies revealed profound mineralization of several tissues, including skin, arterial blood vessels, and retina, while heterozygous animals were indistinguishable from the wild-type mice. Particularly striking was the mineralization of vibrissae, as confirmed by von Kossa and alizarin red stains. Electron microscopy revealed mineralization affecting both elastic structures and collagen fibers. Mineralization of vibrissae was noted as early as 5 weeks of age and was progressive with age in Abcc6−/− mice but was not observed in Abcc6+/− or Abcc6+/+ mice up to 2 years of age. A total body computerized tomography scan of Abcc6−/− mice revealed mineralization in skin and subcutaneous tissue as well as in the kidneys. These data demonstrate aberrant mineralization of soft tissues in PXE-affected organs, and, consequently, these mice recapitulate features of this complex disease. PMID:16135817

  11. On chemical bonding and helium distribution in hcp beryllium

    NASA Astrophysics Data System (ADS)

    Bakai, A. S.; Timoshevskii, A. N.; Yanchitsky, B. Z.

    2011-10-01

    The electron densities of states and spatial distribution of electron density in the system hcp beryllium-helium were investigated by means of ab-initio methods of simulation. It was found that contrary to predictions of the "jelly" model, the energetically more favorable configuration is that where a helium atom is located at the most restricted position, on a triangular face of two adjacent tetrahedrons, and where the charge density of electrons is maximal. It is established that this occurs due to hybridization of electron states of helium and nearest beryllium atom. The helium binding energy is about 5.6 eV. The spatial distribution of the charge density is investigated in details. Calculation of solution energy of helium in hcp beryllium was performed. The helium location at lattice sites in different interstitial positions and in divacancy complexes were considered. It is found that helium implemented into hcp beryllium favors formation of divacancies.

  12. C6-Ceramide Nanoliposomes Target the Warburg Effect in Chronic Lymphocytic Leukemia

    PubMed Central

    Shanmugavelandy, Sriram S.; Fox, Todd E.; Aliaga, Cesar; Broeg, Kathleen; Baab, Kendall Thomas; Young, Megan; Khan, Osman; Haakenson, Jeremy K.; Jarbadan, Nancy Ruth; Liao, Jason; Wang, Hong-Gang; Feith, David J.; Loughran Jr, Thomas P.; Liu, Xin; Kester, Mark

    2013-01-01

    Ceramide is a sphingolipid metabolite that induces cancer cell death. When C6-ceramide is encapsulated in a nanoliposome bilayer formulation, cell death is selectively induced in tumor models. However, the mechanism underlying this selectivity is unknown. As most tumors exhibit a preferential switch to glycolysis, as described in the “Warburg effect”, we hypothesize that ceramide nanoliposomes selectively target this glycolytic pathway in cancer. We utilize chronic lymphocytic leukemia (CLL) as a cancer model, which has an increased dependency on glycolysis. In CLL cells, we demonstrate that C6-ceramide nanoliposomes, but not control nanoliposomes, induce caspase 3/7-independent necrotic cell death. Nanoliposomal ceramide inhibits both the RNA and protein expression of GAPDH, an enzyme in the glycolytic pathway, which is overexpressed in CLL. To confirm that ceramide targets GAPDH, we demonstrate that downregulation of GAPDH potentiates the decrease in ATP after ceramide treatment and exogenous pyruvate treatment as well as GAPDH overexpression partially rescues ceramide-induced necrosis. Finally, an in vivo murine model of CLL shows that nanoliposomal C6-ceramide treatment elicits tumor regression, concomitant with GAPDH downregulation. We conclude that selective inhibition of the glycolytic pathway in CLL cells with nanoliposomal C6-ceramide could potentially be an effective therapy for leukemia by targeting the Warburg effect. PMID:24367685

  13. RGS6 as a Novel Therapeutic Target in CNS Diseases and Cancer.

    PubMed

    Ahlers, Katelin E; Chakravarti, Bandana; Fisher, Rory A

    2016-05-01

    Regulator of G protein signaling (RGS) proteins are gatekeepers regulating the cellular responses induced by G protein-coupled receptor (GPCR)-mediated activation of heterotrimeric G proteins. Specifically, RGS proteins determine the magnitude and duration of GPCR signaling by acting as a GTPase-activating protein for Gα subunits, an activity facilitated by their semiconserved RGS domain. The R7 subfamily of RGS proteins is distinguished by two unique domains, DEP/DHEX and GGL, which mediate membrane targeting and stability of these proteins. RGS6, a member of the R7 subfamily, has been shown to specifically modulate Gαi/o protein activity which is critically important in the central nervous system (CNS) for neuronal responses to a wide array of neurotransmitters. As such, RGS6 has been implicated in several CNS pathologies associated with altered neurotransmission, including the following: alcoholism, anxiety/depression, and Parkinson's disease. In addition, unlike other members of the R7 subfamily, RGS6 has been shown to regulate G protein-independent signaling mechanisms which appear to promote both apoptotic and growth-suppressive pathways that are important in its tumor suppressor function in breast and possibly other tissues. Further highlighting the importance of RGS6 as a target in cancer, RGS6 mediates the chemotherapeutic actions of doxorubicin and blocks reticular activating system (Ras)-induced cellular transformation by promoting degradation of DNA (cytosine-5)-methyltransferase 1 (DNMT1) to prevent its silencing of pro-apoptotic and tumor suppressor genes. Together, these findings demonstrate the critical role of RGS6 in regulating both G protein-dependent CNS pathology and G protein-independent cancer pathology implicating RGS6 as a novel therapeutic target. PMID:27002730

  14. Atomic cascade of muonic and pionic helium atoms

    SciTech Connect

    Landua, R.; Klempt, E.

    1982-06-21

    The cascade of muonic and pionic helium atoms in targets of arbitrary density is investigated. The calculation does not use any free parameters except for strong interaction effects. All measured x-ray intensities are reproduced, in particular also the K/sub ..beta..//K/sub ..cap alpha../ intensity ratios in pionic helium.

  15. Molecular dynamics study of helium bubble pressure in tungsten

    NASA Astrophysics Data System (ADS)

    Cui, Jiechao; Li, Min; Wang, Jun; Hou, Qing

    2015-06-01

    Molecular dynamics simulations were performed to calculate the stress field in a tungsten matrix containing a nano-scale helium bubble. A helium bubble in tungsten is found to consist of a core and an interface of finite thickness of approximately 0.6 nm. The core contains only helium atoms that are uniformly distributed. The interface is composed of both helium and tungsten atoms. In the periphery region of the helium bubble, the stress filed is found to follow the stress formula based on the elasticity theory of solid. The pressure difference between both sides of the interface can be well described by the Young-Laplace equation for the core size of a helium bubble as small as 0.48 nm. A comparison was performed between the pressure in the helium bubble core and the pressure in pure helium. For a core size larger than 0.3 nm, the pressure in the core of a helium bubble is in good agreement with the pressure in pure helium of the same helium density. These results provide guidance to larger scale simulation methods, such as in kinetic Monte Carlo methods and rate theory.

  16. Molecular Targeting of CEACAM6 Using Antibody Probes of Different Sizes

    PubMed Central

    Niu, Gang; Murad, Yanal M.; Gao, Haokao; Hu, Shuo; Guo, Ning; Jacobson, Orit; Nguyen, Thanh-Dung; Zhang, Jianbing; Chen, Xiaoyuan

    2012-01-01

    Carcinocinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) is overexpressed in a number of human malignancies, especially in pancreatic cancer. It has been demonstrated that CEACAM6 is a potential target for monoclonal antibody (mAb) therapy with a safe therapeutic index. Here, we labeled three anti-CEACAM6 antibodies of different sizes, including a single-domain antibody 2A3 (16 kDa), a heavy chain antibody 2A3-mFc (80 kDa) and a full length antibody 9A6 (150 kDa), with 64Cu to image CEACAM6 expression in a xenografted pancreatic tumor model. For positron emission tomography (PET) imaging, the tumor mice were intravenously injected with 64Cu-DOTA-antibodies and static scans were obtained at 5 min, 0.5, 1, 2, 4, 8 and 24 h post-injection (p.i.). All three antibodies showed strong CEACAM6 binding. Ex vivo immunostaining on tumor sections at 24 h after Ab injection demonstrated specific tumor targeting of both 2A3-mFc and 9A6. 64Cu-DOTA-2A3 showed fast BxPC3 tumor uptake and rapid whole-body clearance. At 24 h p.i., the tumor uptakes were 98.2 ± 6.12 %ID/g for 64Cu-DOTA-2A3-mFc and 57.8 ± 3.73 %ID/g for 64Cu-DOTA-9A6, respectively. Compared with the full length antibody 9A6, the heavy chain antibody 2A3-mFc showed higher tumor uptake, lower liver uptake and shorter circulation half-life. All the data supported that the heavy chain antibody 2A3-mFc is superior to the single domain antibody and the full-length antibody with regard to tumor detection and pharmacokinetics, which has great potential to be developed for CEACAM6-targeted pancreatic cancer imaging and therapy. PMID:22568933

  17. Interleukin 6 Receptor Is an Independent Prognostic Factor and a Potential Therapeutic Target of Ovarian Cancer

    PubMed Central

    Isobe, Aki; Sawada, Kenjiro; Kinose, Yasuto; Ohyagi-Hara, Chifumi; Nakatsuka, Erika; Makino, Hiroshi; Ogura, Tomonori; Mizuno, Tomoko; Suzuki, Noriko; Morii, Eiichi; Nakamura, Koji; Sawada, Ikuko; Toda, Aska; Hashimoto, Kae; Mabuchi, Seiji; Ohta, Tsuyoshi; Morishige, Ken-ichirou; Kurachi, Hirohisa; Kimura, Tadashi

    2015-01-01

    Ovarian cancer remains the most lethal gynecologic cancer and new targeted molecular therapies against this miserable disease continue to be challenging. In this study, we analyzed the expressional patterns of Interleukin-6 (IL-6) and its receptor (IL-6R) expression in ovarian cancer tissues, evaluated the impact of these expressions on clinical outcomes of patients, and found that a high-level of IL-6R expression but not IL-6 expression in cancer cells is an independent prognostic factor. In in vitro analyses using ovarian cell lines, while six (RMUG-S, RMG-1, OVISE, A2780, SKOV3ip1 and OVCAR-3) of seven overexpressed IL-6R compared with a primary normal ovarian surface epithelium, only two (RMG-1, OVISE) of seven cell lines overexpressed IL-6, suggesting that IL-6/IL-6R signaling exerts in a paracrine manner in certain types of ovarian cancer cells. Ovarian cancer ascites were collected from patients, and we found that primary CD11b+CD14+ cells, which were predominantly M2-polarized macrophages, are the major source of IL-6 production in an ovarian cancer microenvironment. When CD11b+CD14+ cells were co-cultured with cancer cells, both the invasion and the proliferation of cancer cells were robustly promoted and these promotions were almost completely inhibited by pretreatment with anti-IL-6R antibody (tocilizumab). The data presented herein suggest a rationale for anti-IL-6/IL-6R therapy to suppress the peritoneal spread of ovarian cancer, and represent evidence of the therapeutic potential of anti-IL-6R therapy for ovarian cancer treatment. PMID:25658637

  18. Superfluid helium on orbit transfer (SHOOT)

    NASA Technical Reports Server (NTRS)

    Dipirro, Michael J.

    1987-01-01

    A number of space flight experiments and entire facilities require superfluid helium as a coolant. Among these are the Space Infrared Telescope Facility (SIRTF), the Large Deployable Reflector (LDR), the Advanced X-ray Astrophysics Facility (AXAF), the Particle Astrophysics Magnet Facility (PAMF or Astromag), and perhaps even a future Hubble Space Telescope (HST) instrument. Because these systems are required to have long operational lifetimes, a means to replenish the liquid helium, which is exhausted in the cooling process, is required. The most efficient method of replenishment is to refill the helium dewars on orbit with superfluid helium (liquid helium below 2.17 Kelvin). To develop and prove the technology required for this liquid helium refill, a program of ground and flight testing was begun. The flight demonstration is baselined as a two flight program. The first, described in this paper, will prove the concepts involved at both the component and system level. The second flight will demonstrate active astronaut involvement and semi-automated operation. The current target date for the first launch is early 1991.

  19. Sporothrix schenckii: purification and partial biochemical characterization of glucosamine-6-phosphate synthase, a potential antifungal target.

    PubMed

    González-Ibarra, Joaquín; Milewski, Sławomir; Villagómez-Castro, Julio C; Cano-Canchola, Carmen; López-Romero, Everardo

    2010-02-01

    The first committed step of the biosynthetic pathway leading to uridine-5'-diphospho-N-acetyl-D-glucosamine (UDP-GlcNAc) is catalyzed by glucosamine-6-phosphate synthase (GlcN-6-P synthase), an enzyme proposed as a potential antifungal chemotherapy target. Here, we describe the purification and biochemical characterization of the native enzyme from the dimorphic pathogenic fungus Sporothrix schenckii. The availability of the pure protein facilitated its biochemical characterization. The enzyme exhibited subunit and native molecular masses of 79 and 350+/-5 kDa, respectively, suggesting a homotetrameric structure. Isoelectric point was 6.26 and K(m) values for fructose-6-phosphate and L-glutamine were 1.12+/-0.3 and 2.2+/-0.7 mM, respectively. Inhibition of activity by UDP-GlcNAc was enhanced by Glc-6-P and phosphorylation stimulated GlcN-6-P synthase activity without affecting the enzyme sensitivity to the aminosugar. A glutamine analogue, FMDP [N(3)-(4-methoxyfumaroyl)-L-2,3-diaminopropanoic acid] was a more potent inhibitor of activity than ADMP (2-Amino-2-deoxy-D-mannitol-6-phosphate) but the latter was a stronger inhibitor of growth in two culture media. To our knowledge, this is the first report on the purification and biochemical characterization of a non-recombinant GlcN-6-P synthase from a true dimorphic fungus. Inhibition of enzyme activity and fungal growth by specific inhibitors of GlcN-6-P synthase strongly reinforces the role of this enzyme as a potential target for antifungal chemotherapy. PMID:19353425

  20. Targeting caspase-6 and caspase-8 to promote neuronal survival following ischemic stroke

    PubMed Central

    Shabanzadeh, A P; D'Onofrio, P M; Monnier, P P; Koeberle, P D

    2015-01-01

    Previous studies show that caspase-6 and caspase-8 are involved in neuronal apoptosis and regenerative failure after trauma of the adult central nervous system (CNS). In this study, we evaluated whether caspase-6 or -8 inhibitors can reduce cerebral or retinal injury after ischemia. Cerebral infarct volume, relative to appropriate controls, was significantly reduced in groups treated with caspase-6 or -8 inhibitors. Concomitantly, these treatments also reduced neurological deficits, reduced edema, increased cell proliferation, and increased neurofilament levels in the injured cerebrum. Caspase-6 and -8 inhibitors, or siRNAs, also increased retinal ganglion cell survival at 14 days after ischemic injury. Caspase-6 or -8 inhibition also decreased caspase-3, -6, and caspase-8 cleavage when assayed by western blot and reduced caspase-3 and -6 activities in colorimetric assays. We have shown that caspase-6 or caspase-8 inhibition decreases the neuropathological consequences of cerebral or retinal infarction, thereby emphasizing their importance in ischemic neuronal degeneration. As such, caspase-6 and -8 are potential targets for future therapies aimed at attenuating the devastating functional losses that result from retinal or cerebral stroke. PMID:26539914

  1. Probing of the neutrino magnetic moment at the level of 10{sup -22} μ{sub B} with an intense tritium source of (anti)neutrino and helium target (project)

    SciTech Connect

    Martemyanov, V.P.; Aleshin, V.I.; Tarasenko, V.G.; Tsinoev, V.G.; Sabelnikov, A.A.; Yukhimchuk, A.A.; Popov, V.V.; Baluev, V.V.; Golubkov, A.N.; Klevtsov, V.G.; Kuryakin, A.V.; Sitdikov, D.T.; Bogdanova, L.N.

    2015-03-15

    We present research results of the preparation project for the experimental measurement of the (anti)neutrino magnetic moment at the level of 10{sup -12} μ{sub B} using an intense tritium source of antineutrinos and a liquid helium scintillation detector. The neutrino detection in the scintillation detector is based on the scattering of neutrinos by the electrons of the helium atoms that produces fast electrons able to ionize and exciting helium atoms. The detection of the atomic radiation emitted during the relaxation process of the helium atoms and the knowledge of its parameters will allow us to conclude on the neutrino properties.

  2. HDAC6 is a target for protection and regeneration following injury in the nervous system

    PubMed Central

    Rivieccio, Mark A.; Brochier, Camille; Willis, Dianna E.; Walker, Breset A.; D'Annibale, Melissa A.; McLaughlin, Kathryn; Siddiq, Ambreena; Kozikowski, Alan P.; Jaffrey, Samie R.; Twiss, Jeffery L.; Ratan, Rajiv R.; Langley, Brett

    2009-01-01

    Central nervous system (CNS) trauma can result in tissue disruption, neuronal and axonal degeneration, and neurological dysfunction. The limited spontaneous CNS repair in adulthood and aging is often insufficient to overcome disability. Several investigations have demonstrated that targeting HDAC activity can protect neurons and glia and improve outcomes in CNS injury and disease models. However, the enthusiasm for pan-HDAC inhibition in treating neurological conditions is tempered by their toxicity toward a host of CNS cell types –a biological extension of their anticancer properties. Identification of the HDAC isoform, or isoforms, that specifically mediate the beneficial effects of pan-HDAC inhibition could overcome this concern. Here, we show that pan-HDAC inhibition not only promotes neuronal protection against oxidative stress, a common mediator of injury in many neurological conditions, but also promotes neurite growth on myelin-associated glycoprotein and chondroitin sulfate proteoglycan substrates. Real-time PCR revealed a robust and selective increase in HDAC6 expression due to injury in neurons. Accordingly, we have used pharmacological and genetic approaches to demonstrate that inhibition of HDAC6 can promote survival and regeneration of neurons. Consistent with a cytoplasmic localization, the biological effects of HDAC6 inhibition appear transcription-independent. Notably, we find that selective inhibition of HDAC6 avoids cell death associated with pan-HDAC inhibition. Together, these findings define HDAC6 as a potential nontoxic therapeutic target for ameliorating CNS injury characterized by oxidative stress-induced neurodegeneration and insufficient axonal regeneration. PMID:19884510

  3. miR-135b inhibits tumour metastasis in prostate cancer by targeting STAT6

    PubMed Central

    WANG, NING; TAO, LIANGJUN; ZHONG, HUAN; ZHAO, SIHAI; YU, YING; YU, BIN; CHEN, XIAONONG; GAO, JIANGUO; WANG, RONGJIANG

    2016-01-01

    MicroRNAs (miRNAs) are small non-coding RNAs that participate in several cellular functions and tumour progression. A previous microarray study demonstrated that miR-135b is downregulated in prostate cancer (PCa) cells, but the role and molecular mechanism of miR-135b in the regulation of tumour metastasis remain to be elucidated. In the present study, significant downregulation of miR-135b in PCa tissues, compared with noncancerous tissues, was detected by reverse transcription-quantitative polymerase chain reaction. Furthermore, the expression of miR-135b was demonstrated to be associated with the pathological stage and the levels of total and free prostate-specific antigen (PSA) in PCa cells. In addition, signal transducer and activator of transcription 6 (STAT6) was identified as a target of miR-135b in PCa cells by luciferase activity and western blot assays. The upregulation of miR-135b in PCa cells led to reduced expression of STAT6 in the cytoplasm and nucleus of these cells, while the overexpression of miR-135b and knockdown of STAT6 were able to inhibit the migration and invasion abilities of PCa cells in vitro. Therefore, the results of the present study indicate that miR-135b suppresses tumour metastasis by targeting STAT6. PMID:26870245

  4. Helium abundance enhancements in the solar wind

    NASA Technical Reports Server (NTRS)

    Borrini, G.; Gosling, J. T.; Bame, S. J.; Feldman, W. C.

    1982-01-01

    Evidence for a link between helium enhancements at 1 AU and transient coronal mass ejections is provided by the statistical analysis of 73 large helium abundance enhancement observations made by IMPs 6, 7 and 8 over 1972-1978. These events, in which helium abundance enhancement is greater than about 10%, are sporadic, sometimes clustered in time, occur approximately in phase with the solar cycle, and nearly 50% of them are associated with interplanetary shocks and/or geomagnetic activity sudden commencements. The plasma pattern associated with them is nevertheless independent of shock occurrence, and features high magnetic field strength, low alpha-proton velocity difference, and low proton temperature, suggesting that the enhancement is embedded in a closed, magnetically dominated structure that expands adiabatically. Evidence of an association between helium enhancement at 1 AU and type II and IV radio bursts in the corona is presented.

  5. Interleukin-6 as a potential molecular target in esophageal squamous cell carcinoma

    PubMed Central

    ZHAO, ZHI-FEI; LI, JIAN-XIONG; YE, RUI; WU, XUAN; GAO, LING-LING; NIU, BAO-LONG

    2016-01-01

    Knowledge of potential tumor markers may improve chemotherapeutic efficacy. Interleukin-6 (IL-6) expression in local tumor tissues is associated with cancer progression and poor prognosis in variety of cancer types. The aim of the present study was to investigate the role and potential application of IL-6 in determining the prognosis of esophageal carcinoma. KYSE170 and TE13 esophageal cancer cell lines were used to conduct cell- and animal-based experiments investigating biological changes and tumor behavior. Immunohistochemical analysis revealed that 70–80% of cancer cells exhibited positive staining for IL-6, compared with <15% of non-malignant epithelial cells. These immunohistochemical results were consistent with the mRNA expression levels detetced. The IL-6 silencing vector significantly reduced invasion and proliferation of the two cell lines and attenuated tumor growth in xenograft mouse models (P<0.05). The IL-6 silencing vector markedly reduced the presence of Ki-67 (a typical proliferation marker) and microvessel density, indicating that downregulation of IL-6 levels may greatly affect tumor growth and inhibition. The IL-6 silencing vector increased E-cadherin and matrix metalloproteinase (MMP)-9 expression levels in the two esophageal carcinoma cell lines. This vector also regulated the release of IL-6 in cell supernatant and serum in KYSE170- and TE13-tumor-bearing mice. The secretion of vascular endothelial growth factor and cluster of differentiation 31 (a nuclear protein) immunoreactive molecules were also reduced by the IL-6 silencing vector. Therefore, IL-6 may be an important trigger in the progression of angiogenesis and endothelial tube formation within the tumor, and targeting IL-6 may be a promising strategy for the treatment of esophageal cancer. PMID:26893670

  6. Targeting ceramide synthase 6-dependent metastasis-prone phenotype in lung cancer cells.

    PubMed

    Suzuki, Motoshi; Cao, Ke; Kato, Seiichi; Komizu, Yuji; Mizutani, Naoki; Tanaka, Kouji; Arima, Chinatsu; Tai, Mei Chee; Yanagisawa, Kiyoshi; Togawa, Norie; Shiraishi, Takahiro; Usami, Noriyasu; Taniguchi, Tetsuo; Fukui, Takayuki; Yokoi, Kohei; Wakahara, Keiko; Hasegawa, Yoshinori; Mizutani, Yukiko; Igarashi, Yasuyuki; Inokuchi, Jin-ichi; Iwaki, Soichiro; Fujii, Satoshi; Satou, Akira; Matsumoto, Yoko; Ueoka, Ryuichi; Tamiya-Koizumi, Keiko; Murate, Takashi; Nakamura, Mitsuhiro; Kyogashima, Mamoru; Takahashi, Takashi

    2016-01-01

    Sphingolipids make up a family of molecules associated with an array of biological functions, including cell death and migration. Sphingolipids are often altered in cancer, though how these alterations lead to tumor formation and progression is largely unknown. Here, we analyzed non-small-cell lung cancer (NSCLC) specimens and cell lines and determined that ceramide synthase 6 (CERS6) is markedly overexpressed compared with controls. Elevated CERS6 expression was due in part to reduction of microRNA-101 (miR-101) and was associated with increased invasion and poor prognosis. CERS6 knockdown in NSCLC cells altered the ceramide profile, resulting in decreased cell migration and invasion in vitro, and decreased the frequency of RAC1-positive lamellipodia formation while CERS6 overexpression promoted it. In murine models, CERS6 knockdown in transplanted NSCLC cells attenuated lung metastasis. Furthermore, combined treatment with l-α-dimyristoylphosphatidylcholine liposome and the glucosylceramide synthase inhibitor D-PDMP induced cell death in association with ceramide accumulation and promoted cancer cell apoptosis and tumor regression in murine models. Together, these results indicate that CERS6-dependent ceramide synthesis and maintenance of ceramide in the cellular membrane are essential for lamellipodia formation and metastasis. Moreover, these results suggest that targeting this homeostasis has potential as a therapeutic strategy for CERS6-overexpressing NSCLC. PMID:26650179

  7. Targeting ceramide synthase 6–dependent metastasis-prone phenotype in lung cancer cells

    PubMed Central

    Suzuki, Motoshi; Cao, Ke; Kato, Seiichi; Komizu, Yuji; Mizutani, Naoki; Tanaka, Kouji; Arima, Chinatsu; Tai, Mei Chee; Yanagisawa, Kiyoshi; Togawa, Norie; Shiraishi, Takahiro; Usami, Noriyasu; Taniguchi, Tetsuo; Fukui, Takayuki; Yokoi, Kohei; Wakahara, Keiko; Hasegawa, Yoshinori; Mizutani, Yukiko; Igarashi, Yasuyuki; Inokuchi, Jin-ichi; Iwaki, Soichiro; Fujii, Satoshi; Satou, Akira; Matsumoto, Yoko; Ueoka, Ryuichi; Tamiya-Koizumi, Keiko; Murate, Takashi; Nakamura, Mitsuhiro; Kyogashima, Mamoru; Takahashi, Takashi

    2015-01-01

    Sphingolipids make up a family of molecules associated with an array of biological functions, including cell death and migration. Sphingolipids are often altered in cancer, though how these alterations lead to tumor formation and progression is largely unknown. Here, we analyzed non–small-cell lung cancer (NSCLC) specimens and cell lines and determined that ceramide synthase 6 (CERS6) is markedly overexpressed compared with controls. Elevated CERS6 expression was due in part to reduction of microRNA-101 (miR-101) and was associated with increased invasion and poor prognosis. CERS6 knockdown in NSCLC cells altered the ceramide profile, resulting in decreased cell migration and invasion in vitro, and decreased the frequency of RAC1-positive lamellipodia formation while CERS6 overexpression promoted it. In murine models, CERS6 knockdown in transplanted NSCLC cells attenuated lung metastasis. Furthermore, combined treatment with l-α-dimyristoylphosphatidylcholine liposome and the glucosylceramide synthase inhibitor D-PDMP induced cell death in association with ceramide accumulation and promoted cancer cell apoptosis and tumor regression in murine models. Together, these results indicate that CERS6-dependent ceramide synthesis and maintenance of ceramide in the cellular membrane are essential for lamellipodia formation and metastasis. Moreover, these results suggest that targeting this homeostasis has potential as a therapeutic strategy for CERS6-overexpressing NSCLC. PMID:26650179

  8. Kdm6b and Pmepa1 as Targets of Bioelectrically and Behaviorally Induced Activin A Signaling.

    PubMed

    Link, Andrea S; Kurinna, Svitlana; Havlicek, Steven; Lehnert, Sandra; Reichel, Martin; Kornhuber, Johannes; Winner, Beate; Huth, Tobias; Zheng, Fang; Werner, Sabine; Alzheimer, Christian

    2016-08-01

    The transforming growth factor-β (TGF-β) family member activin A exerts multiple neurotrophic and protective effects in the brain. Activin also modulates cognitive functions and affective behavior and is a presumed target of antidepressant therapy. Despite its important role in the injured and intact brain, the mechanisms underlying activin effects in the CNS are still largely unknown. Our goal was to identify the first target genes of activin signaling in the hippocampus in vivo. Electroconvulsive seizures, a rodent model of electroconvulsive therapy in humans, were applied to C57BL/6J mice to elicit a strong increase in activin A signaling. Chromatin immunoprecipitation experiments with hippocampal lysates subsequently revealed that binding of SMAD2/3, the intracellular effectors of activin signaling, was significantly enriched at the Pmepa1 gene, which encodes a negative feedback regulator of TGF-β signaling in cancer cells, and at the Kdm6b gene, which encodes an epigenetic regulator promoting transcriptional plasticity. Underlining the significance of these findings, activin treatment also induced PMEPA1 and KDM6B expression in human forebrain neurons generated from embryonic stem cells suggesting interspecies conservation of activin effects in mammalian neurons. Importantly, physiological stimuli such as provided by environmental enrichment proved already sufficient to engender a rapid and significant induction of activin signaling concomitant with an upregulation of Pmepa1 and Kdm6b expression. Taken together, our study identified the first target genes of activin signaling in the brain. With the induction of Kdm6b expression, activin is likely to gain impact on a presumed epigenetic regulator of activity-dependent neuronal plasticity. PMID:26215835

  9. Microglia-specific targeting by novel capsid-modified AAV6 vectors

    PubMed Central

    Rosario, Awilda M; Cruz, Pedro E; Ceballos-Diaz, Carolina; Strickland, Michael R; Siemienski, Zoe; Pardo, Meghan; Schob, Keri-Lyn; Li, Andrew; Aslanidi, George V; Srivastava, Arun; Golde, Todd E; Chakrabarty, Paramita

    2016-01-01

    Recombinant adeno-associated viruses (rAAV) have been widely used in gene therapy applications for central nervous system diseases. Though rAAV can efficiently target neurons and astrocytes in mouse brains, microglia, the immune cells of the brain, are refractile to rAAV. To identify AAV capsids with microglia-specific transduction properties, we initially screened the most commonly used serotypes, AAV1–9 and rh10, on primary mouse microglia cultures. While these capsids were not permissive, we then tested the microglial targeting properties of a newly characterized set of modified rAAV6 capsid variants with high tropism for monocytes. Indeed, these newly characterized rAAV6 capsid variants, specially a triply mutated Y731F/Y705F/T492V form, carrying a self-complementary genome and microglia-specific promoters (F4/80 or CD68) could efficiently and selectively transduce microglia in vitro. Delivery of these constructs in mice brains resulted in microglia-specific expression of green fluorescent protein, albeit at modest levels. We further show that CD68 promoter–driven expression of the inflammatory cytokine, interleukin-6, using this capsid variant leads to increased astrogliosis in the brains of wild-type mice. Our study describes the first instance of AAV-targeted microglial gene expression leading to functional modulation of the innate immune system in mice brains. This provides the rationale for utilizing these unique capsid/promoter combinations for microglia-specific gene targeting for modeling or functional studies. PMID:27308302

  10. Histone acetyltransferase inhibitor CPTH6 preferentially targets lung cancer stem-like cells

    PubMed Central

    Di Martile, Marta; Desideri, Marianna; De Luca, Teresa; Gabellini, Chiara; Buglioni, Simonetta; Eramo, Adriana; Sette, Giovanni; Milella, Michele; Rotili, Dante; Mai, Antonello; Carradori, Simone; Secci, Daniela; De Maria, Ruggero; Del Bufalo, Donatella; Trisciuoglio, Daniela

    2016-01-01

    Cancer stem cells (CSCs) play an important role in tumor initiation, progression, therapeutic failure and tumor relapse. In this study, we evaluated the efficacy of the thiazole derivative 3-methylcyclopentylidene-[4-(4′-chlorophenyl)thiazol-2-yl]hydrazone (CPTH6), a novel pCAF and Gcn5 histone acetyltransferase inhibitor, as a small molecule that preferentially targets lung cancer stem-like cells (LCSCs) derived from non-small cell lung cancer (NSCLC) patients. Notably, although CPTH6 inhibits the growth of both LCSC and NSCLC cell lines, LCSCs exhibit greater growth inhibition than established NSCLC cells. Growth inhibitory effect of CPTH6 in LCSC lines is primarily due to apoptosis induction. Of note, differentiated progeny of LCSC lines is more resistant to CPTH6 in terms of loss of cell viability and reduction of protein acetylation, when compared to their undifferentiated counterparts. Interestingly, in LCSC lines CPTH6 treatment is also associated with a reduction of stemness markers. By using different HAT inhibitors we provide clear evidence that inhibition of HAT confers a strong preferential inhibitory effect on cell viability of undifferentiated LCSC lines when compared to their differentiated progeny. In vivo, CPTH6 is able to inhibit the growth of LCSC-derived xenografts and to reduce cancer stem cell content in treated tumors, as evidenced by marked reduction of tumor-initiating capacity in limiting dilution assays. Strikingly, the ability of CPTH6 to inhibit tubulin acetylation is also confirmed in vivo. Overall, our studies propose histone acetyltransferase inhibition as an attractive target for cancer therapy of NSCLC. PMID:26870991

  11. Histone acetyltransferase inhibitor CPTH6 preferentially targets lung cancer stem-like cells.

    PubMed

    Di Martile, Marta; Desideri, Marianna; De Luca, Teresa; Gabellini, Chiara; Buglioni, Simonetta; Eramo, Adriana; Sette, Giovanni; Milella, Michele; Rotili, Dante; Mai, Antonello; Carradori, Simone; Secci, Daniela; De Maria, Ruggero; Del Bufalo, Donatella; Trisciuoglio, Daniela

    2016-03-01

    Cancer stem cells (CSCs) play an important role in tumor initiation, progression, therapeutic failure and tumor relapse. In this study, we evaluated the efficacy of the thiazole derivative 3-methylcyclopentylidene-[4-(4'-chlorophenyl)thiazol-2-yl]hydrazone (CPTH6), a novel pCAF and Gcn5 histone acetyltransferase inhibitor, as a small molecule that preferentially targets lung cancer stem-like cells (LCSCs) derived from non-small cell lung cancer (NSCLC) patients. Notably, although CPTH6 inhibits the growth of both LCSC and NSCLC cell lines, LCSCs exhibit greater growth inhibition than established NSCLC cells. Growth inhibitory effect of CPTH6 in LCSC lines is primarily due to apoptosis induction. Of note, differentiated progeny of LCSC lines is more resistant to CPTH6 in terms of loss of cell viability and reduction of protein acetylation, when compared to their undifferentiated counterparts. Interestingly, in LCSC lines CPTH6 treatment is also associated with a reduction of stemness markers. By using different HAT inhibitors we provide clear evidence that inhibition of HAT confers a strong preferential inhibitory effect on cell viability of undifferentiated LCSC lines when compared to their differentiated progeny. In vivo, CPTH6 is able to inhibit the growth of LCSC-derived xenografts and to reduce cancer stem cell content in treated tumors, as evidenced by marked reduction of tumor-initiating capacity in limiting dilution assays. Strikingly, the ability of CPTH6 to inhibit tubulin acetylation is also confirmed in vivo. Overall, our studies propose histone acetyltransferase inhibition as an attractive target for cancer therapy of NSCLC. PMID:26870991

  12. The E6 Oncoproteins of High-Risk Papillomaviruses Bind to a Novel Putative GAP Protein, E6TP1, and Target It for Degradation

    PubMed Central

    Gao, Qingshen; Srinivasan, Seetha; Boyer, Sarah N.; Wazer, David E.; Band, Vimla

    1999-01-01

    The high-risk human papillomaviruses (HPVs) are associated with carcinomas of the cervix and other genital tumors. Previous studies have identified two viral oncoproteins, E6 and E7, which are expressed in the majority of HPV-associated carcinomas. The ability of high-risk HPV E6 protein to immortalize human mammary epithelial cells (MECs) has provided a single-gene model to study the mechanisms of E6-induced oncogenic transformation. In this system, the E6 protein targets the p53 tumor suppressor protein for degradation, and mutational analyses have shown that E6-induced degradation of p53 protein is required for MEC immortalization. However, the inability of most dominant-negative p53 mutants to induce efficient immortalization of MECs suggests the existence of additional targets of the HPV E6 oncoprotein. Using the yeast two-hybrid system, we have isolated a novel E6-binding protein. This polypeptide, designated E6TP1 (E6-targeted protein 1), exhibits high homology to GTPase-activating proteins for Rap, including SPA-1, tuberin, and Rap1GAP. The mRNA for E6TP1 is widely expressed in tissues and in vitro-cultured cell lines. The gene for E6TP1 localizes to chromosome 14q23.2-14q24.3 within a locus that has been shown to undergo loss of heterozygosity in malignant meningiomas. Importantly, E6TP1 is targeted for degradation by the high-risk but not the low-risk HPV E6 proteins both in vitro and in vivo. Furthermore, the immortalization-competent but not the immortalization-incompetent HPV16 E6 mutants target the E6TP1 protein for degradation. Our results identify a novel target for the E6 oncoprotein and provide a potential link between HPV E6 oncogenesis and alteration of a small G protein signaling pathway. PMID:9858596

  13. Interleukin-6 receptor specific RNA aptamers for cargo delivery into target cells

    PubMed Central

    Meyer, Cindy; Eydeler, Katja; Magbanua, Eileen; Zivkovic, Tijana; Piganeau, Nicolas; Lorenzen, Inken; Grötzinger, Joachim; Mayer, Günter; Rose-John, Stefan; Hahn, Ulrich

    2012-01-01

    Aptamers represent an emerging strategy to deliver cargo molecules, including dyes, drugs, proteins or even genes, into specific target cells. Upon binding to specific cell surface receptors aptamers can be internalized, for example by macropinocytosis or receptor mediated endocytosis. Here we report the in vitro selection and characterization of RNA aptamers with high affinity (Kd = 20 nM) and specificity for the human IL-6 receptor (IL-6R). Importantly, these aptamers trigger uptake without compromising the interaction of IL-6R with its natural ligands the cytokine IL-6 and glycoprotein 130 (gp130). We further optimized the aptamers to obtain a shortened, only 19-nt RNA oligonucleotide retaining all necessary characteristics for high affinity and selective recognition of IL-6R on cell surfaces. Upon incubation with IL-6R presenting cells this aptamer was rapidly internalized. Importantly, we could use our aptamer, to deliver bulky cargos, exemplified by fluorescently labeled streptavidin, into IL-6R presenting cells, thereby setting the stage for an aptamer-mediated escort of drug molecules to diseased cell populations or tissues. PMID:22258147

  14. REG4 is a transcriptional target of GATA6 and is essential for colorectal tumorigenesis.

    PubMed

    Kawasaki, Yoshihiro; Matsumura, Kosuke; Miyamoto, Masaya; Tsuji, Shinnosuke; Okuno, Masumi; Suda, Sakiko; Hiyoshi, Masaya; Kitayama, Joji; Akiyama, Tetsu

    2015-01-01

    The transcription factor GATA6 is a critical regulator of cell proliferation and development in the gastrointestinal tract. We have recently reported that GATA6 induces the expression of the intestinal stem cell marker LGR5 and enhances the clonogenicity and tumorigenicity of colon cancer cells, but not the growth of these cells cultured under adherent conditions. Here we show that REG4, a member of the regenerating islet-derived (REG) family, is also a target of GATA6. We further demonstrate that REG4 is downregulated by overexpression of miR-363, which suppresses GATA6 expression. Moreover, we show that GATA6-mediated activation of REG4 enhances the growth of colon cancer cells under adherent conditions and is required for their tumorigenicity. Taken together, our findings demonstrate that GATA6 simultaneously induces the expression of genes essential for the growth of colon cancer cells under adherent conditions (REG4) and genes required for their clonogenicity (LGR5), and that the miR-363-GATA6-REG4/LGR5 signaling cascade promotes the tumorigenicity of colon cancer cells. PMID:26387746

  15. The Ras Target AF-6 is a Substrate of the Fam Deubiquitinating Enzyme

    PubMed Central

    Taya, Shinichiro; Yamamoto, Takaharu; Kano, Kyoko; Kawano, Yoji; Iwamatsu, Akihiro; Tsuchiya, Tomoko; Tanaka, Keiji; Kanai-Azuma, Masami; Wood, Stephen A.; Mattick, John S.; Kaibuchi, Kozo

    1998-01-01

    The Ras target AF-6 has been shown to serve as one of the peripheral components of cell–cell adhesions, and is thought to participate in cell–cell adhesion regulation downstream of Ras. We here purified an AF-6-interacting protein with a molecular mass of ∼220 kD (p220) to investigate the function of AF-6 at cell–cell adhesions. The peptide sequences of p220 were identical to the amino acid sequences of mouse Fam. Fam is homologous to a deubiquitinating enzyme in Drosophila, the product of the fat facets gene. Recent genetic analyses indicate that the deubiquitinating activity of the fat facets product plays a critical role in controlling the cell fate. We found that Fam accumulated at the cell–cell contact sites of MDCKII cells, but not at free ends of plasma membranes. Fam was partially colocalized with AF-6 and interacted with AF-6 in vivo and in vitro. We also showed that AF-6 was ubiquitinated in intact cells, and that Fam prevented the ubiquitination of AF-6. PMID:9722616

  16. Generation of hard x rays by femtosecond laser pulse interaction with Cu in laminar helium flow in ambient air

    SciTech Connect

    Hou Bixue; Easter, James; Krushelnick, Karl; Nees, John A.

    2008-04-21

    Hard x rays are generated in laminar helium flow in atmosphere (without a vacuum vessel) through the interaction of tightly focused 35 fs laser pulses of varying energy with a Cu target. The energy conversion efficiency from laser to K{alpha} x rays is measured to be 5.4x10{sup -6}, giving a flux of 5.9x10{sup 9} photons/s into 2{pi} sr from a source measuring approximately 9x12 {mu}m{sup 2} in size (verticalxhorizontal). Results are compared to those measured in vacuum and in static helium environments.

  17. Eupatilin inhibits EGF-induced JB6 cell transformation by targeting PI3K.

    PubMed

    Li, Feng; Tao, Ya; Qiao, Yan; Li, Ke; Jiang, Yanan; Cao, Chang; Ren, Shuxin; Chang, Xiaobin; Wang, Xiaona; Wang, Yanhong; Xie, Yifei; Dong, Ziming; Zhao, Jimin; Liu, Kangdong

    2016-09-01

    Phosphatidylinositol 3-kinases (PI3Ks) are lipid kinases that play fundamental roles in regulation of multiple signaling pathways, including cell proliferation, survival and cell cycle. Increasing evidence has shown that abnormal activation of PI3K pathway contributes to tumorigenesis and progression of various malignant tumors. Therefore, it is an attractive target of chemoprevention and chemotherapy. Eupatilin, a natural flavone compound extracted from Artemisia vulgaris, has antitumor and anti-inflammation efficacy. However, the direct target(s) of eupatilin in cancer chemoprevention are still elusive. In the present study, we reported eupatilin suppressed JB6 cell proliferation and its EGF-induced colony formation. Eupatilin attenuated phosphorylation of PI3K downstream signaling molecules. Downregulation of cyclin D1 expression and arresting in G1 phase were induced through eupatilin treatment. Furthermore, we found it could bind to the p110α, a catalytic subunit of PI3K, by computational docking methods. Pull down assay outcomes also verified the binding of eupatilin with PI3K. Taken together, our results suggest that epatilin is a potential chemopreventive agent in inhibition of skin cell transformation by targeting PI3K. PMID:27573489

  18. A Chemical Biology Approach to Reveal Sirt6-targeted Histone H3 Sites in Nucleosomes.

    PubMed

    Wang, Wesley Wei; Zeng, Yu; Wu, Bo; Deiters, Alexander; Liu, Wenshe R

    2016-07-15

    As a member of a highly conserved family of NAD(+)-dependent histone deacetylases, Sirt6 is a key regulator of mammalian genome stability, metabolism, and life span. Previous studies indicated that Sirt6 is hardwired to remove histone acetylation at H3K9 and H3K56. However, how Sirt6 recognizes its nucleosome substrates has been elusive due to the difficulty of accessing homogeneous acetyl-nucleosomes and the low activity of Sirt6 toward peptide substrates. Based on the fact that Sirt6 has an enhanced activity to remove long chain fatty acylation from lysine, we developed an approach to recombinantly synthesize histone H3 with a fatty acylated lysine, N(ε)-(7-octenoyl)-lysine (OcK), installed at a number of lysine sites and used these acyl-H3 proteins to assemble acyl-nucleosomes as active Sirt6 substrates. A chemical biology approach that visualizes OcK in nucleosomes and therefore allows direct sensitization of Sirt6 activities on its acyl-nucleosome substrates was also formulated. By combining these two approaches, we showed that Sirt6 actively removes acylation from H3K9, H3K18, and H3K27; has relatively low activities toward H3K4 and K3K23; but sluggishly removes acylation at H3K14, H3K36, H3K56, and H3K79. Overexpressing Sirt6 in 293T cells led to downregulated acetylation at H3K18 and K3K27, confirming these two novel Sirt6-targeted nucleosome lysine sites in cells. Given that downregulation of H3K18 acetylation is correlated with a poor prognosis of several cancer types and H3K27 acetylation antagonizes repressive gene regulation by di- and trimethylation at H3K27, our current study implies that Sirt6 may serve as a target for cancer intervention and regulatory pathway investigation in cells. PMID:27152839

  19. Annual Cosmic Ray Spectra from 250 MeV up to 1.6 GeV from 1995 - 2014 Measured with the Electron Proton Helium Instrument onboard SOHO

    NASA Astrophysics Data System (ADS)

    Kühl, P.; Gómez-Herrero, R.; Heber, B.

    2016-03-01

    The solar modulation of galactic cosmic rays (GCR) can be studied in detail by examining long-term variations of the GCR energy spectrum ( e.g. on the scales of a solar cycle). With almost 20 years of data, the Electron Proton Helium INstrument (EPHIN) onboard the SOlar and Heliospheric Observatory (SOHO) is well suited for this kind of investigation. Although the design of the instrument is optimised to measure proton and helium isotope spectra up to 50 MeV nucleon^{-1}, the capability exists to determine proton energy spectra from 250 MeV up to above 1.6 GeV. Therefore we developed a sophisticated inversion method to calculate such proton spectra. The method relies on a GEANT4 Monte Carlo simulation of the instrument and a simplified spacecraft model that calculates the energy-response function of EPHIN for electrons, protons, and heavier ions. For validation purposes, proton spectra based on this method are compared to various balloon missions and space instrumentation. As a result we present annual galactic cosmic-ray spectra from 1995 to 2014.

  20. Cyclic Nucleotide-dependent Protein Kinases Target ARHGAP17 and ARHGEF6 Complexes in Platelets.

    PubMed

    Nagy, Zoltan; Wynne, Kieran; von Kriegsheim, Alexander; Gambaryan, Stepan; Smolenski, Albert

    2015-12-11

    Endothelial cells release prostacyclin (PGI2) and nitric oxide (NO) to inhibit platelet functions. PGI2 and NO effects are mediated by cyclic nucleotides, cAMP- and cGMP-dependent protein kinases (PKA, PKG), and largely unknown PKA and PKG substrate proteins. The small G-protein Rac1 plays a key role in platelets and was suggested to be a target of cyclic nucleotide signaling. We confirm that PKA and PKG activation reduces Rac1-GTP levels. Screening for potential mediators of this effect resulted in the identification of the Rac1-specific GTPase-activating protein ARHGAP17 and the guanine nucleotide exchange factor ARHGEF6 as new PKA and PKG substrates in platelets. We mapped the PKA/PKG phosphorylation sites to serine 702 on ARHGAP17 using Phos-tag gels and to serine 684 on ARHGEF6. We show that ARHGAP17 binds to the actin-regulating CIP4 protein in platelets and that Ser-702 phosphorylation interferes with this interaction. Reduced CIP4 binding results in enhanced inhibition of cell migration by ARHGAP17. Furthermore, we show that ARHGEF6 is constitutively linked to GIT1, a GAP of Arf family small G proteins, and that ARHGEF6 phosphorylation enables binding of the 14-3-3 adaptor protein to the ARHGEF6/GIT1 complex. PKA and PKG induced rearrangement of ARHGAP17- and ARHGEF6-associated protein complexes might contribute to Rac1 regulation and platelet inhibition. PMID:26507661

  1. Targeted photodestruction of human colon cancer cells using charged Dougherty chlorine6immunoconjugates

    PubMed Central

    Governatore, M Del; Hamblin, MR; Piccinini, EE; Ugolini, G; Hasan, T

    1999-01-01

    The goal of this study was to develop a strategy for the selective destruction of colorectal cancer cells. Towards this end, photoimmunoconjugates were prepared between the anti-colon cancer monoclonal antibody 17.1A and the photosensitizer (PS) chlorine6(ce6). Polylysine linkers bearing several ce6molecules were covalently attached in a site-specific manner to partially reduced IgG molecules, which allowed photoimmunoconjugates to bear either cationic or anionic charges. The conjugates retained immunoreactivity as shown by enzyme-linked immunosorbent assays and by competition studies with native antibody. The overall charge on the photoimmunoconjugate was an important determinant of PS delivery. The cationic photoimmunoconjugate delivered 4 times more ce6to the cells than the anionic photoimmunoconjugate, and both 17.1A conjugates showed, in comparison to non-specific rabbit IgG conjugates, selectivity for antigen-positive target cells. Illumination with only 3 J cm−2of 666 nm light reduced the number of colony forming cells by more than 90% for the cationic 17.1A conjugate and by 73% for the anionic 17.1A conjugate after incubation with 1 μM ce6equivalent of the respective conjugates. By contrast, 1 μM free ce6gave only a 35% reduction in colonies. These data suggest photoimmunoconjugates may have applications in photoimmunotherapy where destruction of colorectal cancer cells is required. © 2000 Cancer Research Campaign PMID:10638967

  2. The Descending Helium Balloon

    ERIC Educational Resources Information Center

    Helseth, Lars Egil

    2014-01-01

    I describe a simple and fascinating experiment wherein helium leaks out of a rubber balloon, thereby causing it to descend. An estimate of the volumetric leakage rate is made by measuring its rate of descent.

  3. Collisional quenching of rotations in lithium dimers by ultracold helium: The Li2(a 3Σu+) and Li2+(X 2Σg+) targets

    NASA Astrophysics Data System (ADS)

    González-Sánchez, L.; Bodo, E.; Gianturco, F. A.

    2007-12-01

    Quantum coupled-channel scattering calculations have been carried out at ultralow energies (down to 10-5K) for rotational quenching of ionic and spin-stretched states of the lithium dimer in collision with He atoms. Marked cross section differences, to be related to changes in their interactions with He, have been observed with respect to the singlet case while little changes in the collisional behavior are seen to occur upon ionization when the spin-stretched target is considered. Both effects originate from an interplay of structural and dynamical features of the colliding partners which are analyzed in detail.

  4. Collisional electron detachment and decomposition cross sections for SF - 6, SF - 5, and F - on SF6 and rare gas targets

    NASA Astrophysics Data System (ADS)

    Wang, Yicheng; Champion, R. L.; Doverspike, L. D.; Olthoff, J. K.; Van Brunt, R. J.

    1989-08-01

    Absolute total cross sections for collisional electron detachment and collision-induced dissociation (CID) have been measured for binary collisions of SF-6 and SF-5 with rare gas and SF6 targets for laboratory collision energies ranging from about 10 up to 500 eV. The cross sections for electron detachment of SF-6 are found to be surprisingly small, especially for the SF6 target, for relative collision energies below several tens of electron volts. Specifically, detachment onsets are found to occur at around 30 and 90 eV for the rare gas and SF6 targets, respectively. The CID channel which leads to F- as a product is observed to dominate detachment for relative collision energies below 100 eV. The results for the SF-5 projectile are remarkably similar to those exhibited for SF-6. The role of long-lived excited states in the reactant SF6 ion beam is discussed.

  5. Noncavitating Pump For Liquid Helium

    NASA Technical Reports Server (NTRS)

    Hasenbein, Robert; Izenson, Michael; Swift, Walter; Sixsmith, Herbert

    1996-01-01

    Immersion pump features high efficiency in cryogenic service. Simple and reliable centrifugal pump transfers liquid helium with mass-transfer efficiency of 99 percent. Liquid helium drawn into pump by helical inducer, which pressurizes helium slightly to prevent cavitation when liquid enters impeller. Impeller then pressurizes liquid. Purpose of pump to transfer liquid helium from supply to receiver vessel, or to provide liquid helium flow for testing and experimentation.

  6. A Measurement of the neutron electric form factor at very large momentum transfer using polaried electrions scattering from a polarized helium-3 target

    SciTech Connect

    Kelleher, Aidan

    2010-02-01

    Knowledge of the electric and magnetic elastic form factors of the nucleon is essential for an understanding of nucleon structure. Of the form factors, the electric form factor of the neutron has been measured over the smallest range in Q2 and with the lowest precision. Jefferson Lab experiment 02-013 used a novel new polarized 3 He target to nearly double the range of momentum transfer in which the neutron form factor has been studied and to measure it with much higher precision. Polarized electrons were scattered off this target, and both the scattered electron and neutron were detected. Gn E was measured to be 0.0242 ± 0.0020(stat) ± 0.0061(sys) and 0.0247 ± 0.0029(stat) ± 0.0031(sys) at Q2 = 1.7 and 2.5 GeV2 , respectively.

  7. Preclinical validation of a novel compound targeting p70S6 kinase in breast cancer

    PubMed Central

    Segatto, Ilenia; Massarut, Samuele; Boyle, Robert; Baldassarre, Gustavo; Walker, David; Belletti, Barbara

    2016-01-01

    Breast cancer is a frequent and treatable disease. However, when recurrent, breast cancer often becomes refractory to therapy and progresses into metastatic forms that are typically incurable. Thus, understanding and targeting the critical pathways underlying breast cancer recurrence is urgently needed to eradicate primary disease and achieve better prognosis. Recently, we have demonstrated that the ribosomal protein p70S6K is activated in residual breast cancer cells as a result of post-surgical inflammation and that interfering with its activity in the peri-operative setting strongly suppresses recurrence in a mouse model. In order to develop clinically-exploitable treatments targeting p70S6K, we have tested a newly generated compound, called FS-115. FS-115 potently inhibited p70S6K1 (IC50 35nM) with high selectivity over other AGC kinases or PI3K pathway kinases. In vitro, treatment with FS-115 efficiently blocked p70S6K activity in breast cancer cell lines and impaired colony formation and anchorage independent growth. Pharmacokinetic profiling showed that FS-115 exhibited high oral bioavailability, optimal plasma distribution and high brain penetrance. In nude mice, FS-115 strongly suppressed tumor take-rate and primary tumor growth. Oral dosing with FS-115 in a peri-operative schedule was effective in decreasing local recurrence of breast cancer and a long-term treatment schedule was well tolerated and efficiently suppressed distant metastasis formation. Altogether, we propose that FS-115 might be a good candidate for the treatment of breast cancer patients at high risk to relapse. Summary Statement Our results confirm that inhibition of p70S6K represents a valuable opportunity for restraining loco-regional relapse and metastasis in breast cancer and identify in FS-115 a promising candidate-inhibitor to move from preclinical to clinical treatments. PMID:27155197

  8. Targeting of GLUT6 (formerly GLUT9) and GLUT8 in rat adipose cells.

    PubMed Central

    Lisinski, I; Schürmann, A; Joost, H G; Cushman, S W; Al-Hasani, H

    2001-01-01

    The subcellular targeting of the two recently cloned novel mammalian glucose transporters, GLUT6 [previously referred to as GLUT9 [Doege, Bocianski, Joost and Schürmann (2000) Biochem. J. 350, 771-776] and GLUT8, was analysed by expression of haemagglutinin (HA)-epitope-tagged GLUTs in transiently transfected primary rat adipose cells. Similar to HA-GLUT4, both transporters, HA-GLUT6 and HA-GLUT8, were retained in intracellular compartments in non-stimulated cells. In contrast, mutation of the N-terminal dileucine motifs in both constructs led to constitutive expression of the proteins on the plasma membrane. Likewise, when endocytosis was blocked by co-expression of a dominant-negative mutant of the dynamin GTPase, wild-type HA-GLUT6 and HA-GLUT8 accumulated on the cell surface. However, in contrast with HA-GLUT4, no translocation of HA-GLUT6 and HA-GLUT8 to the plasma membrane was observed when the cells were stimulated with insulin, phorbol ester or hyperosmolarity. Thus GLUT6 and GLUT8 appear to recycle in a dynamin-dependent manner between internal membranes and the plasma membrane in rat adipose cells, but are unresponsive to stimuli that induce translocation of GLUT4. PMID:11513753

  9. Precision spectroscopy of Kaonic helium-3 and helium-4 3d-->2p X-rays

    NASA Astrophysics Data System (ADS)

    Ishiwatari, T.; Bazzi, M.; Bhang, H.; Beer, G.; Bombelli, L.; Bragadireanu, A. M.; Cargnelli, M.; Choi, S.; Corradi, G.; Curceanu, C.; d'Uffizi, A.; Enomoto, S.; Fiorini, C.; Frizzi, T.; Fujioka, H.; Fujiwara, Y.; Ghio, F.; Girolami, B.; Guaraldo, C.; Hashimoto, T.; Hayano, R. S.; Hiraiwa, T.; Iio, M.; Iliescu, M.; Ishimoto, S.; Itahashi, K.; Iwasaki, M.; Kienle, P.; Kou, H.; Levi Sandri, P.; Longoni, A.; Lucherini, V.; Marton, J.; Matsuda, Y.; Noumi, H.; Ohnishi, H.; Okada, S.; Outa, H.; Pietreanu, D.; Ponta, T.; Rizzo, A.; Romero Vidal, A.; Sakuma, F.; Sato, M.; Scordo, A.; Sekimoto, M.; Shi, H.; Sirghi, D. L.; Sirghi, F.; Suzuki, T.; Tanida, K.; Tatsuno, H.; Tokuda, M.; Tomono, D.; Toyoda, A.; Tsukada, K.; Tudorache, A.; Tudorache, V.; Vazquez Doce, O.; Widmann, E.; Wünschek, B.; Yamazaki, T.; Zmeskal, J.

    2010-08-01

    Recently, the shift of the kaonic helium-4 2p state was precisely determined by the E570 and SIDDHARTA experiments. Prior to the experiment by E570, the average of three earlier experimental results showed -43±8 eV, while most of the theoretical calculations give ˜0 eV. This five-sigma discrepancy between theory and experiment was known as the "kaonic helium puzzle". A recent theoretical model showed a possible resonance-like shift of maximum 10 eV for a certain value of a deep antikaon-nucleon interaction potential, which is different in helium 3 and helium 4. The E570 experiment determined the shift of the kaonic helium-4 2p state as +2±2 (stat)±2 (sys) eV in 2007. The SIDDHARTA experiment determined the shift as 0±6(stat)±2(sys) eV in 2009. The results of these experiments resolved the long-standing puzzle. A new experiment of the kaonic helium-3 X-ray measurement is being prepared by the J-PARC E17 collaborators, and the kaonic helium-3 X-ray data taken very recently by the SIDDHARTA experiment are on the way to be analyzed. The results of the E570, E17 and SIDDHARTA experiments examine the strong interaction for light nuclei with different isospin, and test furthermore recent theoretical predictions.

  10. Thorium and uranium M-shell x-ray production cross sections for 0.4--4.0 MeV protons, 0.4--6.0 MeV helium ions, 4.5--11.3 mev carbon ions, and 4.5--13.5 MeV oxygen ions

    NASA Astrophysics Data System (ADS)

    Phinney, Lucas C.

    The M-shell x-ray production cross section for thorium and uranium have been determined for protons of energy 0.4--4.0 MeV, helium ions of energy 0.4--6.0 MeV, carbon ions of energy 4.5--11.3 MeV and oxygen ions of energy 4.5--13.5 MeV. The total cross sections and the cross sections for individual x-ray peaks in the spectrum, consisting of the following transitions Mz (M4-N2, M5-N3, M4-N3), Ma (M5-N6,7), Mb (M4-N6, M5-O3, M4-O2), and Mg (M4-O3, M5-P3, M3-N4, M3-N5), were compared to the theoretical values determined from the PWBA + OBKN and ECUSAR. The theoretical values for the carbon and oxygen ions were also modified to take into account the effects of multiple ionizations of the target atom by the heavier ions. It is shown that the results of the ECUSAR theory tend to provide better agreement with the experimental data.

  11. p30, a novel protein target of mouse calcyclin (S100A6).

    PubMed Central

    Filipek, A; Wojda, U

    1996-01-01

    A novel protein target of mouse calcyclin (S100A6) was detected by a gel overlay method with 125I-labelled calcyclin. Interaction of calcyclin with its 30 kDa target protein (p30) present in Ehrlich ascites tumour (EAT) cells depended on the presence of Ca2+ ions. The binding of p30, evidenced by the reaction with 125I-labelled calcyclin, was found to be of higher affinity than the binding between mouse calcyclin and annexin II or glyceraldehyde-3-phosphate dehydrogenase. Examination of tissue extracts by the gel overlay method has shown that p30 is present not only in the EAT cells but also in mouse brain and spleen. This novel target protein of mouse calcyclin was purified to homogeneity from EAT cells by means of Phenyl-Sepharose chromatography, affinity chromatography and CM-cellulose chromatography. Purified p30 was digested with alpha-chymotrypsin and a partial amino acid sequence of one of the resulting peptides was established. A database search analysis revealed that the sequence is unique, with a similarity of less than 55% to any other known protein sequence. PMID:8973570

  12. Comparing MODIS C6 'Deep Blue' and 'Dark Target' Aerosol Data

    NASA Technical Reports Server (NTRS)

    Hsu, N. C.; Sayer, A. M.; Bettenhausen, C.; Lee, J.; Levy, R. C.; Mattoo, S.; Munchak, L. A.; Kleidman, R.

    2014-01-01

    The MODIS Collection 6 Atmospheres product suite includes refined versions of both 'Deep Blue' (DB) and 'Dark Target' (DT) aerosol algorithms, with the DB dataset now expanded to include coverage over vegetated land surfaces. This means that, over much of the global land surface, users will have both DB and DT data to choose from. A 'merged' dataset is also provided, primarily for visualization purposes, which takes retrievals from either or both algorithms based on regional and seasonal climatologies of normalized difference vegetation index (NDVI). This poster present some comparisons of these two C6 aerosol algorithms, focusing on AOD at 550 nm derived from MODIS Aqua measurements, with each other and with Aerosol Robotic Network (AERONET) data, with the intent to facilitate user decisions about the suitability of the two datasets for their desired applications.

  13. Electronic detection of target nucleic acids by a 2,6-disulfonic acid anthraquinone intercalator.

    PubMed

    Wong, Elicia L S; Gooding, J Justin

    2003-08-01

    A DNA hybridization biosensor based on long-range electron transfer that is capable of detecting DNA single-base mismatch is presented. A mixed self-assembled monolayer of single-stranded DNA (ss-DNA), thiolated at the 3' end, and 6-mercapto-1-hexanol was formed on a gold surface. This probe ss-DNA-modified gold surface was incubated in 2,6-disulfonic acid anthraquinone (AQDS) intercalator solution, rinsed, and placed in an AQDS-free buffer solution, whereupon voltammetric experiments were performed. No voltammetric peaks were observed for probe ss-DNA-modified gold electrodes. Upon DNA hybridization and incubation in AQDS, clear voltammetric peaks, consistent with the oxidation and reduction of AQDS, were observed. The absence of AQDS electrochemistry for ss-DNA-modified surfaces clearly shows the electrochemistry is due to long-range electron transfer through the DNA duplex. No peak currents were observed when the probe ss-DNA-modified surface was exposed to noncomplementary target DNA, but there was a diminution in current signal upon hybridization with C-A mismatched and a G-A mismatched targets. PMID:14572052

  14. Therapeutic Targeting of Integrin αvβ6 in Breast Cancer

    PubMed Central

    Moore, Kate M.; Thomas, Gareth J.; Duffy, Stephen W.; Warwick, Jane; Gabe, Rhian; Chou, Patrick; Ellis, Ian O.; Green, Andrew R.; Haider, Syed; Brouilette, Kellie; Saha, Antonio; Vallath, Sabari; Bowen, Rebecca; Chelala, Claude; Eccles, Diana; Tapper, William J.; Thompson, Alastair M.; Quinlan, Phillip; Jordan, Lee; Gillett, Cheryl; Brentnall, Adam; Violette, Shelia; Weinreb, Paul H.; Kendrew, Jane; Barry, Simon T.; Hart, Ian R.; Jones, J. Louise; Marshall, John F.

    2014-01-01

    Background Integrin αvβ6 promotes migration, invasion, and survival of cancer cells; however, the relevance and role of αvβ6 has yet to be elucidated in breast cancer. Methods Protein expression of integrin subunit beta66) was measured in breast cancers by immunohistochemistry (n > 2000) and ITGB6 mRNA expression measured in the Molecular Taxonomy of Breast Cancer International Consortium dataset. Overall survival was assessed using Kaplan Meier curves, and bioinformatics statistical analyses were performed (Cox proportional hazards model, Wald test, and Chi-square test of association). Using antibody (264RAD) blockade and siRNA knockdown of β6 in breast cell lines, the role of αvβ6 in Human Epidermal Growth Factor Receptor 2 (HER2) biology (expression, proliferation, invasion, growth in vivo) was assessed by flow cytometry, MTT, Transwell invasion, proximity ligation assay, and xenografts (n ≥ 3), respectively. A student’s t-test was used for two variables; three-plus variables used one-way analysis of variance with Bonferroni’s Multiple Comparison Test. Xenograft growth was analyzed using linear mixed model analysis, followed by Wald testing and survival, analyzed using the Log-Rank test. All statistical tests were two sided. Results High expression of either the mRNA or protein for the integrin subunit β6 was associated with very poor survival (HR = 1.60, 95% CI = 1.19 to 2.15, P = .002) and increased metastases to distant sites. Co-expression of β6 and HER2 was associated with worse prognosis (HR = 1.97, 95% CI = 1.16 to 3.35, P = .01). Monotherapy with 264RAD or trastuzumab slowed growth of MCF-7/HER2-18 and BT-474 xenografts similarly (P < .001), but combining 264RAD with trastuzumab effectively stopped tumor growth, even in trastuzumab-resistant MCF-7/HER2-18 xenografts. Conclusions Targeting αvβ6 with 264RAD alone or in combination with trastuzumab may provide a novel therapy for treating high-risk and trastuzumab-resistant breast

  15. Helium on Venus - Implications for uranium and thorium

    NASA Technical Reports Server (NTRS)

    Prather, M. J.; Mcelroy, M. B.

    1983-01-01

    Helium is removed at an average rate of 10 to the 6th atoms per square centimeter per second from Venus's atmosphere by the solar wind following ionization above the plasmapause. The surface source of helium-4 on Venus is similar to that on earth, suggesting comparable abundances of crustal uranium and thorium.

  16. Variation in Atmospheric Helium Isotopes

    NASA Astrophysics Data System (ADS)

    Mabry, J. C.; Marty, B.; Burnard, P.; Blard, P.

    2010-12-01

    Anthropogenic activity such as oil and gas exploitation releases crustal helium, which has excess 4He compared to atmospheric helium. This may give rise to both spatial and temporal variations in the atmospheric 3He/4He. Helium is present in trace quantities in the air (5 ppm) and has a very low ratio (3He/4Heair = 1.38 x 10-6), consequently high precision measurements of atmospheric He presents a significant analytical challenge. Recent work by Sano et al. [1] has endeavored to experimentally quantify these potential variations in the atmospheric 3He/4He by measuring the helium isotopes from air samples collected around the globe and from samples of ancient trapped atmosphere. Their results indicate an increase in the atmospheric 3He/4He from northern to southern latitudes of the order 2 - 4 ‰, which they attribute to greater use of fossil fuels in the northern hemisphere. However, since most of their data points overlap at the 2-3 ‰ (2σ) level, additional measurements (with increased precision if possible) are needed. We have constructed an automated extraction line dedicated to measuring He in samples of air which can rapidly switch between measuring aliquots of sample with standards. It additionally features an adjustable bellows on the sample aliquot volume that enables us to adjust the size of a sample aliquot to precisely match the standard, eliminating biases arising from nonlinear pressure effects in the mass spectrometer. The measurements are made using a Helix SFT multi-collector mass spectrometer. At present, repeat measurements of 3He/4He from our standard (purified air) have a reproducibility of 2‰ (2σ), while measurements of local (Nancy, France) air samples have a reproducibility of 3He/4He of 3‰ (2σ), which are at a similar level to the uncertainties reported by Sano. Modifications are underway to improve 3He measurements which are the principal source of error. We have collected atmospheric samples from around the globe over a wide

  17. From CRP to IL-6 to IL-1: Moving Upstream To Identify Novel Targets for Atheroprotection

    PubMed Central

    Ridker, Paul M

    2016-01-01

    Plasma levels of the inflammatory biomarker high sensitivity C-reactive protein (hsCRP) predict vascular risk with an effect estimate as large as that of total or HDL cholesterol. Further, randomized trial data addressing hsCRP have been central to understanding the anti-inflammatory effects of statin therapy and have consistently demonstrated on-treatment hsCRP levels to be as powerful a predictor of residual cardiovascular risk as on-treatment levels of LDL cholesterol. Yet, while hsCRP is clinically useful as a biomarker for risk prediction, most mechanistic studies suggest that CRP itself is unlikely to be a target for intervention. Moving upstream in the inflammatory cascade from CRP to IL-6 to IL-1 provides novel therapeutic opportunities for atheroprotection that focus on the central IL-6 signaling system and ultimately on inhibition of the IL-1β producing NLRP3 inflammasome. Cholesterol crystals, neutrophil extracellular traps (NETs), atheroprone flow, and local tissue hypoxia activate the NLRP3 inflammasome. As such, a unifying concept of hsCRP as a downstream surrogate biomarker upstream IL-1β activity has emerged. From a therapeutic perspective, small ischemia studies show reductions in acute phase hsCRP production with the IL-1 receptor antagonist anakinra and the IL-6 receptor blocker tocilizumab. A phase IIb study conducted among diabetic patients at high vascular risk indicates that canakinumab, a human monoclonal antibody that targets IL-1β, markedly reduces plasma levels of IL-6, hsCRP, and fibrinogen with no change in atherogenic lipids. Canakinumab in now being tested as a method to prevent recurrent cardiovascular events in a randomized trial of 10,065 post-myocardial infarction patients with elevated hsCRP that is fully enrolled and due to complete in 2017. Clinical trials employing alternative anti-inflammatory agents active against the CRP/IL-6/IL-1 axis including low dose methotrexate and colchicine are being explored. If successful

  18. Detection of Charged Particles in Superfluid Helium

    NASA Astrophysics Data System (ADS)

    Bandler, Simon Richard

    1995-01-01

    At the present time the measurement of the flux of neutrinos from the sun remains a challenging experimental problem. The ideal detector would be able to detect neutrinos at high rate, in real time, with good energy resolution and would have a threshold which is low enough for investigation of the entire solar neutrino spectrum. A new detection scheme using superfluid helium as a target has been proposed which has the potential to meet most of the criteria of the ideal detector. In this scheme a neutrino would be detected when it elastically scatters off an atomic electron in superfluid helium. The electron loses energy via a number of processes eventually leading to the generation of phonons and rotons in the liquid. At low temperatures these excitations propagate ballistically through the superfluid helium. When the excitations reach the free surface some of them are able to evaporate helium atoms. These atoms can be detected by an array of calorimeters suspended above the liquid surface. In this thesis, results are presented for a small -scale prototype of this type of detector. Experiments have been performed using various radioactive sources to generate energy depositions in the liquid. The results reveal details about the processes of generation of rotons and phonons, the propagation of these excitations through the superfluid, the evaporation of helium atoms and the adsorption of helium atoms onto the wafer. Results are also presented on the detection of fluorescent photons generated in the liquid. One source of energy depositions was 241{rm Am} which produces monoenergetic 5.5 MeV alpha particles. It was found that the ratio of the energy deposited in a calorimeter to the energy deposited in liquid helium was 0.084 when alpha's are emitted parallel to the liquid surface, and 0.020 for alpha's emitted perpendicular. The difference is due to the anisotropic distribution of helium excitations generated. A 113{rm Sn} source of 360 keV electrons stopped in

  19. Experimental Impacts into Chondritic Targets. Part 1; Disruption of an L6 Chondrite by Multiple Impacts

    NASA Technical Reports Server (NTRS)

    Cintala, Mark J.; Horz, Friedrich

    2007-01-01

    A fragment of an L6 chondrite (ALH 85017,13) with an initial mass (M(sub 0)) of 464.1 g was the target in a series of experimental impacts in which the largest remaining fragment (M(sub R)) after each shot was impacted by a 3.18-mm ceramic sphere at a nominal speed of 2 km/s. This continued until the mass of the largest remaining piece was less than half the mass of the target presented to that shot (M(sub S)). Two chunks of Bushveldt gabbro with similar initial masses were also impacted under the same conditions until M(sub R) was less than half M(sub 0). The two gabbro targets required a total of 1.51x10(exp 7) and 1.75x10(exp 7) erg/g to attain 0.27 and 0.33 M(sub R)/M(sub 0), respectively; the chondrite, however, was considerably tougher, reaching 0.40 and 0.21 M(sub R)/M(sub 0) only after receiving 2.37x10(exp 7) and 3.10x10(exp 7) erg g-1, respectively. The combined ejecta and spallation products from the gabbro impacts were coarser than those from the chondrite and in sufficient quantities that the new surface areas exceeded those from the meteorite until the fifth shot in the chondrite series, which was the number of impacts required to disrupt each gabbro target (i.e., MR/M0 = 0.5). Unlike the behavior shown in previous regolith-evolution series, neither gabbro target produced an enhancement in the size fraction reflecting the mean size of the crystals composing the rock (about 3 mm), an effect possibly related to the width of the shock pulse. The original chondrite was so fine-grained and fractured, and the variance in its grain-size distribution so large, that effects related to grain-size were relegated to the <63- m fraction. Impacts into ALH 85017 produced abundant, fine-grained debris, but otherwise the slopes of its size distributions were comparable to those from other experiments involving natural and fabricated terrestrial targets. The characteristic slopes of the chondrite's size distributions, however, were notably more constant over the entire

  20. Mitochondria Targeted Peptides Protect Against 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine Neurotoxicity

    PubMed Central

    Yang, Lichuan; Zhao, Kesheng; Calingasan, Noel Y.; Luo, Guoxiong; Szeto, Hazel H.

    2009-01-01

    Abstract A large body of evidence suggests that mitochondrial dysfunction and oxidative damage play a role in the pathogenesis of Parkinson's disease (PD). A number of antioxidants have been effective in animal models of PD. We have developed a family of mitochondria-targeted peptides that can protect against mitochondrial swelling and apoptosis (SS peptides). In this study, we examined the ability of two peptides, SS-31 and SS-20, to protect against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity in mice. SS-31 produced dose-dependent complete protection against loss of dopamine and its metabolites in striatum, as well as loss of tyrosine hydroxylase immunoreactive neurons in substantia nigra pars compacta. SS-20, which does not possess intrinsic ability in scavenging reactive oxygen species, also demonstrated significant neuroprotective effects on dopaminergic neurons of MPTP-treated mice. Both SS-31 and SS-20 were very potent (nM) in preventing MPP+ (1-methyl-4-phenylpyridinium)-induced cell death in cultured dopamine cells (SN4741). Studies with isolated mitochondria showed that both SS-31 and SS-20 prevented MPP+-induced inhibition of oxygen consumption and ATP production, and mitochondrial swelling. These findings provide strong evidence that these neuroprotective peptides, which target both mitochondrial dysfunction and oxidative damage, are a promising approach for the treatment of PD. Antioxid. Redox Signal. 11, 2095–2104. PMID:19203217

  1. Helium-refrigeration system

    SciTech Connect

    Specht, J.R.; Millar, B.; Sutherland, A.

    1995-08-01

    The design, procurement, and preliminary construction was completed for adding two more wet expansion engines to two helium refrigerators. These will be added in mid-year FY 1995. In addition a variable speed drive will be added to an existing helium compressor. This is part of an energy conservation upgrade project to reduce operating costs from the use of electricity and liquid nitrogen. This project involves the replacement of Joule-Thompson valves in the refrigerators with expansion engines resulting in system efficiency improvements of about 30% and improved system reliability.

  2. Is solid helium a supersolid?

    SciTech Connect

    Hallock, Robert

    2015-05-15

    Recent experiments suggest that helium-4 atoms can flow through an experimental cell filled with solid helium. But that incompletely understood flow is quite different from the reported superfluid-like motion that so excited physicists a decade ago.

  3. Concerted genomic targeting of H3K27 demethylase REF6 and chromatin-remodeling ATPase BRM in Arabidopsis.

    PubMed

    Li, Chenlong; Gu, Lianfeng; Gao, Lei; Chen, Chen; Wei, Chuang-Qi; Qiu, Qi; Chien, Chih-Wei; Wang, Suikang; Jiang, Lihua; Ai, Lian-Feng; Chen, Chia-Yang; Yang, Songguang; Nguyen, Vi; Qi, Yanhua; Snyder, Michael P; Burlingame, Alma L; Kohalmi, Susanne E; Huang, Shangzhi; Cao, Xiaofeng; Wang, Zhi-Yong; Wu, Keqiang; Chen, Xuemei; Cui, Yuhai

    2016-06-01

    SWI/SNF-type chromatin remodelers, such as BRAHMA (BRM), and H3K27 demethylases both have active roles in regulating gene expression at the chromatin level, but how they are recruited to specific genomic sites remains largely unknown. Here we show that RELATIVE OF EARLY FLOWERING 6 (REF6), a plant-unique H3K27 demethylase, targets genomic loci containing a CTCTGYTY motif via its zinc-finger (ZnF) domains and facilitates the recruitment of BRM. Genome-wide analyses showed that REF6 colocalizes with BRM at many genomic sites with the CTCTGYTY motif. Loss of REF6 results in decreased BRM occupancy at BRM-REF6 co-targets. Furthermore, REF6 directly binds to the CTCTGYTY motif in vitro, and deletion of the motif from a target gene renders it inaccessible to REF6 in vivo. Finally, we show that, when its ZnF domains are deleted, REF6 loses its genomic targeting ability. Thus, our work identifies a new genomic targeting mechanism for an H3K27 demethylase and demonstrates its key role in recruiting the BRM chromatin remodeler. PMID:27111034

  4. Thermal Performance of the XRS Helium Insert

    NASA Technical Reports Server (NTRS)

    Breon, Susan R.; DiPirro, Michael J.; Tuttle, James G.; Shirron, Peter J.; Warner, Brent A.; Boyle, Robert F.; Canavan, Edgar R.

    1999-01-01

    The X-Ray Spectrometer (XRS) is an instrument on the Japanese Astro-E satellite, scheduled for launch early in the year 2000. The XRS Helium Insert comprises a superfluid helium cryostat, an Adiabatic Demagnetization Refrigerator (ADR), and the XRS calorimeters with their cold electronics. The calorimeters are capable of detecting X-rays over the energy range 0.1 to 10 keV with a resolution of 12 eV. The Helium Insert completed its performance and verification testing at Goddard in January 1999. It was shipped to Japan, where it has been integrated with the neon dewar built by Sumitomo Heavy Industries. The Helium Insert was given a challenging lifetime requirement of 2.0 years with a goal of 2.5 years. Based on the results of the thermal performance tests, the predicted on-orbit lifetime is 2.6 years with a margin of 30%. This is the result of both higher efficiency in the ADR cycle and the low temperature top-off, more than compensating for an increase in the parasitic heat load. This paper presents a summary of the key design features and the results of the thermal testing of the XRS Helium Insert.

  5. Radiation effects on microstructure and hardness of a titanium aluminide alloy irradiated by helium ions at room and elevated temperatures

    NASA Astrophysics Data System (ADS)

    Wei, Tao; Zhu, Hanliang; Ionescu, Mihail; Dayal, Pranesh; Davis, Joel; Carr, David; Harrison, Robert; Edwards, Lyndon

    2015-04-01

    A 45XD TiAl alloy possessing a lamellar microstructure was irradiated using 5 MeV helium ions to a fluence of 5 × 1021 ion m-2 (5000 appm) with a dose of about 1 dpa (displacements per atom). A uniform helium ion stopping damage region about 17 μm deep from the target surface was achieved by applying an energy degrading wheel. Radiation damage defects including helium-vacancy clusters and small helium bubbles were found in the microstructure of the samples irradiated at room temperature. With increasing irradiation temperature to 300 °C and 500 °C helium bubbles were clearly observed in both the α2 and γ phases of the irradiated microstructure. By means of nanoindentation significant irradiation hardening was measured. For the samples irradiated at room temperature the hardness increased from 5.6 GPa to 8.5 GPa and the irradiation-hardening effect reduced to approximately 8.0 GPa for the samples irradiated at 300 °C and 500 °C.

  6. Potential therapeutic implications of IL-6/IL-6R/gp130-targeting agents in breast cancer

    PubMed Central

    Heo, Tae-Hwe; Wahler, Joseph; Suh, Nanjoo

    2016-01-01

    Interleukin-6 (IL-6) is a pleiotropic cytokine with known multiple functions in immune regulation, inflammation, and oncogenesis. Binding of IL-6 to the IL-6 receptor (IL-6R) induces homodimerization and recruitment of glycoprotein 130 (gp130), which leads to activation of downstream signaling. Emerging evidence suggests that high levels of IL-6 are correlated with poor prognosis in breast cancer patients. IL-6 appears to play a critical role in the growth and metastasis of breast cancer cells, renewal of breast cancer stem cells (BCSCs), and drug resistance of BCSCs, making anti–IL-6/IL-6R/gp130 therapies promising options for the treatment and prevention of breast cancers. However, preclinical and clinical studies of the applications of anti–IL-6/IL-6R/gp130 therapy in breast cancers are limited. In this review, we summarize the structures, preclinical and clinical studies, mechanisms of action of chemical and biological blockers that directly bind to IL-6, IL-6R, or gp130, and the potential clinical applications of these pharmacological agents as breast cancer therapies. PMID:26840088

  7. Superfluid helium-4 in one dimensional channel

    NASA Astrophysics Data System (ADS)

    Kim, Duk Y.; Banavar, Samhita; Chan, Moses H. W.; Hayes, John; Sazio, Pier

    2013-03-01

    Superfluidity, as superconductivity, cannot exist in a strict one-dimensional system. However, the experiments employing porous media showed that superfluid helium can flow through the pores of nanometer size. Here we report a study of the flow of liquid helium through a single hollow glass fiber of 4 cm in length with an open id of 150 nm between 1.6 and 2.3 K. We found the superfluid transition temperature was suppressed in the hollow cylinder and that there is no flow above the transition. Critical velocity at temperature below the transition temperature was determined. Our results bear some similarity to that found by Savard et. al. studying the flow of helium through a nanohole in a silicon nitrite membrane. Experimental study at Penn State is supported by NSF Grants No. DMR 1103159.

  8. Thermodynamic properties of hydrogen-helium plasmas

    NASA Technical Reports Server (NTRS)

    Nelson, H. F.

    1971-01-01

    The thermodynamic properties of an atomic hydrogen-helium plasma are calculated and tabulated for temperatures from 10,000 to 100,000 K as a function of the mass fraction ratio of atomic hydrogen. The tabulation is for densities from 10 to the minus 10th power to 10 to the minus 6th power gm/cu cm and for hydrogen mass fraction ratios of 0, 0.333, 0.600, 0.800, and 1.0, which correspond to pure helium, 50 percent hydrogen per unit volume, 75 percent hydrogen per unit volume, 89 percent hydrogen per unit volume, and pure hydrogen plasmas, respectively. From an appended computer program, calculations can be made at other densities and mass fractions. The program output agrees well with previous thermodynamic property calculations for limiting cases of pure hydrogen and pure helium plasmas.

  9. Production of thorium-229 using helium nuclei

    DOEpatents

    Mirzadeh, Saed [Knoxville, TN; Garland, Marc Alan [Knoxville, TN

    2010-12-14

    A method for producing .sup.229Th includes the steps of providing .sup.226Ra as a target material, and bombarding the target material with alpha particles, helium-3, or neutrons to form .sup.229Th. When neutrons are used, the neutrons preferably include an epithermal neutron flux of at least 1.times.10.sup.13 n s.sup.-1cm.sup.-2. .sup.228Ra can also be bombarded with thermal and/or energetic neutrons to result in a neutron capture reaction to form .sup.229Th. Using .sup.230Th as a target material, .sup.229Th can be formed using neutron, gamma ray, proton or deuteron bombardment.

  10. Revealing Different Roles of the mTOR-Targets S6K1 and S6K2 in Breast Cancer by Expression Profiling and Structural Analysis

    PubMed Central

    Karlsson, Elin; Magić, Ivana; Bostner, Josefine; Dyrager, Christine; Lysholm, Fredrik; Hallbeck, Anna-Lotta; Stål, Olle; Lundström, Patrik

    2015-01-01

    Background The AKT/mTORC1/S6K pathway is frequently overstimulated in breast cancer, constituting a promising therapeutic target. The benefit from mTOR inhibitors varies, likely as a consequence of tumour heterogeneity, and upregulation of several compensatory feed-back mechanisms. The mTORC1 downstream effectors S6K1, S6K2, and 4EBP1 are amplified and overexpressed in breast cancer, associated with a poor outcome and divergent endocrine treatment benefit. S6K1 and S6K2 share high sequence homology, but evidence of partly distinct biological functions is emerging. The aim of this work was to explore possible different roles and treatment target potentials of S6K1 and S6K2 in breast cancer. Materials and methods Whole-genome expression profiles were compared for breast tumours expressing high levels of S6K1, S6K2 or 4EBP1, using public datasets, as well as after in vitro siRNA downregulation of S6K1 and/or S6K2 in ZR751 breast cancer cells. In silico homology modelling of the S6K2 kinase domain was used to evaluate its possible structural divergences to S6K1. Results Genome expression profiles were highly different in S6K1 and S6K2 high tumours, whereas S6K2 and 4EBP1 profiles showed significant overlaps, both correlated to genes involved in cell cycle progression, among these the master regulator E2F1. S6K2 and 4EBP1 were inversely associated with IGF1 levels, and their prognostic value was shown to be restricted to tumours positive for IGFR and/or HER2. In vitro, S6K1 and S6K2 silencing resulted in upregulation of genes in the mTORC1 and mTORC2 complexes. Isoform-specific silencing also showed distinct patterns, e.g. S6K2 downregulation lead to upregulation of several cell cycle associated genes. Structural analyses of the S6K2 kinase domain showed unique structure patterns, deviating from those of S6K1, facilitating the development of isoform-specific inhibitors. Our data support emerging proposals of distinct biological features of S6K1 and S6K2, suggesting

  11. Low-Density Lipoprotein Receptor-Related Protein 6 (LRP6) Is a Novel Nutritional Therapeutic Target for Hyperlipidemia, Non-Alcoholic Fatty Liver Disease, and Atherosclerosis

    PubMed Central

    Go, Gwang-woong

    2015-01-01

    Low-density lipoprotein receptor-related protein 6 (LRP6) is a member of the low-density lipoprotein receptor family and has a unique structure, which facilitates its multiple functions as a co-receptor for Wnt/β-catenin signaling and as a ligand receptor for endocytosis. The role LRP6 plays in metabolic regulation, specifically in the nutrient-sensing pathway, has recently garnered considerable interest. Patients carrying an LRP6 mutation exhibit elevated levels of LDL cholesterol, triglycerides, and fasting glucose, which cooperatively constitute the risk factors of metabolic syndrome and atherosclerosis. Since the discovery of this mutation, the general role of LRP6 in lipid homeostasis, glucose metabolism, and atherosclerosis has been thoroughly researched. These studies have demonstrated that LRP6 plays a role in LDL receptor-mediated LDL uptake. In addition, when the LRP6 mutant impaired Wnt-LRP6 signaling, hyperlipidemia, non-alcoholic fatty liver disease, and atherosclerosis developed. LRP6 regulates lipid homeostasis and body fat mass via the nutrient-sensing mechanistic target of the rapamycin (mTOR) pathway. Furthermore, the mutant LRP6 triggers atherosclerosis by activating platelet-derived growth factor (PDGF)-dependent vascular smooth muscle cell differentiation. This review highlights the exceptional opportunities to study the pathophysiologic contributions of LRP6 to metabolic syndrome and cardiovascular diseases, which implicate LRP6 as a latent regulator of lipid metabolism and a novel therapeutic target for nutritional intervention. PMID:26046396

  12. Interleukin-6 is a potential therapeutic target in interleukin-6 dependent, estrogen receptor-α-positive breast cancer

    PubMed Central

    Casneuf, Tineke; Axel, Amy E; King, Peter; Alvarez, John D; Werbeck, Jillian L; Verhulst, Tinne; Verstraeten, Karin; Hall, Brett M; Sasser, A Kate

    2016-01-01

    Introduction Interleukin-6 (IL-6) is an important growth factor for estrogen receptor-α (ERα)-positive breast cancer, and elevated serum IL-6 is associated with poor prognosis. Methods The role of the phosphorylated signal transducer and activator of transcription 3 pathway was investigated in ERα-positive breast cancer. A panel of cell lines was treated with exogenous IL-6. An IL-6 specific gene signature was generated by profiling ten ERα-positive breast cancer cell lines alone or following treatment with 10 ng/mL recombinant IL-6 or human marrow stromal cell-conditioned media, with or without siltuximab (a neutralizing anti-IL-6 antibody) and grown in three-dimensional tumor microenvironment-aligned cultures for 4 days, 5 days, or 6 days. The established IL-6 signature was validated against 36 human ERα-positive breast tumor samples with matched serum. A comparative MCF-7 xenograft murine model was utilized to determine the role of IL-6 in estrogen-supplemented ERα-positive breast cancer to assess the efficacy of anti-IL-6 therapy in vivo. Results In eight of nine ERα-positive breast cancer cell lines, recombinant IL-6 increased phosphorylation of tyrosine 705 of STAT3. Differential gene expression analysis identified 17 genes that could be used to determine IL-6 pathway activation by combining their expression intensity into a pathway activation score. The gene signature included a variety of genes involved in immune cell function and migration, cell growth and apoptosis, and the tumor microenvironment. Validation of the IL-6 gene signature in 36 matched human serum and ERα-positive breast tumor samples showed that patients with a high IL-6 pathway activation score were also enriched for elevated serum IL-6 (≥10 pg/mL). When human IL-6 was provided in vivo, MCF-7 cells engrafted without the need for estrogen supplementation, and addition of estrogen to IL-6 did not further enhance engraftment. Subsequently, we prophylactically treated mice at MCF-7

  13. Metabolism of 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine by Mitochondrion-targeted Cytochrome P450 2D6

    PubMed Central

    Bajpai, Prachi; Sangar, Michelle C.; Singh, Shilpee; Tang, Weigang; Bansal, Seema; Chowdhury, Goutam; Cheng, Qian; Fang, Ji-Kang; Martin, Martha V.; Guengerich, F. Peter; Avadhani, Narayan G.

    2013-01-01

    1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxic side product formed in the chemical synthesis of desmethylprodine opioid analgesic, which induces Parkinson disease. Monoamine oxidase B, present in the mitochondrial outer membrane of glial cells, catalyzes the oxidation of MPTP to the toxic 1-methyl-4-phenylpyridinium ion (MPP+), which then targets the dopaminergic neurons causing neuronal death. Here, we demonstrate that mitochondrion-targeted human cytochrome P450 2D6 (CYP2D6), supported by mitochondrial adrenodoxin and adrenodoxin reductase, can efficiently catalyze the metabolism of MPTP to MPP+, as shown with purified enzymes and also in cells expressing mitochondrial CYP2D6. Neuro-2A cells stably expressing predominantly mitochondrion-targeted CYP2D6 were more sensitive to MPTP-mediated mitochondrial respiratory dysfunction and complex I inhibition than cells expressing predominantly endoplasmic reticulum-targeted CYP2D6. Mitochondrial CYP2D6 expressing Neuro-2A cells produced higher levels of reactive oxygen species and showed abnormal mitochondrial structures. MPTP treatment also induced mitochondrial translocation of an autophagic marker, Parkin, and a mitochondrial fission marker, Drp1, in differentiated neurons expressing mitochondrial CYP2D6. MPTP-mediated toxicity in primary dopaminergic neurons was attenuated by CYP2D6 inhibitor, quinidine, and also partly by monoamine oxidase B inhibitors deprenyl and pargyline. These studies show for the first time that dopaminergic neurons expressing mitochondrial CYP2D6 are fully capable of activating the pro-neurotoxin MPTP and inducing neuronal damage, which is effectively prevented by the CYP2D6 inhibitor quinidine. PMID:23258538

  14. Targeting the IL-6 Dependent Phenotype Can Identify Novel Therapies for Cholangiocarcinoma

    PubMed Central

    Kogure, Takayuki; Huang, Nianyuan; Patel, Tushar

    2010-01-01

    Background The need for new therapies for cholangiocarcinoma is highlighted by their poor prognosis and refractoriness to chemotherapy. Increased production of Interleukin-6 promotes cholangiocarcinoma growth and contributes to chemoresistance by activating cell survival mechanisms. We sought to identify biologically active compounds capable of ameliorating the phenotypic effects of IL-6 expression and to explore their potential therapeutic use for cholangiocarcinoma. Methodology A genomic signature associated with Interleukin-6 expression in Mz-ChA-1 human malignant cholangiocytes was derived. Computational bioinformatics analysis was performed to identify compounds that induced inverse gene changes to the signature. The effect of these compounds on cholangiocarcinoma growth was then experimentally verified in vitro and in vivo. Interactions with other therapeutic agents were evaluated using median effects analysis. Principal Findings A group of structurally related compounds, nitrendipine, nifedipine and felodipine was identified. All three compounds were cytotoxic to Mz-ChA-1 cells with an IC50 for felodipine of 26 µM, nitrendipine, 44 µM and nifedipine, 15 µM. Similar results were observed in KMCH-1, CC-LP-1 and TFK-1 cholangiocarcinoma cell lines. At a fractional effect of 0.5, all three agents were synergistic with either camptothecin or gemcitabine in Mz-ChA-1 cells in vitro. Co-administration of felodipine and gemcitabine decreased the growth of Mz-ChA-1 cell xenografts in nude athymic mice. Conclusions Computational bioinformatics analysis of phenotype-based genomic expression can be used to identify therapeutic agents. Using this drug discovery approach based on targeting a defined tumor associated phenotype, we identified compounds with the potential for therapeutic use in cholangiocarcinoma. PMID:21179572

  15. An Assessment of Helium Evolution from Helium-Saturated Propellant Depressurization in Space

    NASA Technical Reports Server (NTRS)

    Nguyen, Bich N.; Best, Frederick; Wong, Tony; Kurwitz, Cable; McConnaughey, H. (Technical Monitor)

    2001-01-01

    Helium evolution from the transfer of helium-saturated propellant in space is quantified to assess its impacts from creating two-phase gas/liquid flow from the supply tank, gas injection into the receiving tank, and liquid discharge from the receiving tank. Propellant transfer takes place between two similar tanks whose maximum storage capacity is approximately 2.55 cubic meters each. The maximum on-orbit propellants transfer capability is 9000 lbm (fuel and oxidizer). The transfer line is approximately 1.27 cm in diameter and 6096 cm in length and comprised of the fluid interconnect system (FICS), the orbiter propellant transfer system (OPTS), and the International Space Station (ISS) propulsion module (ISSPM). The propellant transfer rate begins at approximately 11 liter per minute (lpm) and subsequently drops to approximately 0.5 lpm. The tank nominal operating pressure is approximately 1827 kPa (absolute). The line pressure drops for Monomethy1hydrazine (MMH) and Nitrogen tetroxide (NTO) at 11.3 lpm are approximately 202 kPa and 302 kPa, respectively. The pressure-drop results are based on a single-phase flow. The receiving tank is required to vent from approximately 1827 kPa to a lower pressure to affect propellant transfer. These pressure-drop scenarios cause the helium-saturated propellants to release excess helium. For tank ullage venting, the maximum volumes of helium evolved at tank pressure are approximately 0.5 ft3 for MMH and 2 ft3 for NTO. In microgravity environment, due to lack of body force, the helium evolution from a liquid body acts to propel it, which influences its fluid dynamics. For propellant transfer, the volume fractions of helium evolved at line pressure are 0.1% by volume for MMH and 0.6 % by volume for NTO at 11.3 lpm. The void fraction of helium evolved varies as an approximate second order power function of flow rate.

  16. The Kaonic Helium Case

    NASA Astrophysics Data System (ADS)

    Curceanu (Petrascu), C.; Bragadireanu, A. M.; Curceanu (Petrascu), C.; Ghio, F.; Girolami, B.; Guaraldo, C.; Iliescu, M.; Levi Sandri, P.; Lucherini, V.; Sirghi, D. L.; Sirghi, F.; Cargnelli, M.; Fuhrmann, H.; Ishiwatari, T.; Kienle, P.; Marton, J.; Zmeskal, J.; Fiorini, C.; Longoni, A.; Frizzi, T.; Itahashi, K.; Iwasaki, M.; Koike, T.; Ponta, T.; Soltau, H.; Lechner, P.; Struder, L.

    2005-12-01

    The only three existent kaonic helium X-ray transition measurements at present are referring to the transitions to 2p level. These measurements are more than 30 years old and the obtained results, affected by big errors, are much larger than those predicted by optical models. It is thought that the optical model is inadequate, due to the presence of the ∧(1405) resonance, not properly taken into account. Because the nucleons in the helium nucleus are tightly bound, the effective energy of the K-p interaction (1432 MeV at threshold) is in helium much closer to the energy of the resonance than in other nuclei. It is then planned to measure the kaonic helium X-ray transitions to the 2p level in the framework of the SIDDHARTA (SIlicon Drift Detector for Hadronic Atom Research by Timing Application) experiment, at the DAΦNE collider of Frascati National Laboratories, and to confirm or not the discrepancy reported by the previous experiments with a much smaller error.

  17. On Helium Anions in Helium Droplets: Interpreting Recent Experiments

    NASA Astrophysics Data System (ADS)

    Mauracher, Andreas; Huber, Stefan E.

    2014-10-01

    Helium droplets provide an ideal environment to study elementary processes in atomic systems at very low temperatures. Here, we discuss properties of charged and neutral, atomic and molecular helium species formed in helium droplets upon electron impact. By studying their interaction with atomic ground state helium we find that He, He2 and excited (metastable) He*- are well bound within the helium droplet. In comparison, He* , He2* and He2* are found to be squeezed out due to energetic reasons. We also present the formation pathways of atomic and molecular helium anions in helium droplets. Transition barriers in the energetic lowest He*- - He interaction potentials prevent molecule formation at the extremely low temperatures in helium droplets. In contrast, some excited states allow a barrier-free formation of molecular helium (anions). With these theoretical results at hand we can interpret recent experiments in which the resonant formation of atomic and molecular helium anions was observed. Furthermore, we give an outlook on the implications of the presence of these anionic species in doped helium droplets with regard to charge transfer reactions. Austrian Fund Agency (FWF, I 978-N20, DK+ project Computational Interdisciplinary Modelling W1227-N16)/Austrian Ministry of Science (BMWF, Konjunkturpaket II, UniInfrastrukturprogramm of the Focal Point Scientific Computing).

  18. Helium anion formation inside helium droplets

    NASA Astrophysics Data System (ADS)

    Jabbour Al Maalouf, Elias; Reitshammer, Julia; Ribar, Anita; Scheier, Paul; Denifl, Stephan

    2016-07-01

    The formation of He∗- is examined with improved electron energy resolution of about 100 meV utilizing a hemispherical electron monochromator. The work presented provides a precise determination of the three previously determined resonance peak positions that significantly contribute to the formation of He∗- inside helium nanodroplets in the energy range from 20 eV to 29.5 eV. In addition, a new feature is identified located at 27.69 ± 0.18 eV that we assign to the presence of O2 as a dopant inside the droplet. With increasing droplet size a small blue shift of the resonance positions is observed. Also for the relatively low electron currents used in the present study (i.e., 15-70 nA) a quadratic dependence of the He∗- ion yield on the electron current is observed.

  19. Identification of the amino acid sequence that targets peroxiredoxin 6 to lysosome-like structures of lung epithelial cells.

    PubMed

    Sorokina, Elena M; Feinstein, Sheldon I; Milovanova, Tatyana N; Fisher, Aron B

    2009-11-01

    Peroxiredoxin 6 (Prdx6), an enzyme with glutathione peroxidase and PLA2 (aiPLA2) activities, is highly expressed in respiratory epithelium, where it participates in phospholipid turnover and antioxidant defense. Prdx6 has been localized by immunocytochemistry and subcellular fractionation to acidic organelles (lung lamellar bodies and lysosomes) and cytosol. On the basis of their pH optima, we have postulated that protein subcellular localization determines the balance between the two activities of Prdx6. Using green fluorescent protein-labeled protein expression in alveolar epithelial cell lines, we showed Prdx6 localization to organellar structures resembling lamellar bodies in mouse lung epithelial (MLE-12) cells and lysosomes in A549 cells. Localization within lamellar bodies/lysosomes was in the luminal compartment. Targeting to lysosome-like organelles was abolished by the deletion of amino acids 31-40 from the Prdx6 NH2-terminal region; deletion of the COOH-terminal region had no effect. A green fluorescent protein-labeled peptide containing only amino acids 31-40 showed lysosomal targeting that was abolished by mutation of S32 or G34 within the peptide. Studies with mutated protein indicated that lipid binding was not necessary for Prdx6 targeting. This peptide sequence has no homology to known organellar targeting motifs. These studies indicate that the localization of Prdx6 in acidic organelles and consequent PLA2 activity depend on a novel 10-aa peptide located at positions 31-40 of the protein. PMID:19700648

  20. Selective targeting of BCL6 induces oncogene addiction switching to BCL2 in B-cell lymphoma

    PubMed Central

    Patel, Jayeshkumar; Hatzi, Katerina; Malik, Alka; Tam, Wayne; Martin, Peter; Leonard, John; Melnick, Ari; Cerchietti, Leandro

    2016-01-01

    The BCL6 oncogene plays a crucial role in sustaining diffuse large B-cell lymphomas (DLBCL) through transcriptional repression of key checkpoint genes. BCL6-targeted therapy kills lymphoma cells by releasing these checkpoints. However BCL6 also directly represses several DLBCL oncogenes such as BCL2 and BCL-XL that promote lymphoma survival. Herein we show that DLBCL cells that survive BCL6-targeted therapy induce a phenomenon of “oncogene-addiction switching” by reactivating BCL2-family dependent anti-apoptotic pathways. Thus, most DLBCL cells require concomitant inhibition of BCL6 and BCL2-family members for effective lymphoma killing. Moreover, in DLBCL cells initially resistant to BH3 mimetic drugs, BCL6 inhibition induces a newly developed reliance on anti-apoptotic BCL2-family members for survival that translates in acquired susceptibility to BH3 mimetic drugs ABT-737 and obatoclax. In germinal center B cell-like (GCB)-DLBCL cells, the proteasome inhibitor bortezomib and the NEDD inhibitor MLN4924 post-transcriptionally activated the BH3-only sensitizer NOXA thus counteracting the oncogenic switch to BCL2 induced by BCL6-targeting. Hence our study indicates that BCL6 inhibition induces an on-target feedback mechanism based on the activation of anti-apoptotic BH3 members. This oncogene-addition switching mechanism was harnessed to develop rational combinatorial therapies for GCB-DLBCL. PMID:26657288

  1. Targeting macrophages rescues age-related immune deficiencies in C57BL/6J geriatric mice.

    PubMed

    Jackaman, Connie; Radley-Crabb, Hannah G; Soffe, Zoe; Shavlakadze, Tea; Grounds, Miranda D; Nelson, Delia J

    2013-06-01

    Changes to innate cells, such as macrophages and myeloid-derived suppressor cells (MDSCs), during aging in healthy or tumor-bearing hosts are not well understood. We compared macrophage subpopulations and MDSCs from healthy young (6-8 weeks) C57BL/6J mice to those from healthy geriatric (24-28 months) mice. Spleens, lymph nodes, and bone marrow of geriatric hosts contained significantly more M2 macrophages and MDSCs than their younger counterparts. Peritoneal macrophages from geriatric, but not young, mice co-expressed CD40 and CX3CR1 that are usually mutually exclusively expressed by M1 or M2 macrophages. Nonetheless, macrophages from geriatric mice responded to M1 or M2 stimuli similarly to macrophages from young mice, although they secreted higher levels of TGF-β in response to IL-4. We mimicked conditions that may occur within tumors by exposing macrophages from young vs. geriatric mice to mesothelioma or lung carcinoma tumor cell-derived supernatants. While both supernatants skewed macrophages toward the M2-phenotype regardless of age, only geriatric-derived macrophages produced IL-4, suggesting a more immunosuppressive tumor microenvironment will be established in the elderly. Both geriatric- and young-derived macrophages induced allogeneic T-cell proliferation, regardless of the stimuli used, including tumor supernatant. However, only macrophages from young mice induced T-cell IFN-γ production. We examined the potential of an IL-2/agonist anti-CD40 antibody immunotherapy that eradicates large tumors in young hosts to activate macrophages from geriatric mice. IL-2-/CD40-activated macrophages rescued T-cell production of IFN-γ in geriatric mice. Therefore, targeting macrophages with IL-2/anti-CD40 antibody may improve innate and T-cell immunity in aging hosts. PMID:23442123

  2. The adsorption of helium atoms on coronene cations

    NASA Astrophysics Data System (ADS)

    Kurzthaler, Thomas; Rasul, Bilal; Kuhn, Martin; Lindinger, Albrecht; Scheier, Paul; Ellis, Andrew M.

    2016-08-01

    We report the first experimental study of the attachment of multiple foreign atoms to a cationic polycyclic aromatic hydrocarbon (PAH). The chosen PAH was coronene, C24H12, which was added to liquid helium nanodroplets and then subjected to electron bombardment. Using mass spectrometry, coronene cations decorated with helium atoms were clearly seen and the spectrum shows peaks with anomalously high intensities ("magic number" peaks), which represent ion-helium complexes with added stability. The data suggest the formation of a rigid helium layer consisting of 38 helium atoms that completely cover both faces of the coronene ion. Additional magic numbers can be seen for the further addition of 3 and 6 helium atoms, which are thought to attach to the edge of the coronene. The observation of magic numbers for the addition of 38 and 44 helium atoms is in good agreement with a recent path integral Monte Carlo prediction for helium atoms on neutral coronene. An understanding of how atoms and molecules attach to PAH ions is important for a number of reasons including the potential role such complexes might play in the chemistry of the interstellar medium.

  3. Complete and Incomplete Fusion of {sup 6}He and {sup 6}Li Projectiles with Medium Mass Targets at Energy {approx}10 AMeV

    SciTech Connect

    Krupko, S. A.; Daniel, A. V.; Fomichev, A. S.; Golovkov, M. S.; Gorshkov, V. A.; Oganessian, Yu. Ts.; Popeko, G. S.; Sidorchuk, S. I.; Ter-Akopian, G. M.; Slepnev, R. S.; Chudoba, V.; Standylo, L.; Chepigin, V. I.; Katrasev, D. E.; Malyshev, O. N.; Svirikhin, A. I.; Yeremin, A. V.; Wolski, R.; Briancon, Ch.; Hauschild, K.

    2009-03-04

    Complete fusion (CF) and incomplete fusion (ICF) reactions were studied with the beams of loosely bound {sup 6}He and {sup 6}Li bombarding {sup 166}Er and {sup 165}Ho targets. Experiments were carried out to test an approach exploiting the measured intensities of {gamma} rays emitted at the transitions between the yrast-band levels of reaction products formed after the termination of neutron evaporation. Partial waves feeding the CF [{sup 165}Ho({sup 6}Li,5n){sup 166}Yb, {sup 166}Er({sup 6}He,6n){sup 166}Yb] and ICF [{sup 165}Ho({sup 6}Li,{alpha}3n){sup 164}Er, and {sup 166}Er({sup 6}He,{alpha}4n){sup 164}Er] reaction channels were revealed from the obtained {gamma}-ray data.

  4. Two Components of the RNA-Directed DNA Methylation Pathway Associate with MORC6 and Silence Loci Targeted by MORC6 in Arabidopsis

    PubMed Central

    Liu, Zhang-Wei; Zhou, Jin-Xing; Huang, Huan-Wei; Li, Yong-Qiang; Shao, Chang-Rong; Li, Lin; Cai, Tao; Chen, She

    2016-01-01

    The SU(VAR)3-9 homolog SUVH9 and the double-stranded RNA-binding protein IDN2 were thought to be components of an RNA-directed DNA methylation (RdDM) pathway in Arabidopsis. We previously found that SUVH9 interacts with MORC6 but how the interaction contributes to transcriptional silencing remains elusive. Here, our genetic analysis indicates that SUVH2 and SUVH9 can either act in the same pathway as MORC6 or act synergistically with MORC6 to mediate transcriptional silencing. Moreover, we demonstrate that IDN2 interacts with MORC6 and mediates the silencing of a subset of MORC6 target loci. Like SUVH2, SUVH9, and IDN2, other RdDM components including Pol IV, Pol V, RDR2, and DRM2 are also required for transcriptional silencing at a subset of MORC6 target loci. MORC6 was previously shown to mediate transcriptional silencing through heterochromatin condensation. We demonstrate that the SWI/SNF chromatin-remodeling complex components SWI3B, SWI3C, and SWI3D interact with MORC6 as well as with SUVH9 and then mediate transcriptional silencing. These results suggest that the RdDM components are involved not only in DNA methylation but also in MORC6-mediated heterochromatin condensation. This study illustrates how DNA methylation is linked to heterochromatin condensation and thereby enhances transcriptional silencing at methylated genomic regions. PMID:27171427

  5. Two Components of the RNA-Directed DNA Methylation Pathway Associate with MORC6 and Silence Loci Targeted by MORC6 in Arabidopsis.

    PubMed

    Liu, Zhang-Wei; Zhou, Jin-Xing; Huang, Huan-Wei; Li, Yong-Qiang; Shao, Chang-Rong; Li, Lin; Cai, Tao; Chen, She; He, Xin-Jian

    2016-05-01

    The SU(VAR)3-9 homolog SUVH9 and the double-stranded RNA-binding protein IDN2 were thought to be components of an RNA-directed DNA methylation (RdDM) pathway in Arabidopsis. We previously found that SUVH9 interacts with MORC6 but how the interaction contributes to transcriptional silencing remains elusive. Here, our genetic analysis indicates that SUVH2 and SUVH9 can either act in the same pathway as MORC6 or act synergistically with MORC6 to mediate transcriptional silencing. Moreover, we demonstrate that IDN2 interacts with MORC6 and mediates the silencing of a subset of MORC6 target loci. Like SUVH2, SUVH9, and IDN2, other RdDM components including Pol IV, Pol V, RDR2, and DRM2 are also required for transcriptional silencing at a subset of MORC6 target loci. MORC6 was previously shown to mediate transcriptional silencing through heterochromatin condensation. We demonstrate that the SWI/SNF chromatin-remodeling complex components SWI3B, SWI3C, and SWI3D interact with MORC6 as well as with SUVH9 and then mediate transcriptional silencing. These results suggest that the RdDM components are involved not only in DNA methylation but also in MORC6-mediated heterochromatin condensation. This study illustrates how DNA methylation is linked to heterochromatin condensation and thereby enhances transcriptional silencing at methylated genomic regions. PMID:27171427

  6. Correlation of Helium Solubility in Liquid Nitrogen

    NASA Technical Reports Server (NTRS)

    VanDresar, Neil T.; Zimmerli, Gregory A.

    2012-01-01

    A correlation has been developed for the equilibrium mole fraction of soluble gaseous helium in liquid nitrogen as a function of temperature and pressure. Experimental solubility data was compiled and provided by National Institute of Standards and Technology (NIST). Data from six sources was used to develop a correlation within the range of 0.5 to 9.9 MPa and 72.0 to 119.6 K. The relative standard deviation of the correlation is 6.9 percent.

  7. Feasibility of lunar Helium-3 mining

    NASA Astrophysics Data System (ADS)

    Kleinschneider, Andreas; Van Overstraeten, Dmitry; Van der Reijnst, Roy; Van Hoorn, Niels; Lamers, Marvin; Hubert, Laurent; Dijk, Bert; Blangé, Joey; Hogeveen, Joel; De Boer, Lennaert; Noomen, Ron

    -3 fusion were calculated using a predicted minimum energy price in 2040 of 30.4 Euro/MWh. Annual costs are between 427.7 to 1,347.9 billion Euro, with annual expected profit ranging from -724.0 to 260.0 billion Euro. Due to the large scale of the mission, it has also been evaluated for providing 0.1% and 1% of the global energy demand in 2040. For 1%, the annual costs are 45.6 to 140.3 billion Euro and the expected annual profits are -78.0 to 23.1 billion Euro. For 0.1%, the annual costs are 7.7 to 20.5 billion Euro. The annual expected profits are -14.3 to -0.8 billion Euro. Feasibility has been addressed in three aspects. Technically, the mission is extremely challenging and complex. However, most required technologies exist or could be developed within a reasonable time span. From a political and legal perspective, the current international treaties hardly provide any framework for a lunar mining operation. Financially, the mission only produces a net profit in the best case, and only for medium- to large-scale operations, which require a very large initial investment. To make lunar Helium-3 usage possible, further research should concentrate on the mining operation and costs of fusion plants, as their impact by far outranks all other mission elements. Different transportation concepts may be investigated nevertheless. Many - not only technical - challenges concerning Helium-3 mining are still to be addressed. Although only a starting point for further investigations, this study shows that, despite popular claims, lunar Helium-3 is unsuitable to provide a significant percentage of the global energy demand in 2040.

  8. S6 kinase inactivation impairs growth and translational target phosphorylation in muscle cells maintaining proper regulation of protein turnover.

    PubMed

    Mieulet, Virginie; Roceri, Mila; Espeillac, Catherine; Sotiropoulos, Athanassia; Ohanna, Mickael; Oorschot, Viola; Klumperman, Judith; Sandri, Marco; Pende, Mario

    2007-08-01

    A defect in protein turnover underlies multiple forms of cell atrophy. Since S6 kinase (S6K)-deficient cells are small and display a blunted response to nutrient and growth factor availability, we have hypothesized that mutant cell atrophy may be triggered by a change in global protein synthesis. By using mouse genetics and pharmacological inhibitors targeting the mammalian target of rapamycin (mTOR)/S6K pathway, here we evaluate the control of translational target phosphorylation and protein turnover by the mTOR/S6K pathway in skeletal muscle and liver tissues. The phosphorylation of ribosomal protein S6 (rpS6), eukaryotic initiation factor-4B (eIF4B), and eukaryotic elongation factor-2 (eEF2) is predominantly regulated by mTOR in muscle cells. Conversely, in liver, the MAPK and phosphatidylinositol 3-kinase pathways also play an important role, suggesting a tissue-specific control. S6K deletion in muscle mimics the effect of the mTOR inhibitor rapamycin on rpS6 and eIF4B phosphorylation without affecting eEF2 phosphorylation. To gain insight on the functional consequences of these modifications, methionine incorporation and polysomal distribution were assessed in muscle cells. Rates and rapamycin sensitivity of global translation initiation are not altered in S6K-deficient muscle cells. In addition, two major pathways of protein degradation, autophagy and expression of the muscle-specific atrophy-related E3 ubiquitin ligases, are not affected by S6K deletion. Our results do not support a role for global translational control in the growth defect due to S6K deletion, suggesting specific modes of growth control and translational target regulation downstream of mTOR. PMID:17494629

  9. Applications of Groundwater Helium

    USGS Publications Warehouse

    Kulongoski, Justin T.; Hilton, David R.

    2011-01-01

    Helium abundance and isotope variations have widespread application in groundwater-related studies. This stems from the inert nature of this noble gas and the fact that its two isotopes ? helium-3 and helium-4 ? have distinct origins and vary widely in different terrestrial reservoirs. These attributes allow He concentrations and 3He/4He isotope ratios to be used to recognize and quantify the influence of a number of potential contributors to the total He budget of a groundwater sample. These are atmospheric components, such as air-equilibrated and air-entrained He, as well as terrigenic components, including in situ (aquifer) He, deep crustal and/or mantle He and tritiogenic 3He. Each of these components can be exploited to reveal information on a number of topics, from groundwater chronology, through degassing of the Earth?s crust to the role of faults in the transfer of mantle-derived volatiles to the surface. In this review, we present a guide to how groundwater He is collected from aquifer systems and quantitatively measured in the laboratory. We then illustrate the approach of resolving the measured He characteristics into its component structures using assumptions of endmember compositions. This is followed by a discussion of the application of groundwater He to the types of topics mentioned above using case studies from aquifers in California and Australia. Finally, we present possible future research directions involving dissolved He in groundwater.

  10. Measurement of skin and target dose in post-mastectomy radiotherapy using 4 and 6 MV photon beams

    PubMed Central

    2013-01-01

    Background For patients with high risk breast cancer and mastectomy, radiotherapy is the treatment of choice to improve survival and local control. Target dose is mainly limited due to skin reactions. The feasibility of using 4 MV beams for chest wall treatment was studied and compared to standard 6 MV bolus radiotherapy. Methods Post-mastectomy IMRT was planned on an Alderson-phantom using 4 and 6 MV photon beams without/with a 0.5 cm thick bolus. Dose was measured using TLDs placed at 8 locations in 1 and 3 mm depth to represent skin and superficial target dose, respectively. Results 4 MV and 6 MV beams with bolus perform equally regarding target coverage. The minimum and mean superficial target dose for the 6 MV and 4 MV were 93.0% and 94.7%, and 93.1% and 94.4%, respectively. Regarding skin dose the 4 MV photon beam was advantageous. The minimum and mean skin dose for the 6 MV and 4 MV was 76.7% and 81.6%, and 69.4% and 72.9%, respectively. The TPS was able to predict dose in the build-up region with a precision of around 5%. Conclusions The use of 4 MV photon beams are a good alternative for treating the thoracic wall without the need to place a bolus on the patient. The main limitation of 4 MV beams is the limited dose rate. PMID:24238366

  11. Pharmacological targeting of glucose-6-phosphate dehydrogenase in human erythrocytes by Bay 11-7082, parthenolide and dimethyl fumarate.

    PubMed

    Ghashghaeinia, Mehrdad; Giustarini, Daniela; Koralkova, Pavla; Köberle, Martin; Alzoubi, Kousi; Bissinger, Rosi; Hosseinzadeh, Zohreh; Dreischer, Peter; Bernhardt, Ingolf; Lang, Florian; Toulany, Mahmoud; Wieder, Thomas; Mojzikova, Renata; Rossi, Ranieri; Mrowietz, Ulrich

    2016-01-01

    In mature erythrocytes, glucose-6-phosphate dehydrogenase (G6PDH) and 6-phosphogluconate dehydrogenase (6PGDH) yield NADPH, a crucial cofactor of the enzyme glutathione reductase (GR) converting glutathione disulfide (GSSG) into its reduced state (GSH). GSH is essential for detoxification processes in and survival of erythrocytes. We explored whether the anti-inflammatory compounds Bay 11-7082, parthenolide and dimethyl fumarate (DMF) were able to completely deplete a common target (GSH), and to impair the function of upstream enzymes of GSH recycling and replenishment. Treatment of erythrocytes with Bay 11-7082, parthenolide or DMF led to concentration-dependent eryptosis resulting from complete depletion of GSH. GSH depletion was due to strong inhibition of G6PDH activity. Bay 11-7082 and DMF, but not parthenolide, were able to inhibit the GR activity. This approach "Inhibitors, Detection of their common target that is completely depleted or inactivated when pharmacologically relevant concentrations of each single inhibitor are applied, Subsequent functional analysis of upstream enzymes for this target" (IDS), can be applied to a broad range of inhibitors and cell types according to the selected target. The specific G6PDH inhibitory effect of these compounds may be exploited for the treatment of human diseases with high NADPH and GSH consumption rates, including malaria, trypanosomiasis, cancer or obesity. PMID:27353740

  12. Dendritic Target Region-Specific Formation of Synapses Between Excitatory Layer 4 Neurons and Layer 6 Pyramidal Cells.

    PubMed

    Qi, Guanxiao; Feldmeyer, Dirk

    2016-04-01

    Excitatory connections between neocortical layer 4 (L4) and L6 are part of the corticothalamic feedback microcircuitry. Here we studied the intracortical element of this feedback loop, the L4 spiny neuron-to-L6 pyramidal cell connection. We found that the distribution of synapses onto both putative corticothalamic (CT) and corticocortical (CC) L6 pyramidal cells (PCs) depends on the presynaptic L4 neuron type but is independent of the postsynaptic L6 PC type. L4 spiny stellate cells establish synapses on distal apical tuft dendrites of L6 PCs and elicit slow unitary excitatory postsynaptic potentials (uEPSPs) in L6 somata. In contrast, the majority of L4 star pyramidal neurons target basal and proximal apical oblique dendrites of L6 PCs and show fast uEPSPs. Compartmental modeling suggests that the slow uEPSP time course is primarily the result of dendritic filtering. This suggests that the dendritic target specificity of the 2 L4 spiny neuron types is due to their different axonal projection patterns across cortical layers. The preferential dendritic targeting by different L4 neuron types may facilitate the generation of dendritic Ca(2+) or Na(+) action potentials in L6 PCs; this could play a role in synaptic gain modulation in the corticothalamic pathway. PMID:25595180

  13. Helium anion formation inside helium droplets

    NASA Astrophysics Data System (ADS)

    Maalouf, Elias Jabbour Al; Reitshammer, Julia; Ribar, Anita; Scheier, Paul; Denifl, Stephan

    2016-07-01

    The formation of He∗- is examined with improved electron energy resolution of about 100 meV utilizing a hemispherical electron monochromator. The work presented provides a precise determination of the three previously determined resonance peak positions that significantly contribute to the formation of He∗- inside helium nanodroplets in the energy range from 20 eV to 29.5 eV. In addition, a new feature is identified located at 27.69 ± 0.18 eV that we assign to the presence of O2 as a dopant inside the droplet. With increasing droplet size a small blue shift of the resonance positions is observed. Also for the relatively low electron currents used in the present study (i.e., 15-70 nA) a quadratic dependence of the He∗- ion yield on the electron current is observed. Contribution to the Topical Issue "Advances in Positron and Electron Scattering", edited by Paulo Limao-Vieira, Gustavo Garcia, E. Krishnakumar, James Sullivan, Hajime Tanuma and Zoran Petrovic.

  14. A critical role for alternative polyadenylation factor CPSF6 in targeting HIV-1 integration to transcriptionally active chromatin.

    PubMed

    Sowd, Gregory A; Serrao, Erik; Wang, Hao; Wang, Weifeng; Fadel, Hind J; Poeschla, Eric M; Engelman, Alan N

    2016-02-23

    Integration is vital to retroviral replication and influences the establishment of the latent HIV reservoir. HIV-1 integration favors active genes, which is in part determined by the interaction between integrase and lens epithelium-derived growth factor (LEDGF)/p75. Because gene targeting remains significantly enriched, relative to random in LEDGF/p75 deficient cells, other host factors likely contribute to gene-tropic integration. Nucleoporins 153 and 358, which bind HIV-1 capsid, play comparatively minor roles in integration targeting, but the influence of another capsid binding protein, cleavage and polyadenylation specificity factor 6 (CPSF6), has not been reported. In this study we knocked down or knocked out CPSF6 in parallel or in tandem with LEDGF/p75. CPSF6 knockout changed viral infectivity kinetics, decreased proviral formation, and preferentially decreased integration into transcriptionally active genes, spliced genes, and regions of chromatin enriched in genes and activating histone modifications. LEDGF/p75 depletion by contrast preferentially altered positional integration targeting within gene bodies. Dual factor knockout reduced integration into genes to below the levels observed with either single knockout and revealed that CPSF6 played a more dominant role than LEDGF/p75 in directing integration to euchromatin. CPSF6 complementation rescued HIV-1 integration site distribution in CPSF6 knockout cells, but complementation with a capsid binding mutant of CPSF6 did not. We conclude that integration targeting proceeds via two distinct mechanisms: capsid-CPSF6 binding directs HIV-1 to actively transcribed euchromatin, where the integrase-LEDGF/p75 interaction drives integration into gene bodies. PMID:26858452

  15. The T6SSs of Pseudomonas aeruginosa Strain PAO1 and Their Effectors: Beyond Bacterial-Cell Targeting

    PubMed Central

    Sana, Thibault G.; Berni, Benjamin; Bleves, Sophie

    2016-01-01

    Pseudomonas aeruginosa is an opportunistic pathogen responsible for many diseases such as chronic lung colonization in cystic fibrosis patients and acute infections in hospitals. The capacity of P. aeruginosa to be pathogenic toward several hosts is notably due to different secretion systems. Amongst them, P. aeruginosa encodes three Type Six Secretion Systems (T6SS), named H1- to H3-T6SS, that act against either prokaryotes and/or eukaryotic cells. They are independent from each other and inject diverse toxins that interact with different components in the host cell. Here we summarize the roles of these T6SSs in the PAO1 strain, as well as the toxins injected and their targets. While H1-T6SS is only involved in antiprokaryotic activity through at least seven different toxins, H2-T6SS and H3-T6SS are also able to target prokaryotic as well as eukaryotic cells. Moreover, recent studies proposed that H2- and H3-T6SS have a role in epithelial cells invasion by injecting at least three different toxins. The diversity of T6SS effectors is astounding and other effectors still remain to be discovered. In this review, we present a table with other putative P. aeruginosa strain PAO1 T6SS-dependent effectors. Altogether, the T6SSs of P. aeruginosa are important systems that help fight other bacteria for their ecological niche, and are important in the pathogenicity process. PMID:27376031

  16. Energetic helium particles trapped in the magnetosphere

    NASA Technical Reports Server (NTRS)

    Chen, Jiasheng; Guzik, T. Gregory; Sang, Yeming; Wefel, John P.; Cooper, John F.

    1994-01-01

    High energy (approximately 40-100 MeV/nucleon) geomagnetically trapped helium nuclei have been measured, for the first time, by the ONR-604 instrument during the 1990/1991 Combined Release and Radiation Effects Satellite (CRRES) mission. The helium events observed at L less than 2.3 have a pitch angle distribution peaking perpendicular to the local magnetic field and are contained in peaks located at L = 1.2 and 1.9. The events in each peak can be characterized by power law energy spectra with indices of 10.0 +/- 0.7 for L = 1.9-2.3 and 6.8 +/- 1.0 for L = 1.15-1.3, before the large storm of 24 March 1991. CRRES was active during solar maximum when the anomalous component is excluded from the inner heliosphere, making it unlikely that the observed events derived from the anomalous component. The trapped helium counting rates decrease gradually with time indicating that these high energy ions were not injected by flares during the 1990/91 mission. Flare injection prior to mid-1990 may account for the highest energy particles, while solar wind injection during magnetic storms and subsequent acceleration could account for the helium at lower energies.

  17. Photoionization from excited states of helium

    NASA Technical Reports Server (NTRS)

    Jacobs, V. L.

    1973-01-01

    The cross sections for photoionization from the 2 1S, 2 3S, 2 1P and 2 3P excited states of helium are calculated for photoelectron energies below the n = 2 threshold of He(+) using Hylleraas bound state wave functions and 1s-2s-2p close coupling final state wave functions. The resonant structures associated with the lowest-lying 1S, 1P, 3P, and 1D autoionizing states of helium are found to be characterized by large values of the line profile parameter q. The cross sections and the photoelectron angular distribution asymmetry parameters for the P-states are calculated for various polarization states of the target atom and the incident photon. Experiments which would lead to the separate determinations of the S- and D- wave partial photoionization cross sections are discussed.

  18. Formation of Positively Charged Liquid Helium Clusters in Supercritical Helium and their Solidification upon Compression.

    PubMed

    Tarchouna, Hejer Gharbi; Bonifaci, Nelly; Aitken, Frédéric; Mendoza Luna, Luis Guillermo; von Haeften, Klaus

    2015-08-01

    Positively charged ions were produced in supercritical helium at temperatures from 6 to 10 K and up to 2 MPa using a corona discharge. Their mobility was measured via current-voltage curves, and the hydrodynamic radius was derived using Stokes law. An initial increase and subsequent decrease of hydrodynamic radius was observed and interpreted in terms of growth, compression and solidification of ion clusters. The mobility was modeled using a van der Waals-type thermodynamic state equation for the ion-in-helium mixed system and a temperature-dependent Millikan-Cunningham factor, describing experimental data both in the Knudsen and the Stokes flow region. Regions of maximum hydrodynamic radius and large compressibility were interpreted as boiling points. These points were modeled over a large range of pressures and found to match the Frenkel line of pure helium up to 0.7 MPa, reflecting similarity of density fluctuations in pure supercritical helium and gas-liquid phase transitions of ionic helium clusters. PMID:26267199

  19. Helium jet dispersion to atmosphere

    NASA Astrophysics Data System (ADS)

    Khan, Hasna J.

    On the event of loss of vacuum guard of superinsulated helium dewar, high rate of heat transfer into the tank occurs. The rapid boiling of liquid helium causes the burst disk to rupture at four atmospheres and consequently the helium passes to the atmosphere through vent lines. The gaseous helium forms a vertical buoyant jet as it exits the vent line into a stagnant environment. Characterization of the gaseous jet is achieved by detailed analysis of the axial and radial dependence of the flow parameters.

  20. Helium cryopumping for fusion applications

    SciTech Connect

    Sedgley, D.W.; Batzer, T.H.; Call, W.R.

    1988-05-01

    Large quantities of helium and hydrogen isotopes will be exhausted continuously from fusion power reactors. This paper summarizes two development programs undertaken to address vacuum pumping for this application: (i) A continuous duty cryopump for pumping helium and/or hydrogen species using charcoal sorbent and (ii) a cryopump configuration with an alternative shielding arrangement using charcoal sorbent or argon spray. A test program evaluated automatic pumping of helium, helium pumping by charcoal cryosorption and with argon spray, and cryosorption of helium/hydrogen mixtures. The continuous duty cryopump pumped helium continuously and conveniently. Helium pumping speed was 7.7 l/s/cm/sup 2/ of charcoal, compared to 5.8 l/s/cm/sup 2/ for the alternative pump. Helium speed using argon spray was 18% of that obtained by charcoal cryosorption in the same (W-panel) pump. During continuous duty cryopump mixture tests with helium and hydrogen copumped on charcoal, gas was released sporadically. Testing was insufficient to explain this unacceptable event.

  1. 48 CFR 52.208-8 - Required Sources for Helium and Helium Usage Data.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... Helium and Helium Usage Data. 52.208-8 Section 52.208-8 Federal Acquisition Regulations System FEDERAL... Provisions and Clauses 52.208-8 Required Sources for Helium and Helium Usage Data. As prescribed in 8.505, insert the following clause: Required Sources for Helium and Helium Usage Data (APR 2002) (a)...

  2. 48 CFR 52.208-8 - Required Sources for Helium and Helium Usage Data.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... Helium and Helium Usage Data. 52.208-8 Section 52.208-8 Federal Acquisition Regulations System FEDERAL... Provisions and Clauses 52.208-8 Required Sources for Helium and Helium Usage Data. As prescribed in 8.505, insert the following clause: Required Sources for Helium and Helium Usage Data (APR 2014) (a)...

  3. 48 CFR 52.208-8 - Required Sources for Helium and Helium Usage Data.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... Helium and Helium Usage Data. 52.208-8 Section 52.208-8 Federal Acquisition Regulations System FEDERAL... Provisions and Clauses 52.208-8 Required Sources for Helium and Helium Usage Data. As prescribed in 8.505, insert the following clause: Required Sources for Helium and Helium Usage Data (APR 2002) (a)...

  4. 48 CFR 52.208-8 - Required Sources for Helium and Helium Usage Data.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... Helium and Helium Usage Data. 52.208-8 Section 52.208-8 Federal Acquisition Regulations System FEDERAL... Provisions and Clauses 52.208-8 Required Sources for Helium and Helium Usage Data. As prescribed in 8.505, insert the following clause: Required Sources for Helium and Helium Usage Data (APR 2002) (a)...

  5. 48 CFR 52.208-8 - Required Sources for Helium and Helium Usage Data.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... Helium and Helium Usage Data. 52.208-8 Section 52.208-8 Federal Acquisition Regulations System FEDERAL... Provisions and Clauses 52.208-8 Required Sources for Helium and Helium Usage Data. As prescribed in 8.505, insert the following clause: Required Sources for Helium and Helium Usage Data (APR 2002) (a)...

  6. Pharmacological targeting of glucose-6-phosphate dehydrogenase in human erythrocytes by Bay 11–7082, parthenolide and dimethyl fumarate

    PubMed Central

    Ghashghaeinia, Mehrdad; Giustarini, Daniela; Koralkova, Pavla; Köberle, Martin; Alzoubi, Kousi; Bissinger, Rosi; Hosseinzadeh, Zohreh; Dreischer, Peter; Bernhardt, Ingolf; Lang, Florian; Toulany, Mahmoud; Wieder, Thomas; Mojzikova, Renata; Rossi, Ranieri; Mrowietz, Ulrich

    2016-01-01

    In mature erythrocytes, glucose-6-phosphate dehydrogenase (G6PDH) and 6-phosphogluconate dehydrogenase (6PGDH) yield NADPH, a crucial cofactor of the enzyme glutathione reductase (GR) converting glutathione disulfide (GSSG) into its reduced state (GSH). GSH is essential for detoxification processes in and survival of erythrocytes. We explored whether the anti-inflammatory compounds Bay 11–7082, parthenolide and dimethyl fumarate (DMF) were able to completely deplete a common target (GSH), and to impair the function of upstream enzymes of GSH recycling and replenishment. Treatment of erythrocytes with Bay 11–7082, parthenolide or DMF led to concentration-dependent eryptosis resulting from complete depletion of GSH. GSH depletion was due to strong inhibition of G6PDH activity. Bay 11–7082 and DMF, but not parthenolide, were able to inhibit the GR activity. This approach “Inhibitors, Detection of their common target that is completely depleted or inactivated when pharmacologically relevant concentrations of each single inhibitor are applied, Subsequent functional analysis of upstream enzymes for this target” (IDS), can be applied to a broad range of inhibitors and cell types according to the selected target. The specific G6PDH inhibitory effect of these compounds may be exploited for the treatment of human diseases with high NADPH and GSH consumption rates, including malaria, trypanosomiasis, cancer or obesity. PMID:27353740

  7. Regimes of Helium Burning

    SciTech Connect

    Timmes, F. X.; Niemeyer, J. C.

    2000-07-10

    The burning regimes encountered by laminar deflagrations and Zeldovich von Neumann Doering [ZND] detonations propagating through helium-rich compositions in the presence of buoyancy-driven turbulence are analyzed. Particular attention is given to models of X-ray bursts that start with a thermonuclear runaway on the surface of a neutron star and to the thin-shell helium instability of intermediate-mass stars. In the X-ray burst case, turbulent deflagrations propagating in the lateral or radial direction encounter a transition from the distributed regime to the flamelet regime at a density of {approx}108 g cm-3. In the radial direction, the purely laminar deflagration width is larger than the pressure scale height for densities smaller than {approx}106 g cm-3. Self-sustained laminar deflagrations traveling in the radial direction cannot exist below this density. Similarly, the planar ZND detonation width becomes larger than the pressure scale height at {approx}107 g cm-3, suggesting that steady state, self-sustained detonations cannot come into existence in the radial direction. In the thin helium shell case, turbulent deflagrations traveling in the lateral or radial direction encounter the distributed regime at densities below {approx}107 g cm-3 and the flamelet regime at larger densities. In the radial direction, the purely laminar deflagration width is larger than the pressure scale height for densities smaller than {approx}104 g cm-3, indicating that steady state laminar deflagrations cannot form below this density. The planar ZND detonation width becomes larger than the pressure scale height at {approx}5x10{sup 4} g cm-3, suggesting that steady state, self-sustained detonations cannot come into existence in the radial direction. (c) 2000 The American Astronomical Society.

  8. Mechanistic Target of Rapamycin Complex 1/S6 Kinase 1 Signals Influence T Cell Activation Independently of Ribosomal Protein S6 Phosphorylation

    PubMed Central

    Salmond, Robert J.; Brownlie, Rebecca J.; Meyuhas, Oded

    2015-01-01

    Ag-dependent activation of naive T cells induces dramatic changes in cellular metabolism that are essential for cell growth, division, and differentiation. In recent years, the serine/threonine kinase mechanistic target of rapamycin (mTOR) has emerged as a key integrator of signaling pathways that regulate these metabolic processes. However, the role of specific downstream effectors of mTOR function in T cells is poorly understood. Ribosomal protein S6 (rpS6) is an essential component of the ribosome and is inducibly phosphorylated following mTOR activation in eukaryotic cells. In the current work, we addressed the role of phosphorylation of rpS6 as an effector of mTOR function in T cell development, growth, proliferation, and differentiation using knockin and TCR transgenic mice. Surprisingly, we demonstrate that rpS6 phosphorylation is not required for any of these processes either in vitro or in vivo. Indeed, rpS6 knockin mice are completely sensitive to the inhibitory effects of rapamycin and an S6 kinase 1 (S6K1)–specific inhibitor on T cell activation and proliferation. These results place the mTOR complex 1-S6K1 axis as a crucial determinant of T cell activation independently of its ability to regulate rpS6 phosphorylation. PMID:26453749

  9. An Interaction between RRP6 and SU(VAR)3-9 Targets RRP6 to Heterochromatin and Contributes to Heterochromatin Maintenance in Drosophila melanogaster.

    PubMed

    Eberle, Andrea B; Jordán-Pla, Antonio; Gañez-Zapater, Antoni; Hessle, Viktoria; Silberberg, Gilad; von Euler, Anne; Silverstein, Rebecca A; Visa, Neus

    2015-09-01

    RNA surveillance factors are involved in heterochromatin regulation in yeast and plants, but less is known about the possible roles of ribonucleases in the heterochromatin of animal cells. Here we show that RRP6, one of the catalytic subunits of the exosome, is necessary for silencing heterochromatic repeats in the genome of Drosophila melanogaster. We show that a fraction of RRP6 is associated with heterochromatin, and the analysis of the RRP6 interaction network revealed physical links between RRP6 and the heterochromatin factors HP1a, SU(VAR)3-9 and RPD3. Moreover, genome-wide studies of RRP6 occupancy in cells depleted of SU(VAR)3-9 demonstrated that SU(VAR)3-9 contributes to the tethering of RRP6 to a subset of heterochromatic loci. Depletion of the exosome ribonucleases RRP6 and DIS3 stabilizes heterochromatic transcripts derived from transposons and repetitive sequences, and renders the heterochromatin less compact, as shown by micrococcal nuclease and proximity-ligation assays. Such depletion also increases the amount of HP1a bound to heterochromatic transcripts. Taken together, our results suggest that SU(VAR)3-9 targets RRP6 to a subset of heterochromatic loci where RRP6 degrades chromatin-associated non-coding RNAs in a process that is necessary to maintain the packaging of the heterochromatin. PMID:26389589

  10. An Interaction between RRP6 and SU(VAR)3-9 Targets RRP6 to Heterochromatin and Contributes to Heterochromatin Maintenance in Drosophila melanogaster

    PubMed Central

    Eberle, Andrea B.; Jordán-Pla, Antonio; Gañez-Zapater, Antoni; Hessle, Viktoria; Silberberg, Gilad; von Euler, Anne; Silverstein, Rebecca A.; Visa, Neus

    2015-01-01

    RNA surveillance factors are involved in heterochromatin regulation in yeast and plants, but less is known about the possible roles of ribonucleases in the heterochromatin of animal cells. Here we show that RRP6, one of the catalytic subunits of the exosome, is necessary for silencing heterochromatic repeats in the genome of Drosophila melanogaster. We show that a fraction of RRP6 is associated with heterochromatin, and the analysis of the RRP6 interaction network revealed physical links between RRP6 and the heterochromatin factors HP1a, SU(VAR)3-9 and RPD3. Moreover, genome-wide studies of RRP6 occupancy in cells depleted of SU(VAR)3-9 demonstrated that SU(VAR)3-9 contributes to the tethering of RRP6 to a subset of heterochromatic loci. Depletion of the exosome ribonucleases RRP6 and DIS3 stabilizes heterochromatic transcripts derived from transposons and repetitive sequences, and renders the heterochromatin less compact, as shown by micrococcal nuclease and proximity-ligation assays. Such depletion also increases the amount of HP1a bound to heterochromatic transcripts. Taken together, our results suggest that SU(VAR)3-9 targets RRP6 to a subset of heterochromatic loci where RRP6 degrades chromatin-associated non-coding RNAs in a process that is necessary to maintain the packaging of the heterochromatin. PMID:26389589

  11. Comparison of the effects of couplings to breakup channels in reactions induced by {sup 6}Li and {sup 6}He on the same {sup 64}Zn target

    SciTech Connect

    Fernández-García, J. P. Di Pietro, A.; Figuera, P.; Fisichella, M.; Lattuada, M.; Musumarra, A.; Pellegriti, M. G.; Scuderi, V.; Torresi, D.; Moro, A. M.; Zadro, M.

    2015-10-15

    The experimental elastic scattering angular distributions for the weakly bound nuclei {sup 6,7}Li and for the halo nucleus {sup 6}He on the same {sup 64}Zn target at several energies around the Coulomb barrier were measured at the Laboratori Nazionali del Sud (LNS, Italy) and at the Cyclotron Research Center, Louvain La Neuve (Belgium), respectively. The measured elastic scattering angular distributions of these three systems at the same center of mass energy have been compared. The experimental data of the {sup 6,7}Li+ {sup 64}Zn systems have been analyzed within the CDCC method, while the {sup 6}He+{sup 64}Zn data have been compared with both both CDCC and CRC calculations.

  12. CCR6 regulates EAE pathogenesis by controlling regulatory CD4+ T-cell recruitment to target tissues.

    PubMed

    Villares, Ricardo; Cadenas, Vanessa; Lozano, María; Almonacid, Luis; Zaballos, Angel; Martínez-A, Carlos; Varona, Rosa

    2009-06-01

    The T-cell subsets, characterized by their cytokine production profiles and immune regulatory functions, depend on correct in vivo location to interact with accessory or target cells for effective immune responses. Differentiation of naive CD4(+) T cells into effectors is accompanied by sequentially regulated expression of the chemokine receptors responsible for cell recruitment to specific tissues. We studied CCR6 function in EAE, a CD4(+) T-cell-mediated CNS disease characterized by mononuclear infiltration and demyelination. CCR6(-/-) mice showed an altered time course of EAE development, with delayed onset, a higher clinical score, and more persistent symptoms than in controls. An imbalanced cytokine profile and reduced Foxp3(+) cell frequency characterized CNS tissues from CCR6(-/-) compared with CCR6(+/+) mice during the disease effector phase. Transfer of CCR6(+/+) Treg to CCR6(-/-) mice the day before EAE induction reduced the clinical score associated with an increased in infiltrating Foxp3(+) cells and recovery of the cytokine balance in CCR6(-/-) mouse CNS. Competitive assays between CCR6(+/+) and CCR6(-/-) Treg adoptively transferred to CCR6(-/-) mice showed impaired ability of CCR6(-/-) Treg to infiltrate CNS tissues in EAE-affected mice. Our data indicate a CCR6 requirement by CD4(+) Treg to downregulate the CNS inflammatory process and neurological signs associated with EAE. PMID:19499521

  13. Interactions of satellite-speed helium atoms with satellite surfaces. 2: Energy distributions of reflected helium atoms

    NASA Technical Reports Server (NTRS)

    Liu, S. M.; Knuth, E. L.

    1976-01-01

    Energy transfer in collisions of satellite-speed (7,000 m/sec) helium atoms with a cleaned 6061-T6 satellite-type aluminum surface was investigated using the molecular-beam technique. The amount of energy transferred was determined from the measured energy of the molecular-beam and the measured spatial and energy distributions of the reflected atoms. Spatial distributions of helium atoms scattered from a 6061-T6 aluminum surface were measured. The scattering pattern exhibits a prominent backscattering, probably due to the gross surface roughness and/or the relative lattice softness of the aluminum surface. Energy distributions of reflected helium atoms from the same surface were measured for six different incidence angles. For each incidence angle, distributions were measured at approximately sixty scattering positions. At a given scattering position, the energy spectra of the reflected helium atoms and the background gas were obtained using the retarding-field energy analyzer.

  14. Liquid Oxygen Thermodynamic Vent System Testing with Helium Pressurization

    NASA Technical Reports Server (NTRS)

    VanDresar, Neil T.

    2014-01-01

    This report presents the results of several thermodynamic vent system (TVS) tests with liquid oxygen plus a test with liquid nitrogen. In all tests, the liquid was heated above its normal boiling point to 111 K for oxygen and 100 K for nitrogen. The elevated temperature was representative of tank conditions for a candidate lunar lander ascent stage. An initial test series was conducted with saturated oxygen liquid and vapor at 0.6 MPa. The initial series was followed by tests where the test tank was pressurized with gaseous helium to 1.4 to 1.6 MPa. For these tests, the helium mole fraction in the ullage was quite high, about 0.57 to 0.62. TVS behavior is different when helium is present than when helium is absent. The tank pressure becomes the sum of the vapor pressure and the partial pressure of helium. Therefore, tank pressure depends not only on temperature, as is the case for a pure liquid-vapor system, but also on helium density (i.e., the mass of helium divided by the ullage volume). Thus, properly controlling TVS operation is more challenging with helium pressurization than without helium pressurization. When helium was present, the liquid temperature would rise with each successive TVS cycle if tank pressure was kept within a constant control band. Alternatively, if the liquid temperature was maintained within a constant TVS control band, the tank pressure would drop with each TVS cycle. The final test series, which was conducted with liquid nitrogen pressurized with helium, demonstrated simultaneous pressure and temperature control during TVS operation. The simultaneous control was achieved by systematic injection of additional helium during each TVS cycle. Adding helium maintained the helium partial pressure as the liquid volume decreased because of TVS operation. The TVS demonstrations with liquid oxygen pressurized with helium were conducted with three different fluid-mixer configurations-a submerged axial jet mixer, a pair of spray hoops in the tank

  15. Helium dilution refrigeration system

    DOEpatents

    Roach, P.R.; Gray, K.E.

    1988-09-13

    A helium dilution refrigeration system operable over a limited time period, and recyclable for a next period of operation is disclosed. The refrigeration system is compact with a self-contained pumping system and heaters for operation of the system. A mixing chamber contains [sup 3]He and [sup 4]He liquids which are precooled by a coupled container containing [sup 3]He liquid, enabling the phase separation of a [sup 3]He rich liquid phase from a dilute [sup 3]He-[sup 4]He liquid phase which leads to the final stage of a dilution cooling process for obtaining low temperatures. The mixing chamber and a still are coupled by a fluid line and are maintained at substantially the same level with the still cross sectional area being smaller than that of the mixing chamber. This configuration provides maximum cooling power and efficiency by the cooling period ending when the [sup 3]He liquid is depleted from the mixing chamber with the mixing chamber nearly empty of liquid helium, thus avoiding unnecessary and inefficient cooling of a large amount of the dilute [sup 3]He-[sup 4]He liquid phase. 2 figs.

  16. Helium dilution refrigeration system

    DOEpatents

    Roach, Patrick R.; Gray, Kenneth E.

    1988-01-01

    A helium dilution refrigeration system operable over a limited time period, and recyclable for a next period of operation. The refrigeration system is compact with a self-contained pumping system and heaters for operation of the system. A mixing chamber contains .sup.3 He and .sup.4 He liquids which are precooled by a coupled container containing .sup.3 He liquid, enabling the phase separation of a .sup.3 He rich liquid phase from a dilute .sup.3 He-.sup.4 He liquid phase which leads to the final stage of a dilution cooling process for obtaining low temperatures. The mixing chamber and a still are coupled by a fluid line and are maintained at substantially the same level with the still cross sectional area being smaller than that of the mixing chamber. This configuration provides maximum cooling power and efficiency by the cooling period ending when the .sup.3 He liquid is depleted from the mixing chamber with the mixing chamber nearly empty of liquid helium, thus avoiding unnecessary and inefficient cooling of a large amount of the dilute .sup.3 He-.sup.4 He liquid phase.

  17. Evidence for Prenylation-Dependent Targeting of a Ykt6 SNARE in Plasmodium falciparum

    PubMed Central

    Ayong, Lawrence; DaSilva, Thiago; Mauser, Jennifer; Allen, Charles M.; Chakrabarti, Debopam

    2011-01-01

    Ykt6 proteins are the most versatile fusogens in eukaryotic cells, and the only SNAREs that can be both prenylated and acylated at a C-terminal CAAX motif. Unlike yeast and mammalian cells where a single Ykt6 gene is expressed, the Plasmodium falciparum genome encodes two Ykt6 proteins. We have investigated the expression and prenylation of the Ykt6 orthologue, PfYkt6.1in intra-erythrocytic stages of P. falciparum. PfYkt6.1 localized to the parasite Golgi and other unidentified cytoplasmic compartments, and was partly cytosolic (~50% in early trophozoites). The membrane-association of PfYkt6.1 was dependent on presence of a conserved C-terminal CAAX motif (CCSIM). By expressing full-length and mutant proteins in Escherichia coli, we have shown that PfYkt6.1 indeed serves as substrate for prenylation by P. falciparum farnesyltransferases. Surprisingly, PfYkt6.1 could also be geranylgeranylated by parasite extracts independent of the C-terminal amino acid residue. Deletion of the CAAX motif inhibited both farnesylation and geranylgeranylation activities. Additionally, the PfYkt6.1 heptapeptide KQCCSIM, corresponding to the C-terminal CAAX sequence, inhibited the parasite farnesyltransferase activity with an IC50 of 1 µM. Our findings underscore the importance of CAAX motif-derived peptidomimetics for antimalarial drug development. PMID:21075148

  18. Production Target Design Report

    SciTech Connect

    Woloshun, Keith Albert; Dale, Gregory E.; Olivas, Eric Richard

    2015-07-28

    The Northstar 99Mo production target, a cylindrical length of 100Mo rod, has evolved considerably since its first conception.  The cylinder was very early sliced into disks to increase the heat transfer area, first to 1 mm thick disks then to the current 0.5 mm thick.  The coolant was changed early in the target development from water to helium to eliminate corrosion and dissolution.  The diameter has increased from initially 6 mm to 12 mm, the current diameter of the test target now at ANL, to nominally 28 mm (26-30.6 mm, depending upon optimal beam spot size and shape).  The length has also changed to improve the production to cost ratio, so now the target is nominally 41 mm long (excluding coolant gaps between disks), and irradiated on both ends.  This report summarizes the current status of the plant target design.

  19. Helium-3 and Helium-4 acceleration by high power laser pulses for hadron therapy

    SciTech Connect

    Bulanov, S. S.; Esarey, E.; Schroeder, C. B.; Leemans, W. P.; Bulanov, S. V.; Margarone, D.; Korn, G.; Haberer, T.

    2015-06-24

    The laser driven acceleration of ions is considered a promising candidate for an ion source for hadron therapy of oncological diseases. Though proton and carbon ion sources are conventionally used for therapy, other light ions can also be utilized. Whereas carbon ions require 400 MeV per nucleon to reach the same penetration depth as 250 MeV protons, helium ions require only 250 MeV per nucleon, which is the lowest energy per nucleon among the light ions. This fact along with the larger biological damage to cancer cells achieved by helium ions, than that by protons, makes this species an interesting candidate for the laser driven ion source. Two mechanisms (Magnetic Vortex Acceleration and hole-boring Radiation Pressure Acceleration) of PW-class laser driven ion acceleration from liquid and gaseous helium targets are studied with the goal of producing 250 MeV per nucleon helium ion beams that meet the hadron therapy requirements. We show that He3 ions, having almost the same penetration depth as He4 with the same energy per nucleon, require less laser power to be accelerated to the required energy for the hadron therapy.

  20. ESAT-6 Targeting to DEC205+ Antigen Presenting Cells Induces Specific-T Cell Responses against ESAT-6 and Reduces Pulmonary Infection with Virulent Mycobacterium tuberculosis

    PubMed Central

    Silva-Sánchez, Aarón; Meza-Pérez, Selene; Flores-Langarica, Adriana; Donis-Maturano, Luis; Estrada-García, Iris; Calderón-Amador, Juana; Hernández-Pando, Rogelio; Idoyaga, Juliana; Flores-Romo, Leopoldo

    2015-01-01

    Airways infection with Mycobacterium tuberculosis (Mtb) is contained mostly by T cell responses, however, Mtb has developed evasion mechanisms which affect antigen presenting cell (APC) maturation/recruitment delaying the onset of Ag-specific T cell responses. Hypothetically, bypassing the natural infection routes by delivering antigens directly to APCs may overcome the pathogen’s naturally evolved evasion mechanisms, thus facilitating the induction of protective immune responses. We generated a murine monoclonal fusion antibody (α-DEC-ESAT) to deliver Early Secretory Antigen Target (ESAT)-6 directly to DEC205+ APCs and to assess its in vivo effects on protection associated responses (IFN-γ production, in vivo CTL killing, and pulmonary mycobacterial load). Treatment with α-DEC-ESAT alone induced ESAT-6-specific IFN-γ producing CD4+ T cells and prime-boost immunization prior to Mtb infection resulted in early influx (d14 post-infection) and increased IFN-γ+ production by specific T cells in the lungs, compared to scarce IFN-γ production in control mice. In vivo CTL killing was quantified in relevant tissues upon transferring target cells loaded with mycobacterial antigens. During infection, α-DEC-ESAT-treated mice showed increased target cell killing in the lungs, where histology revealed cellular infiltrate and considerably reduced bacterial burden. Targeting the mycobacterial antigen ESAT-6 to DEC205+ APCs before infection expands specific T cell clones responsible for early T cell responses (IFN-γ production and CTL activity) and substantially reduces lung bacterial burden. Delivering mycobacterial antigens directly to APCs provides a unique approach to study in vivo the role of APCs and specific T cell responses to assess their potential anti-mycobacterial functions. PMID:25915045

  1. Development of a Novel PET Tracer [18F]AlF-NOTA-C6 Targeting MMP2 for Tumor Imaging

    PubMed Central

    Cheng, Chao; Zhang, Dazhi; Zhang, Anyu; Wang, Lizhen; Jiang, Hongdie; Wang, Tao; Liu, Hongrui; Xu, Yuping; Yang, Runlin; Chen, Fei; Yang, Min; Zuo, Changjing

    2015-01-01

    Background and Objective The overexpression of gelatinases, that is, matrix metalloproteinase MMP2 and MMP9, has been associated with tumor progression, invasion, and metastasis. To image MMP2 in tumors, we developed a novel ligand termed [18F]AlF-NOTA-C6, with consideration that: c(KAHWGFTLD)NH2 (herein, C6) is a selective gelatinase inhibitor; Cy5.5-C6 has been visualized in many in vivo tumor models; positron emission tomography (PET) has a higher detection sensitivity and a wider field of view than optical imaging; fluorine-18 (18F) is the optimal PET radioisotope, and the creation of a [18F]AlF-peptide complex is a simple procedure. Methods C6 was conjugated to the bifunctional chelator NOTA (1, 4, 7-triazacyclononanetriacetic acid) for radiolabeling [18F]AlF conjugation. The MMP2-binding characteristics and tumor-targeting efficacy of [18F]AlF-NOTA-C6 were tested in vitro and in vivo. Results The non-decay corrected yield of [18F]AlF-NOTA-C6 was 46.2–64.2%, and the radiochemical purity exceeded 95%. [18F]AlF-NOTA-C6 was favorably retained in SKOV3 and PC3 cells, determined by cell uptake. Using NOTA-C6 as a competitive ligand, the uptake of [18F]AlF-NOTA-C6 in SKOV3 cells decreased in a dose-dependent manner. In biodistribution and PET imaging studies, higher radioactivity concentrations were observed in tumors. Pre-injection of C6 caused a marked reduction in tumor tissue uptake. Immunohistochemistry showed MMP2 in tumor tissues. Conclusions [18F]AlF-NOTA-C6 was easy to synthesize and has substantial potential as an imaging agent that targets MMP2 in tumors. PMID:26540114

  2. Glucose-6-Phosphate Dehydrogenase of Trypanosomatids: Characterization, Target Validation, and Drug Discovery

    PubMed Central

    Gupta, Shreedhara; Igoillo-Esteve, Mariana; Michels, Paul A. M.; Cordeiro, Artur T.

    2011-01-01

    In trypanosomatids, glucose-6-phosphate dehydrogenase (G6PDH), the first enzyme of the pentosephosphate pathway, is essential for the defense of the parasite against oxidative stress. Trypanosoma brucei, Trypanosoma cruzi, and Leishmania mexicana G6PDHs have been characterized. The parasites' G6PDHs contain a unique 37 amino acid long N-terminal extension that in T. cruzi seems to regulate the enzyme activity in a redox-state-dependent manner. T. brucei and T. cruzi G6PDHs, but not their Leishmania spp. counterpart, are inhibited, in an uncompetitive way, by steroids such as dehydroepiandrosterone and derivatives. The Trypanosoma enzymes are more susceptible to inhibition by these compounds than the human G6PDH. The steroids also effectively kill cultured trypanosomes but not Leishmania and are presently considered as promising leads for the development of new parasite-selective chemotherapeutic agents. PMID:22091394

  3. Self-assembled virus-like particles from rotavirus structural protein VP6 for targeted drug delivery.

    PubMed

    Zhao, Qinghuan; Chen, Weihong; Chen, Yuanding; Zhang, Liming; Zhang, Jinping; Zhang, Zhijun

    2011-03-16

    Proteins of viral capsid may self-assemble into virus-like particles (VLPs) that can find many biomedical applications such as platform for drug delivery. In this paper, we describe preparation of VLPs by self-assembly of VP6, a rotavirus capsid protein that was chemically conjugated with doxorubicin (DOX), an anticancer drug. VP6 was first highly expressed in E. Coli, followed by purification and renaturation. DOX was then covalently attached to VP6 to form DOX-VP6 (DVP6) conjugates, which were subsequently self-assembled into VLPs under appropriate condition. Next, lactobionic acid (LA) was chemically linked to the surface of the VLPs. We demonstrated that the aforementioned nanosystem shows specific targeting to hepatoma cell line HepG2. The chemically functionalized VLPs, a kind of biological nanoparticles with excellent biocompatibility and biodegradability, can be prepared in large scale from E. Coli through our method, which may find practical applications in biomedicine. PMID:21338097

  4. Targeted alteration of dietary n-3 and n-6 fatty acids for the treatment of chronic headaches: a randomized trial.

    PubMed

    Ramsden, Christopher E; Faurot, Keturah R; Zamora, Daisy; Suchindran, Chirayath M; Macintosh, Beth A; Gaylord, Susan; Ringel, Amit; Hibbeln, Joseph R; Feldstein, Ariel E; Mori, Trevor A; Barden, Anne; Lynch, Chanee; Coble, Rebecca; Mas, Emilie; Palsson, Olafur; Barrow, David A; Mann, J Douglas

    2013-11-01

    Omega-3 and n-6 fatty acids are biosynthetic precursors to lipid mediators with antinociceptive and pronociceptive properties. We conducted a randomized, single-blinded, parallel-group clinical trial to assess clinical and biochemical effects of targeted alteration in dietary n-3 and n-6 fatty acids for treatment of chronic headaches. After a 4-week preintervention phase, ambulatory patients with chronic daily headache undergoing usual care were randomized to 1 of 2 intensive, food-based 12-week dietary interventions: a high n-3 plus low n-6 (H3-L6) intervention, or a low n-6 (L6) intervention. Clinical outcomes included the Headache Impact Test (HIT-6, primary clinical outcome), Headache Days per month, and Headache Hours per day. Biochemical outcomes included the erythrocyte n-6 in highly unsaturated fatty acids (HUFA) score (primary biochemical outcome) and bioactive n-3 and n-6 derivatives. Fifty-six of 67 patients completed the intervention. Both groups achieved targeted intakes of n-3 and n-6 fatty acids. In intention-to-treat analysis, the H3-L6 intervention produced significantly greater improvement in the HIT-6 score (-7.5 vs -2.1; P<0.001) and the number of Headache Days per month (-8.8 vs -4.0; P=0.02), compared to the L6 group. The H3-L6 intervention also produced significantly greater reductions in Headache Hours per day (-4.6 vs -1.2; P=0.01) and the n-6 in HUFA score (-21.0 vs -4.0%; P<0.001), and greater increases in antinociceptive n-3 pathway markers 18-hydroxy-eicosapentaenoic acid (+118.4 vs +61.1%; P<0.001) and 17-hydroxy-docosahexaenoic acid (+170.2 vs +27.2; P<0.001). A dietary intervention increasing n-3 and reducing n-6 fatty acids reduced headache pain, altered antinociceptive lipid mediators, and improved quality-of-life in this population. PMID:23886520

  5. Ceramide Synthase 6 Is a Novel Target of Methotrexate Mediating Its Antiproliferative Effect in a p53-Dependent Manner

    PubMed Central

    Fekry, Baharan; Esmaeilniakooshkghazi, Amin; Krupenko, Sergey A.; Krupenko, Natalia I.

    2016-01-01

    We previously reported that ceramide synthase 6 (CerS6) is elevated in response to folate stress in cancer cells, leading to enhanced production of C16-ceramide and apoptosis. Antifolate methotrexate (MTX), a drug commonly used in chemotherapy of several types of cancer, is a strong inhibitor of folate metabolism. Here we investigated whether this drug targets CerS6. We observed that CerS6 protein was markedly elevated in several cancer cell lines treated with MTX. In agreement with the enzyme elevation, its product C16-ceramide was also strongly elevated, so as several other ceramide species. The increase in C16-ceramide, however, was eliminated in MTX-treated cells lacking CerS6 through siRNA silencing, while the increase in other ceramides sustained. Furthermore, the siRNA silencing of CerS6 robustly protected A549 lung adenocarcinoma cells from MTX toxicity, while the silencing of another ceramide synthase, CerS4, which was also responsive to folate stress in our previous study, did not interfere with the MTX effect. The rescue effect of CerS6 silencing upon MTX treatment was further confirmed in HCT116 and HepG2 cell lines. Interestingly, CerS6 itself, but not CerS4, induced strong antiproliferative effect in several cancer cell lines if elevated by transient transfection. The effect of MTX on CerS6 elevation was likely p53 dependent, which is in agreement with the hypothesis that the protein is a transcriptional target of p53. In line with this notion, lometrexol, the antifolate inducing cytotoxicity through the p53-independent mechanism, did not affect CerS6 levels. We have also found that MTX induces the formation of ER aggregates, enriched with CerS6 protein. We further demonstrated that such aggregation requires CerS6 and suggests that it is an indication of ER stress. Overall, our study identified CerS6 and ceramide pathways as a novel MTX target. PMID:26783755

  6. Detached divertor operation in DIII-D helium plasmas

    SciTech Connect

    Hill, D. N., LLNL

    1998-05-01

    This paper presents results from operating helium plasmas in DIII-D in which helium gas puffing is used to reduce the peak divertor heat flux by factors of four or more. The threshold density for achieving these conditions is nearly the same as for deuterium plasmas, which is surprising given the fact that lack of chemical sputtering reduces the carbon concentration in the plasma by more than a factor of five. Spectroscopic analysis shows that helium becomes the primary radiation in these plasmas, which is possible because, unlike carbon, it is the primary species present. These plasmas differ from the usual partially detached divertor (PDD) plasmas in that there is no concomitant reduction in target plate ion flux with target plate heat flux in the scrape off later outside the separatrix.

  7. An RNA Aptamer Targets the PDZ-Binding Motif of the HPV16 E6 Oncoprotein

    PubMed Central

    Belyaeva, Tamara A.; Nicol, Clare; Cesur, Özlem; Travé, Gilles; Blair, George Eric; Stonehouse, Nicola J.

    2014-01-01

    Human papillomavirus 16 (HPV16) is a high-risk DNA tumour virus which is the primary causative agent of cervical cancer. Cell transformation arises from deregulated expression of the E6 and E7 oncogenes. E6 has been shown to bind a number of cellular proteins, including p53 and proteins containing a PDZ domain. This study reports the first RNA aptamers to E6. These have been employed as molecular tools to further investigate E6-p53 and E6-PDZ interactions. This study is focussed on two aptamers (termed F2 and F4) which induced apoptosis in cells derived from an HPV16-transformed cervical carcinoma. The molecules were able to inhibit the interaction between E6 and PDZ1 from Magi1, with F2 being the most effective inhibitor. Neither of the aptamers inhibited E6-p53 interaction or p53 degradation. This study shows the specificity of this approach and highlights the potential benefits of the E6 aptamers as potential therapeutic or diagnostic agents in the future. PMID:25062098

  8. Targeting choline phospholipid metabolism: GDPD5 and GDPD6 silencing decrease breast cancer cell proliferation, migration, and invasion.

    PubMed

    Cao, Maria Dung; Cheng, Menglin; Rizwan, Asif; Jiang, Lu; Krishnamachary, Balaji; Bhujwalla, Zaver M; Bathen, Tone F; Glunde, Kristine

    2016-08-01

    Abnormal choline phospholipid metabolism is associated with oncogenesis and tumor progression. We have investigated the effects of targeting choline phospholipid metabolism by silencing two glycerophosphodiesterase genes, GDPD5 and GDPD6, using small interfering RNA (siRNA) in two breast cancer cell lines, MCF-7 and MDA-MB-231. Treatment with GDPD5 and GDPD6 siRNA resulted in significant increases in glycerophosphocholine (GPC) levels, and no change in the levels of phosphocholine or free choline, which further supports their role as GPC-specific regulators in breast cancer. The GPC levels were increased more than twofold during GDPD6 silencing, and marginally increased during GDPD5 silencing. DNA laddering was negative in both cell lines treated with GDPD5 and GDPD6 siRNA, indicating absence of apoptosis. Treatment with GDPD5 siRNA caused a decrease in cell viability in MCF-7 cells, while GDPD6 siRNA treatment had no effect on cell viability in either cell line. Decreased cell migration and invasion were observed in MDA-MB-231 cells treated with GDPD5 or GDPD6 siRNA, where a more pronounced reduction in cell migration and invasion was observed under GDPD5 siRNA treatment as compared with GDPD6 siRNA treatment. In conclusion, GDPD6 silencing increased the GPC levels in breast cancer cells more profoundly than GDPD5 silencing, while the effects of GDPD5 silencing on cell viability/proliferation, migration, and invasion were more severe than those of GDPD6 silencing. Our results suggest that silencing GDPD5 and GDPD6 alone or in combination may have potential as a new molecular targeting strategy for breast cancer treatment. Copyright © 2016 John Wiley & Sons, Ltd. PMID:27356959

  9. Helium segregation on surfaces of plasma-exposed tungsten

    DOE PAGESBeta

    Maroudas, Dimitrios; Blondel, Sophie; Hu, Lin; Hammond, Karl D.; Wirth, Brian D.

    2016-01-21

    Here we report a hierarchical multi-scale modeling study of implanted helium segregation on surfaces of tungsten, considered as a plasma facing component in nuclear fusion reactors. We employ a hierarchy of atomic-scale simulations based on a reliable interatomic interaction potential, including molecular-statics simulations to understand the origin of helium surface segregation, targeted molecular-dynamics (MD) simulations of near-surface cluster reactions, and large-scale MD simulations of implanted helium evolution in plasma-exposed tungsten. We find that small, mobile He-n (1 <= n <= 7) clusters in the near-surface region are attracted to the surface due to an elastic interaction force that provides themore » thermodynamic driving force for surface segregation. Elastic interaction force induces drift fluxes of these mobile Hen clusters, which increase substantially as the migrating clusters approach the surface, facilitating helium segregation on the surface. Moreover, the clusters' drift toward the surface enables cluster reactions, most importantly trap mutation, in the near-surface region at rates much higher than in the bulk material. Moreover, these near-surface cluster dynamics have significant effects on the surface morphology, near-surface defect structures, and the amount of helium retained in the material upon plasma exposure. We integrate the findings of such atomic-scale simulations into a properly parameterized and validated spatially dependent, continuum-scale reaction-diffusion cluster dynamics model, capable of predicting implanted helium evolution, surface segregation, and its near-surface effects in tungsten. This cluster-dynamics model sets the stage for development of fully atomistically informed coarse-grained models for computationally efficient simulation predictions of helium surface segregation, as well as helium retention and surface morphological evolution, toward optimal design of plasma facing components.« less

  10. Helium segregation on surfaces of plasma-exposed tungsten

    NASA Astrophysics Data System (ADS)

    Maroudas, Dimitrios; Blondel, Sophie; Hu, Lin; Hammond, Karl D.; Wirth, Brian D.

    2016-02-01

    We report a hierarchical multi-scale modeling study of implanted helium segregation on surfaces of tungsten, considered as a plasma facing component in nuclear fusion reactors. We employ a hierarchy of atomic-scale simulations based on a reliable interatomic interaction potential, including molecular-statics simulations to understand the origin of helium surface segregation, targeted molecular-dynamics (MD) simulations of near-surface cluster reactions, and large-scale MD simulations of implanted helium evolution in plasma-exposed tungsten. We find that small, mobile He n (1  ⩽  n  ⩽  7) clusters in the near-surface region are attracted to the surface due to an elastic interaction force that provides the thermodynamic driving force for surface segregation. This elastic interaction force induces drift fluxes of these mobile He n clusters, which increase substantially as the migrating clusters approach the surface, facilitating helium segregation on the surface. Moreover, the clusters’ drift toward the surface enables cluster reactions, most importantly trap mutation, in the near-surface region at rates much higher than in the bulk material. These near-surface cluster dynamics have significant effects on the surface morphology, near-surface defect structures, and the amount of helium retained in the material upon plasma exposure. We integrate the findings of such atomic-scale simulations into a properly parameterized and validated spatially dependent, continuum-scale reaction-diffusion cluster dynamics model, capable of predicting implanted helium evolution, surface segregation, and its near-surface effects in tungsten. This cluster-dynamics model sets the stage for development of fully atomistically informed coarse-grained models for computationally efficient simulation predictions of helium surface segregation, as well as helium retention and surface morphological evolution, toward optimal design of plasma facing components.

  11. Helium segregation on surfaces of plasma-exposed tungsten.

    PubMed

    Maroudas, Dimitrios; Blondel, Sophie; Hu, Lin; Hammond, Karl D; Wirth, Brian D

    2016-02-17

    We report a hierarchical multi-scale modeling study of implanted helium segregation on surfaces of tungsten, considered as a plasma facing component in nuclear fusion reactors. We employ a hierarchy of atomic-scale simulations based on a reliable interatomic interaction potential, including molecular-statics simulations to understand the origin of helium surface segregation, targeted molecular-dynamics (MD) simulations of near-surface cluster reactions, and large-scale MD simulations of implanted helium evolution in plasma-exposed tungsten. We find that small, mobile He n (1⩽  n  ⩽  7) clusters in the near-surface region are attracted to the surface due to an elastic interaction force that provides the thermodynamic driving force for surface segregation. This elastic interaction force induces drift fluxes of these mobile He n clusters, which increase substantially as the migrating clusters approach the surface, facilitating helium segregation on the surface. Moreover, the clusters' drift toward the surface enables cluster reactions, most importantly trap mutation, in the near-surface region at rates much higher than in the bulk material. These near-surface cluster dynamics have significant effects on the surface morphology, near-surface defect structures, and the amount of helium retained in the material upon plasma exposure. We integrate the findings of such atomic-scale simulations into a properly parameterized and validated spatially dependent, continuum-scale reaction-diffusion cluster dynamics model, capable of predicting implanted helium evolution, surface segregation, and its near-surface effects in tungsten. This cluster-dynamics model sets the stage for development of fully atomistically informed coarse-grained models for computationally efficient simulation predictions of helium surface segregation, as well as helium retention and surface morphological evolution, toward optimal design of plasma facing components. PMID:26794828

  12. Hypoxia-Targeted Drug Q6 Induces G2-M Arrest and Apoptosis via Poisoning Topoisomerase II under Hypoxia

    PubMed Central

    Wang, Dandan; Ma, Jian; Zhou, Tianyi; Chen, Ying; Sheng, Rong; Hu, Yongzhou; Du, Ying; He, Qiaojun; Yang, Bo; Zhu, Hong

    2015-01-01

    In spite of the tremendous efforts dedicated to developing hypoxia-activated prodrugs, no agents yet have been approved for clinical therapy. In the present study, the hypoxic selective anti-cancer activity as well as the cellular target of a novel tirapazamine (TPZ) analogue, 7-methyl-3-(3-chlorophenyl)-quinoxaline-2-carbonitrile 1,4-dioxide (Q6) were investigated. Q6 implemented anti-cancer effects via poisoning topoisomerase II (topo II) under hypoxia. Modified trapped in agarose DNA immunostaining (TARDIS) assay showed more topo II–DNA cleavage complexes trapped by Q6 than TPZ at even lower concentration. In addition, by introducing ataxia-telangiectasia-mutated (ATM) kinase inhibitors caffeine and KU-60019, we displayed that Q6-triggered apoptosis was attributed, at least partially, to DNA double-strand breaks generated by the topo II-targeting effect. Collectively, Q6 stood out for its better hypoxia-selectivity and topo II-poisoning than the parental compound TPZ. All these data shed light on the research of Q6 as a promising hypoxia-activated prodrug candidate for human hepatocellular carcinoma therapy. PMID:26649750

  13. Solvation of Na+, K+, and Their Dimers in Helium

    PubMed Central

    An der Lan, Lukas; Bartl, Peter; Leidlmair, Christian; Jochum, Roland; Denifl, Stephan; Echt, Olof; Scheier, Paul

    2012-01-01

    Helium atoms bind strongly to alkali cations which, when embedded in liquid helium, form so-called snowballs. Calculations suggest that helium atoms in the first solvation layer of these snowballs form rigid structures and that their number (n) is well defined, especially for the lighter alkalis. However, experiments have so far failed to accurately determine values of n. We present high-resolution mass spectra of Na+Hen, K+Hen, Na2+Hen and K2+Hen, formed by electron ionization of doped helium droplets; the data allow for a critical comparison with several theoretical studies. For sodium and potassium monomers the spectra indicate that the value of n is slightly smaller than calculated. Na2+Hen displays two distinct anomalies at n=2 and n=6, in agreement with theory; dissociation energies derived from experiment closely track theoretical values. K2+Hen distributions are fairly featureless, which also agrees with predictions. PMID:22374575

  14. Deciphering downstream gene targets of PI3K/mTOR/p70S6K pathway in breast cancer

    PubMed Central

    Heinonen, Henna; Nieminen, Anni; Saarela, Matti; Kallioniemi, Anne; Klefström, Juha; Hautaniemi, Sampsa; Monni, Outi

    2008-01-01

    Background The 70 kDa ribosomal protein S6 kinase (RPS6KB1), located at 17q23, is amplified and overexpressed in 10–30% of primary breast cancers and breast cancer cell lines. p70S6K is a serine/threonine kinase regulated by PI3K/mTOR pathway, which plays a crucial role in control of cell cycle, growth and survival. Our aim was to determine p70S6K and PI3K/mTOR/p70S6K pathway dependent gene expression profiles by microarrays using five breast cancer cell lines with predefined gene copy number and gene expression alterations. The p70S6K dependent profiles were determined by siRNA silencing of RPS6KB1 in two breast cancer cell lines overexpressing p70S6K. These profiles were further correlated with gene expression alterations caused by inhibition of PI3K/mTOR pathway with PI3K inhibitor Ly294002 or mTOR inhibitor rapamycin. Results Altogether, the silencing of p70S6K altered the expression of 109 and 173 genes in two breast cancer cell lines and 67 genes were altered in both cell lines in addition to RPS6KB1. Furthermore, 17 genes including VTCN1 and CDKN2B showed overlap with genes differentially expressed after PI3K or mTOR inhibition. The gene expression signatures responsive to both PI3K/mTOR pathway and p70S6K inhibitions revealed previously unidentified genes suggesting novel downstream targets for PI3K/mTOR/p70S6K pathway. Conclusion Since p70S6K overexpression is associated with aggressive disease and poor prognosis of breast cancer patients, the potential downstream targets of p70S6K and the whole PI3K/mTOR/p70S6K pathway identified in our study may have diagnostic value. PMID:18652687

  15. Design, Synthesis and Evaluation of Novel 2,5,6-Trisubstituted Benzimidazoles Targeting FtsZ as Antitubercular Agents

    PubMed Central

    Park, Bora; Awasthi, Divya; Chowdhury, Soumya R.; Melief, Eduard H.; Kumar, Kunal; Knudson, Susan E.; Slayden, Richard A.; Ojima, Iwao

    2014-01-01

    Filamenting temperature-sensitive protein Z (FtsZ), an essential cell division protein, is a promising target for the drug discovery of new-generation antibacterial agents against various bacterial pathogens. As a part of SAR studies on benzimidazoles, we have synthesized a library of 376 novel 2,5,6-trisubstituted benzimidazoles, bearing ether or thioether linkage at the 6-position. In a preliminary HTP screening against Mtb H37Rv, 108 compounds were identified as hits at a cut off concentration of 5 μg/mL. Among those hits, 10 compounds exhibited MIC values in the range of 0.63–12.5 μg/mL. Light scattering assay and TEM analysis with the most potent compound 5a clearly indicate that its molecular target is Mtb-FtsZ. Also, the Kd of 5a with Mtb-FtsZ was determined to be 1.32 μM. PMID:24726304

  16. Precision spectroscopy of Helium

    SciTech Connect

    Cancio, P.; Giusfredi, G.; Mazzotti, D.; De Natale, P.; De Mauro, C.; Krachmalnicoff, V.; Inguscio, M.

    2005-05-05

    Accurate Quantum-Electrodynamics (QED) tests of the simplest bound three body atomic system are performed by precise laser spectroscopic measurements in atomic Helium. In this paper, we present a review of measurements between triplet states at 1083 nm (23S-23P) and at 389 nm (23S-33P). In 4He, such data have been used to measure the fine structure of the triplet P levels and, then, to determine the fine structure constant when compared with equally accurate theoretical calculations. Moreover, the absolute frequencies of the optical transitions have been used for Lamb-shift determinations of the levels involved with unprecedented accuracy. Finally, determination of the He isotopes nuclear structure and, in particular, a measurement of the nuclear charge radius, are performed by using hyperfine structure and isotope-shift measurements.

  17. Comparison of C5 and C6 Aqua-MODIS Dark Target Aerosol Validation

    NASA Technical Reports Server (NTRS)

    Munchak, Leigh A.; Levy, Robert C.; Mattoo, Shana

    2014-01-01

    We compare C5 and C6 validation to compare the C6 10 km aerosol product against the well validated and trusted aerosol product on global and regional scales. Only the 10 km aerosol product is evaluated in this study, validation of the new C6 3 km aerosol product still needs to be performed. Not all of the time series has processed yet for C5 or C6, and the years processed for the 2 products is not exactly the same (this work is preliminary!). To reduce the impact of outlier observations, MODIS is spatially averaged within 27.5 km of the AERONET site, and AERONET is temporatally averaged within 30 minutes of the MODIS overpass time. Only high quality (QA = 3 over land, QA greater than 0 over ocean) pixels are included in the mean.

  18. Identification of BIRC6 as a novel intervention target for neuroblastoma therapy

    PubMed Central

    2012-01-01

    Background Neuroblastoma are pediatric tumors of the sympathetic nervous system with a poor prognosis. Apoptosis is often deregulated in cancer cells, but only a few defects in apoptotic routes have been identified in neuroblastoma. Methods Here we investigated genomic aberrations affecting genes of the intrinsic apoptotic pathway in neuroblastoma. We analyzed DNA profiling data (CGH and SNP arrays) and mRNA expression data of 31 genes of the intrinsic apoptotic pathway in a dataset of 88 neuroblastoma tumors using the R2 bioinformatic platform ( http://r2.amc.nl). BIRC6 was selected for further analysis as a tumor driving gene. Knockdown experiments were performed using BIRC6 lentiviral shRNA and phenotype responses were analyzed by Western blot and MTT-assays. In addition, DIABLO levels and interactions were investigated with immunofluorescence and co-immunoprecipitation. Results We observed frequent gain of the BIRC6 gene on chromosome 2, which resulted in increased mRNA expression. BIRC6 is an inhibitor of apoptosis protein (IAP), that can bind and degrade the cytoplasmic fraction of the pro-apoptotic protein DIABLO. DIABLO mRNA expression was exceptionally high in neuroblastoma but the protein was only detected in the mitochondria. Upon silencing of BIRC6 by shRNA, DIABLO protein levels increased and cells went into apoptosis. Co-immunoprecipitation confirmed direct interaction between DIABLO and BIRC6 in neuroblastoma cell lines. Conclusion Our findings indicate that BIRC6 may have a potential oncogenic role in neuroblastoma by inactivating cytoplasmic DIABLO. BIRC6 inhibition may therefore provide a means for therapeutic intervention in neuroblastoma. PMID:22788920

  19. Antiprotonic helium and CPT invariance

    NASA Astrophysics Data System (ADS)

    Hayano, Ryugo S.; Hori, Masaki; Horváth, Dezso; Widmann, Eberhard

    2007-12-01

    We review recent progress in the laser and microwave spectroscopy of antiprotonic helium atoms (\\barpHe^+ \\equiv \\rme^\\--\\barp - He^{++}) carried out at CERN's Antiproton Decelerator facility (AD). Laser transitions were here induced between Rydberg states (n, ell) and (n ± 1, ell - 1) of \\barpHe^+ (n ~ 40 and ell ≲ n - 1 being the principal and orbital angular momentum quantum numbers of the antiproton orbit). Successive refinements in the experimental techniques improved the fractional precision on the \\barpHe^+ frequencies from 3 parts in 106 to ~1 part in 108. These included a radiofrequency quadrupole decelerator, which reduced the energy of the antiprotons from 5.3 MeV (the energy of the beam emerging from AD) to ~100 keV. This enabled the production of \\barpHe^+ in ultra-low density targets, where collisional effects with other helium atoms are negligible. A continuous wave pulse-amplified dye laser, stabilized against a femtosecond optical frequency comb, was then used to measure the \\barpHe^+ frequencies with ppb-scale precision. This progress in the experimental field was matched by similar advances in computing methods for evaluating the expected transition frequencies in three-body QED calculations. The comparison of experimental (νexp) and theoretical (νth) frequencies for seven transitions in \\barp^4He^+ and five in \\barp^3 He^+ yielded an antiproton-to-electron mass ratio of m_\\bar p/m_{\\rme} = 1836.152\\,674(5) . This agrees with the known proton-to-electron mass ratio at the level of ~2 × 10-9. The experiment also set a limit on any CPT-violating difference between the antiproton and proton charges and masses, (Q_p - |Q_{\\barp}|)/Q_p \\sim (m_p - m_{\\barp})/m_p < 2 \\times 10^{-9} to a 90% confidence level. If on the other hand we assume the validity of the CPT invariance, the m_{\\barp}/m_{\\rme} result can be taken to be equal to mp/me. This can be used as an input to future adjustments of fundamental constants. The hyperfine

  20. IL-6 Inhibits the Targeted Modulation of PDCD4 by miR-21 in Prostate Cancer.

    PubMed

    Dong, Biao; Shi, Zhihao; Wang, Jiaping; Wu, Jing; Yang, Zhaoqing; Fang, Kewei

    2015-01-01

    Prostate cancer is the most common cancer among men in the Unites States. The cytokine IL-6 activates several prostate cancer pathways, but its upstream trans-signaling pathway remains poorly understood. In this study, we evaluated the role of IL-6 in PDCD4 gene expression and how the microRNA miR-21 regulates this process in prostate cancer cell lines PC-3 and LNCaP. The expression pattern of PDCD4 from samples from human prostate cancer, precancerous lesions, and benign prostatic hyperplasia was investigated by immunohistochemistry. PDCD4 transcription and translation were detected by quantitative real-time PCR (qRT-PCR) and Western blot analysis, respectively. The targeted modulation of PDCD4 by miR-21 was analyzed in PC-3 and LNCaP cells, and the effect of IL-6 on the expression of PDCD4 was studied in vitro. PDCD4 expression in samples from the 3 tissue types progressively increased, and the expression levels of PDCD4 and prostate-specific antigen were negatively correlated. The levels of PDCD4 mRNA and protein in PC-3 and LNCaP cells transfected with anti-miR-21 constructs were lower than those in control cells. The expression of PDCD4 was inhibited by IL-6, but this effect was weakened in cell lines with low expression of miR-21. Our study demonstrates that the regulation of PDCD4 by miR-21 is targeted and IL-6 inhibits expression of the PDCD4 gene in PC-3 and LNCaP cells through the targeted function of miR-21 on PDCD4. These findings support the feasibility of future efforts for diagnosis and gene therapy for prostate cancer that are based on IL-6, miR-21, and PDCD4. PMID:26252635

  1. Targets of the StBEL5 Transcription Factor Include the FT Ortholog StSP6A1[OPEN

    PubMed Central

    Lin, Tian

    2016-01-01

    The BEL1-like family of transcription factors is ubiquitous in plants and plays important roles in regulating development. They function in tandem with KNOTTED1 types to bind to a double TTGAC motif in the upstream sequence of target genes. StBEL5 of potato (Solanum tuberosum) functions as a mobile RNA signal that is transcribed in leaves, moves down into stolons in response to short days, and induces tuber formation. Despite their importance, however, very little is known about the targets of BEL1-like transcription factors. To better understand this network, we made use of a phloem-mobile BEL5 induction model, an ethanol-inducible system coupled with RNA sequencing analysis, and a screen for tandem TTGAC cis-elements in the upstream sequence to catalog StBEL5 target genes. Induction of StBEL5 activated several genes that are also induced by StSP6A (S. tuberosum SELF-PRUNING 6A), a FLOWERING LOCUS T coregulator that functions as a signal for tuberization. Both enhancement and suppression of StBEL5 expression were also closely linked to StSP6A transcriptional activity. Site mutagenesis in tandem TTGAC motifs located in the upstream sequence of StSP6A suppressed the short day-induced activity of its promoter in both young tubers and leaves. The expression profile of StBEL5 induced in stolons from plants grown under long-day conditions revealed almost 10,000 differentially expressed genes, including important tuber marker genes and genes involved in cell growth, transcription, floral development, and hormone metabolism. In a random screen of 200 differentially expressed targets of StBEL5, 92% contained tandem TTGAC motifs in the upstream sequence within 3 kb of the transcription start site. PMID:26553650

  2. Efficacy and selectivity of phosphodiesterase-targeted drugs to inhibit photoreceptor phosphodiesterase (PDE6) in retinal photoreceptors*

    PubMed Central

    Zhang, Xiujun; Feng, Qing; Cote, Rick H.

    2005-01-01

    Purpose: Phosphodiesterase (PDE) inhibitors are important therapeutic agents, but their effects on photoreceptor PDE (PDE6) and photoreceptor cells are poorly understood. We characterized the potency and selectivity of various classes of PDE inhibitors on purified rod and cone PDE6 and on intact rod outer segments (ROS). Methods: The inhibition constant (KI) of isozyme-selective PDE inhibitors was determined for purified rod and cone PDE6. Perturbations of cGMP levels in isolated ROS suspensions by PDE inhibitors were quantitated by a cGMP enzyme-linked immunoassay. Results: Most PDE5-selective inhibitors are excellent PDE6 inhibitors. Vardenafil, a potent PDE5 inhibitor (KI = 0.2 nM), is the most potent PDE6 inhibitor tested (KI = 0.7 nM). Zaprinast is the only drug that inhibits PDE6 more potently than PDE5. PDE1-selective inhibitors were equally effective in inhibiting PDE6. In intact ROS, PDE inhibitors elevated cGMP levels but none fully inhibited PDE6. Their potency to elevate cGMP levels in ROS was much lower than their ability to inhibit the purified enzyme. Competition between PDE5/6-selective drugs and the inhibitory γ subunit for the active site of PDE6 is proposed to reduce the effectiveness of drugs at the enzyme active site. Conclusions: Several classes of PDE inhibitors equally well inhibit PDE6 as the PDE family to which they are targeted. In intact ROS, high PDE6 concentrations, binding of the γ subunit to the active site, and calcium feedback mechanisms attenuate the effectiveness of PDE inhibitors to inhibit PDE6 and disrupt the cGMP signaling pathway during visual transduction. PMID:16123402

  3. MiR-361-5p acts as a tumor suppressor in prostate cancer by targeting signal transducer and activator of transcription-6(STAT6)

    SciTech Connect

    Liu, Dachuang; Tao, Tao; Xu, Bin; Chen, Shuqiu; Liu, Chunhui; Zhang, Lei; Lu, Kai; Huang, Yeqing; Jiang, Liang; Zhang, Xiaowen; Huang, Xiaoming; Zhang, Lihua; Han, Conghui; Chen, Ming

    2014-02-28

    Highlights: • The role of miR-361-5p in prostate cancer (PCa) has not been evaluated until date. • We found that the expression of miR-361-5p in CRPC was lower than in ADPC. • MiR-361-5p suppressed DU145 cell proliferation and triggered apoptosis. • STAT6 is a direct target of miR-361-5p. • STAT6 enhances the expression of Bcl-xL at the transcriptional level. - Abstract: Castration-resistant prostate cancer (CRPC), whose pathogenesis is known to be regulated by microRNAs (miRNAs), has a poor prognosis. In our present study, we found that the expression of miR-361-5p in CRPC was lower than in androgen-dependent prostate cancer (ADPC), indicating that miR-361-5p may play an important role in the progression of ADPC to CRPC. The role of miR-361-5p in prostate cancer (PCa) has not been evaluated until date. Our findings suggest that miR-361-5p is a suppressor in CRPC. Signal transducer and activator of transcription-6 (STAT6), a direct target of miR-361-5p, enhances the expression of B-cell lymphoma-extra large (Bcl-xL), while miR-361-5p inhibits its expression through STAT6. Therefore, miR-361-5p has great clinical significance in preventing the malignant progression of PCa.

  4. Tumor targeting using magnetic nanoparticle Hsp70 conjugate in a model of C6 glioma

    PubMed Central

    Shevtsov, Maxim A.; Yakovleva, Ludmila Y.; Nikolaev, Boris P.; Marchenko, Yaroslav Y.; Dobrodumov, Anatolii V.; Onokhin, Kirill V.; Onokhina, Yana S.; Selkov, Sergey A.; Mikhrina, Anastasiia L.; Guzhova, Irina V.; Martynova, Marina G.; Bystrova, Olga A.; Ischenko, Alexander M.; Margulis, Boris A.

    2014-01-01

    Background Superparamagnetic iron oxide nanoparticles (SPIONs), due to their unique magnetic properties, have the ability to function both as magnetic resonance (MR) contrast agents, and can be used for thermotherapy. SPIONs conjugated to the heat shock protein Hsp70 that selectively binds to the CD40 receptor present on glioma cells, could be used for MR contrast enhancement of experimental C6 glioma. Methods The magnetic properties of the Hsp70-SPIONs were measured by NMR relaxometry method. The uptake of nanoparticles was assessed on the C6 glioma cells by confocal and electron microscopes. The tumor selectivity of Hsp70-SPIONs being intravenously administered was analyzed in the experimental model of C6 glioma in the MRI scanner. Results Hsp70-SPIONs relaxivity corresponded to the properties of negative contrast agents with a hypointensive change of resonance signal in MR imaging. A significant accumulation of the Hsp70-SPIONs but not the non-conjugated nanoparticles was observed by confocal microscopy within C6 cells. Negative contrast tumor enhancement in the T2-weighted MR images was higher in the case of Hsp70-SPIONs in comparison to non-modified SPIONs. Histological analysis of the brain sections confirmed the retention of the Hsp70-SPIONs in the glioma tumor but not in the adjacent normal brain tissues. Conclusion The study demonstrated that Hsp70-SPION conjugate intravenously administered in C6 glioma model accumulated in the tumors and enhanced the contrast of their MR images. PMID:24305705

  5. ETV6-NTRK3 as a therapeutic target of small molecule inhibitor PKC412

    SciTech Connect

    Chi, Hoang Thanh; Ly, Bui Thi Kim; Kano, Yasuhiko; Tojo, Arinobu; Sato, Yuko

    2012-12-07

    Highlights: Black-Right-Pointing-Pointer ETV6-NTRK3 is an oncogene with transformation activity in multiple cell lineages. Black-Right-Pointing-Pointer PKC412 could block ETV6-NTRK3 activation. Black-Right-Pointing-Pointer Loss of ETV6-NTRK3 phosphorylation leads to inactivation of its downstream signaling pathway. Black-Right-Pointing-Pointer Inhibition of ETV6-NTRK3 activation by PKC412 could be a novel strategy for the treatment. -- Abstract: The ETV6-NTRK3 (EN) fusion gene which encodes a chimeric tyrosine kinase was first identified by cloning of the t(12;15)(p13;q25) translocation in congenital fibrosarcoma (CFS). Since then, EN has been also found in congenital mesoblastic nephroma (CMN), secretory breast carcinoma (SBC) and acute myelogenous leukemia (AML). Using IMS-M2 and M0-91 cell lines harboring the EN fusion gene, and Ba/F3 cells stably transfected with EN, we demonstrated that PKC412, also known as midostaurin, is an inhibitor of EN. Inhibition of EN activity by PKC412 suppressed the activity of it downstream molecules leading to inhibition of cell proliferation and induction of apoptosis. Our data for the first time suggested that PKC412 could serve as therapeutic drug for treatment of patients with this fusion.

  6. Evaluating MODIS Collection 6 Dark Target Over Water Aerosol Products for Multi-sensor Data Fusion

    NASA Astrophysics Data System (ADS)

    Shi, Y.; Zhang, J.; Reid, J. S.; Hyer, E. J.; McHardy, T. M.; Lee, L.

    2014-12-01

    The Moderate Resolution Imaging Spectroradiometer (MODIS) aerosol products have been widely used in aerosol related climate, visibility, and air quality studies for more than a decade. Recently, the MODIS collection 6 (c6) aerosol products from MODIS-Aqua have been released. The reported changes between Collection 5 and Collection 6 include updates in the retrieving algorithms and a new cloud filtering process for the over-ocean products. Thus it is necessary to fully evaluate the collection 6 products for applications that require high quality MODIS aerosol optical depth data, such as operational aerosol data assimilation. The uncertainties in the MODIS c6 DT over ocean products are studied through both inter-comparing with the Multi-angle Imaging Spectroradiometer (MISR) aerosol products and by evaluation against ground truth. Special attention is given to the low bias in MODIS DT products due to the misclassifications of heavy aerosol plumes as clouds. Finally, a quality assured data assimilation grade aerosol optical product is constructed for aerosol data assimilation related applications.

  7. Targeting Translation Control with p70 S6 Kinase 1 Inhibitors to Reverse Phenotypes in Fragile X Syndrome Mice.

    PubMed

    Bhattacharya, Aditi; Mamcarz, Maggie; Mullins, Caitlin; Choudhury, Ayesha; Boyle, Robert G; Smith, Daniel G; Walker, David W; Klann, Eric

    2016-07-01

    Aberrant neuronal translation is implicated in the etiology of numerous brain disorders. Although mTORC1-p70 ribosomal S6 kinase 1 (S6K1) signaling is critical for translational control, pharmacological manipulation in vivo has targeted exclusively mTORC1 due to the paucity of specific inhibitors to S6K1. However, small molecule inhibitors of S6K1 could potentially ameliorate pathological phenotypes of diseases, which are based on aberrant translation and protein expression. One such condition is fragile X syndrome (FXS), which is considered to be caused by exaggerated neuronal translation and is the most frequent heritable cause of autism spectrum disorder (ASD). To date, potential therapeutic interventions in FXS have focused largely on targets upstream of translational control to normalize FXS-related phenotypes. Here we test the ability of two S6K1 inhibitors, PF-4708671 and FS-115, to normalize translational homeostasis and other phenotypes exhibited by FXS model mice. We found that although the pharmacokinetic profiles of the two S6K1 inhibitors differed, they overlapped in reversing multiple disease-associated phenotypes in FXS model mice including exaggerated protein synthesis, inappropriate social behavior, behavioral inflexibility, altered dendritic spine morphology, and macroorchidism. In contrast, the two inhibitors differed in their ability to rescue stereotypic marble-burying behavior and weight gain. These findings provide an initial pharmacological characterization of the impact of S6K1 inhibitors in vivo for FXS, and have therapeutic implications for other neuropsychiatric conditions involving aberrant mTORC1-S6K1 signaling. PMID:26708105

  8. Resource Letter SH-1: Superfluid Helium.

    ERIC Educational Resources Information Center

    Hallock, Robert B.

    1982-01-01

    Provides an annotated list of books, textbooks, and films on superfluid helium. Also lists research reports/reviews arranged by category, including among others, early history, microscopic understanding, ions in helium, helium in rotation, vortices and quantization, helium films and constricted geometrics, persistence flow, and superfluid helium…

  9. Toolkit for Professional Developers: Training Targets 3?6 Grade Teachers

    ERIC Educational Resources Information Center

    McMunn, Nancy; Dunnivant, Michael; Williamson, Jan; Reagan, Hope

    2004-01-01

    The professional development CAR Toolkit is focused on the assessment of reading process at the text level, rather than at the word level. Most students in grades 3-6 generally need support in comprehending text, not just decoding words. While the assessment of reading methods in the CAR Toolkit will help teachers pinpoint difficulties at the word…

  10. Targeted gene analysis: increased B-cell lymphoma 6 in preeclamptic placentas.

    PubMed

    Louwen, Frank; Muschol-Steinmetz, Cornelia; Friemel, Alexandra; Kämpf, Anne Kristina; Töttel, Eva; Reinhard, Joscha; Yuan, Juping

    2014-06-01

    Preeclampsia is a leading cause for maternal and perinatal mortality and morbidity. Microarray-based transcriptional profiling has been widely used for identifying genes responsible for preeclampsia. These studies deliver multiple pictures of gene signatures, implying the complicated pathophysiology. In the present work, we designed our own gene array containing genes involved in various signaling transduction pathways and analyzed placental samples from patients with preeclampsia and controls. We verify that genes associated with angiogenesis and migration pathways are mostly altered in preeclamptic placentas. Interestingly, several genes including B-cell lymphoma 6 have been identified to be linked to preeclampsia. Increased expression of B-cell lymphoma 6 is correlated with enhanced FLT1 and LEPTIN, the hallmarks of preeclampsia. Moreover, the protein level of B-cell lymphoma 6 is elevated in preeclamptic placentas and is predominantly localized in the nucleus of villous cytotrophoblasts lying directly underneath the syncytial layer, suggestive of an involvement in the function of villous trophoblasts. Altered B-cell lymphoma 6, a key oncogene in B-cell lymphomagenesis, may be involved in the pathogenesis of preeclampsia, and further investigations are required to decipher the molecular mechanisms. PMID:24767250

  11. The interaction between AMPKβ2 and the PP1-targeting subunit R6 is dynamically regulated by intracellular glycogen content.

    PubMed

    Oligschlaeger, Yvonne; Miglianico, Marie; Dahlmans, Vivian; Rubio-Villena, Carla; Chanda, Dipanjan; Garcia-Gimeno, Maria Adelaida; Coumans, Will A; Liu, Yilin; Voncken, J Willem; Luiken, Joost J F P; Glatz, Jan F C; Sanz, Pascual; Neumann, Dietbert

    2016-04-01

    AMP-activated protein kinase (AMPK) is a metabolic stress-sensing kinase. We previously showed that glucose deprivation induces autophosphorylation of AMPKβ at Thr-148, which prevents the binding of AMPK to glycogen. Furthermore, in MIN6 cells, AMPKβ1 binds to R6 (PPP1R3D), a glycogen-targeting subunit of protein phosphatase type 1 (PP1), thereby regulating the glucose-induced inactivation of AMPK. In the present study, we further investigated the interaction of R6 with AMPKβ and the possible dependency on Thr-148 phosphorylation status. Yeast two-hybrid (Y2H) analyses and co-immunoprecipitation (IP) of the overexpressed proteins in human embryonic kidney (HEK) 293T) cells revealed that both AMPKβ1 and AMPK-β2 wild-type (WT) isoforms bind to R6. The AMPKβ-R6 interaction was stronger with the muscle-specific AMPKβ2-WT and required association with the substrate-binding motif of R6. When HEK293T cells or C2C12 myotubes were cultured in high-glucose medium, AMPKβ2-WT and R6 weakly interacted. In contrast, glycogen depletion significantly enhanced this protein interaction. Mutation of AMPKβ2 Thr-148 prevented the interaction with R6 irrespective of the intracellular glycogen content. Treatment with the AMPK activator oligomycin enhanced the AMPKβ2-R6 interaction in conjunction with increased Thr-148 phosphorylation in cells grown in low-glucose medium. These data are in accordance with R6 binding directly to AMPKβ2 when both proteins detach from the diminishing glycogen particle, which is simultaneous with increased AMPKβ2 Thr-148 autophosphorylation. Such a model points to a possible control of AMPK by PP1-R6 upon glycogen depletion in muscle. PMID:26831516

  12. MiR-29b suppresses the proliferation and migration of osteosarcoma cells by targeting CDK6.

    PubMed

    Zhu, Kegan; Liu, Lei; Zhang, Junliang; Wang, Yanbo; Liang, Hongwei; Fan, Gentao; Jiang, Zhenhuan; Zhang, Chen-Yu; Chen, Xi; Zhou, Guangxin

    2016-06-01

    Osteosarcoma is the most common primary sarcoma of bone, and it is a leading cause of cancer death among adolescents and young adults. However, the molecular mechanism underlying osteosarcoma carcinogenesis remains poorly understood. Recently, cyclin-dependent kinase 6 (CDK6) was identified as an important oncogene. We found that CDK6 protein level, rather than CDK6 mRNA level, is much higher in osteosarcoma tissues than in normal adjacent tissues, which indicates a post-transcriptional mechanism involved in CDK6 regulation in osteosarcoma. MiRNAs are small non-coding RNAs that repress gene expression at the post-transcriptional level and have widely been shown to play important roles in many human cancers. In this study, we investigated the role of miR-29b as a novel regulator of CDK6 using bioinformatics methods. We demonstrated that CDK6 can be downregulated by miR-29b via binding to the 3'-UTR region in osteosarcoma cells. Furthermore, we identified an inverse correlation between miR-29b and CDK6 protein levels in osteosarcoma tissues. Finally, we examined the function of miR-29b-driven repression of CDK6 expression in osteosarcoma cells. The results revealed that miR-29b acts as a tumor suppressor of osteosarcoma by targeting CDK6 in the proliferation and migration processes. Taken together, our results highlight an important role for miR-29b in the regulation of CDK6 in osteosarcoma and may open new avenues for future osteosarcoma therapies. PMID:27230400

  13. The preheating effect on the dynamic strength of aluminium containing helium bubbles

    NASA Astrophysics Data System (ADS)

    Glam, B.; Strauss, M.; Eliezer, S.; Moreno, D.

    2014-05-01

    The influence of helium bubbles or boron inclusions in an aluminum target is studied by plane impact experiments with a gas gun and VISAR diagnostic. The experiments were carried out on targets with initial temperatures of 25 °C and near melting at 600 °C. The Hugoniot elastic limit yHEL for all targets becomes substantially higher at 600 °C, related to the phonon drag mechanism at high strain rates and high temperatures. The spall strength for all targets becomes substantially lower at 600 °C. The spall strength of Al-10B with helium bubbles is significantly reduced in comparison to Al-10B without helium, while at 25 °C the spall strength is the same for both cases. This effect might be explained by a local strength reduction of the aluminium at pre-heating conditions, allowing the helium bubbles to be more dominant in the spallation process

  14. The high-risk HPV E6 oncoprotein preferentially targets phosphorylated nuclear forms of hDlg

    SciTech Connect

    Narayan, Nisha; Subbaiah, Vanitha Krishna; Banks, Lawrence

    2009-04-25

    High-risk mucosal HPV E6 oncoproteins target a number of PDZ domain-containing substrates for proteasome mediated degradation. One of these, Discs Large (Dlg), is involved in the regulation of cell polarity and proliferation control. Previous studies had suggested that Dlg when hyperphosphorylated by osmotic shock, or when present in the nucleus could be preferentially targeted by E6. In this study we use phospho-specific antibodies directed against Dlg phosphorylated at residues S158 and S442 to show that these two observations are, in fact, linked. Dlg, when phosphorylated on S158 and S442 by CDK1 or CDK2, shows a preferential nuclear accumulation. However, these forms of Dlg are absent in cells derived from HPV-induced cervical cancers. Upon either proteasome inhibition or siRNA ablation of E6 expression, we see specific rescue of these phosphorylated forms of Dlg. These results demonstrate that nuclear forms of Dlg phosphorylated on its CDK phospho-acceptor sites has enhanced susceptibility to E6-induced degradation and place previous studies on the stress-induced phosphorylation of Dlg into a relevant biological context.

  15. MicroRNA-187 induces diffuse large B-cell lymphoma cell apoptosis via targeting BCL6

    PubMed Central

    HUANG, FANG; JIN, YAOFENG; WEI, YAFENG

    2016-01-01

    MicroRNAs (miRs) are endogenous non-coding RNAs that serve key functions in a wide range of biological processes, including cell growth, development, apoptosis and carcinogenesis. However, the association between miR-187 and B-cell lymphoma 6 (BCL6) has yet to be fully investigated in lymphoma cell apoptosis. The present study hypothesized that a post-translational mechanism may exist for BCL6 expression, which is regulated by miR-187 in lymphoma cells. The present study demonstrated that the expression of miR-187 in diffuse large B-cell lymphoma (DLBCL) cells was significantly decreased, and its expression was negatively correlated with BCL6 expression. It was also observed that miR-187 directly binds to the 3′-untranslated region of BCL6 mRNA and subsequently suppresses the expression of BCL6. Additionally, the induced expression of miR-187 significantly promoted DLBCL cell apoptosis in vitro. The drug sensitivity of human DLBCL SUDHL2 cells was increased following induction of miR-187 overexpression via an miR-187 mimic. In conclusion, the results of the present study suggest that the modulation of miR-187 expression in DLBCL cells may improve the sensitivity of chemotherapy through BCL6 targeting. PMID:27073562

  16. 26 CFR 1.338-6 - Allocation of ADSP and AGUB among target assets.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... Regulatory Commission in a report described in 10 CFR 50.75(b) as providing assurance that funds will be... be used only as permitted by 10 CFR 50.82(a)(8). (iii) Availability of election. P may make the... and on or after September 15, 2004, see § 1.338-6T as contained in 26 CFR part 1 in effect on April...

  17. 26 CFR 1.338-6 - Allocation of ADSP and AGUB among target assets.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... Regulatory Commission in a report described in 10 CFR 50.75(b) as providing assurance that funds will be... be used only as permitted by 10 CFR 50.82(a)(8). (iii) Availability of election. P may make the... and on or after September 15, 2004, see § 1.338-6T as contained in 26 CFR part 1 in effect on April...

  18. 26 CFR 1.338-6 - Allocation of ADSP and AGUB among target assets.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... Regulatory Commission in a report described in 10 CFR 50.75(b) as providing assurance that funds will be... be used only as permitted by 10 CFR 50.82(a)(8). (iii) Availability of election. P may make the... and on or after September 15, 2004, see § 1.338-6T as contained in 26 CFR part 1 in effect on April...

  19. 26 CFR 1.338-6 - Allocation of ADSP and AGUB among target assets.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... be used only as permitted by 10 CFR 50.82(a)(8). (iii) Availability of election. P may make the... and on or after September 15, 2004, see § 1.338-6T as contained in 26 CFR part 1 in effect on April 1... 26 CFR part 1 in effect on April 1, 2004. (d) Examples. The following examples illustrate §§...

  20. 26 CFR 1.338-6 - Allocation of ADSP and AGUB among target assets.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... be used only as permitted by 10 CFR 50.82(a)(8). (iii) Availability of election. P may make the... and on or after September 15, 2004, see § 1.338-6T as contained in 26 CFR part 1 in effect on April 1... 26 CFR part 1 in effect on April 1, 2004. (d) Examples. The following examples illustrate §§...

  1. Low temperature uses of helium

    NASA Technical Reports Server (NTRS)

    Brown, G. V.

    1970-01-01

    Helium is used for purging and pressurizing cryogenic rocket propellants, welding, atmosphere control, leak detection, and refrigeration. It provides the lowest possible liquid-bath temperature and produces superconductivity in certain materials. Its superfluid effects are used in superconducting magnets.

  2. miR-130b-3p Upregulation Contributes to the Development of Thyroid Adenomas Targeting CCDC6 Gene

    PubMed Central

    Leone, Vincenza; Langella, Concetta; Esposito, Francesco; De Martino, Marco; Decaussin-Petrucci, Myriam; Chiappetta, Gennaro; Bianco, Antonio; Fusco, Alfredo

    2015-01-01

    We have previously studied the function of microRNAs (miRNAs) in thyroid cells using the differentiated rat thyroid PC Cl 3 cells that need thyrotropin (TSH) for their growth. The miRNA expression profile examination allowed the detection of a set of miRNAs downregulated and upregulated by TSH. Here, we first demonstrated that upregulation of miR-130b-3p occurs through a protein kinase A-cAMP-responsive element binding protein (CREB)-dependent mechanism. Then, we analyzed its expression in human thyroid follicular adenomas, where a constitutive CREB activation is frequently present. miR-130b-3p results in upregulation with a high fold-change in most thyroid follicular adenomas. Then, we identified CCDC6, coding for a protein that interacts with CREB1 leading to the transcriptional repression of CREB1 target genes, as a target of this miRNA. The targeting of CCDC6 by miR-130b-3p likely accounts for the mechanism by which its upregulation contributes to the development of thyroid adenomas increasing CREB1 activity. PMID:26835423

  3. Targeted disruption of the mouse cation-dependent mannose 6-phosphate receptor results in partial missorting of multiple lysosomal enzymes.

    PubMed Central

    Ludwig, T; Ovitt, C E; Bauer, U; Hollinshead, M; Remmler, J; Lobel, P; Rüther, U; Hoflack, B

    1993-01-01

    In mammalian cells two mannose 6-phosphate receptors (MPRs) are involved in lysosomal enzyme transport. To understand the precise function of the cation-dependent mannose 6-phosphate receptor (CD-MPR), one allele of the corresponding gene has been disrupted in mouse embryonic stem cells and homozygous mice lacking this receptor have been generated. The homozygous mice appear normal, suggesting that other targeting mechanisms can partially compensate for the loss of the CD-MPR in vivo. However, homozygous receptor-deficient cells and animals clearly exhibit defects in targeting of multiple lysosomal enzymes when compared with wild-types. Increased levels of phosphorylated lysosomal enzymes were present in body fluids of homozygous animals. In thymocytes from homozygous mice or in primary cultures of fibroblasts from homozygous embryos, there is a marked increase in the amount of phosphorylated lysosomal enzymes that are secreted into the extracellular medium. The cultured fibroblasts have decreased intracellular levels of multiple lysosomal enzymes and accumulate macromolecules within their endosomal/lysosomal system. Taken together, these results clearly indicate that the CD-MPR is required for efficient intracellular targeting of multiple lysosomal enzymes. Images PMID:8262065

  4. MicroRNA-320 family is downregulated in colorectal adenoma and affects tumor proliferation by targeting CDK6

    PubMed Central

    Tadano, Toshihiro; Kakuta, Yoichi; Hamada, Shin; Shimodaira, Yosuke; Kuroha, Masatake; Kawakami, Yoko; Kimura, Tomoya; Shiga, Hisashi; Endo, Katsuya; Masamune, Atsushi; Takahashi, Seiichi; Kinouchi, Yoshitaka; Shimosegawa, Tooru

    2016-01-01

    AIM: To investigate the microRNA (miRNA) expression during histological progression from colorectal normal mucosa through adenoma to carcinoma within a lesion. METHODS: Using microarray, the sequential changes in miRNA expression profiles were compared in colonic lesions from matched samples; histologically, non-neoplastic mucosa, adenoma, and submucosal invasive carcinoma were microdissected from a tissue sample. Cell proliferation assay was performed to observe the effect of miRNA, and its target genes were predicted using bioinformatics approaches and the expression profile of SW480 transfected with the miRNA mimics. mRNA and protein levels of the target gene in colon cancer cell lines with a mimic control or miRNA mimics were measured using qRT-PCR and Western blotting. The expression levels of miRNA and target gene in colorectal tissue samples were also measured. RESULTS: Microarray analysis identified that the miR-320 family, including miR-320a, miR-320b, miR-320c, miR-320d and miR-320e, were differentially expressed in adenoma and submucosal invasive carcinoma. The miR-320 family, which inhibits cell proliferation, is frequently downregulated in colorectal adenoma and submucosal invasive carcinoma tissues. Seven genes including CDK6 were identified to be common in the results of gene expression array and bioinformatics analyses performed to find the target gene of the miR-320 family. We confirmed that mRNA and protein levels of CDK6 were significantly suppressed in colon cancer cell lines with miR-320 family mimics. CDK6 expression was found to increase from non-neoplastic mucosa through adenoma to submucosal invasive carcinoma tissues and showed an inverse correlation with miR-320 family expression. CONCLUSION: MiR-320 family affects colorectal tumor proliferation by targeting CDK6, plays important role in its growth, and is considered to be a biomarker for its early detection. PMID:27559432

  5. Design, synthesis, and evaluation of 4,6-diaminonicotinamide derivatives as novel and potent immunomodulators targeting JAK3.

    PubMed

    Nakajima, Yutaka; Aoyama, Naohiro; Takahashi, Fumie; Sasaki, Hiroshi; Hatanaka, Keiko; Moritomo, Ayako; Inami, Masamichi; Ito, Misato; Nakamura, Koji; Nakamori, Fumihiro; Inoue, Takayuki; Shirakami, Shohei

    2016-10-01

    In organ transplantation, T cell-mediated immune responses play a key role in the rejection of allografts. Janus kinase 3 (JAK3) is specifically expressed in hematopoietic cells and associated with regulation of T cell development via interleukin-2 signaling pathway. Here, we designed novel 4,6-diaminonicotinamide derivatives as immunomodulators targeting JAK3 for prevention of transplant rejection. Our optimization of C4- and C6-substituents and docking calculations to JAK3 protein confirmed that the 4,6-diaminonicotinamide scaffold resulted in potent inhibition of JAK3. We also investigated avoidance of human ether-a-go-go related gene (hERG) inhibitory activity. Selected compound 28 in combination with tacrolimus prevented allograft rejection in a rat heterotopic cardiac transplantation model. PMID:27544589

  6. CerS6 Is a Novel Transcriptional Target of p53 Protein Activated by Non-genotoxic Stress.

    PubMed

    Fekry, Baharan; Jeffries, Kristen A; Esmaeilniakooshkghazi, Amin; Ogretmen, Besim; Krupenko, Sergey A; Krupenko, Natalia I

    2016-08-01

    Our previous study suggested that ceramide synthase 6 (CerS6), an enzyme in sphingolipid biosynthesis, is regulated by p53: CerS6 was elevated in several cell lines in response to transient expression of p53 or in response to folate stress, which is known to activate p53. It was not clear, however, whether CerS6 gene is a direct transcriptional target of p53 or whether this was an indirect effect through additional regulatory factors. In the present study, we have shown that the CerS6 promoter is activated by p53 in luciferase assays, whereas transcriptionally inactive R175H p53 mutant failed to induce the luciferase expression from this promoter. In vitro immunoprecipitation assays and gel shift analyses have further demonstrated that purified p53 binds within the CerS6 promoter sequence spanning 91 bp upstream and 60 bp downstream of the transcription start site. The Promo 3.0.2 online tool for the prediction of transcription factor binding sites indicated the presence of numerous putative non-canonical p53 binding motifs in the CerS6 promoter. Luciferase assays and gel shift analysis have identified a single motif upstream of the transcription start as a key p53 response element. Treatment of cells with Nutlin-3 or low concentrations of actinomycin D resulted in a strong elevation of CerS6 mRNA and protein, thus demonstrating that CerS6 is a component of the non-genotoxic p53-dependent cellular stress response. This study has shown that by direct transcriptional activation of CerS6, p53 can regulate specific ceramide biosynthesis, which contributes to the pro-apoptotic cellular response. PMID:27302066

  7. 6,7,4'-trihydroxyisoflavone inhibits HCT-116 human colon cancer cell proliferation by targeting CDK1 and CDK2.

    PubMed

    Lee, Dong Eun; Lee, Ki Won; Jung, Sung Keun; Lee, Eun Jung; Hwang, Jung A; Lim, Tae-Gyu; Kim, Bo Yeon; Bode, Ann M; Lee, Hyong Joo; Dong, Zigang

    2011-04-01

    Colon cancer is a common epithelial malignancies worldwide. Epidemiologic evidence has shown that nutrition and dietary components are important environmental factors involved in the development of this disease. We investigated the biological activity of 6,7,4'-trihydroxyisoflavone (6,7,4'-THIF, a metabolite of daidzein) in in vitro and in vivo models of human colon cancer. 6,7,4'-THIF suppressed anchorage-dependent and -independent growth of HCT-116 and DLD1 human colon cancer cells more effectively than daidzein. In addition, 6,7,4'-THIF induced cell cycle arrest at the S and G2/M phases in HCT-116 human colon cancer cells. Western blot analysis revealed that 6,7,4'-THIF effectively suppressed the expression of cyclin-dependent kinase (CDK) 2, but had no effect on other S- or G2/M-phase regulatory proteins such as cyclin A, cyclin B1 or CDK1. Daidzein did not affect the expression of any of these proteins. In kinase and pull-down assays, 6,7,4'-THIF, but not daidzein, inhibited CDK1 and CDK2 activities in HCT-116 cells by directly interacting with CDK1 and CDK2. In a xenograft mouse model, 6,7,4'-THIF significantly decreased tumor growth, volume and weight of HCT-116 xenografts. 6,7,4'-THIF bound directly to CDK1 and CDK2 in vivo, resulting in the suppression of CDK1 and CDK2 activity in tumors corresponding with our in vitro results. Collectively, these results suggest that CDK1 and CDK2 are potential molecular targets of 6,7,4'-THIF to suppress HCT-116 cell proliferation in vitro and in vivo. These findings provide insight into the biological actions of 6,7,4'-THIF and might establish a molecular basis for the development of new cancer therapeutic agents. PMID:21258042

  8. Radiation source for helium magnetometers

    NASA Technical Reports Server (NTRS)

    Slocum, Robert E. (Inventor)

    1991-01-01

    A radiation source (12) for optical magnetometers (10) which use helium isotopes as the resonance element (30) includes an electronically pumped semiconductor laser (12) which produces a single narrow line of radiation which is frequency stabilized to the center frequency of the helium resonance line to be optically pumped. The frequency stabilization is accomplished using electronic feedback (34, 40, 42, 44) to control a current sources (20) thus eliminating the need for mechanical frequency tuning.

  9. Aberrantly activated claudin 6 and 18.2 as potential therapy targets in non-small-cell lung cancer.

    PubMed

    Micke, Patrick; Mattsson, Johanna Sofia Margareta; Edlund, Karolina; Lohr, Miriam; Jirström, Karin; Berglund, Anders; Botling, Johan; Rahnenfuehrer, Jörg; Marincevic, Millaray; Pontén, Fredrik; Ekman, Simon; Hengstler, Jan; Wöll, Stefan; Sahin, Ugur; Türeci, Ozlem

    2014-11-01

    Claudins (CLDNs) are central components of tight junctions that regulate epithelial-cell barrier function and polarity. Altered CLDN expression patterns have been demonstrated in numerous cancer types and lineage-specific CLDNs have been proposed as therapy targets. The objective of this study was to assess which fraction of patients with non-small-cell lung cancer (NSCLC) express CLDN6 and CLDN18 isoform 2 (CLDN18.2). Protein expression of CLDN6 and CLDN18.2 was examined by immunohistochemistry on a tissue microarray (n = 355) and transcript levels were supportively determined based on gene expression microarray data from fresh-frozen NSCLC tissues (n = 196). Both were analyzed with regard to frequency, distribution and association with clinical parameters. Immunohistochemical analysis of tissue sections revealed distinct membranous positivity of CLDN6 (6.5%) and CLDN18.2 (3.7%) proteins in virtually non-overlapping subgroups of adenocarcinomas and large-cell carcinomas. Pneumocytes and bronchial epithelial cells were consistently negative. Corresponding to the protein expression, in subsets of non-squamous lung carcinoma high mRNA levels of CLDN6 (7-16%) and total CLDN18 (5-12%) were observed. Protein expression correlated well with total mRNA expression of the corresponding gene (rho = 0.4-0.8). CLDN18.2 positive tumors were enriched among slowly proliferating, thyroid transcription factor 1 (TTF-1)-negative adenocarcinomas, suggesting that isoform-specific CLDN expression may delineate a specific subtype. Noteworthy, high CLDN6 protein expression was associated with worse prognosis in lung adenocarcinoma in the univariate [hazard ratio (HR): 1.8; p = 0.03] and multivariate COX regression model (HR: 1.9; p = 0.02). These findings encourage further clinical exploration of targeting ectopically activated CLDN expression as a valuable treatment concept in NSCLC. PMID:24710653

  10. MicroRNA-106b targets FUT6 to promote cell migration, invasion, and proliferation in human breast cancer.

    PubMed

    Li, Nana; Liu, Yuejian; Miao, Yuan; Zhao, Lifen; Zhou, Huimin; Jia, Li

    2016-09-01

    It is demonstrated that the maladjustment of microRNA (miRNA) plays significant roles in the occurrence and development of tumors. MicroRNA-106b-5p (miR-106b), a carcinogenic miRNA, is identified as a dysregulated miRNA in human breast cancer. In this article, the expression levels of miR-106b were discovered to be particularly higher in breast cancer tissues than that in the corresponding adjacent tissues. Accordingly, miR-106b was higher expressed in the breast cancer cell lines compared with that in the normal breast cell lines. Moreover, according to the data previously reported, increased expression of miR-106b was significantly associated with advanced clinical stages and poor prognosis in breast cancer. Fucosyltransferase 6 (FUT6), a member of the fucosyltransferase (FUT) family, was found to have a reduced expression in tissues or cells with higher level of miR-106b in breast cancer. Additionally, down-regulation of miR-106b increased the expression of FUT6 and resulted in an obvious decrease of cell migration, invasion, and proliferation in MDA-MB-231 cells. Furthermore, over-expressed FUT6 reversed the impacts of up-regulated miR-106b on cell migration, invasion, and proliferation in MCF-7 cells, indicating that FUT6 might be directly targeted by miR-106b and serve as therapeutic targets for breast cancer. In brief, our results strongly showed that the low expression of FUT6 regulated by miR-106b contributed to cell migration, invasion, and proliferation in human breast cancer. © 2016 IUBMB Life, 68(9):764-775, 2016. PMID:27519168