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Sample records for 119sb a potent auger

  1. Design of a rotary stepped auger for a lunar environment

    NASA Technical Reports Server (NTRS)

    Dardet, Eduardo; Hart, Derek; Herod, Chris; Homiller, Stephen; Meeks, Mickey; Platt, Kirsten

    1988-01-01

    A lunar outpost will have need for deep drilling operations for both explorative and practical purposes. As in any drilling operation, the cuttings must be cleared from the hole. The hard vacuum of the lunar environment renders conventional flushing methods of cutting removal unfeasible, and requires a new system of removal. A rotary stepped auger (RSA) is a simple mechanical method of removing dry cuttings from a deep hole, and is ideally suited to the lunar environment. The RSA consists of a helical auger with stepped ramps which allow cuttings to slide up the helix, but will prevent them from sliding back down. The auger is driven in a pulsed manner by applying a periodic function of acceleration to the auger shaft. These pulses will compel the cuttings to slide up the auger's helix while the stepped ramps prevent the cuttings from backsliding while the auger accelerates. A mathematical model of the RSA was developed and experimentally evaluated. The math model produced a good baseline design, but the experimental model required some tuning to account for the approximations made in the math model. This design is suited for lunar drilling because it is mechanically simple, integral to the drill string, requires no fluids, is suited to the dry soil, and has relatively low weight and power requirements.

  2. Auger-architectomics: introducing a new nanotechnology to infectious disease.

    PubMed

    Swart, Chantel W; Pohl, Carolina H; Kock, Johan L F

    2014-01-01

    In 2010, we developed a new imaging nanotechnology called Auger-architectomics, to study drug biosensors in nano-detail. We succeeded in applying Auger atom electron physics coupled to scanning electron microscopy (SEM) and Argon-etching to cell structure exploration, thereby exposing a new dimension in structure and element composition architecture. Auger-architectomics was used to expose the fate and effect of drugs on cells. This technology should now be expanded to diseased cells. This paper will outline the development, proof of concept, and application of this imaging nanotechnology. A virtual tour is available at: http://vimeo.com/user6296337 .

  3. Differential auger spectrometry

    DOEpatents

    Strongin, Myron; Varma, Matesh Narayan; Anne, Joshi

    1976-06-22

    Differential Auger spectroscopy method for increasing the sensitivity of micro-Auger spectroanalysis of the surfaces of dilute alloys, by alternately periodically switching an electron beam back and forth between an impurity free reference sample and a test sample containing a trace impurity. The Auger electrons from the samples produce representative Auger spectrum signals which cancel to produce an Auger test sample signal corresponding to the amount of the impurity in the test samples.

  4. Production and dosimetric aspects of the potent Auger emitter {sup 58m}Co for targeted radionuclide therapy of small tumors

    SciTech Connect

    Thisgaard, H.; Elema, D.R.; Jensen, M.

    2011-08-15

    Purpose: Based on theoretical calculations, the Auger emitter {sup 58m}Co has been identified as a potent nuclide for targeted radionuclide therapy of small tumors. During the production of this isotope, the coproduction of the long-lived ground state {sup 58g}Co is unfortunately unavoidable, as is ingrowth of the ground state following the isomeric decay of {sup 58m}Co. The impact of {sup 58g}Co as a {beta}{sup +}- and {gamma}-emitting impurity should be included in the dosimetric analysis. The purpose of this study was to investigate this critical part of dosimetry based on experimentally determined production yields of {sup 58m}Co and {sup 58g}Co using a low-energy cyclotron. Also, the cellular S-values for {sup 58m}Co have been calculated and are presented here for the first time. Methods: {sup 58m}Co was produced via the {sup 58}Fe(p,n){sup 58m}Co nuclear reaction on highly enriched {sup 58}Fe metal. In addition, radiochemical separations of produced radio-cobalt from {sup nat}Fe target material were performed. The theoretical subcellular dosimetry calculations for {sup 58m}Co and {sup 58g}Co were performed using the MIRD formalism, and the impact of the increasing ground state impurity on the tumor-to-normal-tissue dose ratios (TND) per disintegration as a function of time after end of bombardment (EOB) was calculated. Results: 192 {+-} 8 MBq of {sup 58m}Co was produced in the irradiation corresponding to a production yield of 10.7 MBq/{mu}Ah. The activity of {sup 58g}Co was measured to be 0.85% {+-} 0.04% of the produced {sup 58m}Co activity at EOB. The radio-cobalt yields in the rapid separations were measured to be >97% with no detectable iron contaminations in the cobalt fractions. Due to the unavoidable coproduction and ingrowth of the long-lived ground state {sup 58g}Co, the TND and the potency of the {sup 58m}Co decrease with time after EOB. If a future treatment with a {sup 58m}Co labeled compound is not initiated before, e.g., 21 h after EOB, the

  5. Upflow bioreactor having a septum and an auger and drive assembly

    DOEpatents

    Hansen, Carl S.; Hansen, Conly L.

    2007-11-06

    An upflow bioreactor includes a vessel having an inlet and an outlet configured for upflow operation. A septum is positioned within the vessel and defines a lower chamber and an upper chamber. The septum includes an aperture that provides fluid communication between the upper chamber and lower chamber. The bioreactor also includes an auger positioned in the aperture of the septum. The vessel includes an opening in the top for receiving the auger. The auger extends from a drive housing, which is position over the opening and provides a seal around the opening. The drive housing is adjustable relative to the vessel. The position of the auger in the aperture can be adjusted by adjusting the drive housing relative to the vessel. The auger adjustment mechanism allows the auger to be accurately positioned within the aperture. The drive housing can also include a fluid to provide an additional seal around the shaft of the auger.

  6. A new technique for Auger analysis of surface species subject to electron-induced desorption

    NASA Technical Reports Server (NTRS)

    Pepper, S. V.

    1973-01-01

    A method is presented to observe surface species subject to electron-induced desorption by Auger electron spectroscopy. The surface to be examined is moved under the electron beam at constant velocity, establishing a time independent condition and eliminating the time response of the electron spectrometer as a limiting factor. The dependence of the Auger signal on the surface velocity, incident electron current, beam diameter, and desorption cross section are analyzed. The method is illustrated by the Auger analysis of PTFE, in which the fluorine is removed by electron induced desorption.

  7. Installation of observation wells on hazardous waste sites in Kansas using a hollow-stem auger

    USGS Publications Warehouse

    Perry, C.A.; Hart, R.J.

    1985-01-01

    Noncontaminating procedures were used during the hollow-stem auger installation of 12 observation wells on three hazardous waste sites in Kansas. Special precautions were taken to ensure that water samples were representative of the ground water in the aquifer and were not subjected to contamination from the land surface or cross contamination from within borehole. Precautions included thorough cleaning of the hollow-stem auger and casing, keeping drill cuttings from falling back into the borehole while drilling, and not adding water to the borehole. These procedures were designed to prevent contamination of the ground water during well installation. Because of the use of water during well installation could contaminate the aquifer or dilute contaminants already present in the aquifer, two methods of well installation that did not introduce outside water to the borehole were used. The first method involved using a slotted 3/4 -inch coupling that was attached to the bit plate of the hollow-stem auger, allowing formation water to enter the auger, thereby preventing sand-plug formation. This method proved to be adequate, except when drilling through clay layers, which tended to clog the slotted coupling. The second method involved screened well swab that allowed only formation water to enter the hollow-stem auger and prevented sand from plugging the hollow-stem auger when the bit plate was removed.

  8. Interchannel interference in resonant Auger scattering from fixed-in-space molecules as a technique for structure determination

    SciTech Connect

    Gel'mukhanov, F.; Minkov, I.

    2004-09-01

    A method for structure determination of polyatomic molecules with equivalent atoms is suggested. The method is based on an interference pattern in the resonant Auger scattering process. This pattern is caused by interference of resonant Auger channels corresponding to a core hole localized on different equivalent atoms. The predicted effect can be observed in angular resolved electron-ion coincidence measurements or, alternatively, using the ordinary Auger technique on surface-oriented molecules.

  9. Absorbed dose evaluation of Auger electron-emitting radionuclides: impact of input decay spectra on dose point kernels and S-values

    NASA Astrophysics Data System (ADS)

    Falzone, Nadia; Lee, Boon Q.; Fernández-Varea, José M.; Kartsonaki, Christiana; Stuchbery, Andrew E.; Kibédi, Tibor; Vallis, Katherine A.

    2017-03-01

    The aim of this study was to investigate the impact of decay data provided by the newly developed stochastic atomic relaxation model BrIccEmis on dose point kernels (DPKs - radial dose distribution around a unit point source) and S-values (absorbed dose per unit cumulated activity) of 14 Auger electron (AE) emitting radionuclides, namely 67Ga, 80mBr, 89Zr, 90Nb, 99mTc, 111In, 117mSn, 119Sb, 123I, 124I, 125I, 135La, 195mPt and 201Tl. Radiation spectra were based on the nuclear decay data from the medical internal radiation dose (MIRD) RADTABS program and the BrIccEmis code, assuming both an isolated-atom and condensed-phase approach. DPKs were simulated with the PENELOPE Monte Carlo (MC) code using event-by-event electron and photon transport. S-values for concentric spherical cells of various sizes were derived from these DPKs using appropriate geometric reduction factors. The number of Auger and Coster–Kronig (CK) electrons and x-ray photons released per nuclear decay (yield) from MIRD-RADTABS were consistently higher than those calculated using BrIccEmis. DPKs for the electron spectra from BrIccEmis were considerably different from MIRD-RADTABS in the first few hundred nanometres from a point source where most of the Auger electrons are stopped. S-values were, however, not significantly impacted as the differences in DPKs in the sub-micrometre dimension were quickly diminished in larger dimensions. Overestimation in the total AE energy output by MIRD-RADTABS leads to higher predicted energy deposition by AE emitting radionuclides, especially in the immediate vicinity of the decaying radionuclides. This should be taken into account when MIRD-RADTABS data are used to simulate biological damage at nanoscale dimensions.

  10. Absorbed dose evaluation of Auger electron-emitting radionuclides: impact of input decay spectra on dose point kernels and S-values.

    PubMed

    Falzone, Nadia; Lee, Boon Q; Fernández-Varea, José M; Kartsonaki, Christiana; Stuchbery, Andrew E; Kibédi, Tibor; Vallis, Katherine A

    2017-03-21

    The aim of this study was to investigate the impact of decay data provided by the newly developed stochastic atomic relaxation model BrIccEmis on dose point kernels (DPKs - radial dose distribution around a unit point source) and S-values (absorbed dose per unit cumulated activity) of 14 Auger electron (AE) emitting radionuclides, namely (67)Ga, (80m)Br, (89)Zr, (90)Nb, (99m)Tc, (111)In, (117m)Sn, (119)Sb, (123)I, (124)I, (125)I, (135)La, (195m)Pt and (201)Tl. Radiation spectra were based on the nuclear decay data from the medical internal radiation dose (MIRD) RADTABS program and the BrIccEmis code, assuming both an isolated-atom and condensed-phase approach. DPKs were simulated with the PENELOPE Monte Carlo (MC) code using event-by-event electron and photon transport. S-values for concentric spherical cells of various sizes were derived from these DPKs using appropriate geometric reduction factors. The number of Auger and Coster-Kronig (CK) electrons and x-ray photons released per nuclear decay (yield) from MIRD-RADTABS were consistently higher than those calculated using BrIccEmis. DPKs for the electron spectra from BrIccEmis were considerably different from MIRD-RADTABS in the first few hundred nanometres from a point source where most of the Auger electrons are stopped. S-values were, however, not significantly impacted as the differences in DPKs in the sub-micrometre dimension were quickly diminished in larger dimensions. Overestimation in the total AE energy output by MIRD-RADTABS leads to higher predicted energy deposition by AE emitting radionuclides, especially in the immediate vicinity of the decaying radionuclides. This should be taken into account when MIRD-RADTABS data are used to simulate biological damage at nanoscale dimensions.

  11. Angle-Resolved Auger Spectroscopy as a Sensitive Access to Vibronic Coupling

    NASA Astrophysics Data System (ADS)

    Knie, A.; Patanen, M.; Hans, A.; Petrov, I. D.; Bozek, J. D.; Ehresmann, A.; Demekhin, Ph. V.

    2016-05-01

    In the angle-averaged excitation and decay spectra of molecules, vibronic coupling may induce the usually weak dipole-forbidden transitions by the excitation intensity borrowing mechanism. The present complementary theoretical and experimental study of the resonant Auger decay of core-to-Rydberg excited CH4 and Ne demonstrates that vibronic coupling plays a decisive role in the formation of the angle-resolved spectra by additionally involving the decay rate borrowing mechanism. Thereby, we propose that the angle-resolved Auger spectroscopy can in general provide very insightful information on the strength of the vibronic coupling.

  12. Characterization of Japanese cedar bio-oil produced using a bench-scale auger pyrolyzer.

    PubMed

    Kato, Yoshiaki; Enomoto, Ryohei; Akazawa, Minami; Kojima, Yasuo

    2016-01-01

    A bench-scale auger reactor was designed for use as a laboratory-scale fast pyrolyzer for producing bio-oil from Japanese cedar. An analytical pyrolysis method was performed simultaneously to determine the distribution of pyrolysis products. The pyrolysis temperature was found to have the greatest influence on the bio-oil characteristics; bio-oil yields increased as the pyrolysis temperature increased from 450 to 550 °C. The concentration of levoglucosan in the bio-oil, however, decreased significantly with increasing pyrolysis temperature, while it increased following analytical pyrolysis. The same results were obtained for 4-vinylguaiacol and E-isoeugenol, which were the major secondary products produced in the present study. Compared to the yields of these major products obtained via analytical pyrolysis, the yields from the auger reactor were very low, indicating that the auger reactor process had a longer vapor residence time than the analytical pyrolysis process, resulting in the acceleration of secondary reactions of the pyrolysates. The pH values and densities of the bio-oils produced in the auger reactor were similar to those reported by researchers using woody biomass, despite their lower viscosities. From these results, it was concluded that the pyrolysis temperature and residence time of the pyrolysates played a significant role in determining the characteristics of the cedar bio-oil.

  13. QS-21: a potent vaccine adjuvant

    Technology Transfer Automated Retrieval System (TEKTRAN)

    QS-21 is an potent adjuvant derived from the bark of a Chilean tree, Quillaja saponaria. One of the advantages of this adjuvant is that it promotes a balanced humoral and cell-mediaed immune response and can be widely applicable to a variety of vaccines. This adjuvant has used for some veterinary va...

  14. Measurements of Auger Electron Diffraction Using a 180° Deflection Toroidal Analyzer

    NASA Astrophysics Data System (ADS)

    Shiraki, Susumu; Ishii, Hideshi; Nihei, Yoshimasa; Owari, Masanori

    A 180° deflection toroidal analyzer is a novel electron spectrometer, which allows the simultaneous registration of the wide range of polar angles in a given azimuth of the sample. Therefore, measurements of photo- and Auger electron intensities over π steradians can be performed rapidly by azimuthal rotation of the sample. Using this analyzer, two-dimensional patterns of electron-beam-excited O KVV and Mg KVV Auger electron diffraction (AED) from a MgO(001) surface were measured in short acquisition times. The AED patterns obtained were compared with theoretical ones calculated by the multiple-scattering scheme. The agreement between experimental and theoretical data was good for both O KVV and Mg KVV transitions.

  15. Education of the Pierre Auger Observatory: The Cinema as a Tool in Science Education.

    NASA Astrophysics Data System (ADS)

    Garcia, B.; Raschia, C.

    2006-08-01

    The Auger collaboration's broad mission in education, outreach and public relations is coordinated in a separate task. Its goals are to encourage and support a wide range of outreach efforts that link schools and the public with the Auger scientists and the science of cosmic rays, particle physics, astrophysics in general, and associated technologies. This report focuses on recent activities and future initiatives and, especially, on a very recent professional production of two educative videos for children between 6 and 11 years: "Messengers of Space" (18 min), and for general audiences: "An Adventure of the Mind" (20 min). The use of new resources, as 2D- and 3D-animation, to teach and learn in sciences is also discussed.

  16. Dmt and opioid peptides: a potent alliance.

    PubMed

    Bryant, Sharon D; Jinsmaa, Yunden; Salvadori, Severo; Okada, Yoshio; Lazarus, Lawrence H

    2003-01-01

    The introduction of the Dmt (2',6'-dimethyl-L-tyrosine)-Tic pharmacophore into the design of opioid ligands produced an extraordinary family of potent delta-opioid receptor antagonists and heralded a new phase in opioid research. First reviewed extensively in 1998, the incorporation of Dmt into a diverse group of opioid molecules stimulated the opioid field leading to the development of unique analogues with remarkable properties. This overview will document the crucial role played by this residue in the proliferation of opioid peptides with high receptor affinity (K(i) equal to or less than 1 nM) and potent bioactivity. The discussion will include the metamorphosis between delta-opioid receptor antagonists to delta-agonists based solely on subtle structural changes at the C-terminal region of the Dmt-Tic pharmacophore as well as their behavior in vivo. Dmt may be considered promiscuous due to the acquisition of potent mu-agonism by dermorphin and endomorphin derivatives as well as by a unique class of opioidmimetics containing two Dmt residues separated by alkyl or pyrazinone linkers. Structural studies on the Dmt-Tic compounds were enhanced tremendously by x-ray diffraction data for three potent and biologically diverse Dmt-Tic opioidmimetics that led to the development of pharmacophores for both delta-opioid receptor agonists and antagonists. Molecular modeling studies of other unique Dmt opioid analogues illuminated structural differences between delta- and mu-receptor ligand interactions. The future of these compounds as therapeutic applications for various medical syndromes including the control of cancer-associated pain is only a matter of time and perseverance.

  17. A study of native oxides of beta-SiC using Auger electron spectroscopy

    NASA Technical Reports Server (NTRS)

    Chaudhry, M. Iqbal

    1989-01-01

    Thermal and anodic oxide films of beta-SiC are analyzed using Auger electron spectroscopy. Auger depth-composition profiles are obtained in order to determine the chemical composition of the oxide films. The position and shape of silicon spectral peaks are used to estimate the chemical bonding of the oxide constituents. It is found that the wet thermal oxide is almost stoichiometric but contains about 14 pct C. Dry oxide, on the other hand, has less than 3 pct C but is highly nonstoichiometric. The C content in the anodic oxide is 12 pct. Anodic oxide films, like dry-oxide films, are nonstoichiometric. A model of the SiC oxidation process is presented.

  18. Auger recombination in sodium iodide

    NASA Astrophysics Data System (ADS)

    McAllister, Andrew; Kioupakis, Emmanouil; Åberg, Daniel; Schleife, André

    2014-03-01

    Scintillators are an important tool used to detect high energy radiation - both in the interest of national security and in medicine. However, scintillator detectors currently suffer from lower energy resolutions than expected from basic counting statistics. This has been attributed to non-proportional light yield compared to incoming radiation, but the specific mechanism for this non-proportionality has not been identified. Auger recombination is a non-radiative process that could be contributing to the non-proportionality of scintillating materials. Auger recombination comes in two types - direct and phonon-assisted. We have used first-principles calculations to study Auger recombination in sodium iodide, a well characterized scintillating material. Our findings indicate that phonon-assisted Auger recombination is stronger in sodium iodide than direct Auger recombination. Computational resources provided by LLNL and NERSC. Funding provided by NA-22.

  19. Application of a new vertical profiling tool (ESASS) for sampling groundwater quality during hollow-stem auger drilling

    USGS Publications Warehouse

    Harte, P.T.; Flanagan, S.M.

    2011-01-01

    A new tool called ESASS (Enhanced Screen Auger Sampling System) was developed by the U.S. Geological Survey. The use of ESASS, because of its unique U.S. patent design (U.S. patent no. 7,631,705 B1), allows for the collection of representative, depth-specific groundwater samples (vertical profiling) in a quick and efficient manner using a 0.305-m long screen auger during hollow-stem auger drilling. With ESASS, the water column in the flights above the screen auger is separated from the water in the screen auger by a specially designed removable plug and collar. The tool fits inside an auger of standard inner diameter (82.55 mm). The novel design of the system constituted by the plug, collar, and A-rod allows the plug to be retrieved using conventional drilling A-rods. After retrieval, standard-diameter (50.8 mm) observation wells can be installed within the hollow-stem augers. Testing of ESASS was conducted at one waste-disposal site with tetrachloroethylene (PCE) contamination and at two reference sites with no known waste-disposal history. All three sites have similar geology and are underlain by glacial, stratified-drift deposits. For the applications tested, ESASS proved to be a useful tool in vertical profiling of groundwater quality. At the waste site, PCE concentrations measured with ESASS profiling at several depths were comparable (relative percent difference <25%) to PCE concentrations sampled from wells. Vertical profiling with ESASS at the reference sites illustrated the vertical resolution achievable in the profile system; shallow groundwater quality varied by a factor of five in concentration of some constituents (nitrate and nitrite) over short (0.61 m) distances. Ground Water Monitoring & Remediation ?? 2011, National Ground Water Association. No claim to original US government works.

  20. Application of a new vertical profiling tool (ESASS) for sampling groundwater quality during hollow-stem auger drilling

    USGS Publications Warehouse

    Harte, Philip T.; Flanagan, Sarah M.

    2011-01-01

    A new tool called ESASS (Enhanced Screen Auger Sampling System) was developed by the U.S. Geological Survey. The use of ESASS, because of its unique U.S. patent design (U.S. patent no. 7,631,705 B1), allows for the collection of representative, depth-specific groundwater samples (vertical profiling) in a quick and efficient manner using a 0.305-m long screen auger during hollow-stem auger drilling. With ESASS, the water column in the flights above the screen auger is separated from the water in the screen auger by a specially designed removable plug and collar. The tool fits inside an auger of standard inner diameter (82.55 mm). The novel design of the system constituted by the plug, collar, and A-rod allows the plug to be retrieved using conventional drilling A-rods. After retrieval, standard-diameter (50.8 mm) observation wells can be installed within the hollow-stem augers. Testing of ESASS was conducted at one waste-disposal site with tetrachloroethylene (PCE) contamination and at two reference sites with no known waste-disposal history. All three sites have similar geology and are underlain by glacial, stratified-drift deposits. For the applications tested, ESASS proved to be a useful tool in vertical profiling of groundwater quality. At the waste site, PCE concentrations measured with ESASS profiling at several depths were comparable (relative percent difference <25%) to PCE concentrations sampled from wells. Vertical profiling with ESASS at the reference sites illustrated the vertical resolution achievable in the profile system; shallow groundwater quality varied by a factor of five in concentration of some constituents (nitrate and nitrite) over short (0.61 m) distances.

  1. Auger North: The Pierre Auger Observatory in the Northern Hemisphere

    SciTech Connect

    Mantsch, Paul M.; /Fermilab

    2009-01-01

    Results from Auger South have settled some fundamental issues about ultra-high energy (UHE) cosmic rays and made clear what is needed now to identify the sources of these particles, to uncover the acceleration process, to establish the particle types, and to test hadronic interaction properties at extreme energies. The cosmic rays above 55 EeV are key. Auger North targets this high energy frontier by increasing the collecting power of the Auger Observatory by a factor of eight for those high energy air showers. Particles above about 40 EeV have been shown to be subject to propagation energy loss, as predicted by Greisen, Zatsepin and Kuzmin (GZK) in 1966. Moreover, it is now evident that there is a detectable flux of particles from extragalactic sources within the GZK sphere. The inhomogeneous distribution of matter in the local universe imprints its anisotropy on the arrival directions of cosmic rays above 55 EeV. The challenge is to collect enough of those arrival directions to identify the class of astrophysical accelerators and measure directly the brightest sources. Auger North will increase the event rate from 25 per year to 200 per year and give the Auger Observatory full sky exposure. The Auger Observatory also has the capability to detect UHE photons and neutrinos from discrete sources or from the decays of GZK pions. With the expanded aperture of Auger North, the detection of GZK photons and neutrinos will provide a complementary perspective of the highest energy phenomena in the contemporary universe. Besides being an observatory for UHE cosmic rays, photons, and neutrinos, the Auger Observatory will serve as a laboratory for the study of hadronic interactions with good statistics over a wide range of center-of-mass energies above what can be reached at the LHC. Auger North will provide statistical power at center-of-mass energies above 250 TeV where the alternative extrapolations of hadronic cross sections diverge. Auger North is ready to go. The

  2. 30 CFR 56.7005 - Augers and drill stems.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 30 Mineral Resources 1 2012-07-01 2012-07-01 false Augers and drill stems. 56.7005 Section 56.7005... Piercing Drilling § 56.7005 Augers and drill stems. Drill crews and others shall stay clear of augers or drill stems that are in motion. Persons shall not pass under or step over a moving stem or auger....

  3. 30 CFR 56.7005 - Augers and drill stems.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 30 Mineral Resources 1 2014-07-01 2014-07-01 false Augers and drill stems. 56.7005 Section 56.7005... Piercing Drilling § 56.7005 Augers and drill stems. Drill crews and others shall stay clear of augers or drill stems that are in motion. Persons shall not pass under or step over a moving stem or auger....

  4. 30 CFR 56.7005 - Augers and drill stems.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Augers and drill stems. 56.7005 Section 56.7005... Piercing Drilling § 56.7005 Augers and drill stems. Drill crews and others shall stay clear of augers or drill stems that are in motion. Persons shall not pass under or step over a moving stem or auger....

  5. 30 CFR 56.7005 - Augers and drill stems.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 30 Mineral Resources 1 2011-07-01 2011-07-01 false Augers and drill stems. 56.7005 Section 56.7005... Piercing Drilling § 56.7005 Augers and drill stems. Drill crews and others shall stay clear of augers or drill stems that are in motion. Persons shall not pass under or step over a moving stem or auger....

  6. 30 CFR 56.7005 - Augers and drill stems.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 30 Mineral Resources 1 2013-07-01 2013-07-01 false Augers and drill stems. 56.7005 Section 56.7005... Piercing Drilling § 56.7005 Augers and drill stems. Drill crews and others shall stay clear of augers or drill stems that are in motion. Persons shall not pass under or step over a moving stem or auger....

  7. Experimental study of underground exploration by auger boring on a Mars rover

    NASA Astrophysics Data System (ADS)

    Kojima, Masaki; Saitou, Kenji; Kaneko, Yutaka; Kawashima, Nobuki

    Results are presented of a system study conducted on the possibility of exploring Mars using a Mars rover; emphasis is focused on the underground exploration of Mars by an auger boring machine. An engineering model was constructed, and a boring test was conducted using simulated Martian soil. It is shown that it is possible to drill soil composed of dust, sand, and gravel measuring 0.007-16 mm in diameter to a depth of 1.5 m. The diffusion of the collected sample can be confined to less than a thickness of 20 cm.

  8. Micro-area Auger analysis of a SiC/Ti fibre composite

    NASA Technical Reports Server (NTRS)

    Zironi, E. P.; Poppa, H.

    1981-01-01

    Micro-area Auger electron spectroscopy with a spatial resolution of less than 50 nm has been used to study the concentration of elements across the reaction zone of a W-reinforced SiC fiber in a titanium matrix. Although the elemental concentrations obtained by this technique are affected by the reaction zone morphology to a greater extent than in the case of X-ray microprobe analysis, the proposed technique has the advantage of a much higher spatial resolution and avoids the problems of bulk averaging that characterize the X-ray technique.

  9. SEARCH FOR A CORRELATION BETWEEN ANTARES NEUTRINOS AND PIERRE AUGER OBSERVATORY UHECRs ARRIVAL DIRECTIONS

    SciTech Connect

    Adrian-Martinez, S.; Ardid, M.; Bou-Cabo, M.; Andre, M.; Anghinolfi, M.; Anton, G.; Anvar, S.; Astraatmadja, T.; Beemster, L. J.; Bogazzi, C.; Bouwhuis, M. C.; Baret, B.; Bouhou, B.; Basa, S.; Biagi, S.; and others

    2013-09-01

    A multimessenger analysis optimized for a correlation of arrival directions of ultra-high energy cosmic rays (UHECRs) and neutrinos is presented and applied to 2190 neutrino candidate events detected in 2007-2008 by the ANTARES telescope and 69 UHECRs observed by the Pierre Auger Observatory between 2004 January 1 and 2009 December 31. No significant correlation is observed. Assuming an equal neutrino flux (E {sup -2} energy spectrum) from all UHECR directions, a 90% CL upper limit on the neutrino flux of 5.0 Multiplication-Sign 10{sup -8} GeV cm{sup -2} s{sup -1} per source is derived.

  10. Auger and carrier-surface phonon interaction processes in graphene on a substrate made of polar materials

    NASA Astrophysics Data System (ADS)

    Mahdouani, M.; Bourguiga, R.

    2017-02-01

    We present a theoretical study of two specific dynamical optical properties, namely Auger and surface electron-phonon interaction processes in monolayer graphene on polar substrates such as SiO2 , HfO2 , SiC and hexagonal BN. Thus the eigenenergies have been derived from the tight-binding Hamiltonian in monolayer graphene. Our results indicate that both Auger and electron-surface phonon interaction processes depend on the polar substrate. Such polar substrates allow for the presence of polar optical phonons localized near the graphene-substrate interface which could be a significant scattering source for graphene carriers across the long-range Fröhlich coupling. Furthermore, the linear, gapless band structure of graphene provides ideal conditions for Auger processes which are Auger recombination (AR) and impact ionization (IMI). These processes are of fundamental interest because they strongly influence the relaxation dynamics of carriers. Likewise, we have investigated the effect of various dielectrics on both Auger and electron-surface phonon scattering rates in single layer graphene by varying the temperature, the charge carrier density and the physical separation between the interface of the dielectric substrate and graphene.

  11. A new route to nanoscale tomographic chemical analysis: Focused ion beam-induced auger electron spectrosocpy

    NASA Astrophysics Data System (ADS)

    Parvaneh, Hamed

    This research project is aimed to study the application of ion-induced Auger electron spectroscopy (IAES) in combination with the characteristics of focused ion beam (FIB) microscopy for performing chemical spectroscopy and further evaluate its potential for 3-dimensional chemical tomography applications. The mechanism for generation of Auger electrons by bombarding ions is very different from its electron induced counterpart. In the conventional electron-induced Auger electron spectroscopy (EAES), an electron beam with energy typically in the range 1-10kV is used to excite inner-shell (core) electrons of the solid. An electron from a higher electron energy state then de-excites to fill the hole and the extra energy is then transferred to either another electron, i.e. the Auger electron, or generation of an X-ray (photon). In both cases the emitting particles have charac-teristic energies and could be used to identify the excited target atoms. In IAES, however, large excitation cross sections can occur by promotion of in-ner shell electrons through crossing of molecular orbitals. Originally such phenomenological excitation processes were first proposed [3] for bi-particle gas phase collision systems to explain the generation of inner shell vacancies in violent collisions. In addition to excitation of incident or target atoms, due to a much heavier mass of ions compared to electrons, there would also be a substantial momentum transfer from the incident to the target atoms. This may cause the excited target atom to recoil from the lattice site or alternatively sputter off the surface with the possibility of de-excitation while the atom is either in motion in the matrix or traveling in vacuum. As a result, one could expect differences between the spectra induced by incident electrons and ions and interpretation of the IAE spectra requires separate consideration of both excitation and decay processes. In the first stage of the project, a state-of-the-art mass

  12. Epidermal Growth Factor Receptor Overexpression as a Target for Auger Electron Radiotherapy of Breast Cancer

    DTIC Science & Technology

    2002-08-01

    pharmacokinetics of ’In-DTPA-hEGF after s.c. injection was studied in non-tumor bearing athymic mice. The mice were first anaesthetized by s.c. injection of...induction of apoptosis [1,23]. DNA damage caused by Auger electron-emitting radiopharmaceuticals is dependent on the proximity of the radionuclide decay...S.H. Kaufmnann, Y.L. Ottaviano, Y. Furuya, J.A. Buckley, J.T. Isaacs, N.E. Davidson. Epidermal growth factor-mediated apoptosis of MDA-MB-468 human

  13. Looking for Auger signatures in III-nitride light emitters: A full-band Monte Carlo perspective

    SciTech Connect

    Bertazzi, Francesco Goano, Michele; Zhou, Xiangyu; Calciati, Marco; Ghione, Giovanni; Matsubara, Masahiko; Bellotti, Enrico

    2015-02-09

    Recent experiments of electron emission spectroscopy (EES) on III-nitride light-emitting diodes (LEDs) have shown a correlation between droop onset and hot electron emission at the cesiated surface of the LED p-cap. The observed hot electrons have been interpreted as a direct signature of Auger recombination in the LED active region, as highly energetic Auger-excited electrons would be collected in long-lived satellite valleys of the conduction band so that they would not decay on their journey to the surface across the highly doped p-contact layer. We discuss this interpretation by using a full-band Monte Carlo model based on first-principles electronic structure and lattice dynamics calculations. The results of our analysis suggest that Auger-excited electrons cannot be unambiguously detected in the LED structures used in the EES experiments. Additional experimental and simulative work are necessary to unravel the complex physics of GaN cesiated surfaces.

  14. Electrical Detection of Quantum Dot Hot Electrons Generated via a Mn(2+)-Enhanced Auger Process.

    PubMed

    Barrows, Charles J; Rinehart, Jeffrey D; Nagaoka, Hirokazu; deQuilettes, Dane W; Salvador, Michael; Chen, Jennifer I L; Ginger, David S; Gamelin, Daniel R

    2017-01-05

    An all-solid-state quantum-dot-based photon-to-current conversion device is demonstrated that selectively detects the generation of hot electrons. Photoexcitation of Mn(2+)-doped CdS quantum dots embedded in the device is followed by efficient picosecond energy transfer to Mn(2+) with a long-lived (millisecond) excited-state lifetime. Electrons injected into the QDs under applied bias then capture this energy via Auger de-excitation, generating hot electrons that possess sufficient energy to escape over a ZnS blocking layer, thereby producing current. This electrically detected hot-electron generation is correlated with a quench in the steady-state Mn(2+) luminescence and the introduction of a new nonradiative excited-state decay process, consistent with electron-dopant Auger cross-relaxation. The device's efficiency at detecting hot-electron generation provides a model platform for the study of hot-electron ionization relevant to the development of novel photodetectors and alternative energy-conversion devices.

  15. Extended x-ray-absorption fine structure—Auger process for surface structure analysis: Theoretical considerations of a proposed experiment

    PubMed Central

    Landman, Uzi; Adams, David L.

    1976-01-01

    A method for surface structure analysis is proposed. The proposed process combines x-ray photoabsorption and Auger electron emission. The extended x-ray-absorption fine structure, occurring for photon energies above an atomic absorption edge, contains structural information of the microscopic environment due to the coupling of the photoelectron final state with the atomic initial state. Measurement of the variations in the intensity of particular Auger lines, as a function of the incident radiation energy, provides a surface sensitive measure of the photoabsorption cross section in the media. Theoretical considerations of the physical processes underlying the proposed experiment and its feasibility, and a discussion of background contributions are presented. PMID:16592339

  16. Vertically reciprocating auger

    NASA Technical Reports Server (NTRS)

    Etheridge, Mark; Morgan, Scott; Fain, Robert; Pearson, Jonathan; Weldi, Kevin; Woodrough, Stephen B., Jr.

    1988-01-01

    The mathematical model and test results developed for the Vertically Reciprocating Auger (VRA) are summarized. The VRA is a device capable of transporting cuttings that result from below surface drilling. It was developed chiefly for the lunar surface, where conventional fluid flushing while drilling would not be practical. The VRA uses only reciprocating motion and transports material through reflections with the surface above. Particles are reflected forward and land ahead of radially placed fences, which prevent the particles from rolling back down the auger. Three input wave forms are considered to drive the auger. A modified sawtooth wave form was chosen for testing, over a modified square wave or sine wave, due to its simplicity and effectiveness. The three-dimensional mathematical model predicted a sand throughput rate of 0.2667 pounds/stroke, while the actual test setup transported 0.075 pounds/stroke. Based on this result, a correction factor of 0.281 is suggested for a modified sawtooth input.

  17. Operations of and Future Plans for the Pierre Auger Observatory

    SciTech Connect

    Abraham, : J.; Abreu, P.; Aglietta, M.; Aguirre, C.; Ahn, E.J.; Allard, D.; Allekotte, I.; Allen, J.; Alvarez-Muniz, J.; Ambrosio, M.; Anchordoqui, L.

    2009-06-01

    These are presentations to be presented at the 31st International Cosmic Ray Conference, in Lodz, Poland during July 2009. It consists of the following presentations: (1) Performance and operation of the Surface Detectors of the Pierre Auger Observatory; (2) Extension of the Pierre Auger Observatory using high-elevation fluorescence telescopes (HEAT); (3) AMIGA - Auger Muons and Infill for the Ground Array of the Pierre Auger Observatory; (4) Radio detection of Cosmic Rays at the southern Auger Observatory; (5) Hardware Developments for the AMIGA enhancement at the Pierre Auger Observatory; (6) A simulation of the fluorescence detectors of the Pierre Auger Observatory using GEANT 4; (7) Education and Public Outreach at the Pierre Auger Observatory; (8) BATATA: A device to characterize the punch-through observed in underground muon detectors and to operate as a prototype for AMIGA; and (9) Progress with the Northern Part of the Pierre Auger Observatory.

  18. Coal-Sizing Auger

    NASA Technical Reports Server (NTRS)

    Lewis, E. V.

    1985-01-01

    Aft end of auger, like forward, face-piercing end, equipped with hard cutting bits such as diamonds. As auger breaks face, pulls broken coal lumps into jaws and forces them into hardened throat section. There, cutting bits chew up lumps: Clearance between throat and auger shaft sets maximum size for coal particles that pass through. Auger motion pushes coal particles into mixing chamber, where paddles combine them with water.

  19. Vertical-Screw-Auger Conveyer Feeder

    NASA Technical Reports Server (NTRS)

    Walton, Otis (Inventor); Vollmer, Hubert J. (Inventor)

    2016-01-01

    A conical feeder is attached to a vertically conveying screw auger. The feeder is equipped with scoops and rotated from the surface to force-feed regolith the auger. Additional scoops are possible by adding a cylindrical section above the conical funnel section. Such then allows the unit to collect material from swaths larger in diameter than the enclosing casing pipe of the screw auger. A third element includes a flexible screw auger. All three can be used in combination in microgravity and zero atmosphere environments to drill and recover a wide area of subsurface regolith and entrained volatiles through a single access point on the surface.

  20. Sifuvirtide, a potent HIV fusion inhibitor peptide

    SciTech Connect

    Wang, Rui-Rui; Yang, Liu-Meng; Wang, Yun-Hua; Pang, Wei; Tam, Siu-Cheung; Tien, Po; Zheng, Yong-Tang

    2009-05-08

    Enfuvirtide (ENF) is currently the only FDA approved HIV fusion inhibitor in clinical use. Searching for more drugs in this category with higher efficacy and lower toxicity seems to be a logical next step. In line with this objective, a synthetic peptide with 36 amino acid residues, called Sifuvirtide (SFT), was designed based on the crystal structure of gp41. In this study, we show that SFT is a potent anti-HIV agent with relatively low cytotoxicity. SFT was found to inhibit replication of all tested HIV strains. The effective concentrations that inhibited 50% viral replication (EC{sub 50}), as determined in all tested strains, were either comparable or lower than benchmark values derived from well-known anti-HIV drugs like ENF or AZT, while the cytotoxic concentrations causing 50% cell death (CC{sub 50}) were relatively high, rendering it an ideal anti-HIV agent. A GST-pull down assay was performed to confirm that SFT is a fusion inhibitor. Furthermore, the activity of SFT on other targets in the HIV life cycle was also investigated, and all assays showed negative results. To further understand the mechanism of action of HIV peptide inhibitors, resistant variants of HIV-1{sub IIIB} were derived by serial virus passage in the presence of increasing doses of SFT or ENF. The results showed that there was cross-resistance between SFT and ENF. In conclusion, SFT is an ideal anti-HIV agent with high potency and low cytotoxicity, but may exhibit a certain extent of cross-resistance with ENF.

  1. Carbapenems: a potent class of antibiotics.

    PubMed

    Nicolau, David P

    2008-01-01

    The purpose of this review is to assess the relative strengths and weaknesses of individual members of the carbapenem class of antibiotics. Clinical trials and review articles were identified from a Medline search (1979 - July 2006), in addition to, reference citations from identified publications, abstracts from the Interscience Conferences on Antimicrobial Agents and Chemotherapy and the 12th International Congress on Infectious Disease, and package inserts. Articles in English were reviewed, with emphasis on those containing efficacy or safety data. Carbapenems bind to critical penicillin-binding proteins, disrupting the growth and structural integrity of bacterial cell walls. They provide enhanced anaerobic and Gram-negative coverage as compared with other beta-lactams and their stability against extended-spectrum beta-lactamases (ESBLs) makes them an effective treatment option. The most common adverse effects are infusion-site complications and gastrointestinal distress. Ertapenem has limited efficacy against non-fermenting, Gram-negative bacteria, restricting its use to community-acquired infections. Imipenem is slightly more effective against Gram-positive organisms and meropenem slightly more effective against Gram-negative organisms. However, both have broad-spectrum activity, including non-fermenting, Gram-negative bacteria. Among non-fermenting, Gram-negatives, resistance to imipenem in particular is increasing. Doripenem is in late-stage clinical development and combines the broad-spectrum coverage of imipenem and meropenem, and more potent activity against Pseudomonas aeruginosa. Due to the increasing challenges represented by ESBLs and multi-drug resistant organisms, the carbapenems are assuming a greater role in the treatment of serious infections. Imipenem and meropenem are presently available and have been shown to be effective against nosocomial infections. Doripenem is an investigational carbapenem that has completed Phase III clinical trials and

  2. A Complete Set of Radiative and Auger Rates for K-vacancy States in Fe XVIII-Fe-XXV

    NASA Technical Reports Server (NTRS)

    Palmeri, P.; Mendoza, C.; Kallman, T. R.; Bautista, M. A.

    2003-01-01

    A complete set of level energies, wavelengths, A-values, and total and partial Auger rates have been computed for transitions involving the K-vacancy states within the n = 2 complex of Fe XVIII-Fe XXV. Three different standard numerical packages are used for this purpose, namel y AUTOSTRUCTURE, the Breit-Pauli R-matrix suite (BPRM) and HFR, which allow reliable estimates of the physical effects involved and of the accuracy of the resulting data sets. The Breit interaction is taken i nto account because its contributions to the small A-values and partial Auger rates cannot be neglected with increasing electron occupancy. Semiempirical adjustments can also lead to large differences in both the radiative and Auger decay data of strongly mixed levels. Several experimental level energies and wavelengths are questioned, and significant discrepancies are found with previously computed decay rates th at are attributed to numerical problems. The statistical accuracy of the present level energies and wavelengths is ranked at +/-3 eV and +/ -2 mA, respectively, and that for A-values and partial Auger rates greater than lO(exp 13)/s at better than 20%.

  3. A Complete Set of Radiative and Auger Rates for K-vacancy States in Fe XVIII-Fe XXV

    NASA Technical Reports Server (NTRS)

    Palmeri, P.; Mendoza, C.; Kallman, T. R.; Bautista, M. A.

    2002-01-01

    A complete set of level energies, wavelengths, A-values, and total and partial Auger rates have been computed for transitions involving the K-vacancy states within the n = 2 complex of Fe XVIII-Fe XXV. Three different standard numerical packages are used for this purpose, namely AUTOSTRUCTURE, the Breit-Pauli R-matrix suite (BPRM) and HFR, which allow reliable estimates of the physical effects involved and of the accuracy of the resulting data sets. It is found that the Breit interaction must be always taken into account as the contributions to the small A-values and partial Auger rates does not decrease with electron occupancy. Semi-empirical adjustments can also lead to large differences in both the radiative and Auger decay data of strongly mixed levels. Several experimental energy levels and wavelengths are questioned, and significant discrepancies are found with previously computed decay rates that are attributed to numerical problems. The statistical accuracy of the present level energies and wavelengths is ranked at plus or minus 3 eV and plus or minus 2 mAngstroms, respectively, whereas that for A-values and partial Auger rates greater than 10(exp 13) per second is estimated at better than 20%.

  4. A Targeted Search for Point Sources of EeV Photons with the Pierre Auger Observatory

    NASA Astrophysics Data System (ADS)

    Aab, A.; Abreu, P.; Aglietta, M.; Samarai, I. Al; Albuquerque, I. F. M.; Allekotte, I.; Almela, A.; Alvarez Castillo, J.; Alvarez-Muñiz, J.; Anastasi, G. A.; Anchordoqui, L.; Andrada, B.; Andringa, S.; Aramo, C.; Arqueros, F.; Arsene, N.; Asorey, H.; Assis, P.; Aublin, J.; Avila, G.; Badescu, A. M.; Balaceanu, A.; Barreira Luz, R. J.; Beatty, J. J.; Becker, K. H.; Bellido, J. A.; Berat, C.; Bertaina, M. E.; Bertou, X.; Biermann, P. L.; Billoir, P.; Biteau, J.; Blaess, S. G.; Blanco, A.; Blazek, J.; Bleve, C.; Boháčová, M.; Boncioli, D.; Bonifazi, C.; Borodai, N.; Botti, A. M.; Brack, J.; Brancus, I.; Bretz, T.; Bridgeman, A.; Briechle, F. L.; Buchholz, P.; Bueno, A.; Buitink, S.; Buscemi, M.; Caballero-Mora, K. S.; Caccianiga, L.; Cancio, A.; Canfora, F.; Caramete, L.; Caruso, R.; Castellina, A.; Cataldi, G.; Cazon, L.; Chavez, A. G.; Chinellato, J. A.; Chudoba, J.; Clay, R. W.; Colalillo, R.; Coleman, A.; Collica, L.; Coluccia, M. R.; Conceição, R.; Contreras, F.; Cooper, M. J.; Coutu, S.; Covault, C. E.; Cronin, J.; D’Amico, S.; Daniel, B.; Dasso, S.; Daumiller, K.; Dawson, B. R.; de Almeida, R. M.; de Jong, S. J.; De Mauro, G.; de Mello Neto, J. R. T.; De Mitri, I.; de Oliveira, J.; de Souza, V.; Debatin, J.; Deligny, O.; Di Giulio, C.; Di Matteo, A.; Díaz Castro, M. L.; Diogo, F.; Dobrigkeit, C.; D’Olivo, J. C.; Dorosti, Q.; dos Anjos, R. C.; Dova, M. T.; Dundovic, A.; Ebr, J.; Engel, R.; Erdmann, M.; Erfani, M.; Escobar, C. O.; Espadanal, J.; Etchegoyen, A.; Falcke, H.; Farrar, G.; Fauth, A. C.; Fazzini, N.; Fick, B.; Figueira, J. M.; Filipčič, A.; Fratu, O.; Freire, M. M.; Fujii, T.; Fuster, A.; Gaior, R.; García, B.; Garcia-Pinto, D.; Gaté, F.; Gemmeke, H.; Gherghel-Lascu, A.; Ghia, P. L.; Giaccari, U.; Giammarchi, M.; Giller, M.; Głas, D.; Glaser, C.; Golup, G.; Gómez Berisso, M.; Gómez Vitale, P. F.; González, N.; Gorgi, A.; Gorham, P.; Grillo, A. F.; Grubb, T. D.; Guarino, F.; Guedes, G. P.; Hampel, M. R.; Hansen, P.; Harari, D.; Harrison, T. A.; Harton, J. L.; Haungs, A.; Hebbeker, T.; Heck, D.; Heimann, P.; Herve, A. E.; Hill, G. C.; Hojvat, C.; Holt, E.; Homola, P.; Hörandel, J. R.; Horvath, P.; Hrabovský, M.; Huege, T.; Hulsman, J.; Insolia, A.; Isar, P. G.; Jandt, I.; Jansen, S.; Johnsen, J. A.; Josebachuili, M.; Kääpä, A.; Kambeitz, O.; Kampert, K. H.; Katkov, I.; Keilhauer, B.; Kemp, E.; Kemp, J.; Kieckhafer, R. M.; Klages, H. O.; Kleifges, M.; Kleinfeller, J.; Krause, R.; Krohm, N.; Kuempel, D.; Kukec Mezek, G.; Kunka, N.; Kuotb Awad, A.; LaHurd, D.; Lauscher, M.; Legumina, R.; Leigui de Oliveira, M. A.; Letessier-Selvon, A.; Lhenry-Yvon, I.; Link, K.; Lopes, L.; López, R.; López Casado, A.; Luce, Q.; Lucero, A.; Malacari, M.; Mallamaci, M.; Mandat, D.; Mantsch, P.; Mariazzi, A. G.; Mariş, I. C.; Marsella, G.; Martello, D.; Martinez, H.; Martínez Bravo, O.; Masías Meza, J. J.; Mathes, H. J.; Mathys, S.; Matthews, J.; Matthews, J. A. J.; Matthiae, G.; Mayotte, E.; Mazur, P. O.; Medina, C.; Medina-Tanco, G.; Melo, D.; Menshikov, A.; Micheletti, M. I.; Middendorf, L.; Minaya, I. A.; Miramonti, L.; Mitrica, B.; Mockler, D.; Mollerach, S.; Montanet, F.; Morello, C.; Mostafá, M.; Müller, A. L.; Müller, G.; Muller, M. A.; Müller, S.; Mussa, R.; Naranjo, I.; Nellen, L.; Nguyen, P. H.; Niculescu-Oglinzanu, M.; Niechciol, M.; Niemietz, L.; Niggemann, T.; Nitz, D.; Nosek, D.; Novotny, V.; Nožka, H.; Núñez, L. A.; Ochilo, L.; Oikonomou, F.; Olinto, A.; Palatka, M.; Pallotta, J.; Papenbreer, P.; Parente, G.; Parra, A.; Paul, T.; Pech, M.; Pedreira, F.; Pȩkala, J.; Pelayo, R.; Peña-Rodriguez, J.; Pereira, L. A. S.; Perlín, M.; Perrone, L.; Peters, C.; Petrera, S.; Phuntsok, J.; Piegaia, R.; Pierog, T.; Pieroni, P.; Pimenta, M.; Pirronello, V.; Platino, M.; Plum, M.; Porowski, C.; Prado, R. R.; Privitera, P.; Prouza, M.; Quel, E. J.; Querchfeld, S.; Quinn, S.; Ramos-Pollan, R.; Rautenberg, J.; Ravignani, D.; Revenu, B.; Ridky, J.; Risse, M.; Ristori, P.; Rizi, V.; Rodrigues de Carvalho, W.; Rodriguez Fernandez, G.; Rodriguez Rojo, J.; Rogozin, D.; Roncoroni, M. J.; Roth, M.; Roulet, E.; Rovero, A. C.; Ruehl, P.; Saffi, S. J.; Saftoiu, A.; Salamida, F.; Salazar, H.; Saleh, A.; Salesa Greus, F.; Salina, G.; Sánchez, F.; Sanchez-Lucas, P.; Santos, E. M.; Santos, E.; Sarazin, F.; Sarmento, R.; Sarmiento, C. A.; Sato, R.; Schauer, M.; Scherini, V.; Schieler, H.; Schimp, M.; Schmidt, D.; Scholten, O.; Schovánek, P.; Schröder, F. G.; Schulz, A.; Schulz, J.; Schumacher, J.; Sciutto, S. J.; Segreto, A.; Settimo, M.; Shadkam, A.; Shellard, R. C.; Sigl, G.; Silli, G.; Sima, O.; Śmiałkowski, A.; Šmída, R.; Snow, G. R.; Sommers, P.; Sonntag, S.; Sorokin, J.; Squartini, R.; Stanca, D.; Stanič, S.; Stasielak, J.; Stassi, P.; Strafella, F.; Suarez, F.; Suarez Durán, M.; Sudholz, T.; Suomijärvi, T.; Supanitsky, A. D.; Swain, J.; Szadkowski, Z.; Taboada, A.; Taborda, O. A.; Tapia, A.; Theodoro, V. M.; Timmermans, C.; Todero Peixoto, C. J.; Tomankova, L.; Tomé, B.; Torralba Elipe, G.; Travnicek, P.; Trini, M.; Ulrich, R.; Unger, M.; Urban, M.; Valdés Galicia, J. F.; Valiño, I.; Valore, L.; van Aar, G.; van Bodegom, P.; van den Berg, A. M.; van Vliet, A.; Varela, E.; Vargas Cárdenas, B.; Varner, G.; Vázquez, J. R.; Vázquez, R. A.; Veberič, D.; Vergara Quispe, I. D.; Verzi, V.; Vicha, J.; Villaseñor, L.; Vorobiov, S.; Wahlberg, H.; Wainberg, O.; Walz, D.; Watson, A. A.; Weber, M.; Weindl, A.; Wiencke, L.; Wilczyński, H.; Winchen, T.; Wirtz, M.; Wittkowski, D.; Wundheiler, B.; Yang, L.; Yelos, D.; Yushkov, A.; Zas, E.; Zavrtanik, D.; Zavrtanik, M.; Zepeda, A.; Zimmermann, B.; Ziolkowski, M.; Zong, Z.; Zuccarello, F.

    2017-03-01

    Simultaneous measurements of air showers with the fluorescence and surface detectors of the Pierre Auger Observatory allow a sensitive search for EeV photon point sources. Several Galactic and extragalactic candidate objects are grouped in classes to reduce the statistical penalty of many trials from that of a blind search and are analyzed for a significant excess above the background expectation. The presented search does not find any evidence for photon emission at candidate sources, and combined p-values for every class are reported. Particle and energy flux upper limits are given for selected candidate sources. These limits significantly constrain predictions of EeV proton emission models from non-transient Galactic and nearby extragalactic sources, as illustrated for the particular case of the Galactic center region.

  5. Application of a Novel Multiple-Scattering Approach to Photoelectron Diffraction and Auger Electron Diffraction.

    NASA Astrophysics Data System (ADS)

    Kaduwela, Ajith P.

    We apply a new separable-Green's-function matrix method due to Rehr and Albers (Phys. Rev. B4l (1990) 8139) to a multiple scattering treatment of photoelectron diffraction and Auger electron diffraction. This cluster -based method permits building up successive orders of scattering and judging the approach to convergence in a convenient and time-saving way. We include multiple scattering up to tenth order and can treat photoelectron emission form any initial state (s, p, d, or f) with full final-state interference. This new approach is used to simulate emission from linear and bent chains of atoms, from epitaxial overlayers and multilayer substrates and from atomic and molecular adsorbates, and various conclusions are drawn concerning the range of utility of the method and the geometric structures for which multiple scattering effects must be considered.

  6. Positron annihilation induced Auger electron spectroscopy

    NASA Technical Reports Server (NTRS)

    Weiss, Alex; Koymen, A. R.; Mehl, David; Jensen, K. O.; Lei, Chun; Lee, K. H.

    1990-01-01

    Recently, Weiss et al. have demonstrated that it is possible to excite Auger transitions by annihilating core electrons using a low energy (less than 30eV) beam of positrons. This mechanism makes possible a new electron spectroscopy, Positron annihilation induced Auger Electron Spectroscopy (PAES). The probability of exciting an Auger transition is proportional to the overlap of the positron wavefunction with atomic core levels. Since the Auger electron energy provides a signature of the atomic species making the transition, PAES makes it possible to determine the overlap of the positron wavefunction with a particular element. PAES may therefore provide a means of detecting positron-atom complexes. Measurements of PAES intensities from clean and adsorbate covered Cu surfaces are presented which indicate that approx. 5 percent of positrons injected into CU at 25eV produce core annihilations that result in Auger transitions.

  7. 30 CFR 77.1501 - Auger mining; inspections.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 30 Mineral Resources 1 2013-07-01 2013-07-01 false Auger mining; inspections. 77.1501 Section 77.1501 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR COAL MINE SAFETY AND... Auger Mining § 77.1501 Auger mining; inspections. (a) The face of all highwalls, to a distance of...

  8. 30 CFR 77.1501 - Auger mining; inspections.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 30 Mineral Resources 1 2014-07-01 2014-07-01 false Auger mining; inspections. 77.1501 Section 77.1501 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR COAL MINE SAFETY AND... Auger Mining § 77.1501 Auger mining; inspections. (a) The face of all highwalls, to a distance of...

  9. 30 CFR 77.1501 - Auger mining; inspections.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 30 Mineral Resources 1 2011-07-01 2011-07-01 false Auger mining; inspections. 77.1501 Section 77.1501 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR COAL MINE SAFETY AND... Auger Mining § 77.1501 Auger mining; inspections. (a) The face of all highwalls, to a distance of...

  10. 30 CFR 77.1501 - Auger mining; inspections.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Auger mining; inspections. 77.1501 Section 77.1501 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR COAL MINE SAFETY AND... Auger Mining § 77.1501 Auger mining; inspections. (a) The face of all highwalls, to a distance of...

  11. 30 CFR 77.1501 - Auger mining; inspections.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 30 Mineral Resources 1 2012-07-01 2012-07-01 false Auger mining; inspections. 77.1501 Section 77.1501 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR COAL MINE SAFETY AND... Auger Mining § 77.1501 Auger mining; inspections. (a) The face of all highwalls, to a distance of...

  12. 30 CFR 819.15 - Auger mining: Hydrologic balance.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 30 Mineral Resources 3 2011-07-01 2011-07-01 false Auger mining: Hydrologic balance. 819.15 Section 819.15 Mineral Resources OFFICE OF SURFACE MINING RECLAMATION AND ENFORCEMENT, DEPARTMENT OF THE... MINING § 819.15 Auger mining: Hydrologic balance. (a) Auger mining shall be planned and conducted...

  13. 30 CFR 819.19 - Auger mining: Backfilling and grading.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 3 2010-07-01 2010-07-01 false Auger mining: Backfilling and grading. 819.19 Section 819.19 Mineral Resources OFFICE OF SURFACE MINING RECLAMATION AND ENFORCEMENT, DEPARTMENT OF THE... MINING § 819.19 Auger mining: Backfilling and grading. (a) General. Auger mining shall be conducted...

  14. 30 CFR 819.19 - Auger mining: Backfilling and grading.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 30 Mineral Resources 3 2012-07-01 2012-07-01 false Auger mining: Backfilling and grading. 819.19 Section 819.19 Mineral Resources OFFICE OF SURFACE MINING RECLAMATION AND ENFORCEMENT, DEPARTMENT OF THE... MINING § 819.19 Auger mining: Backfilling and grading. (a) General. Auger mining shall be conducted...

  15. 30 CFR 819.15 - Auger mining: Hydrologic balance.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 30 Mineral Resources 3 2012-07-01 2012-07-01 false Auger mining: Hydrologic balance. 819.15 Section 819.15 Mineral Resources OFFICE OF SURFACE MINING RECLAMATION AND ENFORCEMENT, DEPARTMENT OF THE... MINING § 819.15 Auger mining: Hydrologic balance. (a) Auger mining shall be planned and conducted...

  16. 30 CFR 819.19 - Auger mining: Backfilling and grading.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 30 Mineral Resources 3 2014-07-01 2014-07-01 false Auger mining: Backfilling and grading. 819.19 Section 819.19 Mineral Resources OFFICE OF SURFACE MINING RECLAMATION AND ENFORCEMENT, DEPARTMENT OF THE... MINING § 819.19 Auger mining: Backfilling and grading. (a) General. Auger mining shall be conducted...

  17. 30 CFR 819.15 - Auger mining: Hydrologic balance.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 30 Mineral Resources 3 2014-07-01 2014-07-01 false Auger mining: Hydrologic balance. 819.15 Section 819.15 Mineral Resources OFFICE OF SURFACE MINING RECLAMATION AND ENFORCEMENT, DEPARTMENT OF THE... MINING § 819.15 Auger mining: Hydrologic balance. (a) Auger mining shall be planned and conducted...

  18. 30 CFR 819.15 - Auger mining: Hydrologic balance.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 30 Mineral Resources 3 2013-07-01 2013-07-01 false Auger mining: Hydrologic balance. 819.15 Section 819.15 Mineral Resources OFFICE OF SURFACE MINING RECLAMATION AND ENFORCEMENT, DEPARTMENT OF THE... MINING § 819.15 Auger mining: Hydrologic balance. (a) Auger mining shall be planned and conducted...

  19. 30 CFR 819.19 - Auger mining: Backfilling and grading.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 30 Mineral Resources 3 2013-07-01 2013-07-01 false Auger mining: Backfilling and grading. 819.19 Section 819.19 Mineral Resources OFFICE OF SURFACE MINING RECLAMATION AND ENFORCEMENT, DEPARTMENT OF THE... MINING § 819.19 Auger mining: Backfilling and grading. (a) General. Auger mining shall be conducted...

  20. 30 CFR 819.15 - Auger mining: Hydrologic balance.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 3 2010-07-01 2010-07-01 false Auger mining: Hydrologic balance. 819.15 Section 819.15 Mineral Resources OFFICE OF SURFACE MINING RECLAMATION AND ENFORCEMENT, DEPARTMENT OF THE... MINING § 819.15 Auger mining: Hydrologic balance. (a) Auger mining shall be planned and conducted...

  1. 30 CFR 819.19 - Auger mining: Backfilling and grading.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 30 Mineral Resources 3 2011-07-01 2011-07-01 false Auger mining: Backfilling and grading. 819.19 Section 819.19 Mineral Resources OFFICE OF SURFACE MINING RECLAMATION AND ENFORCEMENT, DEPARTMENT OF THE... MINING § 819.19 Auger mining: Backfilling and grading. (a) General. Auger mining shall be conducted...

  2. 30 CFR 57.7005 - Augers and drill stems.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 30 Mineral Resources 1 2013-07-01 2013-07-01 false Augers and drill stems. 57.7005 Section 57.7005... Jet Piercing Drilling-Surface Only § 57.7005 Augers and drill stems. Drill crews and others shall stay clear of augers or drill stems that are in motion. Persons shall not pass under or step over a...

  3. 30 CFR 57.7005 - Augers and drill stems.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 30 Mineral Resources 1 2011-07-01 2011-07-01 false Augers and drill stems. 57.7005 Section 57.7005... Jet Piercing Drilling-Surface Only § 57.7005 Augers and drill stems. Drill crews and others shall stay clear of augers or drill stems that are in motion. Persons shall not pass under or step over a...

  4. 30 CFR 57.7005 - Augers and drill stems.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 30 Mineral Resources 1 2014-07-01 2014-07-01 false Augers and drill stems. 57.7005 Section 57.7005... Jet Piercing Drilling-Surface Only § 57.7005 Augers and drill stems. Drill crews and others shall stay clear of augers or drill stems that are in motion. Persons shall not pass under or step over a...

  5. 30 CFR 57.7005 - Augers and drill stems.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 30 Mineral Resources 1 2012-07-01 2012-07-01 false Augers and drill stems. 57.7005 Section 57.7005... Jet Piercing Drilling-Surface Only § 57.7005 Augers and drill stems. Drill crews and others shall stay clear of augers or drill stems that are in motion. Persons shall not pass under or step over a...

  6. 30 CFR 57.7005 - Augers and drill stems.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Augers and drill stems. 57.7005 Section 57.7005... Jet Piercing Drilling-Surface Only § 57.7005 Augers and drill stems. Drill crews and others shall stay clear of augers or drill stems that are in motion. Persons shall not pass under or step over a...

  7. Azachalcones: a new class of potent polyphenol oxidase inhibitors.

    PubMed

    Radhakrishnan, Sini Karanayil; Shimmon, Ronald Gibrial; Conn, Costa; Baker, Anthony T

    2015-04-15

    A library of potent inhibitors of polyphenol oxidase and their structure activity relationships are described. Azachalcone derivatives were synthesized and tested for their tyrosinase inhibitory activity. Their inhibitory activities on mushroom tyrosinase using l-DOPA as a substrate were investigated. Two compounds that are the reduction congeners of the pyridinyl azachalcones strongly inhibited the enzyme activity and were more potent than the positive control kojic acid.

  8. Development of a potent and selective cell penetrant Legumain inhibitor.

    PubMed

    Ness, Kerry A; Eddie, Sharon L; Higgins, Catherine A; Templeman, Amy; D'Costa, Zenobia; Gaddale, Kishore K D; Bouzzaoui, Samira; Jordan, Linda; Janssen, Dominic; Harrison, Timothy; Burkamp, Frank; Young, Andrew; Burden, Roberta; Scott, Christopher J; Mullan, Paul B; Williams, Rich

    2015-12-01

    This Letter describes the continued SAR exploration of small molecule Legumain inhibitors with the aim of developing a potent and selective in vitro tool compound. Work continued in this Letter explores the use of alternative P2-P3 linker units and the P3 group SAR which led to the identification of 10t, a potent, selective and cellularly active Legumain inhibitor. We also demonstrate that 10t has activity in both cancer cell viability and colony formation assays.

  9. Properties of bio-oil generated by a pyrolysis of forest cedar residuals with the movable Auger-type reactor

    SciTech Connect

    Nishimura, Shun; Ebitani, Kohki; Miyazato, Akio

    2016-02-01

    Our research project has developed the new movable reactor for bio-oil production in 2013 on the basis of Auger-type system. This package would be a great impact due to the concept of local production for local consumption in the hilly and mountainous area in not only Japan but also in the world. Herein, we would like to report the properties of the bio-oil generated by the developing Auger-type movable reactor. The synthesized bio-oil possessed C: 46.2 wt%, H: 6.5 wt%, N: wt%, S: <0.1 wt%, O: 46.8 wt% and H{sub 2}O: 18.4 wt%, and served a good calorific value of 18.1 MJ/kg. The spectroscopic and mass analyses such as FT-IR, GC-MS, {sup 13}C-NMR and FT-ICR MS supported that the bio-oil was composed by the fine mixtures of methoxy phenols and variety of alcohol or carboxylic acid functional groups. Thus, it is suggested that the bio-oil generated by the new movable Auger-type reactor has a significant potential as well as the existing bio-oil reported previously.

  10. Properties of bio-oil generated by a pyrolysis of forest cedar residuals with the movable Auger-type reactor

    NASA Astrophysics Data System (ADS)

    Nishimura, Shun; Miyazato, Akio; Ebitani, Kohki

    2016-02-01

    Our research project has developed the new movable reactor for bio-oil production in 2013 on the basis of Auger-type system. This package would be a great impact due to the concept of local production for local consumption in the hilly and mountainous area in not only Japan but also in the world. Herein, we would like to report the properties of the bio-oil generated by the developing Auger-type movable reactor. The synthesized bio-oil possessed C: 46.2 wt%, H: 6.5 wt%, N: wt%, S: <0.1 wt%, O: 46.8 wt% and H2O: 18.4 wt%, and served a good calorific value of 18.1 MJ/kg. The spectroscopic and mass analyses such as FT-IR, GC-MS, 13C-NMR and FT-ICR MS supported that the bio-oil was composed by the fine mixtures of methoxy phenols and variety of alcohol or carboxylic acid functional groups. Thus, it is suggested that the bio-oil generated by the new movable Auger-type reactor has a significant potential as well as the existing bio-oil reported previously.

  11. Demonstration of the waste tire pyrolysis process on pilot scale in a continuous auger reactor.

    PubMed

    Martínez, Juan Daniel; Murillo, Ramón; García, Tomás; Veses, Alberto

    2013-10-15

    This work shows the technical feasibility for valorizing waste tires by pyrolysis using a pilot scale facility with a nominal capacity of 150 kWth. A continuous auger reactor was operated to perform thirteen independent experiments that conducted to the processing of more than 500 kg of shredded waste tires in 100 h of operation. The reaction temperature was 550°C and the pressure was 1 bar in all the runs. Under these conditions, yields to solid, liquid and gas were 40.5 ± 0.3, 42.6 ± 0.1 and 16.9 ± 0.3 wt.% respectively. Ultimate and proximate analyses as well as heating value analysis were conducted for both the solid and liquid fraction. pH, water content, total acid number (TAN), viscosity and density were also assessed for the liquid and compared to the specifications of marine fuels (standard ISO 8217). Gas chromatography was used to calculate the composition of the gaseous fraction. It was observed that all these properties remained practically invariable along the experiments without any significant technical problem. In addition, the reaction enthalpy necessary to perform the waste tire pyrolysis process (907.1 ± 40.0 kJ/kg) was determined from the combustion and formation enthalpies of waste tire and conversion products. Finally, a mass balance closure was performed showing an excellent reliability of the data obtained from the experimental campaign.

  12. A Bayesian analysis of the 69 highest energy cosmic rays detected by the Pierre Auger Observatory

    NASA Astrophysics Data System (ADS)

    Khanin, Alexander; Mortlock, Daniel J.

    2016-08-01

    The origins of ultrahigh energy cosmic rays (UHECRs) remain an open question. Several attempts have been made to cross-correlate the arrival directions of the UHECRs with catalogues of potential sources, but no definite conclusion has been reached. We report a Bayesian analysis of the 69 events, from the Pierre Auger Observatory (PAO), that aims to determine the fraction of the UHECRs that originate from known AGNs in the Veron-Cety & Verson (VCV) catalogue, as well as AGNs detected with the Swift Burst Alert Telescope (Swift-BAT), galaxies from the 2MASS Redshift Survey (2MRS), and an additional volume-limited sample of 17 nearby AGNs. The study makes use of a multilevel Bayesian model of UHECR injection, propagation and detection. We find that for reasonable ranges of prior parameters the Bayes factors disfavour a purely isotropic model. For fiducial values of the model parameters, we report 68 per cent credible intervals for the fraction of source originating UHECRs of 0.09^{+0.05}_{-0.04}, 0.25^{+0.09}_{-0.08}, 0.24^{+0.12}_{-0.10}, and 0.08^{+0.04}_{-0.03} for the VCV, Swift-BAT and 2MRS catalogues, and the sample of 17 AGNs, respectively.

  13. AugerPrime: the upgrade of the Pierre Auger Observatory

    NASA Astrophysics Data System (ADS)

    Sarazin, Frederic; Pierre Auger Collaboration Collaboration

    2017-01-01

    The nature and origin of ultra-high energy cosmic-rays (UHECRs) remain largely a mystery despite a wealth of new information obtained in recent years at the Pierre Auger Observatory and elsewhere. Mass composition studies performed at Auger appear to challenge the historical view that the UHECR primaries (at least for energies greater than 1019 eV) are all protons, and the observation of a GZK-like flux suppression in the cosmic-ray spectrum is counterbalanced by the absence of point source observations and the relatively weak anisotropy of the UHECR sky. In order to resolve this apparent contradiction, the Pierre Auger collaboration is embarking in an upgrade of the Observatory (``AugerPrime'') with the goal of extending the mass composition measurements beyond the observed flux suppression. In this presentation, the science case for the upgrade and its technical realization will be described and discussed especially with regards to the existence of GZK photons and neutrinos. NSF PHY-1506486.

  14. Auger spectrum of a water molecule after single and double core ionization.

    PubMed

    Inhester, L; Burmeister, C F; Groenhof, G; Grubmüller, H

    2012-04-14

    The high intensity of free electron lasers opens up the possibility to perform single-shot molecule scattering experiments. However, even for small molecules, radiation damage induced by absorption of high intense x-ray radiation is not yet fully understood. One of the striking effects which occurs under intense x-ray illumination is the creation of double core ionized molecules in considerable quantity. To provide insight into this process, we have studied the dynamics of water molecules in single and double core ionized states by means of electronic transition rate calculations and ab initio molecular dynamics (MD) simulations. From the MD trajectories, photoionization and Auger transition rates were computed based on electronic continuum wavefunctions obtained by explicit integration of the coupled radial Schrödinger equations. These rates served to solve the master equations for the populations of the relevant electronic states. To account for the nuclear dynamics during the core hole lifetime, the calculated electron emission spectra for different molecular geometries were incoherently accumulated according to the obtained time-dependent populations, thus neglecting possible interference effects between different decay pathways. We find that, in contrast to the single core ionized water molecule, the nuclear dynamics for the double core ionized water molecule during the core hole lifetime leaves a clear fingerprint in the resulting electron emission spectra. The lifetime of the double core ionized water was found to be significantly shorter than half of the single core hole lifetime.

  15. Auger spectrum of a water molecule after single and double core ionization

    SciTech Connect

    Inhester, L.; Burmeister, C. F.; Groenhof, G.; Grubmueller, H.

    2012-04-14

    The high intensity of free electron lasers opens up the possibility to perform single-shot molecule scattering experiments. However, even for small molecules, radiation damage induced by absorption of high intense x-ray radiation is not yet fully understood. One of the striking effects which occurs under intense x-ray illumination is the creation of double core ionized molecules in considerable quantity. To provide insight into this process, we have studied the dynamics of water molecules in single and double core ionized states by means of electronic transition rate calculations and ab initio molecular dynamics (MD) simulations. From the MD trajectories, photoionization and Auger transition rates were computed based on electronic continuum wavefunctions obtained by explicit integration of the coupled radial Schroedinger equations. These rates served to solve the master equations for the populations of the relevant electronic states. To account for the nuclear dynamics during the core hole lifetime, the calculated electron emission spectra for different molecular geometries were incoherently accumulated according to the obtained time-dependent populations, thus neglecting possible interference effects between different decay pathways. We find that, in contrast to the single core ionized water molecule, the nuclear dynamics for the double core ionized water molecule during the core hole lifetime leaves a clear fingerprint in the resulting electron emission spectra. The lifetime of the double core ionized water was found to be significantly shorter than half of the single core hole lifetime.

  16. Auger spectrum of a water molecule after single and double core ionization

    NASA Astrophysics Data System (ADS)

    Inhester, Ludger; Burmeister, Carl F.; Groenhof, Gerrit; Grubmueller, Helmut

    2012-06-01

    The high intensity of Free Electron Lasers (FEL) opens up the possibility to perform single-shot molecule scattering experiments. However, even for small molecules radiation damage induced by absorption of intense x-ray radiation is not yet fully understood. To provide insight into this process, we have studied the dynamics of water molecules in single and double core ionized states by means of electronic transition rate calculations and ab initio molecular dynamics (MD) simulations. From MD trajectories photoionization and Auger transition rates were computed based on electronic continuum wavefunctions obtained by explicit integration of the coupled radial Schr"odinger equations. To account for the nuclear dynamics during the core hole lifetime, the calculated electron emission spectra for different molecular geometries were accumulated according to the obtained time-dependent populations. We find that, in contrast to the single core ionized water molecule, the nuclear dynamics for the double core ionized water molecule during the core hole lifetime leaves a clear fingerprint on the electron emission spectra. In addition, the lifetime of the double core ionized water was found to be significantly shorter than half of the single core hole lifetime.

  17. InGaN/GaN multiple-quantum-well light-emitting diodes with a grading InN composition suppressing the Auger recombination

    SciTech Connect

    Zhang, Zi-Hui; Liu, Wei; Ju, Zhengang; Tan, Swee Tiam; Ji, Yun; Kyaw, Zabu; Zhang, Xueliang; Wang, Liancheng; Sun, Xiao Wei E-mail: VOLKAN@stanfordalumni.org; Demir, Hilmi Volkan E-mail: VOLKAN@stanfordalumni.org

    2014-07-21

    In conventional InGaN/GaN light-emitting diodes (LEDs), thin InGaN quantum wells are usually adopted to mitigate the quantum confined Stark effect (QCSE), caused due to strong polarization induced electric field, through spatially confining electrons and holes in small recombination volumes. However, this inevitably increases the carrier density in quantum wells, which in turn aggravates the Auger recombination, since the Auger recombination scales with the third power of the carrier density. As a result, the efficiency droop of the Auger recombination severely limits the LED performance. Here, we proposed and showed wide InGaN quantum wells with the InN composition linearly grading along the growth orientation in LED structures suppressing the Auger recombination and the QCSE simultaneously. Theoretically, the physical mechanisms behind the Auger recombination suppression are also revealed. The proposed LED structure has experimentally demonstrated significant improvement in optical output power and efficiency droop, proving to be an effective solution to this important problem of Auger recombination.

  18. Proof of principal for staircase auger chip removal theory

    NASA Astrophysics Data System (ADS)

    Barron, Jeffrey B.; Brewer, Steve; Kerns, Kenneth; Moody, Kyle; Rossi, Richard A.

    1987-08-01

    A proof of principal design of the staircase auger theory is provided for lunar drilling. The drill is designed to drill holes 30 meters deep and 0.1 meters in diameter. The action of the auger is 0.01 meter strokes at a varying number of strokes per second. A detailed analysis of the interaction of the auger and particle was done to optimize the parameters of the auger. This optimum design will allow for proper heat removal and reasonable drilling time. The drill bit is designed to scoop the particles into the auger while efficiently cutting through the moon's surface.

  19. Proof of principal for staircase auger chip removal theory

    NASA Technical Reports Server (NTRS)

    Barron, Jeffrey B.; Brewer, Steve; Kerns, Kenneth; Moody, Kyle; Rossi, Richard A.

    1987-01-01

    A proof of principal design of the staircase auger theory is provided for lunar drilling. The drill is designed to drill holes 30 meters deep and 0.1 meters in diameter. The action of the auger is 0.01 meter strokes at a varying number of strokes per second. A detailed analysis of the interaction of the auger and particle was done to optimize the parameters of the auger. This optimum design will allow for proper heat removal and reasonable drilling time. The drill bit is designed to scoop the particles into the auger while efficiently cutting through the moon's surface.

  20. The Pierre Auger Observatory Upgrade

    NASA Astrophysics Data System (ADS)

    Marsella, Giovanni

    2017-03-01

    It is planned to operate the Pierre Auger Observatory until at least the end of 2024. An upgrade of the experiment has been proposed in order to provide additional measurements to allow one to elucidate the mass composition and the origin of the flux suppression at the highest energies, to search for a flux contribution of protons up to the highest energies and to reach a sensitivity to a contribution as small as 10% in the flux suppression region, to study extensive air showers and hadronic multi-particle production. With operation planned until 2024, event statistics will more than double compared with the existing Auger data set, with the critical added advantage that every event will now have mass information. Obtaining additional composition-sensitive information will not only help to better reconstruct the properties of the primary particles at the highest energies, but also improve the measurements in the energy range just above the ankle. Furthermore, measurements with the new detectors will help to reduce systematic uncertainties related to the modelling hadronic showers and to limitations in the reconstruction algorithms. A description of the principal proposed Auger upgrade will be presented. The Auger upgrade promises high-quality future data, and real scope for new physics.

  1. Presidents' Pay Remains a Potent Political Target

    ERIC Educational Resources Information Center

    Stripling, Jack; Fuller, Andrea

    2012-01-01

    In a long-simmering national fight over compensation for public-college presidents, the State of California emerged this year as the primary battleground. More than any other institution in recent memory, California State University has publicly and sometimes bitterly wrestled with a vexing question for higher education: How much does a public…

  2. Dihydro-resveratrol-A potent dietary polyphenol

    SciTech Connect

    Gakh, Andrei A; Anisimova, Natalia Yu; Kiselevsky, Mikhail V; Sadovnikov, Sergey V; Stankov, Ivan N; Yudin, Mikhail V; Rufanov, Konstantin A; Krasavin, Mikhail Yu; Sosnov, Andrey V

    2010-01-01

    Dihydro-resveratrol (dihydro-R), a prominent polyphenol component of red wine, has a profound proliferative effect on hormone-sensitive tumor cell lines such as breast cancer cell line MCF7. We found a significant increase in MCF7 tumor cells growth rates in the presence of picomolar concentrations of this compound. The proliferative effect of dihydro-R was not observed in cell lines that do not express hormone receptors (MDA-MB-231, BT-474, and -562).

  3. Ganoderma lucidum: a potent pharmacological macrofungus.

    PubMed

    Sanodiya, Bhagwan S; Thakur, Gulab Singh; Baghel, Rakesh K; Prasad, G B K S; Bisen, P S

    2009-12-01

    Ganoderma lucidum (Ling Zhi) is a basidiomycete white rot macrofungus which has been used extensively as "the mushroom of immortality" in China, Japan, Korea and other Asian countries for 2000 years. A great deal of work has been carried out on therapeutic potential of Ganoderma lucidum. The basidiocarp, mycelia and spores of Ganoderma lucidum contain approximately 400 different bioactive compounds, which mainly include triterpenoids, polysaccharides, nucleotides, sterols, steroids, fatty acids, proteins/peptides and trace elements which has been reported to have a number of pharmacological effects including immunomodulation, anti-atherosclerotic, anti-inflammatory, analgesic, chemo-preventive, antitumor, chemo and radio protective, sleep promoting, antibacterial, antiviral (including anti-HIV), hypolipidemic, anti-fibrotic, hepatoprotective, anti-diabetic, anti-androgenic, anti-angiogenic, anti-herpetic, antioxidative and radical-scavenging, anti-aging, hypoglycemic, estrogenic activity and anti-ulcer properties. Ganoderma lucidum has now become recognized as an alternative adjuvant in the treatment of leukemia, carcinoma, hepatitis and diabetes. The macrofungus is very rare in nature rather not sufficient for commercial exploitation for vital therapeutic emergencies, therefore, the cultivation on solid substrates, stationary liquid medium or by submerged cultivation has become an essential aspect to meet the driving force towards the increasing demands in the international market. Present review focuses on the pharmacological aspects, cultivation methods and bioactive metabolites playing a significant role in various therapeutic applications.

  4. Honey: a potent agent for wound healing?

    PubMed

    Lusby, P E; Coombes, A; Wilkinson, J M

    2002-11-01

    Although honey has been used as a traditional remedy for burns and wounds, the potential for its inclusion in mainstream medical care is not well recognized. Many studies have demonstrated that honey has antibacterial activity in vitro, and a small number of clinical case studies have shown that application of honey to severely infected cutaneous wounds is capable of clearing infection from the wound and improving tissue healing. The physicochemical properties (eg, osmotic effects and pH) of honey also aid in its antibacterial actions. Research has also indicated that honey may possess antiinflammatory activity and stimulate immune responses within a wound. The overall effect is to reduce infection and to enhance wound healing in burns, ulcers, and other cutaneous wounds. It is also known that honeys derived from particular floral sources in Australia and New Zealand (Leptospermum spp) have enhanced antibacterial activity, and these honeys have been approved for marketing as therapeutic honeys (Medihoney and Active Manuka honey). This review outlines what is known about the medical properties of honey and indicates the potential for honey to be incorporated into the management of a large number of wound types.

  5. Inner-shell ionization of rotating linear molecules in the presence of spin-dependent interactions: Entanglement between a photoelectron and an auger electron

    NASA Astrophysics Data System (ADS)

    Ghosh, R.; Chandra, N.; Parida, S.

    2009-03-01

    This paper reports results of a theoretical study of angle- and spin-resolved photo-Auger electron coincident spectroscopy in the form of entanglement between these two particles emitted from a linear molecule. First, we develop an expression for a density matrix needed for studying spin-entanglement between a photoelectron and an Auger electron. In order to properly represent the molecular symmetries, nuclear rotation, and the spin-dependent interactions (SDIs), we have used symmetry adapted wavefunctions in Hund’s coupling scheme (a) for all the species participating in this two-step process. This expression shows that spin-entanglement in a photo-Auger electron pair in the presence of SDIs very strongly depends upon, among other things, polarization of the ionizing radia- tion, directions of motion and of spin polarization of two ejected electrons, and the dynamics of photoionization and of Auger decay. We have applied this expression, as an example, to a generic linear molecule in its J0, M0 = 0 state. This model calculation clearly brings out the salient features of the spin-entanglement of a photo-Auger electron pair in the presence of the SDIs.

  6. Oleandrin: A cardiac glycosides with potent cytotoxicity

    PubMed Central

    Kumar, Arvind; De, Tanmoy; Mishra, Amrita; Mishra, Arun K.

    2013-01-01

    Cardiac glycosides are used in the treatment of congestive heart failure and arrhythmia. Current trend shows use of some cardiac glycosides in the treatment of proliferative diseases, which includes cancer. Nerium oleander L. is an important Chinese folk medicine having well proven cardio protective and cytotoxic effect. Oleandrin (a toxic cardiac glycoside of N. oleander L.) inhibits the activity of nuclear factor kappa-light-chain-enhancer of activated B chain (NF-κB) in various cultured cell lines (U937, CaOV3, human epithelial cells and T cells) as well as it induces programmed cell death in PC3 cell line culture. The mechanism of action includes improved cellular export of fibroblast growth factor-2, induction of apoptosis through Fas gene expression in tumor cells, formation of superoxide radicals that cause tumor cell injury through mitochondrial disruption, inhibition of interleukin-8 that mediates tumorigenesis and induction of tumor cell autophagy. The present review focuses the applicability of oleandrin in cancer treatment and concerned future perspective in the area. PMID:24347921

  7. Diethylamide of thujic acid: a potent repellent of Aedes aegypti.

    PubMed

    Hach, V; McDonald, E C

    1971-10-08

    A series of novel, representatively substituted amides of thujic acid were prepared and screened for insect repellent and attractant potential. In repel-lency tests the N,N-diethylamide was the most potent compound, surpassing the activity of the standard repellents dimethyl phthalate and fencholic acid. In contrast, the N-monoethylamide displayed attractant activity.

  8. Determination of the solid angle and response function of a hemispherical spectrograph with injection lens for Auger electrons emitted from long lived projectile states

    SciTech Connect

    Doukas, S.; Madesis, I.; Dimitriou, A.; Zouros, T. J. M.; Laoutaris, A.; Benis, E. P.

    2015-04-15

    We present SIMION 8.1 Monte Carlo type simulations of the response function and detection solid angle for long lived Auger states (lifetime τ ∼ 10{sup −9} − 10{sup −5} s) recorded by a hemispherical spectrograph with injection lens and position sensitive detector used for high resolution Auger spectroscopy of ion beams. Also included in these simulations for the first time are kinematic effects particular to Auger emission from fast moving projectile ions such as line broadening and solid angle limitations allowing for a more accurate and realistic line shape modeling. Our results are found to be in excellent agreement with measured electron line shapes of both long lived 1s2s2p{sup 4}P and prompt Auger projectile states formed by electron capture in collisions of 25.3 MeV F{sup 7+} with H{sub 2} and 12.0 MeV C{sup 4+} with Ne recorded at 0{sup ∘} to the beam direction. These results are important for the accurate evaluation of the 1s2s2p {sup 4}P/{sup 2}P ratio of K-Auger cross sections whose observed non-statistical production by electron capture into He-like ions, recently a field of interesting interpretations, awaits further resolution.

  9. Positron annihilation induced Auger electron emission

    SciTech Connect

    Weiss, A.; Jibaly, M.; Lei, Chun; Mehl, D.; Mayer, R.; Lynn, K.G.

    1988-01-01

    We report on measurements of Auger electron emission from Cu and Fe due to core hole excitations produced by the removal of core electrons by matter-antimatter annihilation. Estimates are developed of the probability of positrons annihilating with a 3p electron in these materials. Several important advantages of Positron annihilation induced Auger Electron Spectroscopy (PAES) for surface analysis are suggested. 10 refs., 2 figs.

  10. Auger Emitting Radiopharmaceuticals for Cancer Therapy

    NASA Astrophysics Data System (ADS)

    Falzone, Nadia; Cornelissen, Bart; Vallis, Katherine A.

    Radionuclides that emit Auger electrons have been of particular interest as therapeutic agents. This is primarily due to the short range in tissue, controlled linear paths and high linear energy transfer of these particles. Taking into consideration that ionizations are clustered within several cubic nanometers around the point of decay the possibility of incorporating an Auger emitter in close proximity to the cancer cell DNA has immense therapeutic potential thus making nuclear targeted Auger-electron emitters ideal for precise targeting of cancer cells. Furthermore, many Auger-electron emitters also emit γ-radiation, this property makes Auger emitting radionuclides a very attractive option as therapeutic and diagnostic agents in the molecular imaging and management of tumors. The first requirement for the delivery of Auger emitting nuclides is the definition of suitable tumor-selective delivery vehicles to avoid normal tissue toxicity. One of the main challenges of targeted radionuclide therapy remains in matching the physical and chemical characteristics of the radionuclide and targeting moiety with the clinical character of the tumor. Molecules and molecular targets that have been used in the past can be classified according to the carrier molecule used to deliver the Auger-electron-emitting radionuclide. These include (1) antibodies, (2) peptides, (3) small molecules, (4) oligonucleotides and peptide nucleic acids (PNAs), (5) proteins, and (6) nanoparticles. The efficacy of targeted radionuclide therapy depends greatly on the ability to increase intranuclear incorporation of the radiopharmaceutical without compromising toxicity. Several strategies to achieve this goal have been proposed in literature. The possibility of transferring tumor therapy based on the emission of Auger electrons from experimental models to patients has vast therapeutic potential, and remains a field of intense research.

  11. A quantitative study of valence electron transfer in the skutterudite compound CoP3 by combining x-ray induced Auger and photoelectron spectroscopy

    NASA Astrophysics Data System (ADS)

    Diplas, S.; Prytz, Ø.; Karlsen, O. B.; Watts, J. F.; Taftø, J.

    2007-06-01

    We use the sum of the ionization and Auger energy, the so-called Auger parameter, measured from the x-ray photoelectron spectrum, to study the valence electron distribution in the skutterudite CoP3. The electron transfer between Co and P was estimated using models relating changes in Auger parameter values to charge transfer. It was found that each P atom gains 0.24 e-, and considering the unit formula CoP3 this is equivalent to a donation of 0.72 e- per Co atom. This is in agreement with a recent electron energy-loss spectroscopy study, which indicates a charge transfer of 0.77 e-/atom from Co to P.

  12. High-resolution absorption spectroscopy of photoionized silicon plasma, a step toward measuring the efficiency of Resonant Auger Destruction

    NASA Astrophysics Data System (ADS)

    Loisel, Guillaume; Bailey, James; Hansen, Stephanie; Nagayama, Taisuke; Rochau, Gregory; Liedhal, Duane; Mancini, Roberto

    2013-10-01

    A remarkable opportunity to observe matter in a regime where the effects of General Relativity are significant has arisen through measurements of strongly red-shifted iron x-ray lines emitted from black hole accretion disks. A major uncertainty in the spectral formation models is the efficiency of Resonant Auger Destruction (RAD), in which fluorescent K α photons are resonantly absorbed by neighbor ions. The absorbing ion preferentially decays by Auger ionization, thus reducing the emerging K α intensity. If K α lines from L-shell ions are not observed in iron spectral emission, why are such lines observed from silicon plasma surrounding other accretion powered objects? To help answer this question, we are investigating photoionized silicon plasmas produced using intense x-rays from the Z facility. The incident spectral irradiance is determined with time-resolved absolute power measurements, multiple monochromatic gated images, and a 3-D view factor model. The charge state distribution, electron temperature, and electron density are determined using space-resolved backlit absorption spectroscopy. The measurements constrain photoionized plasma models and set the stage for future emission spectroscopy directly investigating the RAD process. Sandia is a multi-program laboratory operated by Sandia Corporation, a Lockheed Martin Company, for the United States Department of Energy under contract DE-AC04-94AL85000.

  13. Correlation between energy deposition and molecular damage from Auger electrons: A case study of ultra-low energy (5–18 eV) electron interactions with DNA

    SciTech Connect

    Rezaee, Mohammad Hunting, Darel J.; Sanche, Léon

    2014-07-15

    Purpose: The present study introduces a new method to establish a direct correlation between biologically related physical parameters (i.e., stopping and damaging cross sections, respectively) for an Auger-electron emitting radionuclide decaying within a target molecule (e.g., DNA), so as to evaluate the efficacy of the radionuclide at the molecular level. These parameters can be applied to the dosimetry of Auger electrons and the quantification of their biological effects, which are the main criteria to assess the therapeutic efficacy of Auger-electron emitting radionuclides. Methods: Absorbed dose and stopping cross section for the Auger electrons of 5–18 eV emitted by{sup 125}I within DNA were determined by developing a nanodosimetric model. The molecular damages induced by these Auger electrons were investigated by measuring damaging cross section, including that for the formation of DNA single- and double-strand breaks. Nanoscale films of pure plasmid DNA were prepared via the freeze-drying technique and subsequently irradiated with low-energy electrons at various fluences. The damaging cross sections were determined by employing a molecular survival model to the measured exposure–response curves for induction of DNA strand breaks. Results: For a single decay of{sup 125}I within DNA, the Auger electrons of 5–18 eV deposit the energies of 12.1 and 9.1 eV within a 4.2-nm{sup 3} volume of a hydrated or dry DNA, which results in the absorbed doses of 270 and 210 kGy, respectively. DNA bases have a major contribution to the deposited energies. Ten-electronvolt and high linear energy transfer 100-eV electrons have a similar cross section for the formation of DNA double-strand break, while 100-eV electrons are twice as efficient as 10 eV in the induction of single-strand break. Conclusions: Ultra-low-energy electrons (<18 eV) substantially contribute to the absorbed dose and to the molecular damage from Auger-electron emitting radionuclides; hence, they should

  14. UNC1062, a new and potent Mer inhibitor.

    PubMed

    Liu, Jing; Zhang, Weihe; Stashko, Michael A; Deryckere, Deborah; Cummings, Christopher T; Hunter, Debra; Yang, Chao; Jayakody, Chatura N; Cheng, Nancy; Simpson, Catherine; Norris-Drouin, Jacqueline; Sather, Susan; Kireev, Dmitri; Janzen, William P; Earp, H Shelton; Graham, Douglas K; Frye, Stephen V; Wang, Xiaodong

    2013-07-01

    Abnormal activation of Mer kinase has been implicated in the oncogenesis of many human cancers including acute lymphoblastic and myeloid leukemia, non-small cell lung cancer, and glioblastoma. We have discovered a new family of small molecule Mer inhibitors, pyrazolopyrimidine sulfonamides, that potently inhibit the kinase activity of Mer. Importantly, these compounds do not demonstrate significant hERG activity in the PatchXpress assay. Through structure-activity relationship studies, 35 (UNC1062) was identified as a potent (IC50 = 1.1 nM) and selective Mer inhibitor. When applied to live tumor cells, UNC1062 inhibited Mer phosphorylation and colony formation in soft agar. Given the potential of Mer as a therapeutic target, UNC1062 is a promising candidate for further drug development.

  15. UNC1062, a new and potent Mer inhibitor

    PubMed Central

    Liu, Jing; Zhang, Weihe; Stashko, Michael A; DeRyckere, Deborah; Cummings, Christopher T.; Hunter, Debra; Yang, Chao; Jayakody, Chatura N.; Cheng, Nancy; Simpson, Catherine; Norris-Drouin, Jacqueline; Sather, Susan; Kireev, Dmitri; Janzen, William P.; Earp, H Shelton; Graham, Douglas K.; Frye, Stephen V.; Wang, Xiaodong

    2013-01-01

    Abnormal activation of Mer kinase has been implicated in the oncogenesis of many human cancers including acute lymphoblastic and myeloid leukemia, non-small cell lung cancer, and glioblastoma. We have discovered a new family of small molecule Mer inhibitors, pyrazolopyrimidine sulfonamides, that potently inhibit the kinase activity of Mer. Importantly, these compounds do not demonstrate significant hERG activity in the PatchXpress assay. Through structure-activity relationship studies, 35 (UNC1062) was identified as a potent (IC50 = 1.1 nM) and selective Mer inhibitor. When applied to live tumor cells, UNC1062 inhibited Mer phosphorylation and colony formation in soft agar. Given the potential of Mer as a therapeutic target, UNC1062 is a promising candidate for further drug development. PMID:23693152

  16. Specific energy from Auger and conversion electrons of 131I, 188Re-anti-CD20 to a lymphocyte's nucleus

    NASA Astrophysics Data System (ADS)

    Torres-García, E.; Carrillo-Cazares, T. A.

    2011-01-01

    The typical radionuclides used to label anti-CD20 in the treatment of non-Hodgkin's lymphoma are 90Y, 131I, and 188Re, with the emission of beta particles, Auger electrons, and conversion electrons for the latter two. The aim of the present work was to calculate the contribution of high linear energy transfer radiation as Auger electrons (AE) and conversion electrons (CE) of 131I and 188Re-anti-CD20 to mean specific energy into the cell nucleus by Monte Carlo simulation (MCS), so as to infer therapeutic effectiveness on a dosimetric basis. MCS was used to quantify the frequency-mean specific energy into the cell nucleus, where the cell was modeled by two concentric spheres, considering two cell models. The results showed that 10% and 33% of the mean-specific energies (z¯) per disintegration imparted to the cell nucleus for both geometries are due to AE and CE; on the other hand, if the hit of AE and CE occurs, the contribution to (z¯) is about 64% and 86% for 131I and 188Re, respectively. According to the amount of specific energy from AE and CE into the cell nucleus by positive event, they can cause catastrophic effects in the nuclear DNA in the treatment of non-Hodgkin's lymphoma with 131I, 188Re-anti-CD20.

  17. 2-Aminoresorcinol is a potent alpha-glucosidase inhibitor.

    PubMed

    Gao, Hong; Kawabata, Jun

    2008-01-15

    A series of aminoresorcinols and related compounds were tested for rat intestinal alpha-glucosidase inhibition and these results suggested that the 2-aminoresorcinol moiety of 6-amino-5,7-dihydroxyflavone (2) is important to exert the intestinal alpha-glucosidase inhibitory activity and 2-aminoresorcinol (4), itself, is a potent alpha-glucosidase inhibitor and inhibited sucrose-hydrolyzing activity of rat intestinal alpha-glucosidase uncompetitively.

  18. Role of Emission Character in Auger Electron Diffraction

    NASA Astrophysics Data System (ADS)

    Idzerda, Y. U.

    A review of the interpretation of the angle-dependent Auger intensity pattern by both Auger electron diffraction (AED), which is concerned with identifying the nearby atomic structure, and angle-resolved Auger electron spectroscopy (ARAES), which is concerned with identifying the character of the emitted electron source function, is presented. The importance of the emission character of the Auger electron (in terms of its angular momentum, l, and its magnetic quantum number, m) in understanding the generation of the AED and ARAES patterns is described. Understanding of how the various direct and secondary mechanisms for the Auger electron generation can affect the populations of these states can also be used to help identify the multiplet structure within the Auger lineshape as well as elucidate the core hole generation process.

  19. Spin-polarized Auger electrons

    NASA Astrophysics Data System (ADS)

    Merz, H.; Semke, J.

    1990-12-01

    The spin polarization of Auger electrons will be discussed within the standard two-step model of the Auger emission process for different situations: target polarized, projectile polarized, targe and projectile unpolarized. In these three cases different interaction mechanisms are responsible for the polarization of the emitted Auger electrons. The present theoretical and experimental situation will be reviewed.

  20. Daidzin: a potent, selective inhibitor of human mitochondrial aldehyde dehydrogenase.

    PubMed

    Keung, W M; Vallee, B L

    1993-02-15

    Human mitochondrial aldehyde dehydrogenase (ALDH-I) is potently, reversibly, and selectively inhibited by an isoflavone isolated from Radix puerariae and identified as daidzin, the 7-glucoside of 4',7-dihydroxyisoflavone. Kinetic analysis with formaldehyde as substrate reveals that daidzin inhibits ALDH-I competitively with respect to formaldehyde with a Ki of 40 nM, and uncompetitively with respect to the coenzyme NAD+. The human cytosolic aldehyde dehydrogenase isozyme (ALDH-II) is nearly 3 orders of magnitude less sensitive to daidzin inhibition. Daidzin does not inhibit human class I, II, or III alcohol dehydrogenases, nor does it have any significant effect on biological systems that are known to be affected by other isoflavones. Among more than 40 structurally related compounds surveyed, 12 inhibit ALDH-I, but only prunetin and 5-hydroxydaidzin (genistin) combine high selectivity and potency, although they are 7- to 15-fold less potent than daidzin. Structure-function relationships have established a basis for the design and synthesis of additional ALDH inhibitors that could both be yet more potent and specific.

  1. Angle Resolved Photoelectron and Auger Electron Diffraction as a Structural Probe for Surfaces, Interfaces, and Epitaxial Films.

    NASA Astrophysics Data System (ADS)

    Li, Hong

    The recently developed techniques of angle-resolved photoelectron and Auger electron diffraction (ARXPD/AED) have shown promise in identifying the structures of epitaxial films. This is due to the realization that electrons scattered by other atoms are enhanced along the forward direction. In this dissertation research, we have further investigated the capabilities of the ARXPD/AED technique. First, the complete polar angle distribution of the Auger electron intensity from Cu(001) was measured from the (100) to the (110) azimuth. The presentation of the ARAED in the form of a contour map clearly shows the relationship of the constructive and destructive interference of electron scattering to the crystallographic index of the crystal. Secondly, the angular distributions of electron emissions with initial states of 3p, 3d, 4d, and the Auger emission with electron kinetic energies ranging from 348 eV to 1477 eV were measured for single crystal Ag(001). The results show that all of these electron emissions have similar electron forward scattering enhancements along the directions of nearest and next nearest neighbour atoms in the crystal. The forward scattering enhancements do not shift as the electron kinectic energy changes. The ARXPD/AED combined with low energy electron diffraction (LEED) has been demonstrated to be a very powerful technique in probing both the long range order and the short range order of the epitaxial films. The epitaxial films studied include Co on Cu(001), Fe on Ag(001), Co on Ag(001), and Co on an ultra-thin film of Fe(001), which was epitaxially grown on Ag(001). We find that up to 20 ML thickness of high quality metastable fcc Co can be stabilized on Cu(001) at room temperature. We have directly verified that the Fe on Ag(001) is bcc. The Co on Ag(001) is neither bcc nor fcc for coverages of less than 3 ML. Thick films of Co on Ag(001) are disordered, of which a very small portion has a local structure of bcc. The bcc Co phases has been

  2. Auger electron spectroscopy study of oxidation of a PdCr alloy used for high-temperature sensors

    NASA Technical Reports Server (NTRS)

    Boyd, Darwin L.; Zeller, Mary V.; Vargas-Aburto, Carlos

    1993-01-01

    A Pd-13 wt. percent Cr solid solution is a promising high-temperature strain gage alloy. In bulk form it has a number of properties that are desirable in a resistance strain gage material, such as a linear electrical resistance versus temperature curve to 1000 C and stable electrical resistance in air at 1000 C. However, unprotected fine wire gages fabricated from this alloy perform well only to 600 C. At higher temperatures severe oxidation degrades their electrical performance. In this work Auger electron spectroscopy was used to study the oxidation chemistry of the alloy wires and ribbons. Results indicate that the oxidation is caused by a complex mechanism that is not yet fully understood. As expected, during oxidation, a layer of chromium oxide is formed. This layer, however, forms beneath a layer of metallic palladium. The results of this study have increased the understanding of the oxidation mechanism of Pd-13 wt. percent Cr.

  3. A potent alpha-glucosidase inhibitor from Myristica cinnamomea King.

    PubMed

    Sivasothy, Yasodha; Loo, Kong Yong; Leong, Kok Hoong; Litaudon, Marc; Awang, Khalijah

    2016-02-01

    A dimeric acylphenol and a potent α-glucosidase inhibitor, giganteone D (IC50 5.05μM), was isolated and characterized from the bark of Myristica cinnamomea King. The bark also yielded an acylphenol with an unprecedented skeleton for which the name cinnamomeone A (IC50 358.80μM) was proposed. Their structures were established by means of NMR and MS spectrometric analyses. The Lineweaver-Burk plot of giganteone D indicated that it was a mixed-type inhibitor. This is the first report on the α-glucosidase inhibiting potential of acylphenols.

  4. Auger electron spectroscopy, secondary ion mass spectroscopy and optical characterization of a-C-H and BN films

    NASA Technical Reports Server (NTRS)

    Pouch, J. J.; Alterovitz, S. A.; Warner, J. D.

    1986-01-01

    The amorphous dielectrics a-C:H and BN were deposited on III-V semiconductors. Optical band gaps as high as 3 eV were measured for a-C:H generated by C4H10 plasmas; a comparison was made with bad gaps obtained from films prepared by CH4 glow discharges. The ion beam deposited BN films exhibited amorphous behavior with band gaps on the order of 5 eV. Film compositions were studied by Auger electron spectroscopy (AES), x-ray photoelectron spectroscopy (XPS) and secondary ion mass spectrometry (SIMS). The optical properties were characterized by ellipsometry, UV/VIS absorption, and IR reflection and transmission. Etching rates of a-C:H subjected to O2 dicharges were determined.

  5. Auger electron spectroscopy study of initial stages of oxidation in a copper - 19.6-atomic-percent-aluminum alloy

    NASA Technical Reports Server (NTRS)

    Ferrante, J.

    1973-01-01

    Auger electron spectroscopy was used to examine the initial stages of oxidation of a polycrystalline copper - 19.6 a/o-aluminum alloy. The growth of the 55-eV aluminum oxide peak and the decay of the 59-, 62-, and 937-eV copper peaks were examined as functions of temperature, exposure, and pressure. Pressures ranged from 1x10 to the minus 7th power to 0.0005 torr of O2. Temperatures ranged from room temperature to 700 C. A completely aluminum oxide surface layer was obtained in all cases. Complete disappearance of the underlying 937-eV copper peak was obtained by heating at 700 C in O2 at 0.0005 torr for 1 hr. Temperature studies indicated that thermally activated diffusion was important to the oxidation studies. The initial stages of oxidation followed a logarithmic growth curve.

  6. Design and synthesis of a potent histone deacetylase inhibitor.

    PubMed

    Liu, Tao; Kapustin, Galina; Etzkorn, Felicia A

    2007-05-03

    Histone deacetylase (HDAC) inhibitors have potential for cancer therapy. An HDAC inhibitor based on a cyclic peptide mimic of known structure, linked by an aliphatic chain to a hydroxamic acid, was designed and synthesized. The chimeric compound showed potent competitive inhibition of nuclear HDACs, with an IC50 value of 46 nM and a Ki value of 13.7 nM. The designed inhibitor showed 4-fold selectivity for HDAC1 (57 nM) over HDAC8 (231 nM).

  7. Thermal effects in equilibrium surface segregation in a copper/10-atomic-percent-aluminum alloy using Auger electron spectroscopy

    NASA Technical Reports Server (NTRS)

    Ferrante, J.

    1972-01-01

    Equilibrium surface segregation of aluminum in a copper-10-atomic-percent-aluminum single crystal alloy oriented in the /111/ direction was demonstrated by using Auger electron spectroscopy. This crystal was in the solid solution range of composition. Equilibrium surface segregation was verified by observing that the aluminum surface concentration varied reversibly with temperature in the range 550 to 850 K. These results were curve fitted to an expression for equilibrium grain boundary segregation and gave a retrieval energy of 5780 J/mole (1380 cal/mole) and a maximum frozen-in surface coverage three times the bulk layer concentration. Analyses concerning the relative merits of sputtering calibration and the effects of evaporation are also included.

  8. Discovery of a Potent and Orally Bioavailable CCR2 and CCR5 Dual Antagonist

    PubMed Central

    2009-01-01

    This report describes the discovery of a potent, orally bioavailable CC chemokine receptor 2 (CCR2) antagonist which, while optimized for CCR2 potency, also had potent CC chemokine receptor 5 (CCR5) activity.

  9. Observation of four-electron Auger processes

    NASA Astrophysics Data System (ADS)

    Müller, A.; Borovik, A., Jr.; Buhr, T.; Hellhund, J.; Holste, K.; Kilcoyne, A. L. D.; Klumpp, S.; Martins, M.; Ricz, S.; Viefhaus, J.; Schippers, S.

    2015-09-01

    Multiple ionization of ions subsequent to absorption of a single photon has been studied employing a photon-ion merged-beam setup at the PETRA III synchrotron radiation facility of DESY in Hamburg. Absolute cross sections for single, double and triple ionization of C+ ions were measured with emphasis on specific well defined terms of K-shell excited C+. In particular, the terms C+ (1s2s22p2 2D,2P) were excited from the ground level of C+. Subsequent autoionization processes resulted in the production of C2+, C3+ and C4+ ions. The associated decay mechanisms are single-Auger, double-Auger and triple-Auger decay. The observation of C4+ products arising from C+(1s2s22p2 2D,2P) unambiguously confirmed the existence of triple-Auger decay, i.e., a process in which 4 electrons interact with one another such that one fills the K-shell vacancy and the others are simultaneously ejected. The experiment yields branching ratios for the Auger decay channels as well as individual decay rates for autoionization and radiative stabilization of the C+(1s2s22p2 2D,2P) terms.

  10. El proyecto AUGER

    NASA Astrophysics Data System (ADS)

    Etchegoyen, A.

    Hace ya más de 30 años en Volcano Ranch, EE.UU., un extenso chubasco cósmico (ECC) fue detectado con energía en exceso de 1020 eV. Desde entonces, observatorios ubicados en Haverah Park del Reino Unido, Yakutsk de Rusia, AGASA de Japón y Dugway de EE.UU. también han observado ECC con energías mayores que 1020 eV. Poco se sabe de dichos rayos, y en particular cuál es la naturaleza del primario, de dónde provienen, y cómo son acelerados, pero su naturaleza ultrarelativista excluye la mayoría de las respuestas dejando sólo algunas plausibles de ser investigadas experimentalmente. Grupos de científicos de 20 países están trabajando con el fin de construir dos arreglos de detectores gigantes, uno en cada hemisferio a lo largo de 3000 km2 c/u. Dichas dimensiones son necesarias debido al flujo estimado de 1 rayo cósmico/centuria/km2/sr. La sede del Observatorio del Sur es la Argentina. El proyecto fue nombrado Pierre Auger en conmemoración del célebre físico francés que detectó por primera vez chubascos cósmicos en 1938. El proyecto focaliza su interés en rayos cósmicos con energías mayores que 1020 eV.

  11. Adrenomedullin - new perspectives of a potent peptide hormone.

    PubMed

    Schönauer, Ria; Els-Heindl, Sylvia; Beck-Sickinger, Annette G

    2017-02-02

    Adrenomedullin (ADM) is a 52-amino acid multifunctional peptide, which belongs to the calcitonin gene-related peptide (CGRP) superfamily of vasoactive peptide hormones. ADM exhibits a significant vasodilatory potential and plays a key role in various regulatory mechanisms, predominantly in the cardiovascular and lymphatic system. It exerts its effects by activation of the calcitonin receptor-like receptor associated with one of the receptor activity-modifying proteins 2 or 3. ADM was first isolated from human phaeochromocytoma in 1993. Numerous studies revealed a widespread distribution in various tissues and organs, which is reflected by its multiple physiological roles in health and disease. Because of its anti-inflammatory, anti-apoptotic and proliferative properties, ADM exhibits potent protective functions under diverse pathological conditions, but it is also critically involved in tumor progression. ADM has therefore raised great interest in therapeutic applications and several clinical trials already revealed promising results. However, because the receptor activation mode has not yet been fully elucidated, a rational design of potent and selective ligands is still challenging. Detailed information on the binding mode of ADM from a recently reported crystal structure as well as efforts to improve its plasma stability and bioavailability may help to overcome these limitations in the future. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.

  12. Cancer immunotherapy using a potent immunodominant CTL epitope.

    PubMed

    Song, Liwen; Yang, Ming-Chieh; Knoff, Jayne; Sun, Zu-Yue; Wu, T-C; Hung, Chien-Fu

    2014-10-21

    Immunotherapy has emerged as a promising approach that can be used in conjunction with conventional chemotherapy and radiotherapy to further improve the survival rate of patients with advanced cancer. We have recently shown in previous studies that chemotherapy and radiation therapy can alter the tumor microenvironment and allow intratumoral vaccination to prime the adaptive immune system leading to the generation of antigen-specific cell-mediated immune responses. Here, we investigated whether intratumoral injection of a foreign immunodominant peptide (GP33) and the adjuvant CpG into tumors following cisplatin chemotherapy could lead to potent antitumor effects and antigen-specific cell-mediated immune responses. We observed that treatment with all three agents produced the most potent antitumor effects compared to pairwise combinations. Moreover, treatment with cisplatin, CpG and GP33 was able to control tumors at a distant site, indicating that our approach is able to induce cross-presentation of the tumor antigen. Treatment with cisplatin, CpG and GP33 also enhanced the generation of GP33-specific and E7-specific CD8+ T cells and decreased the number of MDSCs in tumor loci, a process found to be mediated by the Fas-FasL apoptosis pathway. The treatment regimen presented here represents a universal approach to cancer control.

  13. Potent inhibition of tau fibrillization with a multivalent ligand

    SciTech Connect

    Honson, Nicolette S.; Jensen, Jordan R.; Darby, Michael V.; Kuret, Jeff

    2007-11-09

    Small-molecule inhibitors of tau fibrillization are under investigation as tools for interrogating the tau aggregation pathway and as potential therapeutic agents for Alzheimer's disease. Established inhibitors include thiacarbocyanine dyes, which can inhibit recombinant tau fibrillization in the presence of anionic surfactant aggregation inducers. In an effort to increase inhibitory potency, a cyclic bis-thiacarbocyanine molecule containing two thiacarbocyanine moieties was synthesized and characterized with respect to tau fibrillization inhibitory activity by electron microscopy and ligand aggregation state by absorbance spectroscopy. Results showed that the inhibitory activity of the bis-thiacarbocyanine was qualitatively similar to a monomeric cyanine dye, but was more potent with 50% inhibition achieved at {approx}80 nM concentration. At all concentrations tested in aqueous solution, the bis-thiacarbocyanine collapsed to form a closed clamshell structure. However, the presence of tau protein selectively stabilized the open conformation. These results suggest that the inhibitory activity of bis-thiacarbocyanine results from multivalency, and reveal a route to more potent tau aggregation inhibitors.

  14. A Synthetic Chalcone as a Potent Inducer of Glutathione Biosynthesis

    PubMed Central

    Kachadourian, Remy; Day, Brian J.; Pugazhenti, Subbiah; Franklin, Christopher C.; Genoux-Bastide, Estelle; Mahaffey, Gregory; Gauthier, Charlotte; Di Pietro, Attilio; Boumendjel, Ahcène

    2014-01-01

    Chalcones continue to attract considerable interest due to their anti-inflammatory and antiangiogenic properties. We recently reported the ability of 2′,5′-dihydroxychalcone (2′,5′-DHC) to induce both breast cancer resistance protein-mediated export of glutathione (GSH) and c-Jun N-terminal kinase-mediated increased intracellular GSH levels. Herein, we report a structure–activity relationship study of a series of 30 synthetic chalcone derivatives with hydroxyl, methoxyl, and halogen (F and Cl) substituents and their ability to increase intracellular GSH levels. This effect was drastically improved with one or two electrowithdrawing groups on phenyl ring B and up to three methoxyl and/or hydroxyl groups on phenyl ring A. The optimal structure, 2-chloro-4′,6′-dimethoxy-2′-hydroxychalcone, induced both a potent NF-E2-related factor 2-mediated transcriptional response and an increased formation of glutamate cysteine ligase holoenzyme, as shown using a human breast cancer cell line stably expressing a luciferase reporter gene driven by antioxidant response elements. PMID:22239485

  15. Auger processes in the 21st century

    PubMed Central

    Howell, Roger W.

    2012-01-01

    Purpose The extreme radiotoxicity of Auger electrons and their exquisite capacity to irradiate specific molecular sites has prompted scientists to extensively investigate their radiobiological effects. Their efforts have been punctuated by quadrennial international symposia that have focused on biophysical aspects of Auger processes. The latest meeting, the 6th International Symposium on Physical, Molecular, Cellular, and Medical Aspects of Auger Processes, was held 5–6 July 2007 at Harvard Medical School in Boston, Massachusetts, USA. This article provides a review of the research in this field that was published during the years 2004–2007, the period that has elapsed since the previous meeting. Conclusion The field has advanced considerably. A glimpse of the potential of this unique form of ionizing radiation to contribute to future progress in a variety of fields of study is proffered. PMID:19061120

  16. Education and public outreach of the Pierre Auger Observatory

    SciTech Connect

    Garcia, B.; Snow, G.

    2005-08-01

    The Auger collaboration's broad mission in education, outreach and public relations is coordinated in a separate task. Its goals are to encourage and support a wide range of outreach efforts that link schools and the public with the Auger scientists and the science of cosmic rays, particle physics, and associated technologies. This report focuses on recent activities and future initiatives.

  17. Quantitative Auger analysis of Nb-Ge superconducting alloys

    SciTech Connect

    Buitrago, R.H.

    1980-01-01

    The feasibility of using Auger electron analysis for quantitative analysis was investigated by studying Nb/sub 3/Ge thin-film Auger data with different approaches. A method base on elemental standards gave consistent quantitative values with reported Nb-Ge data. Alloy sputter yields were also calculated and results were consistent with those for pure elements.

  18. A Potent and Site-Selective Agonist of TRPA1.

    PubMed

    Takaya, Junichiro; Mio, Kazuhiro; Shiraishi, Takuya; Kurokawa, Tatsuki; Otsuka, Shinya; Mori, Yasuo; Uesugi, Motonari

    2015-12-23

    TRPA1 is a member of the transient receptor potential (TRP) cation channel family that is expressed primarily on sensory neurons. This chemosensor is activated through covalent modification of multiple cysteine residues with a wide range of reactive compounds including allyl isothiocyanate (AITC), a spicy component of wasabi. The present study reports on potent and selective agonists of TRPA1, discovered through screening 1657 electrophilic molecules. In an effort to validate the mode of action of hit molecules, we noted a new TRPA1-selective agonist, JT010 (molecule 1), which opens the TRPA1 channel by covalently and site-selectively binding to Cys621 (EC50 = 0.65 nM). The results suggest that a single modification of Cys621 is sufficient to open the TRPA1 channel. The TRPA1-selective probe described herein might be useful for further mechanistic studies of TRPA1 activation.

  19. Nanosulfur: A Potent Fungicide Against Food Pathogen, Aspergillus niger

    NASA Astrophysics Data System (ADS)

    Choudhury, Samrat Roy; Nair, Kishore K.; Kumar, Rajesh; Gogoi, Robin; Srivastava, Chitra; Gopal, Madhuban; Subhramanyam, B. S.; devakumar, C.; Goswami, Arunava

    2010-10-01

    Elemental sulfur (S0), man's oldest eco-friendly fungicide for curing fungal infections in plants and animals, is registered in India as a non-systemic and contact fungicide. However due to its high volume requirement, Indian agrochemical industry and farmers could not effectively use this product till date. We hypothesize that intelligent nanoscience applications might increase the visibility of nanosulfur in Indian agriculture as a potent and eco-safe fungicide. Sulfur nanoparticles (NPs) were synthesized bottom-up via a liquid synthesis method with average particle size in the range of 50-80 nm and the shapes of the NPs were spherical. A comparative study of elemental and nano-sulfur produced has been tested against facultative fungal food pathogen, Aspergillus niger. Results showed that nanosulfur is more efficacious than its elemental form.

  20. Nanosulfur: A Potent Fungicide Against Food Pathogen, Aspergillus niger

    SciTech Connect

    Choudhury, Samrat Roy; Goswami, Arunava; Nair, Kishore K.; Kumar, Rajesh; Gopal, Madhuban; Devakumar, C.; Gogoi, Robin; Srivastava, Chitra; Subhramanyam, B. S.

    2010-10-04

    Elemental sulfur (S{sup 0}), man's oldest eco-friendly fungicide for curing fungal infections in plants and animals, is registered in India as a non-systemic and contact fungicide. However due to its high volume requirement, Indian agrochemical industry and farmers could not effectively use this product till date. We hypothesize that intelligent nanoscience applications might increase the visibility of nanosulfur in Indian agriculture as a potent and eco-safe fungicide. Sulfur nanoparticles (NPs) were synthesized bottom-up via a liquid synthesis method with average particle size in the range of 50-80 nm and the shapes of the NPs were spherical. A comparative study of elemental and nano-sulfur produced has been tested against facultative fungal food pathogen, Aspergillus niger. Results showed that nanosulfur is more efficacious than its elemental form.

  1. Experimentally accessible signatures of Auger scattering in graphene

    NASA Astrophysics Data System (ADS)

    Winzer, Torben; Jago, Roland; Malic, Ermin

    2016-12-01

    The gapless and linear electronic band structure of graphene opens up Auger scattering channels bridging the valence and the conduction band and changing the charge carrier density. Here, we reveal experimentally accessible signatures of Auger scattering in optically excited graphene. To be able to focus on signatures of Auger scattering, we apply a low excitation energy, weak pump fluences, and a cryostatic temperature, so that all relevant processes lie energetically below the optical phonon threshold. In this regime, carrier-phonon scattering is strongly suppressed and Coulomb processes govern the carrier dynamics. Depending on the excitation regime, we find an accumulation or depletion of the carrier occupation close to the Dirac point. This reflects well the behavior predicted from Auger-dominated carrier dynamics. Based on this observation, we propose a multicolor pump-probe experiment to uncover the extreme importance of Auger channels for the nonequilibrium dynamics in graphene.

  2. Latest results from the Pierre Auger Observatory

    NASA Astrophysics Data System (ADS)

    Lhenry-Yvon, Isabelle

    2016-07-01

    The Pierre Auger Observatory has been designed to investigate the origin and nature of Ultra High Energy Cosmic Rays (UHECR) with energies from 1017 to 1020 eV. In this paper we will review some of the most recent results obtained from data of the Pierre Auger Observatory, namely the spectrum of cosmic rays, the anisotropies in arrival directions and the studies related to mass composition and to the number of muons measured at the ground. We will also discuss the implication of these results for assembling a consistent description of the composition, origin and propagation of cosmic rays.

  3. Molecular frame Auger electron energy spectrum from N2

    NASA Astrophysics Data System (ADS)

    Cryan, J. P.; Glownia, J. M.; Andreasson, J.; Belkacem, A.; Berrah, N.; Blaga, C. I.; Bostedt, C.; Bozek, J.; Cherepkov, N. A.; DiMauro, L. F.; Fang, L.; Gessner, O.; Gühr, M.; Hajdu, J.; Hertlein, M. P.; Hoener, M.; Kornilov, O.; Marangos, J. P.; March, A. M.; McFarland, B. K.; Merdji, H.; Messerschmidt, M.; Petrović, V. S.; Raman, C.; Ray, D.; Reis, D. A.; Semenov, S. K.; Trigo, M.; White, J. L.; White, W.; Young, L.; Bucksbaum, P. H.; Coffee, R. N.

    2012-03-01

    Here we present the first angle-resolved, non-resonant (normal) Auger spectra for impulsively aligned nitrogen molecules. We have measured the angular pattern of Auger electron emission following K-shell photoionization by 1.1 keV photons from the Linac Coherent Light Source (LCLS). Using strong-field-induced molecular alignment to make molecular frame measurements is equally effective for both repulsive and quasi-bound final states. The capability to resolve Auger emission angular distributions in the molecular frame of reference provides a new tool for spectral assignments in congested Auger electron spectra that takes advantage of the symmetries of the final diction states. Based on our experimental results and theoretical predictions, we propose the assignment of the spectral features in the Auger electron spectrum.

  4. ATHLETE : Double Auger Anchoring Mechanism

    NASA Technical Reports Server (NTRS)

    Shin, Joseph

    2011-01-01

    The All-Terrain Hex-Legged Extra-Terrestrial Explorer (ATHLETE) is a six-limbed robot designed to support surface explorations on Near Earth Objects, the Moon and Mars. ATHLETE can carry large payloads on its top deck and can carry a fully equipped pressurized habitat in low gravity. The robot has wheels on each of its six articulated limbs, allowing it to actively conform to terrain while driving and to walk when driving is impractical. With the use of a tool adapter, ATHLETE limbs can be equipped with end effectors to support various mission objectives. For work on Near Earth Objects and other microgravity environments, an anchoring mechanism is needed to keep the ATHLETE from floating off the surface. My goal for this spring session at JPL was to design and build a counter rotating, double auger, anchoring mechanism. The mechanism mates to the tool adapter and is driven off the wheel motor. The double auger anchoring mechanism will be tested in a regolith simulant that will determine the uplift capacity of the anchoring mechanism.

  5. Development of a miniature double-pass cylindrical mirror electron energy analyzer (DPCMA), and its application to Auger photoelectron coincidence spectroscopy (APECS)

    NASA Astrophysics Data System (ADS)

    Kobayashi, Eiichi; Seo, Junya; Nambu, Akira; Mase, Kazuhiko

    2007-09-01

    We have developed a miniature double-pass cylindrical mirror electron energy analyzer (DPCMA) with an outer diameter of 26 mm. The DPCMA consists of a shield for the electric field, inner and outer cylinders, two pinholes with a diameter of 2.0 mm, and an electron multiplier. By assembling the DPCMA in a coaxially symmetric mirror electron energy analyzer (ASMA) coaxially and confocally we developed an analyzer for Auger photoelectron coincidence spectroscopy (APECS). The performance was estimated by measuring the Si-LVV-Auger Si-1s-photoelectron coincidence spectra of clean Si(1 1 1). The electron-energy resolution of the DPCMA was estimated to be E/Δ E = 20. This value is better than that of the miniature single-pass CMA ( E/Δ E = 12) that was used in the previous APECS analyzer.

  6. Photoelectron and Auger electron diffraction studies of a sulfur-terminated GaAs(001)-(2×6) surface

    NASA Astrophysics Data System (ADS)

    Shimoda, M.; Tsukamoto, S.; Koguchi, N.

    1998-01-01

    Core-level X-ray photoelectron diffraction (XPD) and Auger electron diffraction (AED) have been applied to investigate the sulfur-terminated GaAs(001)-(2×6) surface. No forward scattering peaks were found in the XPD pattern of S 2s emission, indicating that adsorbed S atoms form a single layer on the GaAs substrate. In accordance with the zincblende structure of GaAs, the AED patterns of Ga L 3M 45M 45 and As L 3M 45M 45 emission almost coincide with each other, if one of the emissions is rotated by 90° around the [001] direction. This fact suggests that the diffraction patterns mainly reflect the structure of the bulk GaAs crystal. In order to investigate the surface structure, AED patterns in large polar angles were analyzed with single scattering cluster (SSC) calculations. The best result was obtained with a model cluster where the S-S bond length was set at 0.28 nm, 30% shorter than the corresponding length of the ideal (1×1) structure, and the adsorption height was set at 0.12-0.13 nm, 10% shorter than the ideal interlayer distance of GaAs(001) planes. These values are in good agreement with the results of STM measurements. A modulation of the inter-dimer distance was also found, suggesting the existence of missing dimers.

  7. A detailed Auger electron spectroscopy study of the first stages of the growth of C60 thin films

    NASA Astrophysics Data System (ADS)

    Vidal, R. A.; Ferrón, J.

    2015-11-01

    In this work we take advantage of the large sensitivity and in-depth resolution of Auger electron spectroscopy (AES) to study in a detailed way the growth of C60 over different substrates, namely Cu(1 1 1), Si(1 0 0) and graphene. The ability of AES, as compared to more local probes like STM or AFM, to follow the process in a dynamic way, allows us to study the growth of C60 below and over one ML, including the change of C60 over either Si or Cu to the growth of C60 over a C60 film. We found that the growth always proceeds layer by layer. This result shows that differences in diffusion barriers are not as important as one may think following the idea of diffusion by a jumping mechanism. We propose that the sticking coefficient, governed by the adsorption energy, is responsible for the differences observed between Cu and Si. Our results also point to a different charge transfer among fullerene molecules and these surfaces. The same result is suggested in the case of C60 over graphene, but in this case our conclusion comes from the variable temperature experiments.

  8. Dosimetry at the sub-cellular scale of Auger-electron emitter 99mTc in a mouse single thyroid follicle.

    PubMed

    Taborda, A; Benabdallah, N; Desbrée, A

    2016-02-01

    The Auger-electrons emitted by (99m)Tc have been recently associated with the induction of thyroid stunning in in vivo experiments in mice, making the dosimetry at the sub-cellular level of (99m)Tc a pertinent and pressing subject. The S-values for (99m)Tc were calculated using MCNP6, which was first validated for studies at the sub-cellular scale and for low energies electrons. The calculation was then performed for (99m)Tc within different cellular compartments in a single mouse thyroid follicle model, considering the radiative and non-radiative transitions of the (99m)Tc radiation spectrum. It was shown that the contribution of the (99m)Tc Auger and low energy electrons to the absorbed dose to the follicular cells' nucleus is important, being at least of the same order of magnitude compared to the emitted photons' contribution and cannot be neglected. The results suggest that Auger-electrons emitted by (99m)Tc play a significant role in the occurrence of the thyroid stunning effect in mice.

  9. HU-444, a Novel, Potent Anti-Inflammatory, Nonpsychotropic Cannabinoid

    PubMed Central

    Haj, Christeene G.; Sumariwalla, Percy F.; Hanuš, Lumír; Kogan, Natalya M.; Yektin, Zhana; Feldmann, Mark

    2015-01-01

    Cannabidiol (CBD) is a component of cannabis, which does not cause the typical marijuana-type effects, but has a high potential for use in several therapeutic areas. In contrast to Δ9-tetrahydrocannabinol (Δ9-THC), it binds very weakly to the CB1 and CB2 cannabinoid receptors. It has potent activity in both in vitro and in vivo anti-inflammatory assays. Thus, it lowers the formation of tumor necrosis factor (TNF)-α, a proinflammatory cytokine, and was found to be an oral antiarthritic therapeutic in murine collagen-induced arthritis in vivo. However, in acidic media, it can cyclize to the psychoactive Δ9-THC. We report the synthesis of a novel CBD derivative, HU-444, which cannot be converted by acid cyclization into a Δ9-THC–like compound. In vitro HU-444 had anti-inflammatory activity (decrease of reactive oxygen intermediates and inhibition of TNF-α production by macrophages); in vivo it led to suppression of production of TNF-α and amelioration of liver damage as well as lowering of mouse collagen-induced arthritis. HU-444 did not cause Δ9-THC–like effects in mice. We believe that HU-444 represents a potential novel drug for rheumatoid arthritis and other inflammatory diseases. PMID:26272937

  10. HU-444, a Novel, Potent Anti-Inflammatory, Nonpsychotropic Cannabinoid.

    PubMed

    Haj, Christeene G; Sumariwalla, Percy F; Hanuš, Lumír; Kogan, Natalya M; Yektin, Zhana; Mechoulam, Raphael; Feldmann, Mark; Gallily, Ruth

    2015-10-01

    Cannabidiol (CBD) is a component of cannabis, which does not cause the typical marijuana-type effects, but has a high potential for use in several therapeutic areas. In contrast to Δ(9)-tetrahydrocannabinol (Δ(9)-THC), it binds very weakly to the CB1 and CB2 cannabinoid receptors. It has potent activity in both in vitro and in vivo anti-inflammatory assays. Thus, it lowers the formation of tumor necrosis factor (TNF)-α, a proinflammatory cytokine, and was found to be an oral antiarthritic therapeutic in murine collagen-induced arthritis in vivo. However, in acidic media, it can cyclize to the psychoactive Δ(9)-THC. We report the synthesis of a novel CBD derivative, HU-444, which cannot be converted by acid cyclization into a Δ(9)-THC-like compound. In vitro HU-444 had anti-inflammatory activity (decrease of reactive oxygen intermediates and inhibition of TNF-α production by macrophages); in vivo it led to suppression of production of TNF-α and amelioration of liver damage as well as lowering of mouse collagen-induced arthritis. HU-444 did not cause Δ(9)-THC-like effects in mice. We believe that HU-444 represents a potential novel drug for rheumatoid arthritis and other inflammatory diseases.

  11. Auger Spectroscopy of Hydrogenated Diamond Surfaces

    NASA Technical Reports Server (NTRS)

    Krainsky, I. L.; Asnin, V. M.; Petukhov, A. G.; Foygel, M.

    1997-01-01

    An energy shift and a change of the line shape of the carbon core-valence-valence Auger spectra are observed for diamond surfaces after their exposure to an electron beam, or annealing at temperatures higher then 950 C. The effect is studied for both natural diamond crystals and chemical-vapor-deposited diamond films. A theoretical model is proposed for Auger spectra of hydrogenated diamond surfaces. The observed changes of the carbon Auger line shape are shown to be related to the redistribution of the valence-band local density of states caused by the hydrogen desorption from the surface. One-electron calculation of Auger spectra of diamond surfaces with various hydrogen coverages are presented. They are based on self-consistent wave functions and matrix elements calculated in the framework of the local-density approximation and the self-consistent linear muffin-tin orbital method with static core-hole effects taken into account. The major features of experimental spectra are explained.

  12. Energy and angular distributions of electrons emitted by direct double auger decay.

    PubMed

    Viefhaus, Jens; Cvejanović, Slobodan; Langer, Burkhard; Lischke, Toralf; Prümper, Georg; Rolles, Daniel; Golovin, Alexander V; Grum-Grzhimailo, Alexei N; Kabachnik, Nikolai M; Becker, Uwe

    2004-02-27

    We have observed the direct L(2,3)MMM double Auger transition after photoionization of the 2p shell of argon by angle-resolved electron-electron coincidence spectroscopy. The process is responsible for about 20% of the observed Auger electron intensity. In contrast to the normal Auger lines, the spectra in double Auger decay show a continuous intensity distribution. The energy and angular distributions of the emitted electrons allow one to obtain information on the electron correlations giving rise to the double Auger process as well as the symmetry of the associated two-electron continuum state.

  13. Hemin as a generic and potent protein misfolding inhibitor

    SciTech Connect

    Liu, Yanqin; Carver, John A.; Ho, Lam H.; Elias, Abigail K.; Musgrave, Ian F.; Pukala, Tara L.

    2014-11-14

    Highlights: • Hemin prevents Aβ42, α-synuclein and RCM-κ-casein forming amyloid fibrils. • Hemin inhibits the β-sheet structure formation of Aβ42. • Hemin reduces the cell toxicity caused by fibrillar Aβ42. • Hemin dissociates partially formed Aβ42 fibrils. • Hemin prevents amorphous aggregation by ADH, catalase and γs-crystallin. - Abstract: Protein misfolding causes serious biological malfunction, resulting in diseases including Alzheimer’s disease, Parkinson’s disease and cataract. Molecules which inhibit protein misfolding are a promising avenue to explore as therapeutics for the treatment of these diseases. In the present study, thioflavin T fluorescence and transmission electron microscopy experiments demonstrated that hemin prevents amyloid fibril formation of kappa-casein, amyloid beta peptide and α-synuclein by blocking β-sheet structure assembly which is essential in fibril aggregation. Further, inhibition of fibril formation by hemin significantly reduces the cytotoxicity caused by fibrillar amyloid beta peptide in vitro. Interestingly, hemin degrades partially formed amyloid fibrils and prevents further aggregation to mature fibrils. Light scattering assay results revealed that hemin also prevents protein amorphous aggregation of alcohol dehydrogenase, catalase and γs-crystallin. In summary, hemin is a potent agent which generically stabilises proteins against aggregation, and has potential as a key molecule for the development of therapeutics for protein misfolding diseases.

  14. Neutralization mechanism of a highly potent antibody against Zika virus

    PubMed Central

    Zhang, Shuijun; Kostyuchenko, Victor A.; Ng, Thiam-Seng; Lim, Xin-Ni; Ooi, Justin S. G.; Lambert, Sebastian; Tan, Ter Yong; Widman, Douglas G.; Shi, Jian; Baric, Ralph S.; Lok, Shee-Mei

    2016-01-01

    The rapid spread of Zika virus (ZIKV), which causes microcephaly and Guillain-Barré syndrome, signals an urgency to identify therapeutics. Recent efforts to rescreen dengue virus human antibodies for ZIKV cross-neutralization activity showed antibody C10 as one of the most potent. To investigate the ability of the antibody to block fusion, we determined the cryoEM structures of the C10-ZIKV complex at pH levels mimicking the extracellular (pH8.0), early (pH6.5) and late endosomal (pH5.0) environments. The 4.0 Å resolution pH8.0 complex structure shows that the antibody binds to E proteins residues at the intra-dimer interface, and the virus quaternary structure-dependent inter-dimer and inter-raft interfaces. At pH6.5, antibody C10 locks all virus surface E proteins, and at pH5.0, it locks the E protein raft structure, suggesting that it prevents the structural rearrangement of the E proteins during the fusion event—a vital step for infection. This suggests antibody C10 could be a good therapeutic candidate. PMID:27882950

  15. Carvacrol as a potent natural acaricide against Dermanyssus gallinae.

    PubMed

    Tabari, Mohaddeseh Abouhosseini; Youssefi, Mohammad Reza; Barimani, Alireza; Araghi, Atefeh

    2015-10-01

    Resistance to conventional synthetic pesticides has been widely reported in Dermanyssus gallinae in poultry production systems. Introducing novel acaricides to poultry industry today is more urgent than ever. Research in this field recently focused on plants and plant-derived compounds as acaricides. In the present study, acaricidal activity of three plant bioactive components, carvacrol, thymol, and farnesol, was assessed against D. gallinae and compared with synthetic pesticide permethrin. Mode of acaricidal action was determined by contact toxicity and fumigant toxicity bioassays. Except farnesol which did not cause any mortality, carvacrol and thymol were found to be toxic to D. gallinae with LD50 values of 1 and 3.15 μg/cm(3), respectively. Permethrin gave the LD50 value of 31.95 μg/cm(3) which was less efficient than carvacrol and thymol. In fumigant toxicity bioassay, mortality rate in carvacrol- and thymol-treated groups in closed method was significantly higher than the open one. On the other hand, permethrin exhibited poor fumigant toxicity as there was no statistically significant difference between mortality rate in open and closed methods. These findings revealed that mechanism of acaricidal activity of carvacrol and thymol but not permethrin was mainly due to fumigant action. Results of the present study suggested that carvacrol and thymol, especially carvacrol, can be developed as a novel potent bioacaricide against D. gallinae.

  16. Acetone Extract from Rhodomyrtus tomentosa: A Potent Natural Antioxidant

    PubMed Central

    Lavanya, Goodla; Voravuthikunchai, Supayang Piyawan; Towatana, Nongporn Hutadilok

    2012-01-01

    Rhodomyrtus tomentosa (Myrtaceae) has been employed in traditional Thai medicine to treat colic diarrhoea, dysentery, abscesses, haemorrhage, and gynaecopathy. In addition, it has been used to formulate skin-whitening, anti-aging and skin beautifying agents. Ethnomedical activities of this plant may be due its antioxidant property. Hence, the aim of this study was to evaluate both in vitro and in vivo antioxidant activities of R. tomentosa leaf extract. In vitro antioxidant activity of the extract was assessed by lipid peroxidation inhibition capacity, ferric reducing antioxidant power, and metal chelating activity. R. tomentosa extract demonstrated its free radical scavenging effects in concentration dependent manner. In vivo antioxidant activity of the extract was conducted in Swiss Albino mice. Levels of thio-barbituric acid reactive substances (TBARS), glutathione (GSH), and the activities of antioxidant enzymes including superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) in blood, liver, and kidney were analyzed using microtitre plate photometer. Administration of CCl4 caused significant increase in TBARS and decrease in GSH, SOD, CAT and GPx levels. In contrast, R. tomentosa extract (0.8 g/kg) effectively prevented these alterations and maintained the antioxidant status. The results suggest that R. tomentosa extract can serve as a potent antioxidant. PMID:23125869

  17. Acetone Extract from Rhodomyrtus tomentosa: A Potent Natural Antioxidant.

    PubMed

    Lavanya, Goodla; Voravuthikunchai, Supayang Piyawan; Towatana, Nongporn Hutadilok

    2012-01-01

    Rhodomyrtus tomentosa (Myrtaceae) has been employed in traditional Thai medicine to treat colic diarrhoea, dysentery, abscesses, haemorrhage, and gynaecopathy. In addition, it has been used to formulate skin-whitening, anti-aging and skin beautifying agents. Ethnomedical activities of this plant may be due its antioxidant property. Hence, the aim of this study was to evaluate both in vitro and in vivo antioxidant activities of R. tomentosa leaf extract. In vitro antioxidant activity of the extract was assessed by lipid peroxidation inhibition capacity, ferric reducing antioxidant power, and metal chelating activity. R. tomentosa extract demonstrated its free radical scavenging effects in concentration dependent manner. In vivo antioxidant activity of the extract was conducted in Swiss Albino mice. Levels of thio-barbituric acid reactive substances (TBARS), glutathione (GSH), and the activities of antioxidant enzymes including superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) in blood, liver, and kidney were analyzed using microtitre plate photometer. Administration of CCl(4) caused significant increase in TBARS and decrease in GSH, SOD, CAT and GPx levels. In contrast, R. tomentosa extract (0.8 g/kg) effectively prevented these alterations and maintained the antioxidant status. The results suggest that R. tomentosa extract can serve as a potent antioxidant.

  18. Soil chip convey of lunar subsurface auger drill

    NASA Astrophysics Data System (ADS)

    Zhao, Deming; Tang, Dewei; Hou, Xuyan; Jiang, Shengyuan; Deng, Zongquan

    2016-05-01

    Celestial body subsurface drilling and sampling is a key aspect of near-earth exploration projects. In these sample return missions, the auger drill system is universally used due to the environment and detector load limits. The common failure that the auger faces is chip chocking, which can raise the torque and cause the drill to stick. This paper builds auger drill models describing chip flow in the auger groove to balance geometric parameters, functional capability, and reliability. The features of chip flow are summarized and verified by a series of discrete element method simulations. In contrast to previous auger design, a convey capability factor is defined to indicate the auger's chip removal capacity, and the role of pitch angle and other parameters is assessed through motion analysis of the lunar soil flow process. The theory is verified by testing the drill penetrating speed limit, which combines drill geometry and motion parameters. This work provides a new method for design and optimization of low speed auger drill systems and research on particle flow with small scale mechanical constraints.

  19. Studies of Cosmic Ray Composition and Air Shower Structure with the Pierre Auger Observatory

    SciTech Connect

    Abraham, : J.; Abreu, P.; Aglietta, M.; Aguirre, C.; Ahn, E.J.; Allard, D.; Allekotte, I.; Allen, J.; Alvarez-Muniz, J.; Ambrosio, M.; Anchordoqui, L.

    2009-06-01

    These are presentations to be presented at the 31st International Cosmic Ray Conference, in Lodz, Poland during July 2009. It consists of the following presentations: (1) Measurement of the average depth of shower maximum and its fluctuations with the Pierre Auger Observatory; (2) Study of the nuclear mass composition of UHECR with the surface detectors of the Pierre Auger Observatory; (3) Comparison of data from the Pierre Auger Observatory with predictions from air shower simulations: testing models of hadronic interactions; (4) A Monte Carlo exploration of methods to determine the UHECR composition with the Pierre Auger Observatory; (5) The delay of the start-time measured with the Pierre Auger Observatory for inclined showers and a comparison of its variance with models; (6) UHE neutrino signatures in the surface detector of the Pierre Auger Observatory; and (7) The electromagnetic component of inclined air showers at the Pierre Auger Observatory.

  20. The Pierre Auger Observatory progress and first results

    SciTech Connect

    Mantsch, Paul M.

    2005-08-01

    The Pierre Auger Observatory was designed for a high statistics, full sky study of cosmic rays at the highest energies. Energy, direction and composition measurements are intended to illuminate the mysteries of the most energetic particles in nature. The Auger Observatory utilizes a surface array together with air fluorescence telescopes which together provide a powerful instrument for air shower reconstruction. The southern part of the Auger Observatory, now under construction in the Province of Mendoza, Argentina, is well over half finished. Active detectors have been recording events for one and a half years. Preliminary results based on this first data set are presented.

  1. Biophysical aspects of Auger processes. American Association of Physicists in Medicine symposium proceedings No. 8

    SciTech Connect

    Howell, R.W.; Narra, V.R.; Rao, D.V. . Dept. of Radiology); Sastry, K.S.R. . Dept. of Physics and Astronomy)

    1992-01-01

    The 2nd International Symposium on Biophysical Aspects of Auger Processes was held in July 1991, at the University of Massachusetts. This conference provided a forum for state-of-the-art information regarding the basic mechanisms of action by which Auger processes effect biological damage, as well as the nature of the radiosensitive targets in the cell nucleus. In addition, new insight into the radiotoxicity of Auger processes arising from photon activation of atoms situated in the DNA were presented. Novel approaches to implement agents radiolabeled with Auger electron emitters for cancer therapy were discussed. The information is organized into three sections: Biological effects of photon induced Auger processes; biological effects of Auger-electron emitting radionuclides; and therapeutic applications of Auger electron emitters. Individual papers have been processed separately for inclusion in the appropriate data bases.

  2. Imipenem: a potent inducer of multidrug resistance in Acinetobacter baumannii.

    PubMed

    Kuo, Han-Yueh; Chang, Kai-Chih; Kuo, Jai-Wei; Yueh, Hui-Wen; Liou, Ming-Li

    2012-01-01

    This study investigated the progression of multidrug resistance upon exposure to imipenem in Acinetobacter baumannii. Eighteen A. baumannii strains, including two reference strains (ATCC 19606 and ATCC 17978), four clinical strains (AB56, AB242, AB273 and AB279) and 12 antibiotic-selected mutant strains, were used in this study. Imipenem-selected mutants were generated from imipenem-susceptible strains (ATCC 19606, ATCC 17978 and AB242) by multistep selection resistance. Amikacin-, ciprofloxacin-, colistin-, meropenem- and ceftazidime-selected mutants were also generated from the two reference strains and were used for comparison. Antibiotic susceptibilities in the absence and presence of the efflux pump inhibitors carbonyl cyanide m-chlorophenylhydrazone (CCCP) and 1-(1-naphthylmethyl)-piperazine (NMP) were examined in the three imipenem-selected mutants and the three clinical multidrug-resistant (MDR) isolates. Expression profiles of the antimicrobial resistance genes in the imipenem-selected mutants and their parental strains were also determined. The results showed that imipenem was more likely, compared with the other antibiotics, to induce a MDR phenotype in the two reference strains. Differences in OXA-51-like carbapenemase, efflux pumps or/and AmpC β-lactamase expression were observed in the three imipenem-selected mutants. Moreover, a reduction in imipenem or amikacin resistance was observed when the imipenem-selected mutants and clinical isolates were exposed to NMP and CCCP. This study concluded that imipenem might be a potent inducer of multidrug resistance in A. baumannii strains. OXA-51-like carbapenemase combined with other resistance mechanisms may contribute to the development of multidrug resistance in A. baumannii. Monitoring the use of carbapenems is required to reduce the spread of MDR A. baumannii in hospitals.

  3. 5% CO2 is a potent, fast acting inhalation anticonvulsant

    PubMed Central

    Tolner, Else A.; Hochman, Daryl W.; Hassinen, Pekka; Otáhal, Jakub; Gaily, Eija; Haglund, Michael M.; Kubová, Hana; Schuchmann, Sebastian; Vanhatalo, Sampsa; Kaila, Kai

    2010-01-01

    Purpose CO2 has been long recognized for its anticonvulsant properties. We aimed to determine whether inhaling 5% CO2 can be used to suppress seizures in epilepsy patients. The effect of CO2 on cortical epileptic activity accompanying behavioral seizures was studied in rats and a non-human primate and based on these data, preliminary tests were carried out in humans. Methods In freely moving rats, cortical afterdischarges paralleled by myoclonic convulsions were evoked by sensorimotor cortex stimulation. 5% CO2 was applied for 5 minutes, 3 minutes before stimulation. In macaque monkeys, hypercarbia was induced by hypoventilation while seizure activity was electrically or chemically evoked in the sensorimotor cortex. Seven patients with drug-resistant partial epilepsy were examined with video-EEG and received 5% CO2 in medical carbogen shortly after electrographic seizure onset. Results In rats, 5% CO2 strongly suppressed cortical afterdischarges, by ca. 75%, while responses to single-pulse stimulation were reduced by about 15% only. In macaques, increasing pCO2 from 37 to 44-45 mmHg (corresponding to inhalation of 5% CO2 or less) suppressed stimulation-induced cortical afterdischarges by about 70% and single, bicuculline-induced epileptiform spikes by ca. 25%. In a pilot trial carried out in 7 patients, a rapid termination of electrographic seizures was seen despite the fact that the application of 5% CO2 was started after seizure generalization. Conclusions 5% CO2 has a fast and potent anticonvulsant action. The present data suggest that medical carbogen with 5% CO2 can be used for acute treatment to suppress seizures in epilepsy patients. PMID:20887367

  4. A search for anisotropy in the arrival directions of ultra high energy cosmic rays recorded at the Pierre Auger Observatory

    SciTech Connect

    Abreu, P.

    2012-01-01

    Observations of cosmic ray arrival directions made with the Pierre Auger Observatory have previously provided evidence of anisotropy at the 99% CL using the correlation of ultra high energy cosmic rays (UHECRs) with objects drawn from the Veron-Cetty Veron catalog. In this paper we report on the use of three catalog independent methods to search for anisotropy. The 2pt-L, 2pt+ and 3pt methods, each giving a different measure of self-clustering in arrival directions, were tested on mock cosmic ray data sets to study the impacts of sample size and magnetic smearing on their results, accounting for both angular and energy resolutions. If the sources of UHECRs follow the same large scale structure as ordinary galaxies in the local Universe and if UHECRs are deflected no more than a few degrees, a study of mock maps suggests that these three methods can efficiently respond to the resulting anisotropy with a P-value = 1.0% or smaller with data sets as few as 100 events. Using data taken from January 1, 2004 to July 31, 2010 we examined the 20, 30, ..., 110 highest energy events with a corresponding minimum energy threshold of about 51 EeV. The minimum P-values found were 13.5% using the 2pt-L method, 1.0% using the 2pt+ method and 1.1% using the 3pt method for the highest 100 energy events. In view of the multiple (correlated) scans performed on the data set, these catalog-independent methods do not yield strong evidence of anisotropy in the highest energy cosmic rays.

  5. A search for anisotropy in the arrival directions of ultra high energy cosmic rays recorded at the Pierre Auger Observatory

    NASA Astrophysics Data System (ADS)

    Pierre Auger Collaboration; Abreu, P.; Aglietta, M.; Ahlers, M.; Ahn, E. J.; Albuquerque, I. F. M.; Allard, D.; Allekotte, I.; Allen, J.; Allison, P.; Almela, A.; Alvarez Castillo, J.; Alvarez-Muñiz, J.; Ambrosio, M.; Aminaei, A.; Anchordoqui, L.; Andringa, S.; Antici'c, T.; Aramo, C.; Arganda, E.; Arqueros, F.; Asorey, H.; Assis, P.; Aublin, J.; Ave, M.; Avenier, M.; Avila, G.; Bäcker, T.; Badescu, A. M.; Balzer, M.; Barber, K. B.; Barbosa, A. F.; Bardenet, R.; Barroso, S. L. C.; Baughman, B.; Bäuml, J.; Beatty, J. J.; Becker, B. R.; Becker, K. H.; Bellétoile, A.; Bellido, J. A.; BenZvi, S.; Berat, C.; Bertou, X.; Biermann, P. L.; Billoir, P.; Blanco, F.; Blanco, M.; Bleve, C.; Blümer, H.; Bohácová, M.; Boncioli, D.; Bonifazi, C.; Bonino, R.; Borodai, N.; Brack, J.; Brancus, I.; Brogueira, P.; Brown, W. C.; Bruijn, R.; Buchholz, P.; Bueno, A.; Burton, R. E.; Caballero-Mora, K. S.; Caccianiga, B.; Caramete, L.; Caruso, R.; Castellina, A.; Catalano, O.; Cataldi, G.; Cazon, L.; Cester, R.; Chauvin, J.; Cheng, S. H.; Chiavassa, A.; Chinellato, J. A.; Chirinos Diaz, J.; Chudoba, J.; Cilmo, M.; Clay, R. W.; Coluccia, M. R.; Conceição, R.; Contreras, F.; Cook, H.; Cooper, M. J.; Coppens, J.; Cordier, A.; Coutu, S.; Covault, C. E.; Creusot, A.; Criss, A.; Cronin, J.; Curutiu, A.; Dagoret-Campagne, S.; Dallier, R.; Dasso, S.; Daumiller, K.; Dawson, B. R.; de Almeida, R. M.; De Domenico, M.; De Donato, C.; de Jong, S. J.; De La Vega, G.; de Mello Junior, W. J. M.; de Mello Neto, J. R. T.; De Mitri, I.; de Souza, V.; de Vries, K. D.; del Peral, L.; del Río, M.; Deligny, O.; Dembinski, H.; Dhital, N.; Di Giulio, C.; Díaz Castro, M. L.; Diep, P. N.; Diogo, F.; Dobrigkeit, C.; Docters, W.; D'Olivo, J. C.; Dong, P. N.; Dorofeev, A.; dos Anjos, J. C.; Dova, M. T.; D'Urso, D.; Dutan, I.; Ebr, J.; Engel, R.; Erdmann, M.; Escobar, C. O.; Espadanal, J.; Etchegoyen, A.; Facal San Luis, P.; Fajardo Tapia, I.; Falcke, H.; Farrar, G.; Fauth, A. C.; Fazzini, N.; Ferguson, A. P.; Fick, B.; Filevich, A.; Filipcic, A.; Fliescher, S.; Fracchiolla, C. E.; Fraenkel, E. D.; Fratu, O.; Fröhlich, U.; Fuchs, B.; Gaior, R.; Gamarra, R. F.; Gambetta, S.; García, B.; Garcia Roca, S. T.; Garcia-Gamez, D.; Garcia-Pinto, D.; Gascon, A.; Gemmeke, H.; Ghia, P. L.; Giaccari, U.; Giller, M.; Glass, H.; Gold, M. S.; Golup, G.; Gomez Albarracin, F.; Gómez Berisso, M.; Gómez Vitale, P. F.; Gonçalves, P.; Gonzalez, D.; Gonzalez, J. G.; Gookin, B.; Gorgi, A.; Gouffon, P.; Grashorn, E.; Grebe, S.; Griffith, N.; Grigat, M.; Grillo, A. F.; Guardincerri, Y.; Guarino, F.; Guedes, G. P.; Guzman, A.; Hague, J. D.; Hansen, P.; Harari, D.; Harmsma, S.; Harrison, T. A.; Harton, J. L.; Haungs, A.; Hebbeker, T.; Heck, D.; Herve, A. E.; Hojvat, C.; Hollon, N.; Holmes, V. C.; Homola, P.; Hörandel, J. R.; Horneffer, A.; Horvath, P.; Hrabovský, M.; Huege, T.; Insolia, A.; Ionita, F.; Italiano, A.; Jarne, C.; Jiraskova, S.; Josebachuili, M.; Kadija, K.; Kampert, K. H.; Karhan, P.; Kasper, P.; Kégl, B.; Keilhauer, B.; Keivani, A.; Kelley, J. L.; Kemp, E.; Kieckhafer, R. M.; Klages, H. O.; Kleifges, M.; Kleinfeller, J.; Knapp, J.; Koang, D.-H.; Kotera, K.; Krohm, N.; Krömer, O.; Kruppke-Hansen, D.; Kuehn, F.; Kuempel, D.; Kulbartz, J. K.; Kunka, N.; La Rosa, G.; Lachaud, C.; Lauer, R.; Lautridou, P.; Le Coz, S.; Leão, M. S. A. B.; Lebrun, D.; Lebrun, P.; Leigui de Oliveira, M. A.; Letessier-Selvon, A.; Lhenry-Yvon, I.; Link, K.; López, R.; Lopez Agüera, A.; Louedec, K.; Lozano Bahilo, J.; Lu, L.; Lucero, A.; Ludwig, M.; Lyberis, H.; Macolino, C.; Maldera, S.; Mandat, D.; Mantsch, P.; Mariazzi, A. G.; Marin, J.; Marin, V.; Maris, I. C.; Marquez Falcon, H. R.; Marsella, G.; Martello, D.; Martin, L.; Martinez, H.; Martínez Bravo, O.; Mathes, H. J.; Matthews, J.; Matthews, J. A. J.; Matthiae, G.; Maurel, D.; Maurizio, D.; Mazur, P. O.; Medina-Tanco, G.; Melissas, M.; Melo, D.; Menichetti, E.; Menshikov, A.; Mertsch, P.; Meurer, C.; Mi'canovi'c, S.; Micheletti, M. I.; Minaya, I. A.; Miramonti, L.; Molina-Bueno, L.; Mollerach, S.; Monasor, M.; Monnier Ragaigne, D.; Montanet, F.; Morales, B.; Morello, C.; Moreno, E.; Moreno, J. C.; Mostafá, M.; Moura, C. A.; Muller, M. A.; Müller, G.; Münchmeyer, M.; Mussa, R.; Navarra, G.; Navarro, J. L.; Navas, S.; Necesal, P.; Nellen, L.; Nelles, A.; Neuser, J.; Nhung, P. T.; Niechciol, M.; Niemietz, L.; Nierstenhoefer, N.; Nitz, D.; Nosek, D.; Nožka, L.; Nyklicek, M.; Oehlschläger, J.; Olinto, A.; Ortiz, M.; Pacheco, N.; Pakk Selmi-Dei, D.; Palatka, M.; Pallotta, J.; Palmieri, N.; Parente, G.; Parizot, E.; Parra, A.; Pastor, S.; Paul, T.; Pech, M.; Pekala, J.; Pelayo, R.; Pepe, I. M.; Perrone, L.; Pesce, R.; Petermann, E.; Petrera, S.; Petrinca, P.; Petrolini, A.; Petrov, Y.; Petrovic, J.; Pfendner, C.; Piegaia, R.; Pierog, T.; Pieroni, P.; Pimenta, M.; Pirronello, V.; Platino, M.; Ponce, V. H.; Pontz, M.; Porcelli, A.; Privitera, P.; Prouza, M.; Quel, E. J.; Querchfeld, S.; Rautenberg, J.; Ravel, O.; Ravignani, D.; Revenu, B.; Ridky, J.; Riggi, S.; Risse, M.; Ristori, P.; Rivera, H.; Rizi, V.; Roberts, J.; Rodrigues de Carvalho, W.; Rodriguez, G.; Rodriguez Martino, J.; Rodriguez Rojo, J.; Rodriguez-Cabo, I.; Rodríguez-Frías, M. D.; Ros, G.; Rosado, J.; Rossler, T.; Roth, M.; Rouillé-d'Orfeuil, B.; Roulet, E.; Rovero, A. C.; Rühle, C.; Saftoiu, A.; Salamida, F.; Salazar, H.; Salesa Greus, F.; Salina, G.; Sánchez, F.; Santo, C. E.; Santos, E.; Santos, E. M.; Sarazin, F.; Sarkar, B.; Sarkar, S.; Sato, R.; Scharf, N.; Scherini, V.; Schieler, H.; Schiffer, P.; Schmidt, A.; Scholten, O.; Schoorlemmer, H.; Schovancova, J.; Schovánek, P.; Schröder, F.; Schulte, S.; Schuster, D.; Sciutto, S. J.; Scuderi, M.; Segreto, A.; Settimo, M.; Shadkam, A.; Shellard, R. C.; Sidelnik, I.; Sigl, G.; Silva Lopez, H. H.; Sima, O.; 'Smiałkowski, A.; Šmída, R.; Snow, G. R.; Sommers, P.; Sorokin, J.; Spinka, H.; Squartini, R.; Srivastava, Y. N.; Stanic, S.; Stapleton, J.; Stasielak, J.; Stephan, M.; Stutz, A.; Suarez, F.; Suomijärvi, T.; Supanitsky, A. D.; Šuša, T.; Sutherland, M. S.; Swain, J.; Szadkowski, Z.; Szuba, M.; Tapia, A.; Tartare, M.; Taşcău, O.; Tavera Ruiz, C. G.; Tcaciuc, R.; Tegolo, D.; Thao, N. T.; Thomas, D.; Tiffenberg, J.; Timmermans, C.; Tkaczyk, W.; Todero Peixoto, C. J.; Toma, G.; Tomé, B.; Tonachini, A.; Travnicek, P.; Tridapalli, D. B.; Tristram, G.; Trovato, E.; Tueros, M.; Ulrich, R.; Unger, M.; Urban, M.; Valdés Galicia, J. F.; Valiño, I.; Valore, L.; van den Berg, A. M.; Varela, E.; Vargas Cárdenas, B.; Vázquez, J. R.; Vázquez, R. A.; Veberic, D.; Verzi, V.; Vicha, J.; Videla, M.; Villaseñor, L.; Wahlberg, H.; Wahrlich, P.; Wainberg, O.; Walz, D.; Watson, A. A.; Weber, M.; Weidenhaupt, K.; Weindl, A.; Werner, F.; Westerhoff, S.; Whelan, B. J.; Widom, A.; Wieczorek, G.; Wiencke, L.; Wilczyńska, B.; Wilczyński, H.; Will, M.; Williams, C.; Winchen, T.; Wommer, M.; Wundheiler, B.; Yamamoto, T.; Yapici, T.; Younk, P.; Yuan, G.; Yushkov, A.; Zamorano, B.; Zas, E.; Zavrtanik, D.; Zavrtanik, M.; Zaw, I.; Zepeda, A.; Zhu, Y.; Zimbres Silva, M.; Ziolkowski, M.

    2012-04-01

    Observations of cosmic ray arrival directions made with the Pierre Auger Observatory have previously provided evidence of anisotropy at the 99% CL using the correlation of ultra high energy cosmic rays (UHECRs) with objects drawn from the Véron-Cetty Véron catalog. In this paper we report on the use of three catalog independent methods to search for anisotropy. The 2pt-L, 2pt+ and 3pt methods, each giving a different measure of self-clustering in arrival directions, were tested on mock cosmic ray data sets to study the impacts of sample size and magnetic smearing on their results, accounting for both angular and energy resolutions. If the sources of UHECRs follow the same large scale structure as ordinary galaxies in the local Universe and if UHECRs are deflected no more than a few degrees, a study of mock maps suggests that these three methods can efficiently respond to the resulting anisotropy with a P-value = 1.0% or smaller with data sets as few as 100 events. Using data taken from January 1, 2004 to July 31, 2010 we examined the 20,30,...,110 highest energy events with a corresponding minimum energy threshold of about 49.3 EeV. The minimum P-values found were 13.5% using the 2pt-L method, 1.0% using the 2pt+ method and 1.1% using the 3pt method for the highest 100 energy events. In view of the multiple (correlated) scans performed on the data set, these catalog-independent methods do not yield strong evidence of anisotropy in the highest energy cosmic rays.

  6. A review on cylindrospermopsin: The global occurrence, detection, toxicity and degradation of a potent cyanotoxin

    EPA Science Inventory

    Abstract: Cylindrospermopsin is now recognized as a potent cyanobacterial toxin found in water bodies worldwide. The ever-increasing and global occurrence of massive and prolonged blooms of cylindrospermopsin-producing cyanobacteria in freshwater poses a potential threat to both ...

  7. Hydroxychavicol: a potent xanthine oxidase inhibitor obtained from the leaves of betel, Piper betle.

    PubMed

    Murata, Kazuya; Nakao, Kikuyo; Hirata, Noriko; Namba, Kensuke; Nomi, Takao; Kitamura, Yoshihisa; Moriyama, Kenzo; Shintani, Takahiro; Iinuma, Munekazu; Matsuda, Hideaki

    2009-07-01

    The screening of Piperaceous plants for xanthine oxidase inhibitory activity revealed that the extract of the leaves of Piper betle possesses potent activity. Activity-guided purification led us to obtain hydroxychavicol as an active principle. Hydroxychavicol is a more potent xanthine oxidase inhibitor than allopurinol, which is clinically used for the treatment of hyperuricemia.

  8. Atomic Auger Doppler effects upon emission of fast photoelectrons.

    PubMed

    Simon, Marc; Püttner, Ralph; Marchenko, Tatiana; Guillemin, Renaud; Kushawaha, Rajesh K; Journel, Loïc; Goldsztejn, Gildas; Piancastelli, Maria Novella; Ablett, James M; Rueff, Jean-Pascal; Céolin, Denis

    2014-06-06

    Studies of photoemission processes induced by hard X-rays including production of energetic electrons have become feasible due to recent substantial improvement of instrumentation. Novel dynamical phenomena have become possible to investigate in this new regime. Here we show a significant change in Auger emission following 1s photoionization of neon, which we attribute to the recoil of the Ne ion induced by the emission of a fast photoelectron. Because of the preferential motion of the ionized Ne atoms along two opposite directions, an Auger Doppler shift is revealed, which manifests itself as a gradual broadening and doubling of the Auger spectral features. This Auger Doppler effect should be a general phenomenon in high-energy photoemission of both isolated atoms and molecules, which will have to be taken into account in studies of other recoil effects such as vibrational or rotational recoil in molecules, and may also have consequences in measurements in solids.

  9. Auger decay of 3p-ionized krypton

    SciTech Connect

    Jonauskas, V.; Kucas, S.; Karazija, R.

    2011-11-15

    A theoretical study of Auger cascades during the decay of 3p{sub 1/2} and 3p{sub 3/2} vacancies in krypton has been performed by level-by-level calculations using a wide configuration interaction basis. Auger spectra for all steps of the cascades are presented and are compared with the existing experimental data. Good agreement of our results with the branching ratios of ions measured by a coincidence technique is obtained.

  10. The Surface Detector System of the Pierre Auger Observatory

    SciTech Connect

    Allekotte, I.; Barbosa, A.F.; Bauleo, P.; Bonifazi, C.; Civit, B.; Escobar, C.O.; Garcia, B.; Guedes, G.; Gomez Berisso, M.; Harton, J.L.; Healy, M.; /Cuyo U. /Buenos Aires, CONICET /Natl. Tech. U., San Rafael /Campinas State U. /UEFS, Feira de Santana /Bahia U. /BUAP, Puebla /Santiago de Compostela U. /Fermilab /UCLA /Colorado State U.

    2007-11-01

    The Pierre Auger Observatory is designed to study cosmic rays with energies greater than 10{sup 19} eV. Two sites are envisaged for the observatory, one in each hemisphere, for complete sky coverage. The southern site of the Auger Observatory, now approaching completion in Mendoza, Argentina, features an array of 1600 water-Cherenkov surface detector stations covering 3000 km{sup 2}, together with 24 fluorescence telescopes to record the air shower cascades produced by these particles. The two complementary detector techniques together with the large collecting area form a powerful instrument for these studies. Although construction is not yet complete, the Auger Observatory has been taking data stably since January 2004 and the first physics results are being published. In this paper we describe the design features and technical characteristics of the surface detector stations of the Pierre Auger Observatory.

  11. A perfect wetting of Mg monolayer on Ag(111) under atomic scale investigation: First principles calculations, scanning tunneling microscopy, and Auger spectroscopy.

    PubMed

    Migaou, Amani; Sarpi, Brice; Guiltat, Mathilde; Payen, Kevin; Daineche, Rachid; Landa, Georges; Vizzini, Sébastien; Hémeryck, Anne

    2016-05-21

    First principles calculations, scanning tunneling microscopy, and Auger spectroscopy experiments of the adsorption of Mg on Ag(111) substrate are conducted. This detailed study reveals that an atomic scale controlled deposition of a metallic Mg monolayer perfectly wets the silver substrate without any alloy formation at the interface at room temperature. A liquid-like behavior of the Mg species on the Ag substrate is highlighted as no dot formation is observed when coverage increases. Finally a layer-by-layer growth mode of Mg on Ag(111) can be predicted, thanks to density functional theory calculations as observed experimentally.

  12. In Vitro Assessment of a Peptide Nucleic Acid (PNA) - Peptide Conjugate Labeled With an Auger-Emitting Radionuclide for Prostate Cell Killing

    DTIC Science & Technology

    2005-02-01

    synthesis of a peptide nucleic acid (PNA) that has an Auger-emitter (1-125) incorporated. By design the PNA will bind with mRNA and DNA associated with...bind with cell surface gastrin -releasing peptide receptors and be internalized (3). Binding with mRNA and nuclear DNA specific to the insulin-like...route proposed to prepare 10 is shown in Figure 1 (compounds 1-10). This synthesis began with the preparation of the base-reactive intermediate 5

  13. Auger spectroscopy of Magnox pressure vessel steels

    SciTech Connect

    Fisher, S.; Knowles, G.; Lee, B.

    1999-10-01

    Magnox Electric maintains a significant microstructural program in support of its safety case for operation of its stations with steel pressure vessels. An important part of this program is the characterization of grain boundary chemistry using Auger spectroscopy. Mechanical testing and subsequent examination of surveillance material has shown that some Charpy specimens display a proportion of intergranular fracture and Auger work has linked this to the presence of phosphorus on the grain boundaries. A feature of particular interest in the study of the boundaries is the co-segregation of carbon. The measurement of the true levels of phosphorus and carbon segregation is complicated by the presence of carbon contamination. This paper describes the simple approach used to overcome this problem.

  14. Directional Auger Electron Spectroscopy — Physical Foundations and Applications

    NASA Astrophysics Data System (ADS)

    Mróz, S.

    Experimental data about the dependence of the Auger signal from crystalline samples on the primary beam direction are presented and discussed. It is shown that, for Auger electrons and elastically and inelastically backscattered electrons, maxima of the signal in its dependence on the polar and azimuth angles of the primary beam (in polar and azimuth profiles, respectively) appear when the primary beam is parallel either to one of the close-packed rows of atoms or to one of the densely packed atomic planes in the sample. This indicates that the diffraction of the primary electron beam is responsible for the dependence mentioned above. Mechanisms proposed for simple explanation of this dependence (channeling and forward focusing of primary electrons) are presented and results of their application are discussed. It is shown that both those mechanisms play an important role in the creation of the Auger signal contrast. The possibilities and limitations of the application of polar and azimuth Auger emission profiles in the determination of the surface layer crystalline structure (directional Auger electron spectroscopy — DAES) are presented and discussed. It is shown that the thickness of the investigated surface layer can be decreased up to a few monolayers. Results obtained with DAES are similar to those provided by X-ray photoelectron diffraction (XPD) and Auger electron diffraction (AED), but the DAES experimental equipment is simple and inexpensive and measurements are fast. Finally, experimental systems for DAES are described and examples of DAES applications are presented.

  15. Recent results from the Pierre Auger Observatory

    SciTech Connect

    Gascón, Alberto; Collaboration: Pierre Auger Collaboration

    2014-07-23

    The Pierre Auger Observatory has been designed to investigate the origin and nature of Ultra High Energy Cosmic Rays (UHECR) using a hybrid detection technique. In this contribution we present some of the most recent results of the observatory, namely the upper-end of the spectrum of cosmic rays, state-of-the-art analyses on mass composition, the measurements of the proton-air cross-section, and the number of muons at ground.

  16. First results from the spectral DCT trigger implemented in the Cyclone V Front-End Board used for a detection of very inclined showers in the Pierre Auger surface detector Engineering Array

    SciTech Connect

    Szadkowski, Zbigniew

    2015-07-01

    The paper presents the first results from the trigger based on the Discrete Cosine Transform (DCT) operating in the new Front-End Boards with Cyclone V FPGA deployed in 8 test surface detectors in the Pierre Auger Engineering Array. The patterns of the ADC traces generated by very inclined showers were obtained from the Auger database and from the CORSIKA simulation package supported next by Offline reconstruction Auger platform which gives a predicted digitized signal profiles. Simulations for many variants of the initial angle of shower, initialization depth in the atmosphere, type of particle and its initial energy gave a boundary of the DCT coefficients used next for the on-line pattern recognition in the FPGA. Preliminary results have proven a right approach. We registered several showers triggered by the DCT for 120 MSps and 160 MSps. (authors)

  17. A computer controlled chemical bevel etching apparatus: applications to Auger analysis of multi-layered structures

    NASA Astrophysics Data System (ADS)

    El-Gomati, M.; Gelsthorpe, A.; Srnanek, R.; Liday, J.; Vogrincic, P.; Kovac, J.

    1999-04-01

    Analysis of thin layer structures can be achieved by chemically etching a bevel and subsequently analysing the surface. However non-linear bevels often result due to differing etch rates of the materials leading to incorrect analysis results. We report on a computer controlled stepper motor reactor whereby the specimen is lowered into the etchant at a rate which compensates for the different etch rates of the various layers constituting the sample. The apparatus is used to produce linear bevels of various magnifications on GaAs/AlGaAs heterostructures. The etchant of H 3PO 4/H 2O 2/H 2O is used for bevel preparation capped by a water layer to suppress the meniscus. Application of the technique to Multi Quantum Wells (MQW) and Bragg diffraction layers is shown. The depth resolution of the bevelled samples are analysed by AES and a comparison is made to conventional ion sputtering techniques.

  18. Epidermal Growth Factor Receptor Overexpression as a Target for Auger Electron Radiotherapy of Breast Cancer

    DTIC Science & Technology

    1999-08-01

    proportion of estrogen receptor-negative and hormone-resistant breast cancers. Our objective is to construct a human epidermal growth factor (hEGF...61 5 INTRODUCTION Overexpression of the epidermal growth factor receptor (EGFR) occurs in a high proportion of estrogen receptor-negative and...Lac Iq promotor induced by isopropyl-b- D -thiogalactopyranoside (IPTG). The DNA sequence of the final hEGF-CH1 construct was confirmed (FUi. 2). BamHJ

  19. Distributed Computing for the Pierre Auger Observatory

    NASA Astrophysics Data System (ADS)

    Chudoba, J.

    2015-12-01

    Pierre Auger Observatory operates the largest system of detectors for ultra-high energy cosmic ray measurements. Comparison of theoretical models of interactions with recorded data requires thousands of computing cores for Monte Carlo simulations. Since 2007 distributed resources connected via EGI grid are successfully used. The first and the second versions of production system based on bash scripts and MySQL database were able to submit jobs to all reliable sites supporting Virtual Organization auger. For many years VO auger belongs to top ten of EGI users based on the total used computing time. Migration of the production system to DIRAC interware started in 2014. Pilot jobs improve efficiency of computing jobs and eliminate problems with small and less reliable sites used for the bulk production. The new system has also possibility to use available resources in clouds. Dirac File Catalog replaced LFC for new files, which are organized in datasets defined via metadata. CVMFS is used for software distribution since 2014. In the presentation we give a comparison of the old and the new production system and report the experience on migrating to the new system.

  20. An expedient route to a potent gastrin/CCK-B receptor antagonist (+)-AG-041R.

    PubMed

    Sato, Shigeki; Shibuya, Masatoshi; Kanoh, Naoki; Iwabuchi, Yoshiharu

    2009-10-02

    An enantiocontrolled synthesis of (+)-AG-041R (1), a potent gastrin/CCK-B receptor antagonist, has been achieved employing a chiral rhodium(II)-catalyzed, oxidative intramolecular aza-spiroannulation as the key step.

  1. Adhesion of metals to a clean iron surface studied with LEED and Auger emission spectroscopy.

    NASA Technical Reports Server (NTRS)

    Buckley, D. H.

    1972-01-01

    Discussion of the results of adhesion experiments conducted with various metals contacting a clean iron surface. The metals included gold, silver, nickel, platinum, lead, tantalum, aluminum, and cobalt. Some of the metals were examined with oxygen present on their surface as well as in the clean state. The results indicate that, with the various metals contacting iron, the cohesively weaker will adhere and transfer to the cohesively stronger. The chemical activity of the metal also influenced the adhesive forces measured. With oxygen present on the metal surface, the adhesive forces measured could be correlated with the binding energy of the metal to oxygen.

  2. A study of the effect of molecular and aerosol conditions in the atmosphere on air fluorescence measurements at the Pierre Auger Observatory

    NASA Astrophysics Data System (ADS)

    Abraham, J.; Abreu, P.; Aglietta, M.; Aguirre, C.; Ahn, E. J.; Allard, D.; Allekotte, I.; Allen, J.; Alvarez-Muñiz, J.; Ambrosio, M.; Anchordoqui, L.; Andringa, S.; Anzalone, A.; Aramo, C.; Arganda, E.; Arisaka, K.; Arqueros, F.; Asch, T.; Asorey, H.; Assis, P.; Aublin, J.; Ave, M.; Avila, G.; Bäcker, T.; Badagnani, D.; Barber, K. B.; Barbosa, A. F.; Barroso, S. L. C.; Baughman, B.; Bauleo, P.; Beatty, J. J.; Beau, T.; Becker, B. R.; Becker, K. H.; Bellétoile, A.; Bellido, J. A.; BenZvi, S.; Berat, C.; Bertou, X.; Biermann, P. L.; Billoir, P.; Blanch-Bigas, O.; Blanco, F.; Bleve, C.; Blümer, H.; Boháčová, M.; Boncioli, D.; Bonifazi, C.; Bonino, R.; Borodai, N.; Brack, J.; Brogueira, P.; Brown, W. C.; Bruijn, R.; Buchholz, P.; Bueno, A.; Burton, R. E.; Busca, N. G.; Caballero-Mora, K. S.; Caramete, L.; Caruso, R.; Castellina, A.; Catalano, O.; Cazon, L.; Cester, R.; Chauvin, J.; Chiavassa, A.; Chinellato, J. A.; Chou, A.; Chudoba, J.; Chye, J.; Clay, R. W.; Colombo, E.; Conceição, R.; Contreras, F.; Cook, H.; Coppens, J.; Cordier, A.; Cotti, U.; Coutu, S.; Covault, C. E.; Creusot, A.; Criss, A.; Cronin, J.; Curutiu, A.; Dagoret-Campagne, S.; Dallier, R.; Daumiller, K.; Dawson, B. R.; de Almeida, R. M.; De Domenico, M.; De Donato, C.; de Jong, S. J.; De La Vega, G.; de Mello Junior, W. J. M.; de Mello Neto, J. R. T.; De Mitri, I.; de Souza, V.; de Vries, K. D.; Decerprit, G.; del Peral, L.; Deligny, O.; Della Selva, A.; Delle Fratte, C.; Dembinski, H.; Di Giulio, C.; Diaz, J. C.; Diep, P. N.; Dobrigkeit, C.; D'Olivo, J. C.; Dong, P. N.; Dorofeev, A.; dos Anjos, J. C.; Dova, M. T.; D'Urso, D.; Dutan, I.; DuVernois, M. A.; Ebr, J.; Engel, R.; Erdmann, M.; Escobar, C. O.; Etchegoyen, A.; Facal San Luis, P.; Falcke, H.; Farrar, G.; Fauth, A. C.; Fazzini, N.; Ferrer, F.; Ferrero, A.; Fick, B.; Filevich, A.; Filipčič, A.; Fleck, I.; Fliescher, S.; Fracchiolla, C. E.; Fraenkel, E. D.; Fulgione, W.; Gamarra, R. F.; Gambetta, S.; García, B.; García Gámez, D.; Garcia-Pinto, D.; Garrido, X.; Gelmini, G.; Gemmeke, H.; Ghia, P. L.; Giaccari, U.; Giller, M.; Glass, H.; Goggin, L. M.; Gold, M. S.; Golup, G.; Gomez Albarracin, F.; Gómez Berisso, M.; Gonçalves, P.; Gonzalez, D.; Gonzalez, J. G.; Góra, D.; Gorgi, A.; Gouffon, P.; Gozzini, S. R.; Grashorn, E.; Grebe, S.; Grigat, M.; Grillo, A. F.; Guardincerri, Y.; Guarino, F.; Guedes, G. P.; Gutiérrez, J.; Hague, J. D.; Halenka, V.; Hansen, P.; Harari, D.; Harmsma, S.; Harton, J. L.; Haungs, A.; Healy, M. D.; Hebbeker, T.; Hebrero, G.; Heck, D.; Hojvat, C.; Holmes, V. C.; Homola, P.; Hörandel, J. R.; Horneffer, A.; Hrabovský, M.; Huege, T.; Hussain, M.; Iarlori, M.; Insolia, A.; Ionita, F.; Italiano, A.; Jiraskova, S.; Kaducak, M.; Kampert, K. H.; Karova, T.; Kasper, P.; Kégl, B.; Keilhauer, B.; Kelley, J.; Kemp, E.; Kieckhafer, R. M.; Klages, H. O.; Kleifges, M.; Kleinfeller, J.; Knapik, R.; Knapp, J.; Koang, D.-H.; Krieger, A.; Krömer, O.; Kruppke-Hansen, D.; Kuehn, F.; Kuempel, D.; Kulbartz, K.; Kunka, N.; Kusenko, A.; La Rosa, G.; Lachaud, C.; Lago, B. L.; Lautridou, P.; Leão, M. S. A. B.; Lebrun, D.; Lebrun, P.; Lee, J.; Leigui de Oliveira, M. A.; Lemiere, A.; Letessier-Selvon, A.; Lhenry-Yvon, I.; López, R.; Lopez Agüera, A.; Louedec, K.; Lozano Bahilo, J.; Lucero, A.; Ludwig, M.; Lyberis, H.; Maccarone, M. C.; Macolino, C.; Maldera, S.; Mandat, D.; Mantsch, P.; Mariazzi, A. G.; Maris, I. C.; Marquez Falcon, H. R.; Marsella, G.; Martello, D.; Martínez Bravo, O.; Mathes, H. J.; Matthews, J.; Matthews, J. A. J.; Matthiae, G.; Maurizio, D.; Mazur, P. O.; McEwen, M.; McNeil, R. R.; Medina-Tanco, G.; Melissas, M.; Melo, D.; Menichetti, E.; Menshikov, A.; Meurer, C.; Micheletti, M. I.; Miller, W.; Miramonti, L.; Mollerach, S.; Monasor, M.; Monnier Ragaigne, D.; Montanet, F.; Morales, B.; Morello, C.; Moreno, J. C.; Morris, C.; Mostafá, M.; Moura, C. A.; Mueller, S.; Muller, M. A.; Mussa, R.; Navarra, G.; Navarro, J. L.; Navas, S.; Necesal, P.; Nellen, L.; Newman-Holmes, C.; Nhung, P. T.; Nierstenhoefer, N.; Nitz, D.; Nosek, D.; Nožka, L.; Nyklicek, M.; Oehlschläger, J.; Olinto, A.; Oliva, P.; Olmos-Gilbaja, V. M.; Ortiz, M.; Pacheco, N.; Pakk Selmi-Dei, D.; Palatka, M.; Pallotta, J.; Palmieri, N.; Parente, G.; Parizot, E.; Parlati, S.; Parsons, R. D.; Pastor, S.; Paul, T.; Pavlidou, V.; Payet, K.; Pech, M.; Peķala, J.; Pepe, I. M.; Perrone, L.; Pesce, R.; Petermann, E.; Petrera, S.; Petrinca, P.; Petrolini, A.; Petrov, Y.; Petrovic, J.; Pfendner, C.; Piegaia, R.; Pierog, T.; Pimenta, M.; Pirronello, V.; Platino, M.; Ponce, V. H.; Pontz, M.; Privitera, P.; Prouza, M.; Quel, E. J.; Rautenberg, J.; Ravel, O.; Ravignani, D.; Redondo, A.; Revenu, B.; Rezende, F. A. S.; Ridky, J.; Riggi, S.; Risse, M.; Rivière, C.; Rizi, V.; Robledo, C.; Rodriguez, G.; Rodriguez Martino, J.; Rodriguez Rojo, J.; Rodriguez-Cabo, I.; Rodríguez-Frías, M. D.; Ros, G.; Rosado, J.; Rossler, T.; Roth, M.; Rouillé-d'Orfeuil, B.; Roulet, E.; Rovero, A. C.; Salamida, F.; Salazar, H.; Salina, G.; Sánchez, F.; Santander, M.; Santo, C. E.; Santos, E.; Santos, E. M.; Sarazin, F.; Sarkar, S.; Sato, R.; Scharf, N.; Scherini, V.; Schieler, H.; Schiffer, P.; Schmidt, A.; Schmidt, F.; Schmidt, T.; Scholten, O.; Schoorlemmer, H.; Schovancova, J.; Schovánek, P.; Schroeder, F.; Schulte, S.; Schüssler, F.; Schuster, D.; Sciutto, S. J.; Scuderi, M.; Segreto, A.; Semikoz, D.; Settimo, M.; Shellard, R. C.; Sidelnik, I.; Siffert, B. B.; Sigl, G.; Śmiałkowski, A.; Šmída, R.; Snow, G. R.; Sommers, P.; Sorokin, J.; Spinka, H.; Squartini, R.; Strazzeri, E.; Stutz, A.; Suarez, F.; Suomijärvi, T.; Supanitsky, A. D.; Sutherland, M. S.; Swain, J.; Szadkowski, Z.; Tamashiro, A.; Tamburro, A.; Tarutina, T.; Taşcău, O.; Tcaciuc, R.; Tcherniakhovski, D.; Tegolo, D.; Thao, N. T.; Thomas, D.; Ticona, R.; Tiffenberg, J.; Timmermans, C.; Tkaczyk, W.; Todero Peixoto, C. J.; Tomé, B.; Tonachini, A.; Torres, I.; Travnicek, P.; Tridapalli, D. B.; Tristram, G.; Trovato, E.; Tueros, M.; Ulrich, R.; Unger, M.; Urban, M.; Valdés Galicia, J. F.; Valiño, I.; Valore, L.; van den Berg, A. M.; Vázquez, J. R.; Vázquez, R. A.; Veberič, D.; Velarde, A.; Venters, T.; Verzi, V.; Videla, M.; Villaseñor, L.; Vorobiov, S.; Voyvodic, L.; Wahlberg, H.; Wahrlich, P.; Wainberg, O.; Warner, D.; Watson, A. A.; Westerhoff, S.; Whelan, B. J.; Wieczorek, G.; Wiencke, L.; Wilczyńska, B.; Wilczyński, H.; Winchen, T.; Winnick, M. G.; Wu, H.; Wundheiler, B.; Yamamoto, T.; Younk, P.; Yuan, G.; Yushkov, A.; Zas, E.; Zavrtanik, D.; Zavrtanik, M.; Zaw, I.; Zepeda, A.; Ziolkowski, M.; Pierre Auger Collaboration

    2010-03-01

    The air fluorescence detector of the Pierre Auger Observatory is designed to perform calorimetric measurements of extensive air showers created by cosmic rays of above 1018eV. To correct these measurements for the effects introduced by atmospheric fluctuations, the Observatory contains a group of monitoring instruments to record atmospheric conditions across the detector site, an area exceeding 3000 km 2. The atmospheric data are used extensively in the reconstruction of air showers, and are particularly important for the correct determination of shower energies and the depths of shower maxima. This paper contains a summary of the molecular and aerosol conditions measured at the Pierre Auger Observatory since the start of regular operations in 2004, and includes a discussion of the impact of these measurements on air shower reconstructions. Between 1018 and 1020eV, the systematic uncertainties due to all atmospheric effects increase from 4% to 8% in measurements of shower energy, and 4gcm to 8gcm in measurements of the shower maximum.

  3. Normal Auger processes with ultrashort x-ray pulses in neon

    NASA Astrophysics Data System (ADS)

    Sullivan, Raymond; Jia, Junteng; Vázquez-Mayagoitia, Álvaro; Picón, Antonio

    2016-10-01

    Modern x-ray sources enable the production of coherent x-ray pulses with a pulse duration in the same order as the characteristic lifetimes of core-hole states of atoms and molecules. These pulses enable the manipulation of the core-hole population during Auger-decay processes, modifying the line shape of the electron spectra. In this work, we present a theoretical model to study those effects in neon. We identify effects in the Auger-electron-photoelectron coincidence spectrum due to the duration and intensity of the pulses. The normal Auger line shape is recovered in Auger-electron spectra integrated over all photoelectron energies.

  4. Relative extent of double and single Auger decay in molecules containing C, N and O atoms.

    PubMed

    Roos, A Hult; Eland, J H D; Andersson, J; Zagorodskikh, S; Singh, R; Squibb, R J; Feifel, R

    2016-09-14

    We show that the proportion of double Auger decay following creation of single 1s core holes in molecules containing C, N and O atoms is greater than usually assumed, amounting to about 10% of single Auger decay in many cases. It varies from molecule to molecule, where the size of the molecule has a positive correlation to the amount of double Auger decay. In neon, examined as a related benchmark, the proportion of double Auger decay is similar to that in methane, and is in the order of 5%.

  5. Evaluation of the Dmt-Tic pharmacophore: conversion of a potent delta-opioid receptor antagonist into a potent delta agonist and ligands with mixed properties.

    PubMed

    Balboni, Gianfranco; Guerrini, Remo; Salvadori, Severo; Bianchi, Clementina; Rizzi, Daniela; Bryant, Sharon D; Lazarus, Lawrence H

    2002-01-31

    Analogues of the 2',6'-dimethyl-L-tyrosine (Dmt)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic) pharmacophore were prepared to test the hypothesis that a "spacer" and a third aromatic center in opioid peptides are required to convert a delta-antagonist into ligands with delta-agonist or with mixed delta-antagonist/mu-agonist properties. Potent delta-agonists and bifunctional compounds with high delta- and mu-opioid receptor affinities were obtained by varying the spacer length [none, NH-CH(2), NH-CH(2)-CH(2), Gly-NH-CH(2)] and C-terminal aromatic nucleus [1H-benzimidazole-2-yl, phenyl (Ph) and benzyl groups]. C-terminal modification primarily affected mu-opioid receptor affinities, which increased maximally 1700-fold relative to the prototype delta-antagonist H-Dmt-Tic-NH(2) and differentially modified bioactivity. In the absence of a spacer (1), the analogue exhibited dual delta-agonism (pEC(50), 7.28) and delta-antagonism (pA(2), 7.90). H-Dmt-Tic-NH-CH(2)-1H-benzimidazole-2-yl (Bid) (2) became a highly potent delta-agonist (pEC(50), 9.90), slightly greater than deltorphin C (pEC(50), 9.56), with mu-agonism (pE(50), 7.57), while H-Dmt-Tic-Gly-NH-CH(2)-Bid (4) retained potent delta-antagonism (pA(2), 9.0) but with an order of magnitude less mu-agonism. Similarly, H-Dmt-Tic-Gly-NH-Ph (5) had nearly equivalent high delta-agonism (pEC(50), 8.52) and mu-agonism (pEC(50), 8.59), while H-Dmt-Tic-Gly-NH-CH(2)-Ph (6) whose spacer was longer by a single methylene group exhibited potent delta-antagonism (pA(2), 9.25) and very high mu-agonism (pEC(50), 8.57). These data confirm that the distance between the Dmt-Tic pharmacophore and a third aromatic nucleus is an important criterion in converting Dmt-Tic from a highly potent delta-antagonist into a potent delta-agonist or into ligands with mixed delta- and mu-opioid properties.

  6. Multiple cell upset cross-section modeling: A possible interpretation for the role of the ion energy-loss straggling and Auger recombination

    NASA Astrophysics Data System (ADS)

    Zebrev, G. I.; Zemtsov, K. S.

    2016-08-01

    We found that the energy deposition fluctuations in the sensitive volumes may cause the multiple cell upset (MCU) multiplicity scatter in the nanoscale (with feature sizes less than 100 nm) memories. A microdosimetric model of the MCU cross-section dependence on LET is proposed. It was shown that ideally a staircase-shaped cross-section vs LET curve spreads due to the energy-loss straggling impact into a quasi-linear dependence with a slope depending on the memory cell area, the cell critical energy and efficiency of charge collection. This paper also presents a new model of the Auger recombination as a limiting process of the electron-hole charge yield, especially at the high-LET ion impact. A modified form of the MCU cross-section vs LET data interpolation is proposed, discussed and validated.

  7. On the Equivalent Dose for Auger Electron Emitters

    PubMed Central

    Howell, Roger W.; Narra, Venkat R.; Sastry, Kandula S. R.; Rao, Dandamudi V.

    2012-01-01

    Radionuclides that emit Auger electrons are widely used in nuclear medicine (e.g., 99mTc, 123I, 201T1) and biomedical research (e.g., 51Cr, 125I), and they are present in the environment (e.g., 40K, 55Fe). Depending on the subcellular distribution of the radionuclide, the biological effects caused by tissue-incorporated Auger emitters can be as severe as those from high-LET α particles. However, the recently adopted recommendations of the International Commission on Radiological Protection (ICRP) provide no guidance with regard to calculating the equivalent dose for these radionuclides. The present work, using spermatogenesis in mouse testis as the experimental model, shows that the lethality of the prolific Auger emitter 125I is linearly dependent on the fraction of the radioactivity in the organ that is bound to DNA. This suggests that the equivalent dose for Auger emitters may have a similar linear dependence. Accordingly, a formalism for calculating the equivalent dose for Auger emitters is advanced within the ICRP framework. PMID:8475256

  8. WE-AB-204-12: Dosimetry at the Sub-Cellular Scale of Auger-Electron Emitter 99m-Tc in a Mouse Single Thyroid Follicle Model

    SciTech Connect

    Taborda, A; Benabdallah, N; Desbree, A

    2015-06-15

    Purpose: To perform a dosimetry study at the sub-cellular scale of Auger-electron emitter 99m-Tc using a mouse single thyroid cellular model to investigate the contribution of the 99m-Tc Auger-electrons to the absorbed dose and possible link to the thyroid stunning in in vivo experiments in mice, recently reported in literature. Methods: The simulation of S-values for Auger-electron emitting radionuclides was performed using both the recent MCNP6 software and the Geant4-DNA extension of the Geant4 toolkit. The dosimetric calculations were validated through comparison with results from literature, using a simple model of a single cell consisting of two concentric spheres of unit density water and for six Auger-electron emitting radionuclides. Furthermore, the S-values were calculated using a single thyroid follicle model for uniformly distributed 123-I and 125-I radionuclides and compared with published S-values. After validation, the simulation of the S-values was performed for the 99m-Tc radionuclide within the several mouse thyroid follicle cellular compartments, considering the radiative and non-radiative transitions of the 99m-Tc radiation spectrum. Results: The calculated S-values using MCNP6 are in good agreement with the results from literature, validating its use for the 99m-Tc S-values calculations. The most significant absorbed dose corresponds to the case where the radionuclide is uniformly distributed in the follicular cell’s nucleus, with a S-value of 7.8 mGy/disintegration, due mainly to the absorbed Auger-electrons. The results show that, at a sub-cellular scale, the emitted X-rays and gamma particles do not contribute significantly to the absorbed dose. Conclusion: In this work, MCNP6 was validated for dosimetric studies at the sub-cellular scale. It was shown that the contribution of the Auger-electrons to the absorbed dose is important at this scale compared to the emitted photons’ contribution and can’t be neglected. The obtained S

  9. Auger recombination in scintillator materials from first principles

    NASA Astrophysics Data System (ADS)

    McAllister, Andrew; Kioupakis, Emmanouil; Åberg, Daniel; Schleife, André

    2015-03-01

    Scintillators convert high energy radiation into lower energy photons which are easier to detect and analyze. One of the uses of these devices is identifying radioactive materials being transported across national borders. However, scintillating materials have a non-proportional light yield in response to incident radiation, which makes this task difficult. One possible cause of the non-proportional light yield is non-radiative Auger recombination. Auger recombination can occur in two ways - direct and phonon-assisted. We have studied both types of Auger recombination from first principles in the common scintillating material sodium iodide. Our results indicate that the phonon-assisted process, assisted primarily by short-range optical phonons, dominates the direct process. The corresponding Auger coefficients are 5 . 6 +/- 0 . 3 ×10-32cm6s-1 for the phonon-assisted process versus 1 . 17 +/- 0 . 01 ×10-33cm6s-1 for the direct process. At higher electronic temperatures the direct Auger recombination rate increases but remains lower than the phonon-assisted rate. This research was supported by the National Science Foundation CAREER award through Grant No. DMR-1254314 and NA-22. Computational Resources provide by LLNL and DOE NERSC Facility.

  10. Radiolabeling and in vitro evaluation of 67Ga-NOTA-modular nanotransporter – A potential Auger electron emitting EGFR-targeted radiotherapeutic

    PubMed Central

    Koumarianou, Eftychia; Slastnikova, Tatiana A.; Pruszynski, Marek; Rosenkranz, Andrey A.; Vaidyanathan, Ganesan; Sobolev, Alexander S.; Zalutsky, Michael R.

    2014-01-01

    Introduction Modular nanotransporters (MNTs) are vehicles designed to transport drugs from the cell surface via receptor-mediated endocytosis and endosomal escape to nucleus. Hence their conjugation to Auger electron emitters, can cause severe cell killing, by nuclear localization. Herein we evaluate the use of MNT as a platform for targeted radiotherapy with 67Ga. Methods EGF was the targeting ligand on the MNT, and NOTA was selected for its radiolabeling with 67Ga. In the radiolabeling study we dealt with the precipitation of MNT (pI 5.7) at the labeling pH (4.5–5.5) of 67Ga. Cellular and nuclei uptake of 67Ga-NOTA-MNT by the A431 cell line was determined. Its specific cytotoxicity was compared to that of 67Ga-EDTA, 67Ga-NOTA-BSA and 67Ga-NOTA-hEGF, in A431 and U87MGWTT, cell lines, by clonogenic assay. Dosimetry studies were also performed. Results 67Ga-NOTA-MNT was produced with 90% yield and specific activity of 25.6 mCi/mg. The in vitro kinetics revealed an increased uptake over 24 h. 55% of the internalized radioactivity was detected in the nuclei at 1 h. The cytotoxicity of 67Ga-NOTA-MNT on A431 cell line was 17 and 385-fold higher when compared to non-specific 67Ga-NOTA-BSA and 67Ga-EDTA. While its cytotoxic potency was 13 and 72 – fold higher when compared to 67Ga-NOTA-hEGF in the A431 and the U87MGWTT cell lines, respectively, validating its nuclear localization. The absorbed dose, for 63% cell killing, was 9 Gy, confirms the high specific index of 67Ga. Conclusion These results demonstrate the feasibility of using MNT as a platform for single cell kill targeted radiotherapy by Auger electron emitters. PMID:24776093

  11. Discovery of a Potent and Selective BCL-XL Inhibitor with in Vivo Activity.

    PubMed

    Tao, Zhi-Fu; Hasvold, Lisa; Wang, Le; Wang, Xilu; Petros, Andrew M; Park, Chang H; Boghaert, Erwin R; Catron, Nathaniel D; Chen, Jun; Colman, Peter M; Czabotar, Peter E; Deshayes, Kurt; Fairbrother, Wayne J; Flygare, John A; Hymowitz, Sarah G; Jin, Sha; Judge, Russell A; Koehler, Michael F T; Kovar, Peter J; Lessene, Guillaume; Mitten, Michael J; Ndubaku, Chudi O; Nimmer, Paul; Purkey, Hans E; Oleksijew, Anatol; Phillips, Darren C; Sleebs, Brad E; Smith, Brian J; Smith, Morey L; Tahir, Stephen K; Watson, Keith G; Xiao, Yu; Xue, John; Zhang, Haichao; Zobel, Kerry; Rosenberg, Saul H; Tse, Chris; Leverson, Joel D; Elmore, Steven W; Souers, Andrew J

    2014-10-09

    A-1155463, a highly potent and selective BCL-XL inhibitor, was discovered through nuclear magnetic resonance (NMR) fragment screening and structure-based design. This compound is substantially more potent against BCL-XL-dependent cell lines relative to our recently reported inhibitor, WEHI-539, while possessing none of its inherent pharmaceutical liabilities. A-1155463 caused a mechanism-based and reversible thrombocytopenia in mice and inhibited H146 small cell lung cancer xenograft tumor growth in vivo following multiple doses. A-1155463 thus represents an excellent tool molecule for studying BCL-XL biology as well as a productive lead structure for further optimization.

  12. Potent complement C3a receptor agonists derived from oxazole amino acids: Structure-activity relationships.

    PubMed

    Singh, Ranee; Reed, Anthony N; Chu, Peifei; Scully, Conor C G; Yau, Mei-Kwan; Suen, Jacky Y; Durek, Thomas; Reid, Robert C; Fairlie, David P

    2015-12-01

    Potent ligands for the human complement C3a receptor (C3aR) were developed from the almost inactive tripeptide Leu-Ala-Arg corresponding to the three C-terminal residues of the endogenous peptide agonist C3a. The analogous Leu-Ser-Arg was modified by condensing the serine side chain with the leucine carbonyl with elimination of water to form leucine-oxazole-arginine. Subsequent elaboration with a variety of N-terminal amide capping groups produced agonists as potent as human C3a itself in stimulating Ca(2+) release from human macrophages. Structure-activity relationships are discussed.

  13. Auger tension leg platform cathodic protection system

    SciTech Connect

    Goolsby, A.D.; Smith, J.D.

    1995-11-01

    In 1986, Shell began investigating corrosion control systems for a generic 3,000 ft. water depth Tension Leg Platform (TLP) type structure to be located in the north-central Gulf of Mexico. In 1987, the 2,850 ft. deep Garden Banks block 426 ``Auger`` location was chosen for the first TLP, and the detailed design process began in earnest. During late 1993 and early 1994, the Auger hull was mated with the other components at its permanent site, and first oil and gas production began April 15, 1994. This paper describes the corrosion control design for the exterior submerged and buried steel surfaces of the 2,850 ft. (869 m) water depth Auger Tension Leg Platform structure. Each major type of component (hull, subsea marine wellhead/guidebase, tendon foundation template, tendon, and production riser) has its own combination of coating system and cathodic protection system designed for a thirty five year lifetime. Cathodic protection (CP) is achieved using a variety of sacrificial anode alloys and geometries (e.g. bracelet, flush-mount, and standoff anodes). Anode and cathode CP design parameters for each component depend upon water depth, and were developed using field test data, laboratory studies, field measurements on existing structures, and available literature information. CP design was performed using design spreadsheets constructed for each component, which optimized anode geometries. Extensive quality assurance efforts were part of the anode procurement process, to ensure performance for the intended life of the corrosion-control systems. Results of early in-service CP surveys of the tendons and guidebases are presented, showing the successful achievement of cathodic protection against seawater corrosion. Corrosion control of one additional system, the eight point lateral mooring system, is not addressed here.

  14. From Auger to AugerPrime: Understanding Ultrahigh-Energy Cosmic Rays

    NASA Astrophysics Data System (ADS)

    Montanet, F.; Pierre Auger Collaboration

    2016-12-01

    Ultrahigh-energy cosmic rays (UHECRs), whose origin is still mysterious, provide a unique probe of the most extreme environments in the universe, of the intergalactic space and of particle physics beyond the reach of terrestrial accelerators. The Pierre Auger Observatory started operating more than a decade ago. Outperforming preceding experiments both in size and in precision, it has boosted forward the field of UHECRs as witnessed by a wealth of results. These include the study of the energy spectrum beyond 1 EeV with its spectral suppression around 40 EeV, of the large-scale anisotropy, of the mass composition, as well as stringent limits on photon and neutrino fluxes. But any harvest of new results also calls for new questions: what is the true nature of the spectral suppression: a propagation effect (so-called Greisen, Zatsepin and Kuz'min or GZK cutoff) or cosmic accelerators running out of steam? What is the composition of UHECRs at the highest energies? In order to answer these questions, the Auger Collaboration is undertaking a major upgrade program of its detectors, the AugerPrime project. The science case and motivations, the technical strategy and the scientific prospects are presented.

  15. Discovery and Evaluation of BMS-708163, a Potent, Selective and Orally Bioavailable γ-Secretase Inhibitor

    PubMed Central

    2010-01-01

    During the course of our research efforts to develop a potent and selective γ-secretase inhibitor for the treatment of Alzheimer's disease, we investigated a series of carboxamide-substituted sulfonamides. Optimization based on potency, Notch/amyloid-β precursor protein selectivity, and brain efficacy after oral dosing led to the discovery of 4 (BMS-708163). Compound 4 is a potent inhibitor of γ-secretase (Aβ40 IC50 = 0.30 nM), demonstrating a 193-fold selectivity against Notch. Oral administration of 4 significantly reduced Aβ40 levels for sustained periods in brain, plasma, and cerebrospinal fluid in rats and dogs. PMID:24900185

  16. High Spatial Resolution Auger Spectroscopy and Nucleation and Growth Studies of SILVER/SILICON(100)

    NASA Astrophysics Data System (ADS)

    Luo, Frank C. H.

    1990-01-01

    The ability to analyse the composition of a sample at high spatial resolution using Auger Electron Spectroscopy is very desirable for both industrial and academic research. The spatial resolution of the traditional Auger instrument is typically limited by the incident beam size to the range of 0.1-1 mum. This dissertation reports the efforts of construction, testing and utilizing a new Auger spectrometer with a nanometer incident probe in a scanning transmission electron microscopy (STEM). In order to use the 100 keV electron beam of the STEM for the Auger experiment, a low energy electron beam deflection system was designed and constructed. The testing of such deflection system and the spectrometer, both in a test chamber with different hardware configuration and in the microscope, was very extensive. Both Auger spectra and images can be obtained in the microscope with excellent energy resolution in a relatively short time. Quantitative analysis of the data showed a spatial resolution of less than 10 nm was achieved with a good collection efficiency. More quantitative work was carried on the Silver/Silicon(100) system as the application of the Auger instrument. Nucleation and growth phenomena of Ag on Si at both room and elevated temperatures was studied with the microscope operating both in Auger and scanning electron microscopy (SEM) mode. Suggestions for the further improvement of the Auger instrument and the Ag/Si(100) case study are made.

  17. First identification of xanthone sulfonamides as potent acyl-CoA:cholesterol acyltransferase (ACAT) inhibitors.

    PubMed

    Hu, Honggang; Liao, Hongli; Zhang, Jun; Wu, Weifeng; Yan, Jufang; Yan, Yonghong; Zhao, Qingjie; Zou, Yan; Chai, Xiaoyun; Yu, Shichong; Wu, Qiuye

    2010-05-15

    Inhibitors of acyl-CoA:cholesterol acyltransferase (ACAT) would be useful anti-atherogenic agents, since an absence of ACAT affects the absorption and transformation of cholesterol, indirectly resulting in the reduction of cholesteryl ester accumulation in blood vessels. This report discloses xanthone sulfonamides as novel class small molecule inhibitors of ACAT. A series of xanthone sulfonamides were synthesized and evaluated to result in the identification of several potent ACAT inhibitors, among which 2n proved to be more potent than the positive control Sandoz58-35. Moreover, a molecular model for the binding between 2n and the active site of ACAT-2 was provided based computational docking results.

  18. Auger recombination in sodium-iodide scintillators from first principles

    NASA Astrophysics Data System (ADS)

    McAllister, Andrew; Åberg, Daniel; Schleife, André; Kioupakis, Emmanouil

    2015-04-01

    Scintillator radiation detectors suffer from low energy resolution that has been attributed to non-linear light yield response to the energy of the incident gamma rays. Auger recombination is a key non-radiative recombination channel that scales with the third power of the excitation density and may play a role in the non-proportionality problem of scintillators. In this work, we study direct and phonon-assisted Auger recombination in NaI using first-principles calculations. Our results show that phonon-assisted Auger recombination, mediated primarily by short-range phonon scattering, dominates at room temperature. We discuss our findings in light of the much larger values obtained by numerical fits to z-scan experiments.

  19. Auger recombination in sodium-iodide scintillators from first principles

    SciTech Connect

    McAllister, Andrew; Åberg, Daniel; Schleife, André; Kioupakis, Emmanouil

    2015-04-06

    Scintillator radiation detectors suffer from low energy resolution that has been attributed to non-linear light yield response to the energy of the incident gamma rays. Auger recombination is a key non-radiative recombination channel that scales with the third power of the excitation density and may play a role in the non-proportionality problem of scintillators. In this work, we study direct and phonon-assisted Auger recombination in NaI using first-principles calculations. Our results show that phonon-assisted Auger recombination, mediated primarily by short-range phonon scattering, dominates at room temperature. We discuss our findings in light of the much larger values obtained by numerical fits to z-scan experiments.

  20. The Pierre Auger Observatory Upgrade - Preliminary Design Report

    SciTech Connect

    Aab, Alexander

    2016-04-12

    The Pierre Auger Observatory has begun a major Upgrade of its already impressive capabilities, with an emphasis on improved mass composition determination using the surface detectors of the Observatory. Known as AugerPrime, the upgrade will include new 4 m2 plastic scintillator detectors on top of all 1660 water-Cherenkov detectors, updated and more flexible surface detector electronics, a large array of buried muon detectors, and an extended duty cycle for operations of the fluorescence detectors. This Preliminary Design Report was produced by the Collaboration in April 2015 as an internal document and information for funding agencies. It outlines the scientific and technical case for AugerPrime. We now release it to the public via the arXiv server. We invite you to review the large number of fundamental results already achieved by the Observatory and our plans for the future.

  1. Multielectron spectroscopy: Auger decays of the krypton 3d hole

    SciTech Connect

    Palaudoux, J.; Lablanquie, P.; Penent, F.; Andric, L.; Ito, K.; Shigemasa, E.; Eland, J. H. D.; Jonauskas, V.; Kucas, S.; Karazija, R.

    2010-10-15

    The emission of one or two Auger electrons, following Kr 3d inner-shell ionization by synchrotron light, has been investigated both experimentally and theoretically. All electrons emitted in the process are detected in coincidence and analyzed in energy thanks to a magnetic-bottle electron time-of-flight spectrometer. In addition, noncoincident high-resolution electron spectra have been measured to characterize the cascade double-Auger paths more fully. Combination of the two experimental approaches and of our calculations allows a full determination of the decay pathways and branching ratios in the case of Kr 3d single- and double-Auger decays. The Kr{sup 3+} threshold is found at 74.197{+-}0.020 eV.

  2. Fire for Effect: Calling for a More Potent Energy System

    DTIC Science & Technology

    2008-05-22

    reactor ( PBMR ) could do a better job as a very compact and powerful source of electrical power, especially when a unit requires a small footprint and...advocates using nitrogen as the working gas in a closed cycle Pebble Bed Modular Reactor ( PBMR ).. The September/October 2001 Army Logistician article...further discusses pebble bed modular reactors. PBMRs contain a sub-critical core of uranium oxide in billiard-ball sized spheres coated with layers of

  3. A Search for Ultra-High Energy Neutrinos in Highly Inclined Events at the Pierre Auger Observatory

    SciTech Connect

    Abreu, P

    2011-12-30

    The Surface Detector of the Pierre Auger Observatory is sensitive to neutrinos of all flavors above 0.1 EeV. These interact through charged and neutral currents in the atmosphere giving rise to extensive air showers. When interacting deeply in the atmosphere at nearly horizontal incidence, neutrinos can be distinguished from regular hadronic cosmic rays by the broad time structure of their shower signals in the water-Cherenkov detectors. In this paper we present for the first time an analysis based on down-going neutrinos. We describe the search procedure, the possible sources of background, the method to compute the exposure and the associated systematic uncertainties. No candidate neutrinos have been found in data collected from 1 January 2004 to 31 May 2010. Assuming an E-2 differential energy spectrum the limit on the single-flavor neutrino is E2dN/dE < 1.74 x 10-7 GeV cm-2s-1sr-1 at 90% C.L. in the energy range 1 x 1017eV < E < 1 x 1020 eV.

  4. A Search for Ultra-High Energy Neutrinos in Highly Inclined Events at the Pierre Auger Observatory

    DOE PAGES

    Abreu, P

    2011-12-30

    The Surface Detector of the Pierre Auger Observatory is sensitive to neutrinos of all flavors above 0.1 EeV. These interact through charged and neutral currents in the atmosphere giving rise to extensive air showers. When interacting deeply in the atmosphere at nearly horizontal incidence, neutrinos can be distinguished from regular hadronic cosmic rays by the broad time structure of their shower signals in the water-Cherenkov detectors. In this paper we present for the first time an analysis based on down-going neutrinos. We describe the search procedure, the possible sources of background, the method to compute the exposure and the associatedmore » systematic uncertainties. No candidate neutrinos have been found in data collected from 1 January 2004 to 31 May 2010. Assuming an E-2 differential energy spectrum the limit on the single-flavor neutrino is E2dN/dE < 1.74 x 10-7 GeV cm-2s-1sr-1 at 90% C.L. in the energy range 1 x 1017eV < E < 1 x 1020 eV.« less

  5. Spin polarization in the resonant Auger decay of argon

    NASA Astrophysics Data System (ADS)

    Snell, Gyorgy; Langer, Burkhard; Canton, Sophie; Martins, Michael; Berrah, Nora

    2001-05-01

    The dynamics of the photoionization and Auger decay processes can be fully described by the dipole and Coulomb transition matrix elements, respectively. A complete set of matrix elements, amplitudes and phase shifts, enables the prediction of all parameters of the emission process, such as the angular distribution and spin polarization of the electrons. For this reason, big advancements were made in complete photoionization experiments in recent years [1,2]. In contrast, there have been only very few studies of the Auger decay process beyond Auger intensities and angular distributions [3], although Auger spectroscopy is an important field of research in gas-phase, solid state and surface physics. We have made the first measurement of spin polarization of resonant Auger electrons emitted from the decay of the Ar 2p-1->4s and 2p-1->3d excited states. We used monochromatized, circularly and linearly polarized light of 245 eV photon energy from the new elliptical polarization undulator (EPU) beamline of the Advanced Light Source (ALS) to carry out the experiment. Some of the Auger lines show a high degree of polarization, which will possibly enable the determination of Coulomb matrix elements. [1] U. Heinzmann and N. A. Cherepkov, in VUV- und soft X-ray photoionization, eds. U. Becker and D. A. Shirley, p. 521 (Plenum Press, New York, 1996). [2] G. Snell, B. Langer, M. Drescher, N. Müller, U. Hergenhahn, J. Viefhaus, U. Heinzmann, and U. Becker, Phys. Rev. Lett. 82, 2480 (1999). [3] U. Hergenhahn, G. Snell, M. Drescher, B. Schmidtke, N. Müller, U. Heinzmann, M. Wiedenhöft, and U. Becker, Phys. Rev. Lett. 82, 5020 (1999).

  6. A Highly Arginolytic Streptococcus Species That Potently Antagonizes Streptococcus mutans.

    PubMed

    Huang, Xuelian; Palmer, Sara R; Ahn, Sang-Joon; Richards, Vincent P; Williams, Matthew L; Nascimento, Marcelle M; Burne, Robert A

    2016-01-29

    The ability of certain oral biofilm bacteria to moderate pH through arginine metabolism by the arginine deiminase system (ADS) is a deterrent to the development of dental caries. Here, we characterize a novel Streptococcus strain, designated strain A12, isolated from supragingival dental plaque of a caries-free individual. A12 not only expressed the ADS pathway at high levels under a variety of conditions but also effectively inhibited growth and two intercellular signaling pathways of the dental caries pathogen Streptococcus mutans. A12 produced copious amounts of H2O2 via the pyruvate oxidase enzyme that were sufficient to arrest the growth of S. mutans. A12 also produced a protease similar to challisin (Sgc) of Streptococcus gordonii that was able to block the competence-stimulating peptide (CSP)-ComDE signaling system, which is essential for bacteriocin production by S. mutans. Wild-type A12, but not an sgc mutant derivative, could protect the sensitive indicator strain Streptococcus sanguinis SK150 from killing by the bacteriocins of S. mutans. A12, but not S. gordonii, could also block the XIP (comX-inducing peptide) signaling pathway, which is the proximal regulator of genetic competence in S. mutans, but Sgc was not required for this activity. The complete genome sequence of A12 was determined, and phylogenomic analyses compared A12 to streptococcal reference genomes. A12 was most similar to Streptococcus australis and Streptococcus parasanguinis but sufficiently different that it may represent a new species. A12-like organisms may play crucial roles in the promotion of stable, health-associated oral biofilm communities by moderating plaque pH and interfering with the growth and virulence of caries pathogens.

  7. A Highly Arginolytic Streptococcus Species That Potently Antagonizes Streptococcus mutans

    PubMed Central

    Huang, Xuelian; Palmer, Sara R.; Ahn, Sang-Joon; Richards, Vincent P.; Williams, Matthew L.; Nascimento, Marcelle M.

    2016-01-01

    The ability of certain oral biofilm bacteria to moderate pH through arginine metabolism by the arginine deiminase system (ADS) is a deterrent to the development of dental caries. Here, we characterize a novel Streptococcus strain, designated strain A12, isolated from supragingival dental plaque of a caries-free individual. A12 not only expressed the ADS pathway at high levels under a variety of conditions but also effectively inhibited growth and two intercellular signaling pathways of the dental caries pathogen Streptococcus mutans. A12 produced copious amounts of H2O2 via the pyruvate oxidase enzyme that were sufficient to arrest the growth of S. mutans. A12 also produced a protease similar to challisin (Sgc) of Streptococcus gordonii that was able to block the competence-stimulating peptide (CSP)–ComDE signaling system, which is essential for bacteriocin production by S. mutans. Wild-type A12, but not an sgc mutant derivative, could protect the sensitive indicator strain Streptococcus sanguinis SK150 from killing by the bacteriocins of S. mutans. A12, but not S. gordonii, could also block the XIP (comX-inducing peptide) signaling pathway, which is the proximal regulator of genetic competence in S. mutans, but Sgc was not required for this activity. The complete genome sequence of A12 was determined, and phylogenomic analyses compared A12 to streptococcal reference genomes. A12 was most similar to Streptococcus australis and Streptococcus parasanguinis but sufficiently different that it may represent a new species. A12-like organisms may play crucial roles in the promotion of stable, health-associated oral biofilm communities by moderating plaque pH and interfering with the growth and virulence of caries pathogens. PMID:26826230

  8. A Potent, Versatile Disulfide-Reducing Agent from Aspartic Acid

    PubMed Central

    2013-01-01

    Dithiothreitol (DTT) is the standard reagent for reducing disulfide bonds between and within biological molecules. At neutral pH, however, >99% of DTT thiol groups are protonated and thus unreactive. Herein, we report on (2S)-2-amino-1,4-dimercaptobutane (dithiobutylamine or DTBA), a dithiol that can be synthesized from l-aspartic acid in a few high-yielding steps that are amenable to a large-scale process. DTBA has thiol pKa values that are ∼1 unit lower than those of DTT and forms a disulfide with a similar E°′ value. DTBA reduces disulfide bonds in both small molecules and proteins faster than does DTT. The amino group of DTBA enables its isolation by cation-exchange and facilitates its conjugation. These attributes indicate that DTBA is a superior reagent for reducing disulfide bonds in aqueous solution. PMID:22353145

  9. Discovery of a Potent, Dual Serotonin and Norepinephrine Reuptake Inhibitor

    PubMed Central

    2013-01-01

    The objective of the described research effort was to identify a novel serotonin and norepinephrine reuptake inhibitor (SNRI) with improved norepinephrine transporter activity and acceptable metabolic stability and exhibiting minimal drug–drug interaction. We describe herein the discovery of a series of 3-substituted pyrrolidines, exemplified by compound 1. Compound 1 is a selective SNRI in vitro and in vivo, has favorable ADME properties, and retains inhibitory activity in the formalin model of pain behavior. Compound 1 thus represents a potential new probe to explore utility of SNRIs in central nervous system disorders, including chronic pain conditions. PMID:24900709

  10. The Marine Cyanobacterial Metabolite Gallinamide A is a Potent and Selective Inhibitor of Human Cathepsin L

    PubMed Central

    Miller, Bailey; Friedman, Aaron J; Choi, Hyukjae; Hogan, James; McCammon, J. Andrew; Hook, Vivian; Gerwick, William H.

    2014-01-01

    A number of marine natural products are potent inhibitors of proteases, an important drug target class in human diseases. Hence, marine cyanobacterial extracts were assessed for inhibitory activity to human cathepsin L. Herein, we have shown that gallinamide A potently and selectively inhibits the human cysteine protease, cathepsin L. With 30 min of preincubation, gallinamide A displayed an IC50 of 5.0 nM, and kinetic analysis demonstrated an inhibition constant of ki = 9000 ± 260 M−1 s−1. Preincubation-dilution and activity-probe experiments revealed an irreversible mode of inhibition, and comparative IC50 values display a 28- to 320- fold greater selectivity toward cathepsin L than closely related human cysteine cathepsins V or B. Molecular docking and molecular dynamics simulations were used to determine the pose of gallinamide in the active site of cathepsin L. These data resulted in the identification of a pose characterized by high stability, a consistent hydrogen bond network, and the reactive Michael acceptor enamide of gallinamide A positioned near the active site cysteine of the protease, leading to a proposed mechanism of covalent inhibition. These data reveal and characterize the novel activity of gallinamide A as a potent inhibitor of human cathepsin L. PMID:24364476

  11. Alstroemeria. A new and potent allergen for florists.

    PubMed

    Adams, R M; Daily, A D; Brancaccio, R R; Dhillon, I P; Gendler, E C

    1990-01-01

    Alstroemeria (Peruvian or Inca lily) has found particular favor because of its beauty and durability. However, it may induce a dermatitis so severe that workers have to change jobs. The dermatitis is chronic, with fissuring at the tips of the fingers bilaterally. Itching is often a less prominent symptom. Preventative measures are of little benefit, and many floral shops are vanishing the plant.

  12. Faculty Leadership: A Dynamic, Potent Force for Comprehensive Institutional Development.

    ERIC Educational Resources Information Center

    Franklin, Homer D.; And Others

    Responding to the crisis in leadership at community colleges, scholars and practitioners alike have called for a new style of leadership capable of adapting and responding easily to an uncertain political and social climate. Although community colleges are rooted historically in a hierarchical leadership mode, there seems to be broad consensus…

  13. Nitric oxide as a potent fumigant for postharvest pest control

    Technology Transfer Automated Retrieval System (TEKTRAN)

    There is a great demand for safe and effective alternative fumigants to replace methyl bromide and other toxic fumigants for pest control. Nitric oxide, a common signal molecule in biological systems, was found to be effective and safe to control insects under ultralow oxygen conditions. Fumigatio...

  14. National Cost Implications of a Potentional Perchlorate Regulation

    EPA Pesticide Factsheets

    In this study, a screening level cost assessment was conducted to evaluate the national cost implications of five potential regulatory levels for perchlorate in drinking water 4, 6, 12, 18, and 24 ?g/L.

  15. A Potent Vector: Assessing Chinese Cruise Missile Developments

    DTIC Science & Technology

    2014-01-01

    and Yuan 101 sea-skimming sprint vehicle that travels the last 20 km to the target at a speed of Mach 2.9. The 3M54E ASCM has a 200- kg semi-armor...attack at 7 to 10 meters . With Table 1. PLA Antiship Cruise Missiles (Major Systems) Type Manufacturer Launch Platform Range (km) Payload (kg) Speed ...post-launch counterforce attacks. The potential combination of supersonic speed , small radar signature, and very low altitude flight profile enables

  16. Studies Toward the Pharmacophore of Salvinorin A, a Potent Kappa Opioid Receptor Agonist

    PubMed Central

    Munro, Thomas A.; Rizzacasa, Mark A.; Roth, Bryan L.; Toth, Beth A.; Yan, Feng

    2009-01-01

    Salvinorin A (1), from the sage Salvia divinorum, is a potent and selective kappa opioid receptor (KOR) agonist. We screened other salvinorins and derivatives for binding affinity and functional activity at opioid receptors. Our results suggest that the methyl ester and furan ring are required for activity, but that the lactone and ketone functionalities are not. Other salvinorins showed negligible binding affinity at the KOR. None of the compounds bound to mu or delta opioid receptors. PMID:15658846

  17. Studies toward the pharmacophore of salvinorin A, a potent kappa opioid receptor agonist.

    PubMed

    Munro, Thomas A; Rizzacasa, Mark A; Roth, Bryan L; Toth, Beth A; Yan, Feng

    2005-01-27

    Salvinorin A (1), from the sage Salvia divinorum, is a potent and selective kappa opioid receptor (KOR) agonist. We screened other salvinorins and derivatives for binding affinity and functional activity at opioid receptors. Our results suggest that the methyl ester and furan ring are required for activity but that the lactone and ketone functionalities are not. Other salvinorins showed negligible binding affinity at the KOR. None of the compounds bound to mu or delta opioid receptors.

  18. Studies of liquid metal surfaces using Auger spectroscopy

    NASA Technical Reports Server (NTRS)

    Hardy, S.; Fine, J.

    1982-01-01

    The surface composition of liquid gallium-tin alloys is studied in an Auger electron spectrometer as a function of bulk composition and temperature. The sessile drop samples are cleaned by argon ion bombardment sputtering of the liquid. This technique produces surfaces that are entirely free of impurities within the sensitivity of the spectrometer and remain so for many days. Tin is found to be strongly adsorbed at the liquid-vacuum interface. Surface concentrations based on Auger measurements are found to be in reasonably good agreement with values calculated from surface tension measurements interpreted in terms of a monolayer depth distribution model for the adsorbed tin.

  19. [Bryophytes, a potent source of drugs for tomorrow's medicine?].

    PubMed

    Krzaczkowski, Lucie; Wright, Michel; Gairin, Jean Edouard

    2008-11-01

    Although secondary plant metabolites provided numerous leads for the development of a wide array of therapeutic drugs, the discovery of new drugs with novel structures has declined in the past few years. Indeed higher plants have a similar evolutionary history and so produce similar metabolites. Search for novel sources of new therapeutic compounds within unexplored parts of biodiversity is thus an attractive challenge. Bryophytes, a group of small terrestrial plants remain relatively untouched in the drug discovery process whereas some have been used as medicinal plants. Studies of their secondary metabolites are recent but reveal original compounds, some of which not synthesized by higher plants. However investigations often meet difficulties during harvest or isolation of active compounds. In consequence, small quantities of substances obtained may be the main reason for the lack of biological tests. Strategies to overcome those troubles may exist and then lead to innovative medicinal applications.

  20. Synthesis of a potent new antimalarial through natural products conjugation

    PubMed Central

    Bruno, Michela; Trucchi, Beatrice; Monti, Diego; Romeo, Sergio; Kaiser, Marcel; Verotta, Luisella

    2013-01-01

    Three natural products have been assembled to obtain a new antimalarial hit. (+)-Usnic acid was used as scaffold to design and synthesize new products, that were tested on asexual development for P. falciparum and P. berghei. Among them, the ester of (+)-usnic acid-4-aminobutyric acid 14 with dihydroartemisinin shows considerable in vivo antimalarial activity against P. berghei in mice, similar to the synthetic drug artesunate. Compound 14 behaves as a delivery system for dihydroartemisinin and combine the effects of the endoperoxide with the redox properties of the phenolic portions of (+)-usnic acid. PMID:23307699

  1. Angular Correlation between Photoelectrons and Auger Electrons from K-Shell Ionization of Neon

    NASA Astrophysics Data System (ADS)

    Landers, A. L.; Robicheaux, F.; Jahnke, T.; Schöffler, M.; Osipov, T.; Titze, J.; Lee, S. Y.; Adaniya, H.; Hertlein, M.; Ranitovic, P.; Bocharova, I.; Akoury, D.; Bhandary, A.; Weber, Th.; Prior, M. H.; Cocke, C. L.; Dörner, R.; Belkacem, A.

    2009-06-01

    We have used cold target recoil ion momentum spectroscopy to study the continuum correlation between the photoelectron of core-photoionized neon and the subsequent Auger electron. We observe a strong angular correlation between the two electrons. Classical trajectory Monte Carlo calculations agree quite well with the photoelectron energy distribution that is shifted due to the potential change associated with Auger decay. However, a striking discrepancy results in the distribution of the relative angle between Auger and photoelectron. The classical model predicts a shift in photoelectron flux away from the Auger emission direction, and the data strikingly reveal that the flux is lost rather than diverted, indicating that the two-step interpretation of photoionization followed by Auger emission is insufficient to fully describe the core-photoionization process.

  2. Angular Correlation between Photoelectrons and Auger Electrons from K-Shell Ionization of Neon

    SciTech Connect

    Landers, A. L.; Robicheaux, F.; Bhandary, A.; Jahnke, T.; Schoeffler, M.; Titze, J.; Akoury, D.; Doerner, R.; Osipov, T.; Lee, S. Y.; Adaniya, H.; Hertlein, M.; Weber, Th.; Prior, M. H.; Belkacem, A.; Ranitovic, P.; Bocharova, I.; Cocke, C. L.

    2009-06-05

    We have used cold target recoil ion momentum spectroscopy to study the continuum correlation between the photoelectron of core-photoionized neon and the subsequent Auger electron. We observe a strong angular correlation between the two electrons. Classical trajectory Monte Carlo calculations agree quite well with the photoelectron energy distribution that is shifted due to the potential change associated with Auger decay. However, a striking discrepancy results in the distribution of the relative angle between Auger and photoelectron. The classical model predicts a shift in photoelectron flux away from the Auger emission direction, and the data strikingly reveal that the flux is lost rather than diverted, indicating that the two-step interpretation of photoionization followed by Auger emission is insufficient to fully describe the core-photoionization process.

  3. Angular correlation between photoelectrons and auger electrons from K-shell ionization of neon.

    PubMed

    Landers, A L; Robicheaux, F; Jahnke, T; Schöffler, M; Osipov, T; Titze, J; Lee, S Y; Adaniya, H; Hertlein, M; Ranitovic, P; Bocharova, I; Akoury, D; Bhandary, A; Weber, Th; Prior, M H; Cocke, C L; Dörner, R; Belkacem, A

    2009-06-05

    We have used cold target recoil ion momentum spectroscopy to study the continuum correlation between the photoelectron of core-photoionized neon and the subsequent Auger electron. We observe a strong angular correlation between the two electrons. Classical trajectory Monte Carlo calculations agree quite well with the photoelectron energy distribution that is shifted due to the potential change associated with Auger decay. However, a striking discrepancy results in the distribution of the relative angle between Auger and photoelectron. The classical model predicts a shift in photoelectron flux away from the Auger emission direction, and the data strikingly reveal that the flux is lost rather than diverted, indicating that the two-step interpretation of photoionization followed by Auger emission is insufficient to fully describe the core-photoionization process.

  4. Hydrogen sulfide as a potent cardiovascular protective agent.

    PubMed

    Yu, Xiao-Hua; Cui, Li-Bao; Wu, Kai; Zheng, Xi-Long; Cayabyab, Francisco S; Chen, Zhi-Wei; Tang, Chao-Ke

    2014-11-01

    Hydrogen sulfide (H2S) is a well-known toxic gas with the characteristic smell of rotten eggs. It is synthesized endogenously in mammals from the sulfur-containing amino acid l-cysteine by the action of several distinct enzymes: cystathionine-γ-lyase (CSE), cystathionine-ß-synthase (CBS), and 3-mercaptopyruvate sulfurtransferase (3-MST) along with cysteine aminotransferase (CAT). In particular, CSE is considered to be the major H2S-producing enzyme in the cardiovascular system. As the third gasotransmitter next to nitric oxide (NO) and carbon monoxide (CO), H2S plays an important role in the regulation of vasodilation, angiogenesis, inflammation, oxidative stress and apoptosis. Growing evidence has demonstrated that this gas exerts a significant protective effect against the progression of cardiovascular diseases by a number of mechanisms such as vasorelaxation, inhibition of cardiovascular remodeling and resistance to form foam cells. The aim of this review is to provide an overview of the physiological functions of H2S and its protection against several major cardiovascular diseases, and to explore its potential health and therapeutic benefits. A better understanding will help develop novel H2S-based therapeutic interventions for these diseases.

  5. Calixtyrosol: a Novel Calixarene Based Potent Radical Scavenger

    PubMed Central

    Nasuhi Pur, Fazel; Akbari Dilmaghani, Karim

    2015-01-01

    The oxidative stress causes many diseases in human, therefore antioxidants have a special position in the medicinal chemistry. Tyrosol is an important antioxidant with a plenty of biological properties. There are many strategies such as clustering single drug units in order to develop new drugs. The cluster effect can increase drug effects relative to single drug unit. Calixtyrosol is the novel cluster of tyrosol that shows a more effective antioxidant activity than single tyrosol. In fact, tyrosol can be considered as 1/4 of the cluster. Four hydroxyethyl moieties have been grafted at the upper rim of the calix[4]arene in all-syn orientation, giving novel agent in the field of antioxidant agents. Free radical scavenging tests were determined by the 2, 2-diphenyl-1-picrylhydrazyl radical in methanol for four antioxidants: calixtyrosol, tyrosol, hydroxytyrosol and 3, 5-di-tert-buty l-4-hydroxytoluene to compare their antioxidant activity. Free radical scavenging test showed that calixtyrosol has enhanced antioxidant activity in comparison to the corresponding single tyrosol unit (> 5 fold), it has even more active than the other test antioxidants (2 fold). Presumably, it is attributed to tethering and arraying of four impacted tyrosol units, which make a synergistic effect in interactions with radicals for creating effective radical scavenging activity. This method is in debt of synergistic effect, tethering and arraying of single units in the cluster structure. PMID:26664385

  6. Calixtyrosol: a Novel Calixarene Based Potent Radical Scavenger.

    PubMed

    Nasuhi Pur, Fazel; Akbari Dilmaghani, Karim

    2015-01-01

    The oxidative stress causes many diseases in human, therefore antioxidants have a special position in the medicinal chemistry. Tyrosol is an important antioxidant with a plenty of biological properties. There are many strategies such as clustering single drug units in order to develop new drugs. The cluster effect can increase drug effects relative to single drug unit. Calixtyrosol is the novel cluster of tyrosol that shows a more effective antioxidant activity than single tyrosol. In fact, tyrosol can be considered as 1/4 of the cluster. Four hydroxyethyl moieties have been grafted at the upper rim of the calix[4]arene in all-syn orientation, giving novel agent in the field of antioxidant agents. Free radical scavenging tests were determined by the 2, 2-diphenyl-1-picrylhydrazyl radical in methanol for four antioxidants: calixtyrosol, tyrosol, hydroxytyrosol and 3, 5-di-tert-buty l-4-hydroxytoluene to compare their antioxidant activity. Free radical scavenging test showed that calixtyrosol has enhanced antioxidant activity in comparison to the corresponding single tyrosol unit (> 5 fold), it has even more active than the other test antioxidants (2 fold). Presumably, it is attributed to tethering and arraying of four impacted tyrosol units, which make a synergistic effect in interactions with radicals for creating effective radical scavenging activity. This method is in debt of synergistic effect, tethering and arraying of single units in the cluster structure.

  7. A new antibiotic with potent activity targets MscL

    PubMed Central

    Iscla, Irene; Wray, Robin; Blount, Paul; Larkins-Ford, Jonah; Conery, Annie L; Ausubel, Frederick M; Ramu, Soumya; Kavanagh, Angela; Huang, Johnny X; Blaskovich, Mark A; Cooper, Matthew A; Obregon-Henao, Andres; Orme, Ian; Tjandra, Edwin S; Stroeher, Uwe H; Brown, Melissa H; Macardle, Cindy; van Holst, Nick; Ling Tong, Chee; Slattery, Ashley D; Gibson, Christopher T; Raston, Colin L; Boulos, Ramiz A

    2015-01-01

    The growing problem of antibiotic-resistant bacteria is a major threat to human health. Paradoxically, new antibiotic discovery is declining, with most of the recently approved antibiotics corresponding to new uses for old antibiotics or structurally similar derivatives of known antibiotics. We used an in silico approach to design a new class of nontoxic antimicrobials for the bacteria-specific mechanosensitive ion channel of large conductance, MscL. One antimicrobial of this class, compound 10, is effective against methicillin-resistant Staphylococcus aureus with no cytotoxicity in human cell lines at the therapeutic concentrations. As predicted from in silico modeling, we show that the mechanism of action of compound 10 is at least partly dependent on interactions with MscL. Moreover we show that compound 10 cured a methicillin-resistant S. aureus infection in the model nematode Caenorhabditis elegans. Our work shows that compound 10, and other drugs that target MscL, are potentially important therapeutics against antibiotic-resistant bacterial infections. PMID:25649856

  8. Antidiabetic Indian Plants: A Good Source of Potent Amylase Inhibitors

    PubMed Central

    Bhat, Menakshi; Zinjarde, Smita S.; Bhargava, Shobha Y.; Kumar, Ameeta Ravi; Joshi, Bimba N.

    2011-01-01

    Diabetes is known as a multifactorial disease. The treatment of diabetes (Type II) is complicated due to the inherent patho-physiological factors related to this disease. One of the complications of diabetes is post-prandial hyperglycemia (PPHG). Glucosidase inhibitors, particularly α-amylase inhibitors are a class of compounds that helps in managing PPHG. Six ethno-botanically known plants having antidiabetic property namely, Azadirachta indica Adr. Juss.; Murraya koenigii (L.) Sprengel; Ocimum tenuflorum (L.) (syn: Sanctum); Syzygium cumini (L.) Skeels (syn: Eugenia jambolana); Linum usitatissimum (L.) and Bougainvillea spectabilis were tested for their ability to inhibit glucosidase activity. The chloroform, methanol and aqueous extracts were prepared sequentially from either leaves or seeds of these plants. It was observed that the chloroform extract of O. tenuflorum; B. spectabilis; M. koenigii and S. cumini have significant α-amylase inhibitory property. Plants extracts were further tested against murine pancreatic, liver and small intestinal crude enzyme preparations for glucosidase inhibitory activity. The three extracts of O. tenuflorum and chloroform extract of M. koenigi showed good inhibition of murine pancreatic and intestinal glucosidases as compared with acarbose, a known glucosidase inhibitor. PMID:18955350

  9. A new antibiotic with potent activity targets MscL.

    PubMed

    Iscla, Irene; Wray, Robin; Blount, Paul; Larkins-Ford, Jonah; Conery, Annie L; Ausubel, Frederick M; Ramu, Soumya; Kavanagh, Angela; Huang, Johnny X; Blaskovich, Mark A; Cooper, Matthew A; Obregon-Henao, Andres; Orme, Ian; Tjandra, Edwin S; Stroeher, Uwe H; Brown, Melissa H; Macardle, Cindy; van Holst, Nick; Ling Tong, Chee; Slattery, Ashley D; Gibson, Christopher T; Raston, Colin L; Boulos, Ramiz A

    2015-07-01

    The growing problem of antibiotic-resistant bacteria is a major threat to human health. Paradoxically, new antibiotic discovery is declining, with most of the recently approved antibiotics corresponding to new uses for old antibiotics or structurally similar derivatives of known antibiotics. We used an in silico approach to design a new class of nontoxic antimicrobials for the bacteria-specific mechanosensitive ion channel of large conductance, MscL. One antimicrobial of this class, compound 10, is effective against methicillin-resistant Staphylococcus aureus with no cytotoxicity in human cell lines at the therapeutic concentrations. As predicted from in silico modeling, we show that the mechanism of action of compound 10 is at least partly dependent on interactions with MscL. Moreover we show that compound 10 cured a methicillin-resistant S. aureus infection in the model nematode Caenorhabditis elegans. Our work shows that compound 10, and other drugs that target MscL, are potentially important therapeutics against antibiotic-resistant bacterial infections.

  10. Comprehensive Review on Betulin as a Potent Anticancer Agent

    PubMed Central

    Kiełbus, Michał; Stepulak, Andrzej

    2015-01-01

    Numerous plant-derived substances, and their derivatives, are effective antitumour and chemopreventive agents. Yet, there are also a plethora of tumour types that do not respond, or become resistant, to these natural substances. This requires the discovery of new active compounds. Betulin (BE) is a pentacyclic triterpene and secondary metabolite of plants abundantly found in the outer bark of the birch tree Betulaceae sp. BE displays a broad spectrum of biological and pharmacological properties, among which the anticancer and chemopreventive activity attract most of the attention. In this vein, BE and its natural and synthetic derivatives act specifically on cancer cells with low cytotoxicity towards normal cells. Although the antineoplastic mechanism of action of BE is not well understood yet, several interesting aspects of BE's interactions are coming to light. This review will summarize the anticancer and chemopreventive potential of BE in vitro and in vivo by carefully dissecting and comparing the doses and tumour lines used in previous studies, as well as focusing on mechanisms underlying its activity at cellular and molecular level, and discuss future prospects. PMID:25866796

  11. Comprehensive review on betulin as a potent anticancer agent.

    PubMed

    Król, Sylwia Katarzyna; Kiełbus, Michał; Rivero-Müller, Adolfo; Stepulak, Andrzej

    2015-01-01

    Numerous plant-derived substances, and their derivatives, are effective antitumour and chemopreventive agents. Yet, there are also a plethora of tumour types that do not respond, or become resistant, to these natural substances. This requires the discovery of new active compounds. Betulin (BE) is a pentacyclic triterpene and secondary metabolite of plants abundantly found in the outer bark of the birch tree Betulaceae sp. BE displays a broad spectrum of biological and pharmacological properties, among which the anticancer and chemopreventive activity attract most of the attention. In this vein, BE and its natural and synthetic derivatives act specifically on cancer cells with low cytotoxicity towards normal cells. Although the antineoplastic mechanism of action of BE is not well understood yet, several interesting aspects of BE's interactions are coming to light. This review will summarize the anticancer and chemopreventive potential of BE in vitro and in vivo by carefully dissecting and comparing the doses and tumour lines used in previous studies, as well as focusing on mechanisms underlying its activity at cellular and molecular level, and discuss future prospects.

  12. Capsaicin: a potent inhibitor of carbonic anhydrase isoenzymes.

    PubMed

    Arabaci, Betul; Gulcin, Ilhami; Alwasel, Saleh

    2014-07-10

    Carbonic anhydrase (CA, EC 4.2.1.1) is a zinc containing metalloenzyme that catalyzes the rapid and reversible conversion of carbon dioxide (CO2) and water (H2O) into a proton (H+) and bicarbonate (HCO3-) ion. On the other hand, capsaicin is the main component in hot chili peppers and is used extensively used in spices, food additives and drugs; it is responsible for their spicy flavor and pungent taste. There are sixteen known CA isoforms in humans. Human CA isoenzymes I, and II (hCA I and hCA II) are ubiquitous cytosolic isoforms. In this study, the inhibition properties of capsaicin against the slow cytosolic isoform hCA I, and the ubiquitous and dominant rapid cytosolic isozymes hCA II were studied. Both CA isozymes were inhibited by capsaicin in the micromolar range. This naturally bioactive compound has a Ki of 696.15 µM against hCA I, and of 208.37 µM against hCA II.

  13. Domoic acid is a potent neurotoxin to neonatal rats.

    PubMed

    Xi, D; Peng, Y G; Ramsdell, J S

    1997-01-01

    Domoic acid induces a time-dependent neuroexcitotoxic effect in neonatal rats characterized by hyperactivity, stereotypic scratching, convulsions, and death with observable behaviors occurring at exposures 40 times lower by body weight in neonates than reported in adults. Low doses of domoic acid (0.1 mg/kg) induced c-fos in the central nervous system which was inhibited in part by 2-amino-5-phosphonovaleric acid, an NMDA receptor antagonist. Domoic acid caused no evidence of structural alteration in the brain of neonates as assessed by Nissel staining and cupric silver histochemistry. Domoic acid induced reproducible behavioral effects at doses as low as 0.05 mg/kg and induced seizures doses as low as 0.2 mg/kg. Determination of serum domoic acid levels after 60 min exposure indicated that serum levels of domoic acid in the neonates corresponded closely to the serum levels that induce similar symptoms in adult rats and mice. We conclude that neonatal rats are highly sensitive to the neuroexcitatory and lethal effects of domoic acid and that the increased sensitivity results from higher than expected serum levels of domoic acid. These findings are consistent with other findings that reduced serum clearance of domoic acid is a predisposing factor to domoic acid toxicity.

  14. Auger analysis of films formed on metals in sliding contact with halogenated polymers

    NASA Technical Reports Server (NTRS)

    Pepper, S. V.

    1974-01-01

    The use of Auger electron spectroscopy (AES) to search for transferred polymer must contend with the fact that there has been no published work on Auger analysis of polymers. Since this is a new area for AES, the Auger spectra of polymers and of halogenated polymers in particular is discussed. It is shown that the Auger spectra of halogenated polymers have certain characteristics that permit an assessment of whether a polymeric transfer film has been established by sliding contact. The discussion is general and the concepts should be useful in considering the Auger analysis of any polymer. The polymers chosen for this study are the halogenated polymers polytetrafluoroethylene (PTFE), polyvinyl chloride (PVC), and polychlorotrifluorethylene (PCTFE).

  15. Nanomedicine as a potent strategy in melanoma tumor microenvironment.

    PubMed

    Pautu, Vincent; Leonetti, Daniela; Lepeltier, Elise; Clere, Nicolas; Passirani, Catherine

    2017-02-20

    Melanoma originated from melanocytes is the most aggressive type of skin cancer. Despite considerable progresses in clinical treatment with the discovery of BRAF or MEK inhibitors and monoclonal antibodies, the durability of response to treatment is often limited to the development of acquired resistance and systemic toxicity. The limited success of conventional treatment highlights the importance of understanding the role of melanoma tumor microenvironment in tumor developement and drug resistance. Nanoparticles represent a promising strategy for the development of new cancer treatments able to improve the bioavailability of drugs and increase their penetration by targeting specifically tumors cells and/or tumor environment. In this review, we will discuss the main influence of tumor microenvironment in melanoma growth and treatment outcome. Furthermore, third generation loaded nanotechnologies represent an exciting tool for detection, treatment, and escape from possible mechanism of resistance mediated by tumor microenvironment, and will be highlighted in this review.

  16. CGS 8216: receptor binding characteristics of a potent benzodiazepine antagonist.

    PubMed

    Czernik, A J; Petrack, B; Kalinsky, H J; Psychoyos, S; Cash, W D; Tsai, C; Rinehart, R K; Granat, F R; Lovell, R A; Brundish, D E; Wade, R

    1982-01-25

    CGS 8216 is a novel nonbenzodiazepine that inhibited 3H-flunitrazepam (3H-FLU) binding to rat synaptosomal membranes in vitro at subnanomolar concentrations. It prevented the in vivo labeling of brain benzodiazepine receptors by 3H-FLU with the same potency as diazepam when given orally to mice. Pharmacologic tests showed that it was devoid of benzodiazepine-like activity but it antagonized the actions of diazepam in these tests. It did not interact with alpha- or beta- adrenergic, H1-histaminergic or GABA receptors but it inhibited adenosine-activation of cyclic AMP formation. Studies with 3H-CGS 8216 demonstrated that it bound specifically and with high affinity to rat forebrain membranes and was displaced by drugs with an order of potencies similar to that observed when 3H-diazepam and 3H-FLU were used as radioligands. The regional distribution of 3H-CGS 8216 binding sites in the brain was also similar to that of 3H-FLU. Dissociation of 3H-CGS 8216 binding was slow at 0 degrees C but increased with temperature and was almost complete within 1 min at 37 degrees C. Scatchard analyses were linear, yielding KD values of 0.044, 0.11 and 0.18 nM at 0, 25 and 37 degrees C, respectively; the Bmax value did not change appreciably with temperature and was approximately 1000 fmoles/mg protein. Using 3H-FLU, the value for Bmax as well as for the KD increased with temperature. The total number of binding sites determined for 3H-FLU was greater than that for 3H-CGS 8216 at each temperature. CGS 8216 exhibited mixed-type inhibition of 3H-FLU binding. GABA did not stimulate 3H-CGS 8216 binding whereas it enhanced 3H-FLU binding. CGS 8216 may be a useful ligand for probing the antagonist properties of the benzodiazepine receptor and is likely to exhibit interesting therapeutic effects.

  17. The antibiotic micrococcin is a potent inhibitor of growth and protein synthesis in the malaria parasite.

    PubMed

    Rogers, M J; Cundliffe, E; McCutchan, T F

    1998-03-01

    The antibiotic micrococcin is a potent growth inhibitor of the human malaria parasite Plasmodium falciparum, with a 50% inhibitory concentration of 35 nM. This is comparable to or less than the corresponding levels of commonly used antimalarial drugs. Micrococcin, like thiostrepton, putatively targets protein synthesis in the plastid-like organelle of the parasite.

  18. Psymberin, a potent sponge-derived cytotoxin from Psammocinia distantly related to the pederin family.

    PubMed

    Cichewicz, Robert H; Valeriote, Frederick A; Crews, Phillip

    2004-06-10

    [structure: see text] Bioassay-guided fractionation of the sponge Psammocinia sp. afforded psymberin (1) possessing 5S,8S,9S,11R,13R,15S,16R,17R stereochemistry. Psymberin exhibits structural similarities to the pederin family metabolites. The potent cytotoxicty and unique structural features of 1 make it a promising lead for therapeutic development.

  19. Highly potent stem cells from full-term amniotic fluid: A realistic perspective.

    PubMed

    Hamid, Adila A; Joharry, Muhammad Khair; Mun-Fun, Hoo; Hamzah, Siti Nurusaadah; Rejali, Zulida; Yazid, Mohd Nazri; Karuppiah, Thilakavathy; Nordin, Norshariza

    2017-03-01

    Amniotic fluid (AF) is now known to harbor highly potent stem cells, making it an excellent source for cell therapy. However, most of the stem cells isolated are from AF of mid-term pregnancies in which the collection procedure involves an invasive technique termed amniocentesis. This has limited the access in getting the fluid as the technique imposes certain level of risks to the mother as well as to the fetus. Alternatively, getting AF from full-term pregnancies or during deliveries would be a better resolution. Unfortunately, very few studies have isolated stem cells from AF at this stage of gestation, the fluid that is merely discarded. The question remains whether full-term AF harbors stem cells of similar potency as of the stem cells of mid-term AF. Here, we aim to review the prospect of having this type of stem cells by first looking at the origin and contents of AF particularly during different gestation period. We will then discuss the possibility that the AF, at full term, contains a population of highly potent stem cells. These stem cells are distinct from, and probably more potent than the AF mesenchymal stem cells (AF-MSCs) isolated from full-term AF. By comparing the studies on stem cells isolated from mid-term versus full-term AF from various species, we intend to address the prospect of having highly potent amniotic fluid stem cells from AF of full-term pregnancies in human and animals.

  20. Lining material tests for the AUGER PROJECT surface detector

    NASA Astrophysics Data System (ADS)

    Escobar, C. O.; Fauth, A. C.; Guzzo, M. M.; Shibuya, E. H.

    1999-03-01

    We are trying to obtain a suitable material to compose the lining of a water Cerenkov tank for the surface detector. part of a hybrid detector of the Auger Project. Results of tests were compared with DuPont 1073Tyvek TM and obtained a reasonable performance for (PVC+BaSO 4) material.

  1. Performance of the fluorescence detectors of the pierre auger observatory

    SciTech Connect

    Bellido, Jose A.; /Adelaide U.

    2005-08-01

    Fluorescence detectors of the Pierre Auger Observatory have been operating in a stable manner since January 2004. After a brief review of the physical characteristics of the detectors, the associated atmospheric monitoring, the calibration infrastructure and the detector aperture, we will describe the steps required for the reconstruction of fluorescence event data, with emphasis on the shower profile parameters and primary energy.

  2. Auger tension leg platform: Conquering the deepwater Gulf of Mexico

    SciTech Connect

    Bourgeois, T.M.

    1994-12-31

    Conquering the ultra-deepwater Gulf of Mexico (GOM) is among the greatest challenges facing the oil and gas industry today. Explorationists have found significant quantities of hydrocarbons in the ultra-deep GOM. Since Shell Offshore Inc. (Shell) has over one-third of the deepwater GOM acreage under lease today, development of this vast new oil and gas reservoir represents a major opportunity. Shell`s Auger field, located in Garden Banks 426, was discovered in 1987 in 2,860 feet of water. This discovery kicked off a project of mammoth proportions for Shell and the industry. Shell designed and built a Tension Leg Platform (TLP) and related drilling and producing facilities for the major discovery at Prospect Auger. A TLP is a floating structure which is tethered to the seafloor. This $1.2 billion development is located in a world record shattering water depth of 2,860 feet. Integrating the complexities of this floating structure with the challenges of the subsurface makes Auger the most complex project ever undertaken by Shell`s Production Department. The Auger Project, which was conceived in 1989, is now installed within three months of the original target and $100 million under the original estimate. This is a significant success for Shell and the industry in the deepwater GOM as it opens the ultra-deepwater GOM frontier as an energy source to fuel America for decades to come.

  3. The Pierre Auger Observatory status and latest results

    NASA Astrophysics Data System (ADS)

    Berat, Corinne

    2017-03-01

    The Pierre Auger Observatory, in Argentina, is the present flagship experiment studying ultrahigh-energy cosmic rays (UHECRs). Facing the challenge due to low cosmic-ray flux at the highest energies, the Observatory has been taking data for more than a decade, reaching an exposure of over 50 000 km2 sr yr. The combination of a large surface detector array and fluorescence telescopes provides a substantial improvement in energy calibration and extensive air shower measurements, resulting in data of unprecedented quality. Moreover, the installation of a denser subarray has allowed extending the sensitivity to lower energies. Altogether, this contributes to provide important information on key questions in the UHECR field in the energy range from 0.1 EeV up to 100 EeV. A review of main results from the Pierre Auger Observatory is presented with a particular focus on the energy spectrum measurements, the mass composition studies, the arrival directions analyses, the search for neutral cosmic messengers, and the investigation of high-energy hadronic interactions. Despite this large amount of valuable results, the understanding of the nature of UHECRs and of their origin remains an open science case that the Auger collaboration is planning to address with the AugerPrime project to upgrade the Observatory.

  4. Suppression of auger recombination in ""giant"" core/shell nanocrystals

    SciTech Connect

    Garcia Santamaria, Florencio; Vela, Javier; Schaller, Richard D; Hollingsworth, Jennifer A; Klimov, Victor I; Chen, Yongfen

    2009-01-01

    Many potential applications of semiconductor nanocrystals are hindered by nonradiative Auger recombination wherein the electron-hole (exciton) recombination energy is transferred to a third charge carrier. This process severely limits the lifetime and bandwidth of optical gain, leads to large nonradiative losses in light emitting diodes and photovoltaic cells, and is believed to be responsible for intermittency ('blinking') of emission from single nanocrystals. The development of nanostructures in which Auger recombination is suppressed has been a longstanding goal in colloidal nanocrystal research. Here, we demonstrate that such suppression is possible using so-called 'giant' nanocrystals that consist of a small CdSe core and a thick CdS shell. These nanostructures exhibit a very long biexciton lifetime ({approx}10 ns) that is likely dominated by radiative decay instead of non-radiative Auger recombination. As a result of suppressed Auger recombination, even high-order multiexcitons exhibit high emission efficiencies, which allows us to demonstrate optical amplification with an extraordinarily large bandwidth (>500 me V) and record low excitation thresholds.

  5. Observation of suppressed Auger mechanism in type-I quantum well structures with delocalized electron-hole wavefunctions

    SciTech Connect

    Hassani Nia, Iman; Fathipour, Vala; Mohseni, Hooman

    2015-08-15

    We report the first observation of non-threshold Auger mechanism for a quantum well structure with Type-I band alignment. Excitation-dependent photoluminescence measurements were used to extract the Auger recombination coefficients from 77 K up to room temperature. The results verify the role of interface mediated momentum exchange as well as suppression of Auger recombination for delocalized electron-hole wavefunctions.

  6. 3,4-Disubstituted indole acylsulfonamides: a novel series of potent and selective human EP3 receptor antagonists.

    PubMed

    Zhou, Nian; Zeller, Wayne; Krohn, Michael; Anderson, Herb; Zhang, Jun; Onua, Emmanuel; Kiselyov, Alex S; Ramirez, Jose; Halldorsdottir, Gułrún; Andrésson, Thornorkell; Gurney, Mark E; Singh, Jasbir

    2009-01-01

    A series of potent and selective EP(3) receptor antagonists are described. Utilizing a pharmacophore model developed for the EP(3) receptor, a series of 3,4-disubstituted indoles were shown to be high affinity ligands for this target. These compounds showed high selectivity over IP, FP and other EP receptors and are potent antagonists in functional assays.

  7. Ultrafast X-ray Auger probing of photoexcited molecular dynamics

    DOE PAGES

    McFarland, B. K.; Farrell, J. P.; Miyabe, S.; ...

    2014-06-23

    Here, molecules can efficiently and selectively convert light energy into other degrees of freedom. Disentangling the underlying ultrafast motion of electrons and nuclei of the photoexcited molecule presents a challenge to current spectroscopic approaches. Here we explore the photoexcited dynamics of molecules by an interaction with an ultrafast X-ray pulse creating a highly localized core hole that decays via Auger emission. We discover that the Auger spectrum as a function of photoexcitation—X-ray-probe delay contains valuable information about the nuclear and electronic degrees of freedom from an element-specific point of view. For the nucleobase thymine, the oxygen Auger spectrum shifts towardsmore » high kinetic energies, resulting from a particular C–O bond stretch in the ππ* photoexcited state. A subsequent shift of the Auger spectrum towards lower kinetic energies displays the electronic relaxation of the initial photoexcited state within 200 fs. Ab-initio simulations reinforce our interpretation and indicate an electronic decay to the nπ* state.« less

  8. Ultrafast X-ray Auger probing of photoexcited molecular dynamics

    SciTech Connect

    McFarland, B. K.; Farrell, J. P.; Miyabe, S.; Tarantelli, F.; Aguilar, A.; Berrah, N.; Bostedt, C.; Bozek, J. D.; Bucksbaum, P. H.; Castagna, J. C.; Coffee, R. N.; Cryan, J. P.; Fang, L.; Feifel, R.; Gaffney, K. J.; Glownia, J. M.; Martinez, T. J.; Mucke, M.; Murphy, B.; Natan, A.; Osipov, T.; Petrović, V. S.; Schorb, S.; Schultz, Th.; Spector, L. S.; Swiggers, M.; Tenney, I.; Wang, S.; White, J. L.; White, W.; Gühr, M.

    2014-06-23

    Here, molecules can efficiently and selectively convert light energy into other degrees of freedom. Disentangling the underlying ultrafast motion of electrons and nuclei of the photoexcited molecule presents a challenge to current spectroscopic approaches. Here we explore the photoexcited dynamics of molecules by an interaction with an ultrafast X-ray pulse creating a highly localized core hole that decays via Auger emission. We discover that the Auger spectrum as a function of photoexcitation—X-ray-probe delay contains valuable information about the nuclear and electronic degrees of freedom from an element-specific point of view. For the nucleobase thymine, the oxygen Auger spectrum shifts towards high kinetic energies, resulting from a particular C–O bond stretch in the ππ* photoexcited state. A subsequent shift of the Auger spectrum towards lower kinetic energies displays the electronic relaxation of the initial photoexcited state within 200 fs. Ab-initio simulations reinforce our interpretation and indicate an electronic decay to the nπ* state.

  9. ET-22CONVECTION-ENHANCED DELIVERY OF THE AUGER-ELECTRON-EMITTER 125I-UdR: A HIGHLY EFFICIENT THERAPY IN AN ORTHOTOPIC GLIOBLASTOMA XENOGRAFT MODEL

    PubMed Central

    Halle, Bo; Thisgaard, Helge; Aaberg-Jessen, Charlotte; Olsen, Birgitte; Dam, Johan; Langkjær, Niels; Munthe, Sune; Någren, Kjell; Høilund-Carlsen, Poul Flemming; Kristensen, Bjarne

    2014-01-01

    BACKGROUND: Glioblastomas (GBMs), the most common and malignant primary brain tumors, always recur after standard treatment. In order to develop more efficient therapies, we tested a novel therapeutic approach using the radioactive Auger-electron-emitter (AEE) [125I]5-Iodo-2'-deoxyuridine (125I-UdR). This drug incorporates into DNA of dividing cells and upon decay emission of Auger-electrons causes clusters of double strand breaks leading to cell death. METHODS: In vitro, cells from two GBM spheroid cultures (T78 & T87) were exposed to either 125I-UdR or 127I-UdR (non-radioactive analogue) and tumor cell viability and migration were measured. In vivo, nude rats were implanted orthotopically with T87 cells and after tumor formation micro infusion pumps were implanted enabling direct intratumoral convection-enhanced delivery (CED). Animals were divided into three groups (I-III). Group I (n = 8) was treated with 127I-UdR by CED, group II (n = 7) with neoadjuvant methotrexate (MTX) + 125I-UdR by CED and group III with neoadjuvant MTX + 125I-UdR by CED and concomitant systemic temozolomide (TMZ). Rats were followed for 180 days post-treatment with repeated [11C]methylaminoisobutyric acid ([11C]MeAIB) positron emission tomography scans and blood sampling. Single photon emission computed tomography/computed tomography (SPECT/CT) scans were performed to evaluate 125I-UdR distribution. Additionally, post-mortem histological examination of brain, liver, kidneys and thyroid gland was performed. RESULTS: In vitro, 125I-UdR significantly decreased GBM cell viability and migration. In group I, no animals (8/8) survived longer than 23 days after treatment start. In group II, 4/7 animals survived the entire observation period of 180 days. In group III, all animals (8/8) survived the entire observation period. SPECT/CT showed a widespread intracerebral distribution of 125I-UdR, while blood samples and post-mortem histology revealed no signs of dose-limiting adverse effects

  10. X-ray excited Auger transitions of Pu compounds

    SciTech Connect

    Nelson, Art J. Grant, William K.; Stanford, Jeff A.; Siekhaus, Wigbert J.; Allen, Patrick G.; McLean, William

    2015-05-15

    X-ray excited Pu core–valence–valence and core–core–valence Auger line-shapes were used in combination with the Pu 4f photoelectron peaks to characterize differences in the oxidation state and local electronic structure for Pu compounds. The evolution of the Pu 4f core-level chemical shift as a function of sputtering depth profiling and hydrogen exposure at ambient temperature was quantified. The combination of the core–valence–valence Auger peak energies with the associated chemical shift of the Pu 4f photoelectron line defines the Auger parameter and results in a reliable method for definitively determining oxidation states independent of binding energy calibration. Results show that PuO{sub 2}, Pu{sub 2}O{sub 3}, PuH{sub 2.7}, and Pu have definitive Auger line-shapes. These data were used to produce a chemical state (Wagner) plot for select plutonium oxides. This Wagner plot allowed us to distinguish between the trivalent hydride and the trivalent oxide, which cannot be differentiated by the Pu 4f binding energy alone.

  11. First test results from the Front-End Board with Cyclone V as a test high-resolution platform for the Auger-Beyond-2015 Front End Electronics

    SciTech Connect

    Szadkowski, Zbigniew

    2015-07-01

    The paper presents the first results from the Front- End Board (FEB) with the biggest Cyclone{sup R} V E FPGA 5CEFA9F31I7N, supporting 8 channels sampled up to 250 MSps at 14-bit resolution. Considered sampling for the SD is 120 MSps, however, the FEB has been developed with external anti-aliasing filters to keep a maximal flexibility. Six channels are targeted to the SD, two the rest for other experiments like: Auger Engineering Radio Array and additional muon counters. More channels and higher sampling generate larger size of registered events. We used the standard radio channel for a radio transmission from the detectors to the Central Data Acquisition Station (CDAS) to avoid at present a significant modification of a software in both sides: the detector and the CDAS (planned in a future for a final design). Seven FEBs have been deployed in the test detectors on a dedicated Engineering Array in a hexagon. Several variants of the FPGA code were tested for 120, 160, 200 and even 240 MSps DAQ. Tests confirmed a stability and reliability of the FEB design in real pampas conditions with more than 40 deg. C daily temperature variation and a strong sun exposition with a limited power budget only from a single solar panel. (authors)

  12. Auger electron spectroscopy study of reactor walls in transition from an O{sub 2} to a Cl{sub 2} plasma

    SciTech Connect

    Guha, Joydeep; Donnelly, Vincent M.

    2009-05-15

    In plasma etching processes, the reactor wall conditions can change over time due to a number of intentional and unintentional reasons, leading to a variability in the radical number densities in the plasma, caused by changes in the probabilities for reactions such as recombination at the walls. This leads to loss of reproducibility in the etching process. Here the authors isolated one such effect in which the feed gas was changed in the absence of a substrate. The transient surface composition of an anodized aluminum surface was determined for inductively coupled plasmas as the gas was switched from Cl{sub 2} to O{sub 2} and vice versa. The study was carried out with the spinning wall method and Auger electron spectroscopy. When the surface was first conditioned in an O{sub 2} plasma and then exposed to Cl{sub 2} plasmas, a rapid uptake of Cl was found in the first tens of seconds, followed by a slow approach to a steady-state value within {approx}5 min of plasma exposure. Conversely, when the surface was exposed to a Cl{sub 2} plasma for a long time and then switched to an O{sub 2} plasma, the anodized aluminum surface underwent a rapid dechlorination in the first few seconds and then a slow approach to steady state over {approx}3 min. Throughout these treatments, the coverages of Si (from erosion of the quartz discharge tube) and O were nearly constant.

  13. A novel curcumin analogue is a potent chemotherapy candidate for human hepatocellular carcinoma

    PubMed Central

    Zhao, Ji-An; Sang, Mei-Xiang; Geng, Cui-Zhi; Wang, Shi-Jie; Shan, Bao-En

    2016-01-01

    Curcumin (CUR) has been demonstrated to protect against carcinogenesis and to prevent tumor development in cancer; however, the clinical application of CUR is limited by its instability and poor metabolic properties. The present study offers an strategy for a novel CUR analogue, (1E,4E)-1,5-bis(2-bromophenyl)penta-1,4-dien-3-one (GL63), to be used as a potential therapeutic agent for hepatocellular carcinoma (HCC) in vitro and in vivo. The current study demonstrated that GL63 exhibited more potent inhibition of proliferation of HCC cells than CUR. GL63 induced G0/G1 phase cell cycle arrest and apoptosis in SK-HEP-1 cells in a dose-dependent manner, and was more potent than CUR, according to the flow cytometry data. The present study demonstrated for the first time that the inhibition of the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway by GL63 resulted in a protective effect against HCC cell growth. GL63 was more effective than CUR in regulating STAT3 downstream targets, which contributed to the suppression of cell proliferation and the induction of cell apoptosis. In addition, the effects of GL63 were tested in a model of N-nitrosodiethylamine (DEN)-induced HCC in Wistar rats. Although macroscopic and microscopic features suggested that both GL63 and CUR were effective in inhibiting DEN-induced hepatocarcinogenesis, GL63 exerted a stronger effect than CUR. Immunohistochemical analysis for proliferating cell nuclear antigen demonstrated significant differences among the DEN-bearing non-treated, DEN-bearing GL63-treated and DEN-bearing, CUR-treated groups (P=0.039). It was concluded that GL63 was a potent agent able to suppress the proliferation of HCC cells by inhibition of the JAK2/STAT3 signaling pathway, with more favorable pharmacological activity than CUR, and may be a more potent compound for the prevention of DEN-induced hepatocarcinogenesis in rats than CUR. PMID:27895800

  14. Optimization of a Dibenzodiazepine Hit to a Potent and Selective Allosteric PAK1 Inhibitor

    PubMed Central

    2015-01-01

    The discovery of inhibitors targeting novel allosteric kinase sites is very challenging. Such compounds, however, once identified could offer exquisite levels of selectivity across the kinome. Herein we report our structure-based optimization strategy of a dibenzodiazepine hit 1, discovered in a fragment-based screen, yielding highly potent and selective inhibitors of PAK1 such as 2 and 3. Compound 2 was cocrystallized with PAK1 to confirm binding to an allosteric site and to reveal novel key interactions. Compound 3 modulated PAK1 at the cellular level and due to its selectivity enabled valuable research to interrogate biological functions of the PAK1 kinase. PMID:26191365

  15. Vacuolin-1 potently and reversibly inhibits autophagosome-lysosome fusion by activating RAB5A

    PubMed Central

    Lu, Yingying; Dong, Shichen; Hao, Baixia; Li, Chang; Zhu, Kaiyuan; Guo, Wenjing; Wang, Qian; Cheung, King-Ho; Wong, Connie WM; Wu, Wu-Tian; Markus, Huss; Yue, Jianbo

    2014-01-01

    Autophagy is a catabolic lysosomal degradation process essential for cellular homeostasis and cell survival. Dysfunctional autophagy has been associated with a wide range of human diseases, e.g., cancer and neurodegenerative diseases. A large number of small molecules that modulate autophagy have been widely used to dissect this process and some of them, e.g., chloroquine (CQ), might be ultimately applied to treat a variety of autophagy-associated human diseases. Here we found that vacuolin-1 potently and reversibly inhibited the fusion between autophagosomes and lysosomes in mammalian cells, thereby inducing the accumulation of autophagosomes. Interestingly, vacuolin-1 was less toxic but at least 10-fold more potent in inhibiting autophagy compared with CQ. Vacuolin-1 treatment also blocked the fusion between endosomes and lysosomes, resulting in a defect in general endosomal-lysosomal degradation. Treatment of cells with vacuolin-1 alkalinized lysosomal pH and decreased lysosomal Ca2+ content. Besides marginally inhibiting vacuolar ATPase activity, vacuolin-1 treatment markedly activated RAB5A GTPase activity. Expression of a dominant negative mutant of RAB5A or RAB5A knockdown significantly inhibited vacuolin-1-induced autophagosome-lysosome fusion blockage, whereas expression of a constitutive active form of RAB5A suppressed autophagosome-lysosome fusion. These data suggest that vacuolin-1 activates RAB5A to block autophagosome-lysosome fusion. Vacuolin-1 and its analogs present a novel class of drug that can potently and reversibly modulate autophagy. PMID:25483964

  16. Nanodosimetry of Auger electrons: A case study from the decay of 125I and 0-18-eV electron stopping cross sections of cytosine

    NASA Astrophysics Data System (ADS)

    Michaud, M.; Bazin, M.; Sanche, L.

    2013-03-01

    Radiopharmaceuticals emitting Auger electrons are often injected into patients undergoing cancer treatment with targeted radionuclide therapy (TRT). In this type of radiotherapy, the radiation source is radial and most of the emitted primary particles are low-energy electrons (LEEs) having kinetic energies distributed mostly from zero to a few hundred electron volts with very short ranges in biological media. These LEEs generate a high density of energy deposits and clustered damage, thus offering a relative biological effectiveness comparable to that of alpha particles. In this paper, we present a simple model and corresponding measurements to assess the energy deposited near the site of the radiopharmaceuticals in TRT. As an example, a calculation is performed for the decay of a single 125I radionuclide surrounded by a 1-nm-radius spherical shell of cytosine molecules using the energy spectrum of LEEs emitted by 125I along with their stopping cross sections between 0 and 18 eV. The dose absorbed by the cytosine shell, which occupies a volume of 4 nm3, is extremely high. It amounts to 79 kGy per decay of which 3%, 39%, and 58% is attributed to vibrational excitations, electronic excitations, and ionization processes, respectively.

  17. "Appearance potent"? A content analysis of UK gay and straight men's magazines.

    PubMed

    Jankowski, Glen S; Fawkner, Helen; Slater, Amy; Tiggemann, Marika

    2014-09-01

    With little actual appraisal, a more 'appearance potent' (i.e., a reverence for appearance ideals) subculture has been used to explain gay men's greater body dissatisfaction in comparison to straight men's. This study sought to assess the respective appearance potency of each subculture by a content analysis of 32 issues of the most read gay (Attitude, Gay Times) and straight men's magazines (Men's Health, FHM) in the UK. Images of men and women were coded for their physical characteristics, objectification and nudity, as were the number of appearance adverts and articles. The gay men's magazines featured more images of men that were appearance ideal, nude and sexualized than the straight men's magazines. The converse was true for the images of women and appearance adverts. Although more research is needed to understand the effect of this content on the viewer, the findings are consistent with a more appearance potent gay male subculture.

  18. Analysis of switchgrass-derived bio-oil and associated aqueous phase generated in a semi-pilot scale auger pyrolyzer

    SciTech Connect

    Ren, Shoujie; Ye, X. Philip; Borole, Abhijeet P.; Kim, Pyoungchung; Labbé, Ncole

    2016-03-30

    To efficiently utilize water-soluble compounds in bio-oil and evaluate the potential effects of these compounds on processes such as microbial electrolysis, our study investigated the physico-chemical properties of bio-oil and the associated aqueous phase generated from switchgrass using a semi-pilot scale auger pyrolyzer. Combining separation and detection strategies with organic solvent extraction, an array of analytical instruments and methods were used to identify and quantify the chemical constituents. Separation of an aqueous phase from crude bio-oil was achieved by adding water (water: crude bio-oil at 4:1 in weight), which resulted in a partition of 61 wt.% of the organic compounds into a bio-oil aqueous phase (BOAP). GC/MS analysis for BOAP identified over 40 compounds of which 16 were quantified. Acetic acid, propionic acid, and levoglucosan are the major components in BOAP. In addition, a significant portion of chemicals that have the potential to be upgraded to hydrocarbon fuels were extracted to BOAP (77 wt.% of the alcohols, 61 wt.% of the furans, and 52 wt.% of the phenolic compounds in crude bio-oil). Valorization of the BOAP may require conversion methods capable of accommodating a very broad substrate specificity. Ultimately, a better separation strategy is needed to selectively remove the acidic and polar components from crude bio-oil to improve economic feasibility of biorefinery operations.

  19. Analysis of switchgrass-derived bio-oil and associated aqueous phase generated in a semi-pilot scale auger pyrolyzer

    DOE PAGES

    Ren, Shoujie; Ye, X. Philip; Borole, Abhijeet P.; ...

    2016-03-30

    To efficiently utilize water-soluble compounds in bio-oil and evaluate the potential effects of these compounds on processes such as microbial electrolysis, our study investigated the physico-chemical properties of bio-oil and the associated aqueous phase generated from switchgrass using a semi-pilot scale auger pyrolyzer. Combining separation and detection strategies with organic solvent extraction, an array of analytical instruments and methods were used to identify and quantify the chemical constituents. Separation of an aqueous phase from crude bio-oil was achieved by adding water (water: crude bio-oil at 4:1 in weight), which resulted in a partition of 61 wt.% of the organic compoundsmore » into a bio-oil aqueous phase (BOAP). GC/MS analysis for BOAP identified over 40 compounds of which 16 were quantified. Acetic acid, propionic acid, and levoglucosan are the major components in BOAP. In addition, a significant portion of chemicals that have the potential to be upgraded to hydrocarbon fuels were extracted to BOAP (77 wt.% of the alcohols, 61 wt.% of the furans, and 52 wt.% of the phenolic compounds in crude bio-oil). Valorization of the BOAP may require conversion methods capable of accommodating a very broad substrate specificity. Ultimately, a better separation strategy is needed to selectively remove the acidic and polar components from crude bio-oil to improve economic feasibility of biorefinery operations.« less

  20. UNC2025, a Potent and Orally Bioavailable MER/FLT3 Dual Inhibitor

    PubMed Central

    2015-01-01

    We previously reported a potent small molecule Mer tyrosine kinase inhibitor UNC1062. However, its poor PK properties prevented further assessment in vivo. We report here the sequential modification of UNC1062 to address DMPK properties and yield a new potent and highly orally bioavailable Mer inhibitor, 11, capable of inhibiting Mer phosphorylation in vivo, following oral dosing as demonstrated by pharmaco-dynamic (PD) studies examining phospho-Mer in leukemic blasts from mouse bone marrow. Kinome profiling versus more than 300 kinases in vitro and cellular selectivity assessments demonstrate that 11 has similar subnanomolar activity against Flt3, an additional important target in acute myelogenous leukemia (AML), with pharmacologically useful selectivity versus other kinases examined. PMID:25068800

  1. UNC2025, a potent and orally bioavailable MER/FLT3 dual inhibitor.

    PubMed

    Zhang, Weihe; DeRyckere, Deborah; Hunter, Debra; Liu, Jing; Stashko, Michael A; Minson, Katherine A; Cummings, Christopher T; Lee, Minjung; Glaros, Trevor G; Newton, Dianne L; Sather, Susan; Zhang, Dehui; Kireev, Dmitri; Janzen, William P; Earp, H Shelton; Graham, Douglas K; Frye, Stephen V; Wang, Xiaodong

    2014-08-28

    We previously reported a potent small molecule Mer tyrosine kinase inhibitor UNC1062. However, its poor PK properties prevented further assessment in vivo. We report here the sequential modification of UNC1062 to address DMPK properties and yield a new potent and highly orally bioavailable Mer inhibitor, 11, capable of inhibiting Mer phosphorylation in vivo, following oral dosing as demonstrated by pharmaco-dynamic (PD) studies examining phospho-Mer in leukemic blasts from mouse bone marrow. Kinome profiling versus more than 300 kinases in vitro and cellular selectivity assessments demonstrate that 11 has similar subnanomolar activity against Flt3, an additional important target in acute myelogenous leukemia (AML), with pharmacologically useful selectivity versus other kinases examined.

  2. Discovery of DS-1558: A Potent and Orally Bioavailable GPR40 Agonist

    PubMed Central

    2015-01-01

    GPR40 is a G protein-coupled receptor that is predominantly expressed in pancreatic β-cells. GPR40 agonists stimulate insulin secretion in the presence of high glucose concentration. On the basis of this mechanism, GPR40 agonists are possible novel insulin secretagogues with reduced or no risk of hypoglycemia. The improvement of in vitro activity and metabolic stability of compound 1 led to the discovery of 13, (3S)-3-ethoxy-3-(4-{[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]oxy}phenyl)propanoic acid, as a potent and orally available GPR40 agonist. Compound 13 (DS-1558) was found to have potent glucose lowering effects during an oral glucose tolerance test in ZDF rats. PMID:25815144

  3. Combretastatin linked 1,3,4-oxadiazole conjugates as a Potent Tubulin Polymerization inhibitors.

    PubMed

    Kamal, Ahmed; Srikanth, P S; Vishnuvardhan, M V P S; Kumar, G Bharath; Suresh Babu, Korrapati; Hussaini, S M Ali; Kapure, Jeevak Sopanrao; Alarifi, Abdullah

    2016-04-01

    A new class of combretastatin linked 1,3,4-oxadiazoles were designed, synthesized and screened for their cytotoxic activity against five human cancer cell lines such as HeLa, DU-145, A549, MDA-MB-231 and B16. These compounds showed significant cytotoxicity with IC50 values in the range 0.118-54.32μM. Conjugate 5m displayed potent antiproliferative activity against DU-145 cell line. Flow cytometric analysis revealed that these compounds arrested the cell cycle in G2/M phase. Moreover, the tubulin polymerization assay and immunofluorescence analysis indicate that 5m exhibits potent inhibitory effect on the tubulin assembly. Further, DNA fragmentation and Hoecst staining assays confirm that 5m induces apoptosis. Molecular docking studies and competitive binding assay indicated that 5m effectively bind at the colchicine binding site of the tubulin.

  4. A Synthetic 7,8-Dihydroxyflavone Derivative Promotes Neurogenesis and Exhibits Potent Antidepressant Effect

    PubMed Central

    Liu, Xia; Chan, Chi-Bun; Jang, Sung-Wuk; Pradoldej, Sompol; Huang, Junjian; He, Kunyan; Phun, Lien H.; France, Stefan; Xiao, Ge; Jia, Yonghui; Luo, Hongbo R.; Ye, Keqiang

    2011-01-01

    7,8-Dihydroxyflavone is a recently identified small molecular tropomyosin-receptor-kinase B (TrkB) agonist. Our preliminary structural activity relationship (SAR) study showed that the 7,8-dihydroxy groups are essential for the agonistic effect. To improve the lead compound's agonistic activity, we have conducted an extensive SAR study and synthesized numerous derivatives. We have successfully identified 4'-dimethylamino-7,8-dihydroxyflavone that displays higher TrkB agonistic activity than the lead. This novel compound also exhibits a more robust and longer TrkB activation effect in animals. Consequently, this new compound reveals more potent anti-apoptotic activity. Interestingly, chronic oral administration of 4'-dimethylamino-7,8-dihydroxyflavone and its lead strongly promotes neurogenesis in dentate gyrus and demonstrates marked antidepressant effects. Hence, our data support that the synthetic 4'-dimethylamino-7,8-dihydroxyflavone and its lead both are orally bioavailable TrkB agonists and possess potent antidepressant effects. PMID:21073191

  5. A-ring modified betulinic acid derivatives as potent cancer preventive agents.

    PubMed

    Hung, Hsin-Yi; Nakagawa-Goto, Kyoko; Tokuda, Harukuni; Iida, Akira; Suzuki, Nobutaka; Bori, Ibrahim D; Qian, Keduo; Lee, Kuo-Hsiung

    2014-02-01

    Ten new 3,4-seco betulinic acid (BA) derivatives were designed and synthesized. Among them, compounds 7-15 exhibited enhanced chemopreventive ability in an in vitro short-term 12-O-tetradecanoylphorbol-13-acetate (TPA) induced Epstein-Barr virus early antigen (EBV-EA) activation assay in Raji cells. Specifically, analogs with a free C-28 carboxylic acid, including 7, 8, 11, and 13, inhibited EBV-EA activation significantly. The most potent compound 8 displayed 100% inhibition at 1×10(3) mol ratio/TPA and 73.4%, 35.9%, and 8.4% inhibition at 5×10(2), 1×10(2), and 1×10 mol ratio/TPA, respectively, comparable with curcumin at high concentration and better than curcumin at low concentration. The potent chemopreventive activity of novel seco A-ring BAs (8 and 11) was further confirmed in an in vivo mouse skin carcinogenesis assay.

  6. Effect of Auger Recombination on Lasing in Heterostructured Quantum Dots with Engineered Core/Shell Interfaces.

    PubMed

    Park, Young-Shin; Bae, Wan Ki; Baker, Thomas; Lim, Jaehoon; Klimov, Victor I

    2015-11-11

    Nanocrystal quantum dots (QDs) are attractive materials for applications as laser media because of their bright, size-tunable emission and the flexibility afforded by colloidal synthesis. Nonradiative Auger recombination, however, hampers optical amplification in QDs by rapidly depleting the population of gain-active multiexciton states. In order to elucidate the role of Auger recombination in QD lasing and isolate its influence from other factors that might affect optical gain, we study two types of CdSe/CdS core/shell QDs with the same core radii and the same total sizes but different properties of the core/shell interface ("sharp" vs "smooth"). These samples exhibit distinctly different biexciton Auger lifetimes but are otherwise virtually identical. The suppression of Auger recombination in the sample with a smooth (alloyed) interface results in a notable improvement in the optical gain performance manifested in the reduction of the threshold for amplified spontaneous emission and the ability to produce dual-color lasing involving both the band-edge (1S) and the higher-energy (1P) electronic states. We develop a model, which explicitly accounts for the multiexciton nature of optical gain in QDs, and use it to analyze the competition between stimulated emission from multiexcitons and their decay via Auger recombination. These studies re-emphasize the importance of Auger recombination control for the realization of real-life QD-based lasing technologies and offer practical strategies for suppression of Auger recombination via "interface engineering" in core/shell structures.

  7. Temperature effects on Li4Ti5O12 electrode/electrolyte interfaces at the first cycle: A X-ray Photoelectron Spectroscopy and Scanning Auger Microscopy study

    NASA Astrophysics Data System (ADS)

    Gieu, J.-B.; Courrèges, C.; El Ouatani, L.; Tessier, C.; Martinez, H.

    2016-06-01

    Li4Ti5O12-based negative electrodes for Lithium-ion batteries are of interest because of the high reversibility of Li+ insertion/extraction. In this study, the surface of cycled electrodes is analysed by X-ray Photoelectron Spectroscopy (XPS) and Scanning Auger Microscopy (SAM) to investigate the effects of cycling temperature (room temperature, 60 °C and 85 °C) upon the solid electrolyte interphase (SEI) formation, which plays a major role in batteries electrochemical performances. Half-cells, with a vinylene carbonate containing electrolyte, are galvanostatically cycled at different steps of the first cycle: the mid-plateau during the first discharge, the end of the first discharge at 1.2 V and the end of the first charge at 2.0 V. XPS analysis evidences that higher temperatures promote the formation of a thicker SEI, which can explain the increase of the irreversible capacity with temperature. SAM mappings (allowing high spatial resolution ∼10-100 nm) evidence that this SEI homogeneously covers the electrode surface, regardless of the cycling temperature. During charge, the SEI is partially dissolved at room temperature, more slightly at 60 °C whereas at 85 °C, no clear evidence of layer thinning is observed. The SEI chemical composition is also investigated and reveals a majority of organic species and an increasing proportion of LiF with the temperature.

  8. Results of a self-triggered prototype system for radio-detection of extensive air showers at the Pierre Auger Observatory

    NASA Astrophysics Data System (ADS)

    Abreu, P.; Acounis, S.; Aglietta, M.; Ahlers, M.; Ahn, E. J.; Albuquerque, I. F. M.; Allekotte, I.; Allen, J.; Allison, P.; Almela, A.; Alvarez Castillo, J.; Alvarez-Muñiz, J.; Alves Batista, R.; Ambrosio, M.; Aminaei, A.; Anchordoqui, L.; Andringa, S.; Anti&cbreve; i'c, T.; Aramo, C.; Arqueros, F.; Asorey, H.; Assis, P.; Aublin, J.; Ave, M.; Avenir, M.; Avila, G.; Badescu, A. M.; Barber, K. B.; Barbosa, A. F.; Bardenet, R.; Baughman, B.; Bäuml, J.; Baus, C.; Beatty, J. J.; Becker, K. H.; Bellétoile, A.; Bellido, J. A.; BenZvi, S.; Berat, C.; Bertou, X.; Biermann, P. L.; Billoir, P.; Blaess, S. G.; Blanco, F.; Blanco, M.; Bleve, C.; Blümer, H.; Boháčová, M.; Boncioli, D.; Bonifazi, C.; Bonino, R.; Borodai, N.; Brack, J.; Brancus, I.; Brogueira, P.; Brown, W. C.; Buchholz, P.; Bueno, A.; Buroker, L.; Burton, R. E.; Buscemi, M.; Caballero-Mora, K. S.; Caccianiga, B.; Caramete, L.; Caruso, R.; Castellina, A.; Cataldi, G.; Cazon, L.; Cester, R.; Charrier, D.; Chauvin, J.; Cheng, S. H.; Chiavassa, A.; Chinellato, J. A.; Chirinos Diaz, J.; Chudoba, J.; Cilmo, M.; Clay, R. W.; Cocciolo, G.; Colalillo, R.; Collica, L.; Coluccia, M. R.; Conceição, R.; Contreras, F.; Cook, H.; Cooper, M. J.; Coppens, J.; Coutu, S.; Covault, C. E.; Criss, A.; Cronin, J.; Curutiu, J.; Dallier, R.; Daniel, B.; Dasso, S.; Daumiller, K.; Dawson, B. R.; de Almeida, R. M.; De Domenico, M.; De Donato, C.; de Jong, S. J.; De La Vega, G.; de Mello Junior, W. J. M.; de Mello Neto, J. R. T.; De Mitri, I.; de Souza, V.; de Vries, K. D.; del Peral, L.; Deligny, O.; Dembinski, H.; Dhital, N.; Di Giulio, C.; Díaz Castro, M. L.; Diep, P. N.; Diogo, F.; Dobrigkeit, C.; Docters, W.; D'Olivo, J. C.; Dong, P. N.; Dorofeev, A.; dos Anjos, J. C.; Dova, M. T.; D'Urso, D.; Ebr, J.; Engel, R.; Erdmann, M.; Escobar, C. O.; Espadanal, J.; Etchegoyen, A.; Facal San Luis, P.; Falcke, H.; Fang, K.; Farrar, G.; Fauth, A. C.; Fazzini, N.; Ferguson, A. P.; Fick, B.; Figueira, J. M.; Filevich, A.; Filipčič, A.; Fliescher, S.; Fox, B.; Fracchiolla, C. E.; Fraenkel, E. D.; Fratu, O.; Fröhlich, U.; Fuchs, B.; Gaior, R.; Gamarra, R. F.; Gambetta, S.; García, B.; Garcia Roca, S. T.; Garcia-Gamez, D.; Garcia-Pinto, D.; Garçon, T.; Garilli, G.; Gascon Bravo, A.; Gemmeke, H.; Ghia, P. L.; Giller, M.; Gitto, J.; Glass, H.; Gold, M. S.; Golup, G.; Gomez Albarracin, F.; Gómez Berisso, M.; Gómez Vitale, P. F.; Gonçalves, P.; Gonzalez, J. G.; Gookin, B.; Gorgi, A.; Gorham, P.; Gouffon, P.; Grashorn, E.; Grebe, S.; Griffith, N.; Grillo, A. F.; Guardincerri, Y.; Guarino, F.; Guedes, G. P.; Hansen, P.; Harari, D.; Harrison, T. A.; Harton, J. L.; Haungs, A.; Hebbeker, T.; Heck, D.; Herve, A. E.; Hill, G. C.; Hojvat, C.; Hollon, N.; Holmes, V. C.; Homola, P.; Hörandel, J. R.; Horvath, P.; Hrabovský, M.; Huber, D.; Huege, T.; Insolia, A.; Ionita, F.; Jansen, S.; Jarne, C.; Jiraskova, S.; Josebachuili, M.; Kadija, K.; Kampert, K. H.; Karhan, P.; Kasper, P.; Katkov, I.; Kégl, B.; Keilhauer, B.; Keivani, A.; Kelley, J. L.; Kemp, E.; Kieckhafer, R. M.; Klages, H. O.; Kleifges, M.; Kleinfeller, J.; Knapp, J.; Koang, D.-H.; Kotera, K.; Krohm, N.; Krömer, O.; Kruppke-Hansen, D.; Kuempel, D.; Kulbartz, J. K.; Kunka, N.; La Rosa, G.; LaHurd, D.; Latronico, L.; Lauer, R.; Lauscher, M.; Lautridou, P.; Le Coz, S.; Leão, M. S. A. B.; Lebrun, D.; Lebrun, P.; Leigui de Oliveira, M. A.; Letessier-Selvon, A.; Lhenry-Yvon, I.; Link, K.; López, R.; Lopez Agüera, A.; Louedec, K.; Lozano Bahilo, J.; Lu, L.; Lucero, A.; Ludwig, M.; Lyberis, H.; Maccarone, M. C.; Macolino, C.; Malacari, M.; Maldera, S.; Maller, J.; Mandat, D.; Mantsch, P.; Mariazzi, A. G.; Marin, J.; Marin, V.; Maris, I. C.; Marquez Falcon, H. R.; Marsella, G.; Martello, D.; Martin, L.; Martinez, H.; Martínez Bravo, O.; Martraire, D.; Masías Meza, J. J.; Mathes, H. J.; Matthews, J.; Matthews, J. A. J.; Matthiae, G.; Maurel, D.; Maurizio, D.; Mayotte, E.; Mazur, P. O.; Medina-Tanco, G.; Melissas, M.; Melo, D.; Menichetti, E.; Menshikov, A.; Mertsch, P.; Messina, S.; Meurer, C.; Meyhandan, R.; Mi'canovi'c, S.; Micheletti, M. I.; Minaya, I. A.; Miramonti, L.; Mitrica, B.; Molina-Bueno, L.; Mollerach, S.; Monasor, M.; Monnier Ragaigne, D.; Montanet, F.; Morales, B.; Morello, C.; Moreno, J. C.; Mostafá, M.; Moura, C. A.; Muller, M. A.; Müller, G.; Münchmeyer, M.; Mussa, R.; Navarra, G.; Navarro, J. L.; Navas, S.; Necesal, P.; Nellen, L.; Nelles, A.; Neuser, J.; Nhung, P. T.; Niechciol, M.; Niemietz, L.; Nierstenhoefer, N.; Niggemann, T.; Nitz, D.; Nosek, D.; Nožka, L.; Oehlschläger, J.; Olinto, A.; Oliveira, M.; Ortiz, M.; Pacheco, N.; Pakk Selmi-Dei, D.; Palatka, M.; Pallotta, J.; Palmieri, N.; Parente, G.; Parra, A.; Pastor, S.; Paul, T.; Pech, M.; Pȩkala, J.; Pelayo, R.; Pepe, I. M.; Perrone, L.; Pesce, R.; Petermann, E.; Petrera, S.; Petrolini, A.; Petrov, Y.; Pfendner, C.; Piegaia, R.; Pierog, T.; Pieroni, P.; Pimenta, M.; Pirronello, V.; Platino, M.; Plum, M.; Ponce, V. H.; Pontz, M.; Porcelli, A.; Privitera, P.; Prouza, M.; Quel, E. J.; Querchfeld, S.; Rautenberg, J.; Ravel, O.; Ravignani, D.; Revenu, B.; Ridky, J.; Riggi, S.; Risse, M.; Ristori, P.; Rivera, H.; Rivière, C.; Rizi, V.; Roberts, J.; Rodrigues de Carvalho, W.; Rodriguez Cabo, I.; Rodriguez Fernandez, G.; Rodriguez Martino, J.; Rodriguez Rojo, J.; Rodríguez-Frías, M. D.; Ros, G.; Rosado, J.; Rossler, T.; Roth, M.; Rouillé-d'Orfeuil, B.; Roulet, E.; Rovero, A. C.; Rühle, C.; Saffi, S. J.; Saftoiu, A.; Salamida, F.; Salazar, H.; Salesa Greus, F.; Salina, G.; Sánchez, F.; Santo, C. E.; Santos, E.; Santos, E. M.; Sarazin, F.; Sarkar, B.; Sarkar, S.; Sato, R.; Scharf, N.; Scherini, V.; Schieler, H.; Schiffer, P.; Schmidt, A.; Scholten, O.; Schoorlemmer, H.; Schovancova, J.; Schovánek, P.; Schröder, F.; Schulz, J.; Schuster, D.; Sciutto, S. J.; Scuderi, M.; Segreto, A.; Settimo, M.; Shadkam, A.; Shellard, R. C.; Sidelnik, I.; Sigl, G.; Silva Lopez, H. H.; Sima, O.; Śmiałkowski, A.; Šmída, R.; Snow, G. R.; Sommers, P.; Sorokin, J.; Spinka, H.; Squartini, R.; Srivastava, Y. N.; Stanic, S.; Stapleton, J.; Stasielak, J.; Stassi, P.; Stephan, M.; Straub, M.; Stutz, A.; Suarez, F.; Suomijärvi, T.; Supanitsky, A. D.; Šuša, T.; Sutherland, M. S.; Swain, J.; Szadkowski, Z.; Szuba, M.; Tapia, A.; Tartare, M.; Taşcău, O.; Tcaciuc, R.; Thao, N. T.; Thomas, D.; Tiffenberg, J.; Timmermans, C.; Tkaczyj, W.; Todero Peixoto, C. J.; Toma, G.; Tomankova, L.; Tomé, B.; Tonachini, A.; Torralba Elipe, G.; Torres Machado, D.; Travnicek, P.; Tridapalli, D. B.; Trovato, E.; Tueros, M.; Ulrich, R.; Unger, M.; Urban, M.; Valdés Galicia, J. F.; Valiño, I.; Valore, L.; van Aar, G.; van den Berg, A. M.; van Velzen, S.; van Vliet, A.; Varela, E.; Vargas Cárdenas, B.; Varner, G.; Vázquez, J. R.; Vázquez, R. A.; Veberič, D.; Verzi, V.; Vicha, J.; Videla, M.; Villaseñor, L.; Wahlberg, H.; Wahrlich, P.; Wainberg, O.; Walz, D.; Watson, A. A.; Weber, M.; Weidenhaupt, K.; Weindl, A.; Werner, F.; Westerhoff, S.; Whelan, B. J.; Widom, A.; Wieczorek, G.; Wiencke, L.; Wilczyńska, B.; Wilczyński, H.; Will, M.; Williams, C.; Winchen, T.; Wommer, M.; Wundheiler, B.; Yamamoto, T.; Yapici, T.; Younk, P.; Yuan, G.; Yushkov, A.; Zamorano Garcia, B.; Zas, E.; Zavrtanik, D.; Zavrtanik, M.; Zaw, I.; Zepeda, A.; Zhou, J.; Zhu, Y.; Zimbres Silva, M.; Ziolkowski, M.

    2012-11-01

    We describe the experimental setup and the results of RAuger, a small radio-antenna array, consisting of three fully autonomous and self-triggered radio-detection stations, installed close to the center of the Surface Detector (SD) of the Pierre Auger Observatory in Argentina. The setup has been designed for the detection of the electric field strength of air showers initiated by ultra-high energy cosmic rays, without using an auxiliary trigger from another detection system. Installed in December 2006, RAuger was terminated in May 2010 after 65 registered coincidences with the SD. The sky map in local angular coordinates (i.e., zenith and azimuth angles) of these events reveals a strong azimuthal asymmetry which is in agreement with a mechanism dominated by a geomagnetic emission process. The correlation between the electric field and the energy of the primary cosmic ray is presented for the first time, in an energy range covering two orders of magnitude between 0.1 EeV and 10 EeV. It is demonstrated that this setup is relatively more sensitive to inclined showers, with respect to the SD. In addition to these results, which underline the potential of the radio-detection technique, important information about the general behavior of self-triggering radio-detection systems has been obtained. In particular, we will discuss radio self-triggering under varying local electric-field conditions.

  9. Influence of the "surface effect" on the segregation parameters of S in Fe(100): A multi-scale modelling and Auger Electron Spectroscopy study

    NASA Astrophysics Data System (ADS)

    Barnard, P. E.; Terblans, J. J.; Swart, H. C.

    2015-12-01

    The article takes a new look at the process of atomic segregation by considering the influence of surface relaxation on the segregation parameters; the activation energy (Q), segregation energy (ΔG), interaction parameter (Ω) and the pre-exponential factor (D0). Computational modelling, namely Density Functional Theory (DFT) and the Modified Darken Model (MDM) in conjunction with Auger Electron Spectroscopy (AES) was utilized to study the variation of the segregation parameters for S in the surface region of Fe(100). Results indicate a variation in each of the segregation parameters as a function of the atomic layer under consideration. Values of the segregation parameters varied more dramatically as the surface layer is approached, with atomic layer 2 having the largest deviations in comparison to the bulk values. This atomic layer had the highest Q value and formed the rate limiting step for the segregation of S towards the Fe(100) surface. It was found that the segregation process is influenced by two sets of segregation parameters, those of the surface region formed by atomic layer 2, and those in the bulk material. This article is the first to conduct a full scale investigation on the influence of surface relaxation on segregation and labelled it the "surface effect".

  10. Identification of a potent microbial lipid antigen for diverse Natural Killer T cells1

    PubMed Central

    Wolf, Benjamin J.; Tatituri, Raju V. V.; Almeida, Catarina F.; Le Nours, Jérôme; Bhowruth, Veemal; Johnson, Darryl; Uldrich, Adam P.; Hsu, Fong-Fu; Brigl, Manfred; Besra, Gurdyal S.; Rossjohn, Jamie; Godfrey, Dale I.; Brenner, Michael B.

    2016-01-01

    Invariant Natural Killer T (iNKT) cells are a well-characterized CD1d-restricted T cell subset. The availability of potent antigens and tetramers for iNKT cells has allowed this population to be extensively studied and has revealed their central roles in infection, autoimmunity, and tumor immunity. In contrast, diverse Natural Killer T (dNKT) cells are poorly understood because the lipid antigens they recognize are largely unknown. We sought to identify dNKT cell lipid antigen(s) by interrogating a panel of dNKT mouse cell hybridomas with lipid extracts from the pathogen Listeria monocytogenes. We identified Listeria phosphatidylglycerol (PG) as a microbial antigen that was significantly more potent than a previously characterized dNKT cell antigen, mammalian PG. Further, while mammalian PG loaded CD1d tetramers did not stain dNKT cells, the Listeria-derived PG loaded tetramers did. The structure of Listeria PG was distinct from mammalian PG since it contained shorter, fully-saturated anteiso fatty acid lipid tails. CD1d binding lipid displacement studies revealed that the microbial PG antigen binds significantly better to CD1d than counterparts with the same headgroup. These data reveal a highly-potent microbial lipid antigen for a subset of dNKT cells and provide an explanation for its increased antigen potency compared to the mammalian counterpart. PMID:26254340

  11. 30 CFR 77.1500 - Auger mining; planning.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 30 Mineral Resources 1 2011-07-01 2011-07-01 false Auger mining; planning. 77.1500 Section 77.1500... MANDATORY SAFETY STANDARDS, SURFACE COAL MINES AND SURFACE WORK AREAS OF UNDERGROUND COAL MINES Auger Mining § 77.1500 Auger mining; planning. Auger mining shall be planned and conducted by the operator to...

  12. 30 CFR 77.1500 - Auger mining; planning.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Auger mining; planning. 77.1500 Section 77.1500... MANDATORY SAFETY STANDARDS, SURFACE COAL MINES AND SURFACE WORK AREAS OF UNDERGROUND COAL MINES Auger Mining § 77.1500 Auger mining; planning. Auger mining shall be planned and conducted by the operator to...

  13. 30 CFR 77.1500 - Auger mining; planning.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 30 Mineral Resources 1 2013-07-01 2013-07-01 false Auger mining; planning. 77.1500 Section 77.1500... MANDATORY SAFETY STANDARDS, SURFACE COAL MINES AND SURFACE WORK AREAS OF UNDERGROUND COAL MINES Auger Mining § 77.1500 Auger mining; planning. Auger mining shall be planned and conducted by the operator to...

  14. 30 CFR 77.1500 - Auger mining; planning.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 30 Mineral Resources 1 2014-07-01 2014-07-01 false Auger mining; planning. 77.1500 Section 77.1500... MANDATORY SAFETY STANDARDS, SURFACE COAL MINES AND SURFACE WORK AREAS OF UNDERGROUND COAL MINES Auger Mining § 77.1500 Auger mining; planning. Auger mining shall be planned and conducted by the operator to...

  15. 30 CFR 77.1500 - Auger mining; planning.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 30 Mineral Resources 1 2012-07-01 2012-07-01 false Auger mining; planning. 77.1500 Section 77.1500... MANDATORY SAFETY STANDARDS, SURFACE COAL MINES AND SURFACE WORK AREAS OF UNDERGROUND COAL MINES Auger Mining § 77.1500 Auger mining; planning. Auger mining shall be planned and conducted by the operator to...

  16. Analysis of passivated A-286 stainless steel surfaces for mass spectrometer inlet systems by Auger electron and X-ray photoelectron spectroscopy and scanning electron microscopy

    DOE PAGES

    Ajo, Henry; Blankenship, Donnie; Clark, Elliot

    2014-07-25

    In this study, various commercially available surface treatments are being explored for use on stainless steel components in mass spectrometer inlet systems. Type A-286 stainless steel coupons, approximately 12.5 mm in diameter and 3 mm thick, were passivated with one of five different surface treatments; an untreated coupon served as a control. The surface and near-surface microstructure and chemistry of the coupons were investigated using sputter depth profiling using Auger electron spectroscopy, x-ray photoelectron spectroscopy, and scanning electron microscopy (SEM). All the surface treatments studied appeared to change the surface morphology dramatically, as evidenced by lack of tool marks onmore » the treated samples in SEM images. In terms of the passivation treatment, Vendors A-D appeared to have oxide layers that were very similar in thickness to each other (0.7–0.9 nm thick), as well as to the untreated samples (the untreated sample oxide layers appeared to be somewhat larger). Vendor E’s silicon coating appears to be on the order of 200 nm thick.« less

  17. The change of the LMM auger spectra in 3d-metals due to oxidation and its correlation with the change of the atomic magnetic moment.

    PubMed

    Zheltysheva, Olga R; Surnin, Dmitry V; Guy, Dmitry E; Gil'mutdinov, Faat Z; Ruts, Yuri V; Grebennikov, Vladimir I

    2005-12-01

    The surfaces of crystalline samples of 3d-metals (Mn, Fe, Co, Ni, and Cu) and their stoichiometric oxides have been studied by Auger spectroscopy. A correlation between the change in the LVV (L-inner level-valence-valence electron transition) Auger intensities and the change of the squares of the corresponding atomic-magnetic moments has been observed. This is because of the complicated nature of the Auger process. That is, the Auger electron emission is a result of the inner atomic level excitation by electron impact and Auger annihilation of the inner-level hole. Therefore, the Auger process has been considered a second-order process, and spin polarization of the valence states has been taken into account for the LMM (L-inner level-M-inner level-M-inner level electron transition) Auger spectra of 3d-metals.

  18. 1,3,4-Thiadiazoles: a potent multi targeted pharmacological scaffold.

    PubMed

    Haider, Saqlain; Alam, Mohammad Sarwar; Hamid, Hinna

    2015-03-06

    Despite a significant work on thiadiazoles, continuous efforts are still being made to identify novel heterocyclic compounds with potent biological activities. This review may help the medicinal chemists to develop new leads possessing 1,3,4-thiadiazole nucleus with higher efficacy and reduced side effects. This review throws light on the detailed synthetic approaches which have been used for the synthesis of thiadiazoles. This has been followed by the in depth analysis of the thiadiazoles with respect to their medicinal significance.

  19. A Potent and Highly Efficacious Bcl-2/Bcl-xL Inhibitor

    PubMed Central

    McEachern, Donna; Yang, Chao-Yie; Meagher, Jennifer; Stuckey, Jeanne; Wang, Shaomeng

    2013-01-01

    Our previously reported Bcl-2/Bcl-xL inhibitor, 4, effectively inhibited tumor growth but failed to achieve complete regression in vivo. We have now performed extensive modifications on its pyrrole core structure, which has culminated in the discovery of 32 (BM-1074). Compound 32 binds to Bcl-2 and Bcl-xL proteins with Ki values of < 1 nM and inhibits cancer cell growth with IC50 values of 1-2 nM in four small-cell lung cancer cell lines sensitive to potent and specific Bcl-2/Bcl-xL inhibitors. Compound 32 is capable of achieving rapid, complete and durable tumor regression in vivo at a well-tolerated dose-schedule. Compound 32 is the most potent and efficacious Bcl-2/Bcl-xL inhibitor reported to date. PMID:23448298

  20. Incident-beam effects in electron-stimulated Auger-electron diffraction

    NASA Astrophysics Data System (ADS)

    Gao, Y.; Cao, Jianming

    1991-04-01

    We have examined incident-beam effects in electron-stimulated Auger-electron diffraction (AED) on a cleaved GaAs(110) surface. The results indicate that incident-beam diffraction is significant in an AED experiment, and that the dissipative nature of the incident beam in contributing to the Auger process must be accounted for. We have developed a qualitative model that describes the trend of the polar-angle dependence of the Auger intensity for both the incident and exit beams. In calculating the diffraction features, we used a zeroth-order approximation to simulate the dissipation of the incident beam, which is found to adequately describe the experimental data.

  1. A Potent, Selective and Cell-Active Allosteric Inhibitor of Protein Arginine Methyltransferase 3 (PRMT3)**

    PubMed Central

    Kaniskan, H. Ümit; Szewczyk, Magdalena M.; Yu, Zhengtian; Eram, Mohammad S.; Yang, Xiaobao; Schmidt, Keith; Luo, Xiao; Dai, Miao; He, Feng; Zang, Irene; Lin, Ying; Kennedy, Steven; Li, Fengling; Dobrovetsky, Elena; Dong, Aiping; Smil, David; Min, Sun-Joon; Landon, Melissa; Lin-Jones, Jennifer; Huang, Xi-Ping; Roth, Bryan L.; Schapira, Matthieu; Atadja, Peter; Barsyte-Lovejoy, Dalia; Arrowsmith, Cheryl H.; Brown, Peter J.; Zhao, Kehao; Jin, Jian; Vedadi, Masoud

    2015-01-01

    PRMT3 catalyzes the asymmetric dimethylation of arginine residues of various proteins. It is essential for maturation of ribosomes, may have a role in lipogenesis, and is implicated in several diseases. A potent, selective, and cell- active PRMT3 inhibitor would be a valuable tool for further investigating PRMT3 biology. Here we report the discovery of the first PRMT3 chemical probe, SGC707, by structure-based optimization of the allosteric PRMT3 inhibitors we reported previously, and thorough characterization of this probe in biochemical, biophysical, and cellular assays. SGC707 is a potent PRMT3 inhibitor (IC50 = 31 ± 2 nm, KD = 53 ± 2 nm) with outstanding selectivity (selective against 31 other methyltransferases and more than 250 non-epigenetic targets). The mechanism of action studies and crystal structure of the PRMT3-SGC707 complex confirm the allosteric inhibition mode. Importantly, SGC707 engages PRMT3 and potently inhibits its methyltransferase activity in cells. It is also bioavailable and suitable for animal studies. This well- characterized chemical probe is an excellent tool to further study the role of PRMT3 in health and disease. PMID:25728001

  2. The preclinical biology of a new potent and selective progestin: trimegestone.

    PubMed

    Winneker, Richard C; Bitran, Daniel; Zhang, Zhiming

    2003-11-01

    Trimegestone (TMG) is a 19-norpregnane progestin being developed, in combination with an estrogen, for the treatment of postmenopausal symptoms. TMG binds to the human progesterone receptor with an affinity greater than medroxyprogesterone acetate (MPA), norethindrone (NET), and levonorgestrel (LNG). In contrast, TMG binds with low affinity to the androgen, glucocorticoid and mineralocorticoid receptor and has no measurable affinity for the estrogen receptor. Compared to other progestins, TMG demonstrates an improved separation of its PR affinity from its affinity to other classical steroid hormone receptors. In vivo, TMG has potent progestin activity. For example, TMG produces glandular differentiation of the uterine endometrium in rabbits and is about 30 and 60 times more potent than MPA and NET, respectively. In the rat, TMG maintains pregnancy, induces deciduoma formation, inhibits ovulation and has uterine anti-estrogenic activity. With respect to these endpoints, TMG appears to be more potent and selective on uterine epithelial responses than other classical progestin responses. In vivo, TMG does not have significant androgenic, glucocorticoid, anti-glucocorticoid or mineralocorticoid activity but does have anti-mineralocorticoid activity and modest anti-androgenic effects. This overall profile is qualitatively similar to progesterone. When TMG is administered chronically, it antagonizes the effect of estradiol on the uterus but does not antagonize the beneficial bone sparing activity of estradiol. In rat studies evaluating CNS GABAA receptor modulatory activity, TMG is less active on this likely undesirable endpoint than progesterone and norethindrone acetate, which may translate into fewer mood-related side effects. The results indicate that TMG is a potent and selective progestin with a preclinical profile well suited for hormone replacement therapy.

  3. Synthesis of organic nitrates of luteolin as a novel class of potent aldose reductase inhibitors.

    PubMed

    Wang, Qi-Qin; Cheng, Ning; Zheng, Xiao-Wei; Peng, Sheng-Ming; Zou, Xiao-Qing

    2013-07-15

    Aldose reductase (AR) plays an important role in the design of drugs that prevent and treat diabetic complications. Aldose reductase inhibitors (ARIs) have received significant attentions as potent therapeutic drugs. Based on combination principles, three series of luteolin derivatives were synthesised and evaluated for their AR inhibitory activity and nitric oxide (NO)-releasing capacity in vitro. Eighteen compounds were found to be potent ARIs with IC50 values ranging from (0.099±0.008) μM to (2.833±0.102) μM. O(7)-Nitrooxyethyl-O(3'),O(4')-ethylidene luteolin (La1) showed the most potent AR inhibitory activity [IC50=(0.099±0.008) μM]. All organic nitrate derivatives released low concentrations of NO in the presence of l-cysteine. Structure-activity relationship studies suggested that introduction of an NO donor, protection of the catechol structure, and the ether chain of a 2-carbon spacer as a coupling chain on the luteolin scaffold all help increase the AR inhibitory activity of the resulting compound. This class of NO-donor luteolin derivatives as efficient ARIs offer a new concept for the development and design of new drug for preventive and therapeutic drugs for diabetic complications.

  4. A Class of 5-Nitro-2-furancarboxylamides with Potent Trypanocidal Activity against Trypanosoma brucei in Vitro

    PubMed Central

    2013-01-01

    Recently, the World Health Organization approved the nifurtimox–eflornithine combination therapy for the treatment of human African trypanosomiasis, renewing interest in nitroheterocycle therapies for this and associated diseases. In this study, we have synthesized a series of novel 5-nitro-2-furancarboxylamides that show potent trypanocidal activity, ∼1000-fold more potent than nifurtimox against in vitro Trypanosoma brucei with very low cytotoxicity against human HeLa cells. More importantly, the most potent analogue showed very limited cross-resistance to nifurtimox-resistant cells and vice versa. This implies that our novel, relatively easy to synthesize and therefore cheap, 5-nitro-2-furancarboxylamides are targeting a different, but still essential, biochemical process to those targeted by nifurtimox or its metabolites in the parasites. The significant increase in potency (smaller dose probably required) has the potential for greatly reducing unwanted side effects and also reducing the likelihood of drug resistance. Collectively, these findings have important implications for the future therapeutic treatment of African sleeping sickness. PMID:23281892

  5. Latest results from the Pierre Auger Observatory

    NASA Astrophysics Data System (ADS)

    Dembinski, Hans P.; Pierre Auger Collaboration

    2012-02-01

    The Pierre Auger Observatory, located in the Province of Mendoza, Argentina, is the World's largest detector for cosmic rays at ultra-high energies. In its seven years of operation it has collected an exposure of more than 20000 km2 sr yr, larger than all previous experiments combined. Its original design, optimized for the energy range 1018 eV to 1020 eV, is currently enhanced to cover energies down to almost 1017 eV. We give an overview of the latest results with a focus on the prospect to study nuclear interactions with cosmic rays and conclude with a brief outlook on developments and extensions of the observatory. Full author list

  6. Auger analysis of silver-glass interfaces

    NASA Astrophysics Data System (ADS)

    Bastasz, R.

    1980-09-01

    Moderate annealing in vacuum of evaporated silver films on float glass (used as mirrors in solar energy concentrators) was found to have little effect on either the composition at the silver/glass interface or the profile of the boundary region. The interface remained free of any contaminants that could be detected by Auger spectroscopy. Limited diffusion of silver with glass components was observed, but the process resulted in only slight broadening of the interface during short annealing treatments and could be described by a diffusion coefficient of less than 1 x 10 to the -15th sq cm/s at 200 C. It is concluded that moderate annealing in the absence of contamination does not significantly alter the characteristics of a silver/glass interface.

  7. Identifying clouds over the Pierre Auger Observatory using infrared satellite data

    NASA Astrophysics Data System (ADS)

    Abreu, P.; Aglietta, M.; Ahlers, M.; Ahn, E. J.; Albuquerque, I. F. M.; Allekotte, I.; Allen, J.; Allison, P.; Almela, A.; Alvarez Castillo, J.; Alvarez-Muñiz, J.; Alves Batista, R.; Ambrosio, M.; Aminaei, A.; Anchordoqui, L.; Andringa, S.; Antičić, T.; Aramo, C.; Arqueros, F.; Asorey, H.; Assis, P.; Aublin, J.; Ave, M.; Avenier, M.; Avila, G.; Badescu, A. M.; Barber, K. B.; Barbosa, A. F.; Bardenet, R.; Baughman, B.; Bäuml, J.; Baus, C.; Beatty, J. J.; Becker, K. H.; Bellétoile, A.; Bellido, J. A.; BenZvi, S.; Berat, C.; Bertou, X.; Biermann, P. L.; Billoir, P.; Blanco, F.; Blanco, M.; Bleve, C.; Blümer, H.; Boháčová, M.; Boncioli, D.; Bonifazi, C.; Bonino, R.; Borodai, N.; Brack, J.; Brancus, I.; Brogueira, P.; Brown, W. C.; Buchholz, P.; Bueno, A.; Buroker, L.; Burton, R. E.; Buscemi, M.; Caballero-Mora, K. S.; Caccianiga, B.; Caccianiga, L.; Caramete, L.; Caruso, R.; Castellina, A.; Cataldi, G.; Cazon, L.; Cester, R.; Cheng, S. H.; Chiavassa, A.; Chinellato, J. A.; Chirinos, J.; Chudoba, J.; Cilmo, M.; Clay, R. W.; Cocciolo, G.; Colalillo, R.; Collica, L.; Coluccia, M. R.; Conceição, R.; Contreras, F.; Cook, H.; Cooper, M. J.; Coutu, S.; Covault, C. E.; Criss, A.; Cronin, J.; Curutiu, A.; Dallier, R.; Daniel, B.; Dasso, S.; Daumiller, K.; Dawson, B. R.; de Almeida, R. M.; De Domenico, M.; de Jong, S. J.; De La Vega, G.; de Mello, W. J. M.; de Mello Neto, J. R. T.; De Mitri, I.; de Souza, V.; de Vries, K. D.; del Peral, L.; Deligny, O.; Dembinski, H.; Dhital, N.; Di Giulio, C.; Diaz, J. C.; Díaz Castro, M. L.; Diep, P. N.; Diogo, F.; Dobrigkeit, C.; Docters, W.; D'Olivo, J. C.; Dong, P. N.; Dorofeev, A.; dos Anjos, J. C.; Dova, M. T.; D'Urso, D.; Ebr, J.; Engel, R.; Erdmann, M.; Escobar, C. O.; Espadanal, J.; Etchegoyen, A.; Facal San Luis, P.; Falcke, H.; Fang, K.; Farrar, G.; Fauth, A. C.; Fazzini, N.; Ferguson, A. P.; Fick, B.; Figueira, J. M.; Filevich, A.; Filipčič, A.; Fliescher, S.; Fox, B. D.; Fracchiolla, C. E.; Fraenkel, E. D.; Fratu, O.; Fröhlich, U.; Fuchs, B.; Gaior, R.; Gamarra, R. F.; Gambetta, S.; García, B.; Garcia Roca, S. T.; Garcia-Gamez, D.; Garcia-Pinto, D.; Garilli, G.; Gascon Bravo, A.; Gemmeke, H.; Ghia, P. L.; Giller, M.; Gitto, J.; Glaser, C.; Glass, H.; Golup, G.; Gomez Albarracin, F.; Gómez Berisso, M.; Gómez Vitale, P. F.; Gonçalves, P.; Gonzalez, J. G.; Gookin, B.; Gorgi, A.; Gorham, P.; Gouffon, P.; Grebe, S.; Griffith, N.; Grillo, A. F.; Grubb, T. D.; Guardincerri, Y.; Guarino, F.; Guedes, G. P.; Hansen, P.; Harari, D.; Harrison, T. A.; Harton, J. L.; Haungs, A.; Hebbeker, T.; Heck, D.; Herve, A. E.; Hill, G. C.; Hojvat, C.; Hollon, N.; Holmes, V. C.; Homola, P.; Hörandel, J. R.; Horvath, P.; Hrabovský, M.; Huber, D.; Huege, T.; Insolia, A.; Jansen, S.; Jarne, C.; Jiraskova, S.; Josebachuili, M.; Kadija, K.; Kampert, K. H.; Karhan, P.; Kasper, P.; Katkov, I.; Kégl, B.; Keilhauer, B.; Keivani, A.; Kelley, J. L.; Kemp, E.; Kieckhafer, R. M.; Klages, H. O.; Kleifges, M.; Kleinfeller, J.; Knapp, J.; Krause, R.; Krohm, N.; Krömer, O.; Kruppke-Hansen, D.; Kuempel, D.; Kulbartz, J. K.; Kunka, N.; La Rosa, G.; LaHurd, D.; Latronico, L.; Lauer, R.; Lauscher, M.; Lautridou, P.; Le Coz, S.; Leão, M. S. A. B.; Lebrun, D.; Lebrun, P.; Leigui de Oliveira, M. A.; Letessier-Selvon, A.; Lhenry-Yvon, I.; Link, K.; López, R.; Lopez Agüera, A.; Louedec, K.; Lozano Bahilo, J.; Lu, L.; Lucero, A.; Ludwig, M.; Lyberis, H.; Maccarone, M. C.; Macolino, C.; Malacari, M.; Maldera, S.; Maller, J.; Mandat, D.; Mantsch, P.; Mariazzi, A. G.; Marin, J.; Marin, V.; Mariş, I. C.; Marquez Falcon, H. R.; Marsella, G.; Martello, D.; Martin, L.; Martinez, H.; Martínez Bravo, O.; Martraire, D.; Masías Meza, J. J.; Mathes, H. J.; Matthews, J.; Matthews, J. A. J.; Matthiae, G.; Maurel, D.; Maurizio, D.; Mayotte, E.; Mazur, P. O.; Medina-Tanco, G.; Melissas, M.; Melo, D.; Menichetti, E.; Menshikov, A.; Messina, S.; Meyhandan, R.; Mićanović, S.; Micheletti, M. I.; Middendorf, L.; Minaya, I. A.; Miramonti, L.; Mitrica, B.; Molina-Bueno, L.; Mollerach, S.; Monasor, M.; Monnier Ragaigne, D.; Montanet, F.; Morales, B.; Morello, C.; Moreno, J. C.; Mostafá, M.; Moura, C. A.; Muller, M. A.; Müller, G.; Münchmeyer, M.; Mussa, R.; Navarra, G.; Navarro, J. L.; Navas, S.; Necesal, P.; Nellen, L.; Nelles, A.; Neuser, J.; Nhung, P. T.; Niechciol, M.; Niemietz, L.; Nierstenhoefer, N.; Niggemann, T.; Nitz, D.; Nosek, D.; Nožka, L.; Oehlschläger, J.; Olinto, A.; Oliveira, M.; Ortiz, M.; Pacheco, N.; Pakk Selmi-Dei, D.; Palatka, M.; Pallotta, J.; Palmieri, N.; Parente, G.; Parra, A.; Pastor, S.; Paul, T.; Pech, M.; Peķala, J.; Pelayo, R.; Pepe, I. M.; Perrone, L.; Pesce, R.; Petermann, E.; Petrera, S.; Petrolini, A.; Petrov, Y.; Pfendner, C.; Piegaia, R.; Pierog, T.; Pieroni, P.; Pimenta, M.; Pirronello, V.; Platino, M.; Plum, M.; Ponce, V. H.; Pontz, M.; Porcelli, A.; Privitera, P.; Prouza, M.; Quel, E. J.; Querchfeld, S.; Rautenberg, J.; Ravel, O.; Ravignani, D.; Revenu, B.; Ridky, J.; Riggi, S.; Risse, M.; Ristori, P.; Rivera, H.; Rizi, V.; Roberts, J.; Rodrigues de Carvalho, W.; Rodriguez Cabo, I.; Rodriguez Fernandez, G.; Rodriguez Martino, J.; Rodriguez Rojo, J.; Rodríguez-Frías, M. D.; Ros, G.; Rosado, J.; Rossler, T.; Roth, M.; Rouillé-d'Orfeuil, B.; Roulet, E.; Rovero, A. C.; Rühle, C.; Saffi, S. J.; Saftoiu, A.; Salamida, F.; Salazar, H.; Salesa Greus, F.; Salina, G.; Sánchez, F.; Santo, C. E.; Santos, E.; Santos, E. M.; Sarazin, F.; Sarkar, B.; Sato, R.; Scharf, N.; Scherini, V.; Schieler, H.; Schiffer, P.; Schmidt, A.; Scholten, O.; Schoorlemmer, H.; Schovancova, J.; Schovánek, P.; Schröder, F. G.; Schulz, J.; Schuster, D.; Sciutto, S. J.; Scuderi, M.; Segreto, A.; Settimo, M.; Shadkam, A.; Shellard, R. C.; Sidelnik, I.; Sigl, G.; Sima, O.; Śmiałkowski, A.; Šmída, R.; Snow, G. R.; Sommers, P.; Sorokin, J.; Spinka, H.; Squartini, R.; Srivastava, Y. N.; Stanič, S.; Stapleton, J.; Stasielak, J.; Stephan, M.; Straub, M.; Stutz, A.; Suarez, F.; Suomijärvi, T.; Supanitsky, A. D.; Šuša, T.; Sutherland, M. S.; Swain, J.; Szadkowski, Z.; Szuba, M.; Tapia, A.; Tartare, M.; Taşcău, O.; Tcaciuc, R.; Thao, N. T.; Thomas, D.; Tiffenberg, J.; Timmermans, C.; Tkaczyk, W.; Todero Peixoto, C. J.; Toma, G.; Tomankova, L.; Tomé, B.; Tonachini, A.; Torralba Elipe, G.; Torres Machado, D.; Travnicek, P.; Tridapalli, D. B.; Trovato, E.; Tueros, M.; Ulrich, R.; Unger, M.; Urban, M.; Valdés Galicia, J. F.; Valiño, I.; Valore, L.; van Aar, G.; van den Berg, A. M.; van Velzen, S.; van Vliet, A.; Varela, E.; Vargas Cárdenas, B.; Varner, G.; Vázquez, J. R.; Vázquez, R. A.; Veberič, D.; Verzi, V.; Vicha, J.; Videla, M.; Villaseñor, L.; Wahlberg, H.; Wahrlich, P.; Wainberg, O.; Walz, D.; Watson, A. A.; Weber, M.; Weidenhaupt, K.; Weindl, A.; Werner, F.; Westerhoff, S.; Whelan, B. J.; Widom, A.; Wieczorek, G.; Wiencke, L.; Wilczyńska, B.; Wilczyński, H.; Will, M.; Williams, C.; Winchen, T.; Wundheiler, B.; Yamamoto, T.; Yapici, T.; Younk, P.; Yuan, G.; Yushkov, A.; Zamorano Garcia, B.; Zas, E.; Zavrtanik, D.; Zavrtanik, M.; Zaw, I.; Zepeda, A.; Zhou, J.; Zhu, Y.; Zimbres Silva, M.; Ziolkowski, M.

    2013-12-01

    We describe a new method of identifying night-time clouds over the Pierre Auger Observatory using infrared data from the Imager instruments on the GOES-12 and GOES-13 satellites. We compare cloud identifications resulting from our method to those obtained by the Central Laser Facility of the Auger Observatory. Using our new method we can now develop cloud probability maps for the 3000 km2 of the Pierre Auger Observatory twice per hour with a spatial resolution of ˜2.4 km by ˜5.5 km. Our method could also be applied to monitor cloud cover for other ground-based observatories and for space-based observatories.

  8. Chemical effects of F KVV Auger spectra induced by photon impact

    NASA Astrophysics Data System (ADS)

    Uda, M.; Maeda, K.; Koyama, A.; Sasa, Y.

    1984-03-01

    F KVV Auger emissions were measured with NaF, MgF2, A1F3, and Teflon [(CF2)n], which were induced by photoionization. Chemical effects were reflected in line broadening and change in intensity ratios of the spectra emitted from singly and doubly ionized initial states, |K1L0> and |K1L1>. Reduction in Auger peak intensities which originated from |K1L1> is in the order of the covalencies of the fluorides or the natural widths of F L shells. This is caused by the refilling of a F L-shell vacancy by one of the ligand electrons prior to Auger emission.

  9. Auger electron intensity variations in oxygen-exposed large grain polycrystalline silver

    NASA Technical Reports Server (NTRS)

    Lee, W. S.; Outlaw, R. A.; Hoflund, G. B.; Davidson, M. R.

    1989-01-01

    Auger electron spectroscopic studies of the grains in oxygen-charged polycrystal-line silver show significant intensity variations as a function of crystallographic orientation. These intensity variations were observed by studies of the Auger images and line scans of the different grains (randomly selected) for each silver transition energy. The results can be attributed to the diffraction of the ejected Auger electrons and interpreted by corresponding changes in the electron mean-free path for inelastic scattering and by oxygen atom accumulation in the subsurface. The subsurface (second layer) octahedral sites increased in size because of surface relaxation and serve as a stable reservoir for the dissolved oxygen.

  10. Identifying clouds over the Pierre Auger Observatory using infrared satellite data

    SciTech Connect

    Abreu, Pedro; et al.,

    2013-12-01

    We describe a new method of identifying night-time clouds over the Pierre Auger Observatory using infrared data from the Imager instruments on the GOES-12 and GOES-13 satellites. We compare cloud identifications resulting from our method to those obtained by the Central Laser Facility of the Auger Observatory. Using our new method we can now develop cloud probability maps for the 3000 km^2 of the Pierre Auger Observatory twice per hour with a spatial resolution of ~2.4 km by ~5.5 km. Our method could also be applied to monitor cloud cover for other ground-based observatories and for space-based observatories.

  11. Angular resolution of the Pierre Auger Observatory

    SciTech Connect

    Bonifazi, C.

    2005-08-01

    We studied the angular resolution of the Pierre Auger Detector using data collected from January 2004 to May 2005. The detector consists of two independent components, the fluorescence detector and the surface detector. Hybrid events, observed simultaneously by both components, have smaller reconstruction uncertainties than the events observed with only one component. The hybrid resolution is extracted from artificial showers generated by laser shots, while the surface detector angular accuracy is then determined from the comparison of the hybrid geometrical fit with the one obtained from the surface detector alone. We used adjacent surface detector stations to cross check our methods. The angular reconstruction accuracy of the surface detector events is given as a function of station multiplicity.

  12. Generation of pure spin currents via Auger recombination in quantum wells with Rashba splitting

    SciTech Connect

    Afanasiev, A. N. Greshnov, A. A. Greshnov, A. A.

    2015-10-15

    We propose a nonoptical mechanism for generating spin current via Auger recombination in semiconductor quantum wells (QWs) with spin–orbit splitting associated with structural QW asymmetry. It is shown that Auger recombination in narrow-bandgap semiconductors makes it possible to produce spin currents that exceed those that are obtained in the case of intraband as well as interband optical excitation. Analysis shows that the interference term in the expression for the Auger-recombination rate is responsible for the generation of spin currents.

  13. Survey of the Pierre Auger Observatory

    NASA Astrophysics Data System (ADS)

    Dova, T.; Pierre Auger Observatory Collaboration

    The question of the origin and nature of cosmic ray particles with energies exceeding the predicted GZK spectral cutoff is one of the present great challenges of astroparticle physics. The Pierre Auger Observatory (PAO), currently under construction in Province of Mendoza, Argentina, is a broadly based international effort to explore the upper-end of the cosmic ray energy spectrum. The PAO is the first experiment designed to work in a hybrid detection mode. The combination of two complementary detection techniques -water Cerenkov tank arrays overlooked by atmospheric fluorescence detectorsto observe extensive air showers guarantees high-quality and statistically significant data. An updated overview of the science prospects for the PAO is presented. The concept of the experiment as well as the current status is described. 1 Physics motivation for the Pierre Auger Observatory The puzzle set by the existence of cosmic rays with energies above 1020 eV (Lawrence et al., 1991; Hayashida et al., 1994; Bird et al., 1995; Abu-Zayyad et al, 1999), which may be an indication of new physics or exotic particles, is at present one of the hot topics in high energy astroparticle physics. The underlying problem in trying to explain the origin of these extremely high energy cosmic rays (EHECR) is the well-known GZK (Greisen-Zatsepin-Kuzmin) effect: if the cosmic rays are extragalactic in origin, then a sharp cutoff at around several times 1019 eV in the observed spectrum is expected due to energy degradation of the cosmic ray particles through interaction with photons of the microwave background radiation (Greisen, 1965; Zatsepin and Kuzmin, 1966). This process limits the distance of the sources of particles with energies above 1020 eV to less than 100 Mpc from the Earth (Aharonian and Cronin, 1994; Puget et al., 1976; Stecker and Salomon, 1999; Berezinsky, 1970; Protheroe and Biermann, 1996). Since the energy loss mechanism depends on

  14. Photooxygenation of an amino-thienopyridone yields a more potent PTP4A3 inhibitor.

    PubMed

    Salamoun, Joseph M; McQueeney, Kelley E; Patil, Kalyani; Geib, Steven J; Sharlow, Elizabeth R; Lazo, John S; Wipf, Peter

    2016-07-06

    The phosphatase PTP4A3 is an attractive anticancer target, but knowledge of its exact role in cells remains incomplete. A potent, structurally novel inhibitor of the PTP4A family was obtained by photooxygenation of a less active, electron-rich thienopyridone (1). Iminothienopyridinedione 13 displays increased solution stability and is readily obtained by two new synthetic routes that converge in the preparation of 1. The late-stage photooxygenation of 1 to give 13 in high yield highlights the potential of this reaction to modify the structure and properties of a biological lead compound and generate value for expanding the scope of an SAR investigation. Analog 13 should become a valuable tool for further exploration of the role of PTP4A3 in tumor progression.

  15. Yucasin is a potent inhibitor of YUCCA, a key enzyme in auxin biosynthesis.

    PubMed

    Nishimura, Takeshi; Hayashi, Ken-Ichiro; Suzuki, Hiromi; Gyohda, Atsuko; Takaoka, Chihiro; Sakaguchi, Yusuke; Matsumoto, Sachiko; Kasahara, Hiroyuki; Sakai, Tatsuya; Kato, Jun-Ichi; Kamiya, Yuji; Koshiba, Tomokazu

    2014-02-01

    Indole-3-acetic acid (IAA), an auxin plant hormone, is biosynthesized from tryptophan. The indole-3-pyruvic acid (IPyA) pathway, involving the tryptophan aminotransferase TAA1 and YUCCA (YUC) enzymes, was recently found to be a major IAA biosynthetic pathway in Arabidopsis. TAA1 catalyzes the conversion of tryptophan to IPyA, and YUC produces IAA from IPyA. Using a chemical biology approach with maize coleoptiles, we identified 5-(4-chlorophenyl)-4H-1,2,4-triazole-3-thiol (yucasin) as a potent inhibitor of IAA biosynthesis in YUC-expressing coleoptile tips. Enzymatic analysis of recombinant AtYUC1-His suggested that yucasin strongly inhibited YUC1-His activity against the substrate IPyA in a competitive manner. Phenotypic analysis of Arabidopsis YUC1 over-expression lines (35S::YUC1) demonstrated that yucasin acts in IAA biosynthesis catalyzed by YUC. In addition, 35S::YUC1 seedlings showed resistance to yucasin in terms of root growth. A loss-of-function mutant of TAA1, sav3-2, was hypersensitive to yucasin in terms of root growth and hypocotyl elongation of etiolated seedlings. Yucasin combined with the TAA1 inhibitor l-kynurenine acted additively in Arabidopsis seedlings, producing a phenotype similar to yucasin-treated sav3-2 seedlings, indicating the importance of IAA biosynthesis via the IPyA pathway in root growth and leaf vascular development. The present study showed that yucasin is a potent inhibitor of YUC enzymes that offers an effective tool for analyzing the contribution of IAA biosynthesis via the IPyA pathway to plant development and physiological processes.

  16. Potent neutralization of hepatitis A virus reveals a receptor mimic mechanism and the receptor recognition site

    PubMed Central

    Wang, Xiangxi; Zhu, Ling; Dang, Minghao; Hu, Zhongyu; Gao, Qiang; Yuan, Shuai; Sun, Yao; Zhang, Bo; Ren, Jingshan; Kotecha, Abhay; Walter, Thomas S.; Wang, Junzhi; Fry, Elizabeth E.; Stuart, David I.; Rao, Zihe

    2017-01-01

    Hepatitis A virus (HAV) infects ∼1.4 million people annually and, although there is a vaccine, there are no licensed therapeutic drugs. HAV is unusually stable (making disinfection problematic) and little is known of how it enters cells and releases its RNA. Here we report a potent HAV-specific monoclonal antibody, R10, which neutralizes HAV infection by blocking attachment to the host cell. High-resolution cryo-EM structures of HAV full and empty particles and of the complex of HAV with R10 Fab reveal the atomic details of antibody binding and point to a receptor recognition site at the pentamer interface. These results, together with our observation that the R10 Fab destabilizes the capsid, suggest the use of a receptor mimic mechanism to neutralize virus infection, providing new opportunities for therapeutic intervention. PMID:28074040

  17. Potent neutralization of hepatitis A virus reveals a receptor mimic mechanism and the receptor recognition site.

    PubMed

    Wang, Xiangxi; Zhu, Ling; Dang, Minghao; Hu, Zhongyu; Gao, Qiang; Yuan, Shuai; Sun, Yao; Zhang, Bo; Ren, Jingshan; Kotecha, Abhay; Walter, Thomas S; Wang, Junzhi; Fry, Elizabeth E; Stuart, David I; Rao, Zihe

    2017-01-24

    Hepatitis A virus (HAV) infects ∼1.4 million people annually and, although there is a vaccine, there are no licensed therapeutic drugs. HAV is unusually stable (making disinfection problematic) and little is known of how it enters cells and releases its RNA. Here we report a potent HAV-specific monoclonal antibody, R10, which neutralizes HAV infection by blocking attachment to the host cell. High-resolution cryo-EM structures of HAV full and empty particles and of the complex of HAV with R10 Fab reveal the atomic details of antibody binding and point to a receptor recognition site at the pentamer interface. These results, together with our observation that the R10 Fab destabilizes the capsid, suggest the use of a receptor mimic mechanism to neutralize virus infection, providing new opportunities for therapeutic intervention.

  18. A PEGylated bovine hemoglobin as a potent hemoglobin-based oxygen carrier.

    PubMed

    Wang, Ying; Wang, Linli; Yu, Weili; Gao, Dawei; You, Guoxing; Li, Penglong; Zhang, Shan; Zhang, Jun; Hu, Tao; Zhao, Lian; Zhou, Hong

    2017-01-01

    Hemoglobin (Hb)-based oxygen carriers (HBOCs) have been used as blood substitutes in surgery medicine and oxygen therapeutics for ischemic stroke. As a potent HBOC, the PEGylated Hb has received much attention for its oxygen delivery and plasma expanding ability. Two PEGylated Hbs, Euro-Hb, and MP4 have been developed for clinical trials, using human adult hemoglobin (HbA) as the original substrate. However, HbA was obtained from outdated human blood and its quantity available from this source may not be sufficient for mass production of PEGylated HbA. In contrast, bovine Hb (bHb) has no quantity constraints for its ample resource. Thus, bHb is of potential to function as an alternative substrate to obtain a PEGylated bHb (bHb-PEG). bHb-PEG was prepared under the same reaction condition as HbA-PEG, using maleimide chemistry. The structural, functional, solution and physiological properties of bHb-PEG were determined and compared with those of HbA-PEG. bHb-PEG showed higher hydrodynamic volume, colloidal osmotic pressure, viscosity and P50 than HbA-PEG. The high P50 of bHb can partially compensate the PEGylation-induced perturbation in the R to T state transition of HbA. bHb-PEG was non-vasoactive and could efficiently recover the mean arterial pressure of mice suffering from hemorrhagic shock. Thus, bHb-PEG is expected to function as a potent HBOC for its high oxygen delivery and strong plasma expanding ability. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 33:252-260, 2017.

  19. A Highly Potent and Selective Caspase 1 Inhibitor that Utilizes a Key 3-Cyanopropanoic Acid Moiety

    PubMed Central

    Boxer, Matthew B.; Quinn, Amy M.; Shen, Min; Jadhav, Ajit; Leister, William; Simeonov, Anton; Auld, Douglas S.; Thomas, Craig J.

    2011-01-01

    Herein we examine the potential of a nitrile-containing proprionic acid moiety as an electrophile for covalent attack by the active site cysteine residue of caspase 1. The syntheses of several cyanopropanate containing small molecules based upon the optimized peptidic scaffold of the prodrug VX-765 were accomplished and found to be potent inhibitors of caspase 1 (IC50s ≤ 1 nM). Examination of these novel small molecules versus a caspase panel demonstrated an impressive degree of selectivity for caspase 1 inhibition. Assessment of hydrolytic stability and selected ADME properties highlighted these agents as potentially useful tools for studying caspase 1 down-regulation in various settings including in vivo analyses. PMID:20229566

  20. Low-energy Auger electron diffraction: influence of multiple scattering and angular momentum

    NASA Astrophysics Data System (ADS)

    Chassé, A.; Niebergall, L.; Kucherenko, Yu.

    2002-04-01

    The angular dependence of Auger electrons excited from single-crystal surfaces is treated theoretically within a multiple-scattering cluster model taking into account the full Auger transition matrix elements. In particular the model has been used to discuss the influence of multiple scattering and angular momentum of the Auger electron wave on Auger electron diffraction (AED) patterns in the region of low kinetic energies. Theoretical results of AED patterns are shown and discussed in detail for Cu(0 0 1) and Ni(0 0 1) surfaces, respectively. Even though Cu and Ni are very similar in their electronic and scattering properties recently strong differences have been found in AED patterns measured in the low-energy region. It is shown that the differences may be caused to superposition of different electron diffraction effects in an energy-integrated experiment. A good agreement between available experimental and theoretical results has been achieved.

  1. Stereoselective synthesis of protectin D1: A potent anti-inflammatory and proresolving lipid mediator

    PubMed Central

    Aursnes, M.; Tungen, J. E.; Vik, A.; Dalli, J.; Hansen, T. V.

    2014-01-01

    A convergent stereoselective synthesis of the potent anti-inflammatory, proresolving and neuroprotective lipid mediator protectin D1 (2) has been achieved in 15% yield over eight steps. The key features were a stereocontrolled Evans-aldol reaction with Nagao’s chiral auxiliary and a highly selective Lindlar reduction of internal alkyne 23, allowing the sensitive conjugated E,E,Z-triene to be introduced late in the preparation of 2. The UV and LC/MS-MS data of synthetic protectin D1 (2) matched those obtained from endogenously produced material PMID:24253202

  2. Ecteinascidins. A review of the chemistry, biology and clinical utility of potent tetrahydroisoquinoline antitumor antibiotics.

    PubMed

    Le, V H; Inai, M; Williams, R M; Kan, T

    2015-02-01

    The ecteinascidin family comprises a number of biologically active compounds, containing two to three tetrahydroisoquinoline subunits. Although isolated from marine tunicates, these compounds share a common pentacyclic core with several antimicrobial compounds found in terrestrial bacteria. Among the tetrahydroisoquinoline natural products, ecteinascidin 743 (Et-743) stands out as the most potent antitumor antibiotics that it is recently approved for treatment of a number of soft tissue sarcomas. In this article, we will review the backgrounds, the mechanism of action, the biosynthesis, and the synthetic studies of Et-743. Also, the development of Et-743 as an antitumor drug is discussed.

  3. Discovery of a Selective Inhibitor of Oncogenic B-Raf Kinase With Potent Antimelanoma Activity

    SciTech Connect

    Tsai, J.; Lee, J.T.; Wang, W.; Zhang, J.; Cho, H.; Mamo, S.; Bremer, R.; Gillette, S.; Kong, J.; Haass, N.K.; Sproesser, K.; Li, L.; Smalley, K.S.M.; Fong, D.; Zhu, Y.-L.; Marimuthu, A.; Nguyen, H.; Lam, B.; Liu, J.; Cheung, I.; Rice, J.

    2009-05-26

    BRAF{sup V600E} is the most frequent oncogenic protein kinase mutation known. Furthermore, inhibitors targeting 'active' protein kinases have demonstrated significant utility in the therapeutic repertoire against cancer. Therefore, we pursued the development of specific kinase inhibitors targeting B-Raf, and the V600E allele in particular. By using a structure-guided discovery approach, a potent and selective inhibitor of active B-Raf has been discovered. PLX4720, a 7-azaindole derivative that inhibits B-Raf{sup V600E} with an IC{sub 50} of 13 nM, defines a class of kinase inhibitor with marked selectivity in both biochemical and cellular assays. PLX4720 preferentially inhibits the active B-Raf{sup V600E} kinase compared with a broad spectrum of other kinases, and potent cytotoxic effects are also exclusive to cells bearing the V600E allele. Consistent with the high degree of selectivity, ERK phosphorylation is potently inhibited by PLX4720 in B-Raf{sup V600E}-bearing tumor cell lines but not in cells lacking oncogenic B-Raf. In melanoma models, PLX4720 induces cell cycle arrest and apoptosis exclusively in B-Raf{sup V600E}-positive cells. In B-Raf{sup V600E}-dependent tumor xenograft models, orally dosed PLX4720 causes significant tumor growth delays, including tumor regressions, without evidence of toxicity. The work described here represents the entire discovery process, from initial identification through structural and biological studies in animal models to a promising therapeutic for testing in cancer patients bearing B-Raf{sup V600E}-driven tumors.

  4. 6-Methoxypurine arabinoside as a selective and potent inhibitor of varicella-zoster virus.

    PubMed Central

    Averett, D R; Koszalka, G W; Fyfe, J A; Roberts, G B; Purifoy, D J; Krenitsky, T A

    1991-01-01

    Seven 6-alkoxypurine arabinosides were synthesized and evaluated for in vitro activity against varicella-zoster virus (VZV). The simplest of the series, 6-methoxypurine arabinoside (ara-M), was the most potent, with 50% inhibitory concentrations ranging from 0.5 to 3 microM against eight strains of VZV. This activity was selective. The ability of ara-M to inhibit the growth of a variety of human cell lines was at least 30-fold less (50% effective concentration, greater than 100 microM) than its ability to inhibit the virus. Enzyme studies suggested the molecular basis for these results. Of the seven 6-alkoxypurine arabinosides, ara-M was the most efficient substrate for VZV-encoded thymidine kinase as well as the most potent antiviral agent. In contrast, it was not detectably phosphorylated by any of the three major mammalian nucleoside kinases. Upon direct comparison, ara-M was appreciably more potent against VZV than either acyclovir or adenine arabinoside (ara-A). However, in the presence of an adenosine deaminase inhibitor, the arabinosides of adenine and 6-methoxypurine were equipotent but not equally selective; the adenine congener had a much less favorable in vitro chemotherapeutic index. Again, this result correlated with data from enzyme studies in that ara-A, unlike ara-M, was a substrate for two mammalian nucleoside kinases. Unlike acyclovir and ara-A, ara-M had no appreciable activity against other viruses of the herpes group. The potency and selectivity of ara-M as an anti-VZV agent in vitro justify its further study. PMID:1649571

  5. Auger electron angular distribution of double core-hole states in the molecular reference frame.

    PubMed

    Cryan, James P; Glownia, J M; Andreasson, J; Belkacem, A; Berrah, N; Blaga, C I; Bostedt, C; Bozek, J; Buth, C; DiMauro, L F; Fang, L; Gessner, O; Guehr, M; Hajdu, J; Hertlein, M P; Hoener, M; Kornilov, O; Marangos, J P; March, A M; McFarland, B K; Merdji, H; Petrović, V S; Raman, C; Ray, D; Reis, D; Tarantelli, F; Trigo, M; White, J L; White, W; Young, L; Bucksbaum, P H; Coffee, R N

    2010-08-20

    The Linac Coherent Light Source free electron laser is a source of high brightness x rays, 2×10(11) photons in a ∼5 fs pulse, that can be focused to produce double core vacancies through rapid sequential ionization. This enables double core vacancy Auger electron spectroscopy, an entirely new way to study femtosecond chemical dynamics with Auger electrons that probe the local valence structure of molecules near a specific atomic core. Using 1.1 keV photons for sequential x-ray ionization of impulsively aligned molecular nitrogen, we observed a rich single-site double core vacancy Auger electron spectrum near 413 eV, in good agreement with ab initio calculations, and we measured the corresponding Auger electron angle dependence in the molecular frame.

  6. Auger Electron Angular Distribution of Double Core-Hole States in the Molecular Reference Frame

    NASA Astrophysics Data System (ADS)

    Cryan, James P.; Glownia, J. M.; Andreasson, J.; Belkacem, A.; Berrah, N.; Blaga, C. I.; Bostedt, C.; Bozek, J.; Buth, C.; Dimauro, L. F.; Fang, L.; Gessner, O.; Guehr, M.; Hajdu, J.; Hertlein, M. P.; Hoener, M.; Kornilov, O.; Marangos, J. P.; March, A. M.; McFarland, B. K.; Merdji, H.; Petrović, V. S.; Raman, C.; Ray, D.; Reis, D.; Tarantelli, F.; Trigo, M.; White, J. L.; White, W.; Young, L.; Bucksbaum, P. H.; Coffee, R. N.

    2010-08-01

    The Linac Coherent Light Source free electron laser is a source of high brightness x rays, 2×1011 photons in a ˜5fs pulse, that can be focused to produce double core vacancies through rapid sequential ionization. This enables double core vacancy Auger electron spectroscopy, an entirely new way to study femtosecond chemical dynamics with Auger electrons that probe the local valence structure of molecules near a specific atomic core. Using 1.1 keV photons for sequential x-ray ionization of impulsively aligned molecular nitrogen, we observed a rich single-site double core vacancy Auger electron spectrum near 413 eV, in good agreement with ab initio calculations, and we measured the corresponding Auger electron angle dependence in the molecular frame.

  7. Auger electron diffraction in thin CoO films on Au(1 1 1)

    NASA Astrophysics Data System (ADS)

    Chassé, A.; Niebergall, L.; Heiler, M.; Neddermeyer, H.; Schindler, K.-M.

    The local structure of thin CoO films grown on a single crystal Au(1 1 1) surface has been studied by Auger electron diffraction (AED). Therefore, the angular dependence of the Auger electron intensity of Co-LMM and O-KLL Auger electrons was recorded in the total half-space above the film. Such 2 π-scans immediately reflect the symmetry of the surface and the local structure of the film. The experimental data are compared to multiple-scattering cluster calculations, where both the influence of multiple-scattering effects and effects of Auger transition matrix elements have been investigated. We have found that the AED patterns of a CoO film in forward-scattering conditions do not always provide straightforward information on the local structure of the film, whereas the multiple-scattering approximation applied gives very good agreement between experimental and theoretical results.

  8. A naturally occurring naringenin derivative exerts potent bone anabolic effects by mimicking oestrogen action on osteoblasts

    PubMed Central

    Swarnkar, Gaurav; Sharan, Kunal; Siddiqui, Jawed A; Mishra, Jay Sharan; Khan, Kainat; Khan, Mohd Parvez; Gupta, Varsha; Rawat, Preeti; Maurya, Rakesh; Dwivedi, Anil K; Sanyal, Sabyasachi; Chattopadhyay, Naibedya

    2012-01-01

    BACKGROUND AND PURPOSE Naringenin and its derivatives have been assessed in bone health for their oestrogen-‘like’ effects but low bioavailability impedes clinical potential. This study was aimed at finding a potent form of naringenin with osteogenic action. EXPERIMENTAL APPROACH Osteoblast cultures were harvested from mouse calvaria to study differentiation by naringenin, isosakuranetin, poncirin, phloretin and naringenin-6-C-glucoside (NCG). Balb/cByJ ovariectomized (OVx) mice without or with osteopenia were given naringenin, NCG, 17β-oestradiol (E2) or parathyroid hormone (PTH). Efficacy was evaluated by bone microarchitecture using microcomputed tomography and determination of new bone formation by fluorescent labelling of bone. Plasma levels of NCG and naringenin were determined by HPLC. KEY RESULTS NCG stimulated osteoblast differentiation more potently than naringenin, while isosakuranetin, poncirin or phloretin had no effect. NCG had better oral bioavailability than naringenin. NCG increased the mRNA levels of oestrogen receptors (ERs) and bone morphogenetic protein (an ER responsive gene) in vivo, more than naringenin. In OVx mice, NCG treatment in a preventive protocol increased bone formation rate (BFR) and improved trabecular microarchitecture more than naringenin or E2. In osteopenic mice, NCG but not naringenin, in a therapeutic protocol, increased BFR and improved trabecular microarchitecture, comparable with effects of PTH treatment. Stimulatory effects of NCG on osteoblasts were abolished by an ER antagonist. NCG transactivated ERβ but not ERα. NCG exhibited no uterine oestrogenicity unlike naringenin. CONCLUSIONS AND IMPLICATIONS NCG is a potent derivative of naringenin that has bone anabolic action through the activation of osteoblast ERs and exhibited substantial oral bioavailability. PMID:21864313

  9. A new potent inhibitor of horse liver alcohol dehydrogenase: p-methylbenzyl hydroperoxide.

    PubMed

    Skurský, L; Khan, A N; Saleem, M N; al-Tamer, Y Y

    1992-04-01

    A product of p-xylene auto-oxidation, p-methylbenzyl hydroperoxide, acts as a very strong reversible inhibitor of the ethanol dehydrogenating activity of horse liver alcohol dehydrogenase. Concentrations of hydroperoxide as low as that of the enzyme active site (about 10(-8) mol.dm-3) in the assay depresses the activity by 50%. Somewhat less potent is benzyl hydroperoxide (derived from toluene) while the (secondary) hydroperoxide derived from ethylbenzene and tert.butyl hydroperoxide and cumyl hydroperoxide do not inhibit HLAD appreciably.

  10. In Situ Click Chemistry for the Identification of a Potent D-Amino Acid Oxidase Inhibitor.

    PubMed

    Toguchi, Shohei; Hirose, Tomoyasu; Yorita, Kazuko; Fukui, Kiyoshi; Sharpless, K Barry; Ōmura, Satoshi; Sunazuka, Toshiaki

    2016-07-01

    In situ click chemistry is a target-guided synthesis approach for discovering novel lead compounds by assembling organic azides and alkynes into triazoles inside the affinity site of target biogenic molecules such as proteins. We report in situ click chemistry screening with human D-amino acid oxidase (hDAO), which led to the identification of a more potent hDAO inhibitor. The hDAO inhibitors have chemotherapeutic potential as antipsychotic agents. The new inhibitor displayed competitive inhibition of hDAO and showed significantly increased inhibitory activity against hDAO compared with that of an anchor molecule of in situ click chemistry.

  11. HIV Integrase Inhibitors with Nucleobase Scaffolds: Discovery of a Highly Potent anti-HIV Agent

    PubMed Central

    Nair, Vasu; Chi, Guochen; Ptak, Roger; Neamati, Nouri

    2008-01-01

    HIV integrase is essential for HIV replication. However, there are currently no integrase inhibitors in clinical use for AIDS. We have discovered a conceptually new β-diketo acid that is a powerful inhibitor of both the 3′-processing and strand transfer steps of HIV-1 integrase. The in vitro anti-HIV data of this inhibitor were remarkable as exemplified by its highly potent antiviral therapeutic efficacy against HIVTEKI and HIV-1NL4-3 replication in PBMC (TI >4,000 and >10,000, respectively). PMID:16420027

  12. Chiral Proton Catalysis of Secondary Nitroalkane Additions to Azomethine: Synthesis of a Potent GlyT1 Inhibitor

    PubMed Central

    Davis, Tyler A.; Danneman, Michael W.; Johnston, Jeffrey N.

    2014-01-01

    The first enantioselective synthesis of a potent GlyT1 inhibitor is described. A 3-nitroazetidine donor is used in an enantioselective aza-Henry reaction catalyzed by a bis(amidine)-triflic acid salt organocatalyst, delivering the key intermediate with 92% ee. This adduct is reductively denitrated and converted to the target through a short sequence, thereby allowing assignment of the absolute configuration of the more potent enantiomer. PMID:22543734

  13. Potent Selective Inhibition of Monoamine Oxidase A by Alternariol Monomethyl Ether Isolated from Alternaria brassicae.

    PubMed

    Lee, Hyun Woo; Kim, Yeon Ji; Nam, Sang-Jip; Kim, Hoon

    2017-02-28

    Alternariol monomethyl ether (AME), a dibenzopyrone derivative, was isolated from Alternaria brassicae along with altertoxin II (ATX-II). The compounds were tested for the inhibitory activity of monoamine oxidase (MAO), which catalyzes neurotransmitting monoamines. AME was found to be a highly potent and selective inhibitor of human MAO-A with an IC50 value of 1.71 µM; however, it was found to be ineffective for MAO-B inhibition. ATX-II was not effective for the inhibition of either MAO-A or MAO-B. The inhibition of MAO-A using AME was apparently instantaneous. MAO-A activity was almost completely recovered after the dilution of the inhibited enzyme with an excess amount of AME, suggesting AME is a reversible inhibitor. AME showed mixed inhibition for MAO-A in Lineweaver-Burk plots with a Ki value of 0.34 µM. The findings of this study suggest that microbial metabolites and dibenzopyrone could be potent MAO inhibitors. In addition, AME could be a useful lead compound for developing reversible MAO-A inhibitors to treat depression, Parkinson's disease, and Alzheimer's disease.

  14. Aromatic lipoxin A4 and lipoxin B4 analogues display potent biological activities.

    PubMed

    O'Sullivan, Timothy P; Vallin, Karl S A; Shah, Syed Tasadaque Ali; Fakhry, Jérôme; Maderna, Paola; Scannell, Michael; Sampaio, Andre L F; Perretti, Mauro; Godson, Catherine; Guiry, Patrick J

    2007-11-29

    Lipoxins are a group of biologically active eicosanoids typically formed by transcellular lipoxygenase activity. Lipoxin A4 (LXA4) and Lipoxin B4 (LXB4) biosynthesis has been detected in a variety of inflammatory conditions. The native lipoxins LXA4 and LXB4 demonstrate potent antiinflammatory and proresolution bioactions. However, their therapeutic potential is compromised by rapid metabolic inactivation by PG dehydrogenase-mediated oxidation and reduction. Here we report on the stereoselective synthesis of aromatic LXA4 and LXB4 analogues by employing Sharpless epoxidation, Pd-mediated Heck coupling, and diastereoselective reduction as the key transformations. Subsequent biological testing has shown that these analogues display potent biological activities. Phagocytic clearance of apoptotic leukocytes plays a critical role in the resolution of inflammation. Both LXA4 analogues (1R)-3a and (1S)-3a were found to stimulate a significant increase in phagocytosis of apoptotic polymorphonuclear leukocytes (PMN) by macrophages, with comparable efficacy to the effect of native LXA4, albeit greater potency, while the LXB4 analogue also stimulated phagocytosis with a maximum effect observed at 10-11 M. LX-stimulated phagocytosis was associated with rearrangement of the actin cytoskeleton consistent with that reported for native lipoxins. Using zymosan-induced peritonitis as a murine model of acute inflammation (1R)-3a significantly reduced PMN accumulation.

  15. Basis Tetrapeptides as Potent Intracellular Inhibitors of type A Botulinum Neurotoxin Protease Activity

    SciTech Connect

    Hale, M.; Swaminathan, S.; Oyler, G.; Ahmed, S. A.

    2011-01-21

    Botulinum neurotoxins (BoNT) are the most potent of all toxins that cause flaccid muscle paralysis leading to death. They are also potential biothreat agents. A systematic investigation of various short peptide inhibitors of the BoNT protease domain with a 17-residue peptide substrate led to arginine-arginine-glycine-cysteine having a basic tetrapeptide structure as the most potent inhibitor. When assayed in the presence of dithiothreitol (DTT), the inhibitory effect was drastically reduced. Replacing the terminal cysteine with one hydrophobic residue eliminated the DTT effect but with two hydrophobic residues made the pentapeptide a poor inhibitor. Replacing the first arginine with cysteine or adding an additional cysteine at the N terminus did not improve inhibition. When assessed using mouse brain lysates, the tetrapeptides also inhibited BoNT/A cleavage of the endogenous SNAP-25. The peptides penetrated the neuronal cell lines, N2A and BE(2)-M17, without adversely affecting metabolic functions as measured by ATP production and P-38 phosphorylation. Biological activity of the peptides persisted within cultured chick motor neurons and rat and mouse cerebellar neurons for more than 40 h and inhibited BoNT/A protease action inside the neurons in a dose- and time-dependent fashion. Our results define a tetrapeptide as the smallest peptide inhibitor in the backdrop of a large substrate protein of 200+ amino acids having multiple interaction regions with its cognate enzyme. The inhibitors should also be valuable candidates for drug development.

  16. In silico design, synthesis and evaluation of 3'-O-benzylated analogs of salacinol, a potent α-glucosidase inhibitor isolated from an Ayurvedic traditional medicine "Salacia".

    PubMed

    Tanabe, Genzoh; Nakamura, Shinya; Tsutsui, Nozomi; Balakishan, Gorre; Xie, Weijia; Tsuchiya, Satoshi; Akaki, Junji; Morikawa, Toshio; Ninomiya, Kiyofumi; Nakanishi, Isao; Yoshikawa, Masayuki; Muraoka, Osamu

    2012-09-07

    With the aid of an in silico method, α-glucosidase inhibitors with far more potent activities than salacinol (1), a potent natural α-glucosidase inhibitor isolated from an Ayurvedic traditional medicine Salacia reticulata, have been developed.

  17. Targeting Two Coagulation Cascade Proteases with a Bivalent Aptamer Yields a Potent and Antidote-Controllable Anticoagulant

    PubMed Central

    Soule, Erin E.; Bompiani, Kristin M.; Woodruff, Rebecca S.

    2016-01-01

    Potent and rapid-onset anticoagulation is required for several clinical settings, including cardiopulmonary bypass surgery. In addition, because anticoagulation is associated with increased bleeding following surgery, the ability to rapidly reverse such robust anticoagulation is also important. Previously, we observed that no single aptamer was as potent as heparin for anticoagulating blood. However, we discovered that combinations of two aptamers were as potent as heparin. Herein, we sought to combine two individual anticoagulant aptamers into a single bivalent RNA molecule in an effort to generate a single molecule that retained the potent anticoagulant activity of the combination of individual aptamers. We created four bivalent aptamers that can inhibit Factor X/Xa and prothrombin/thrombin and anticoagulate plasma, as well as the combination of individual aptamers. Detailed characterization of the shortest bivalent aptamer indicates that each aptamer retains full binding and functional activity when presented in the bivalent context. Finally, reversal of this bivalent aptamer with a single antidote was explored, and anticoagulant activity could be rapidly turned off in a dose-dependent manner. These studies demonstrate that bivalent anticoagulant aptamers represent a novel and potent approach to actively and reversibly control coagulation. PMID:26584417

  18. Targeting Two Coagulation Cascade Proteases with a Bivalent Aptamer Yields a Potent and Antidote-Controllable Anticoagulant.

    PubMed

    Soule, Erin E; Bompiani, Kristin M; Woodruff, Rebecca S; Sullenger, Bruce A

    2016-02-01

    Potent and rapid-onset anticoagulation is required for several clinical settings, including cardiopulmonary bypass surgery. In addition, because anticoagulation is associated with increased bleeding following surgery, the ability to rapidly reverse such robust anticoagulation is also important. Previously, we observed that no single aptamer was as potent as heparin for anticoagulating blood. However, we discovered that combinations of two aptamers were as potent as heparin. Herein, we sought to combine two individual anticoagulant aptamers into a single bivalent RNA molecule in an effort to generate a single molecule that retained the potent anticoagulant activity of the combination of individual aptamers. We created four bivalent aptamers that can inhibit Factor X/Xa and prothrombin/thrombin and anticoagulate plasma, as well as the combination of individual aptamers. Detailed characterization of the shortest bivalent aptamer indicates that each aptamer retains full binding and functional activity when presented in the bivalent context. Finally, reversal of this bivalent aptamer with a single antidote was explored, and anticoagulant activity could be rapidly turned off in a dose-dependent manner. These studies demonstrate that bivalent anticoagulant aptamers represent a novel and potent approach to actively and reversibly control coagulation.

  19. Auger Prime the new stage of the Pierre Auger Observatory, using Universality

    NASA Astrophysics Data System (ADS)

    Parra, Alejandra; Martínez, Oscar; Salazar, Humberto

    2016-10-01

    The Pierre Auger Observatory is currently in an update stage denominated AugerPrime. The Observatory will have scintillator detectors on top of each of the surface stations (WCD). The main goal of AugerPrime is to improve the studies on mass composition for ultra high energy cosmic rays, for this purpose AugerPrime will use Universality. The model will parameterize the signal in four principal components, the objective is an adequate discrimination of the muonic and electromagnetic components. We are interested in the discrimination of these two components using simulations. To do that, we are working with OfflineTrunk (the official software of the Collaboration). Our work is focused on the development of some modules for analysis and study of the signal from AugerPrime.

  20. Highly potent first examples of dual aromatase-steroid sulfatase inhibitors based on a biphenyl template.

    PubMed

    Woo, L W Lawrence; Jackson, Toby; Putey, Aurélien; Cozier, Gyles; Leonard, Philip; Acharya, K Ravi; Chander, Surinder K; Purohit, Atul; Reed, Michael J; Potter, Barry V L

    2010-03-11

    Single agents against multiple drug targets are of increasing interest. Hormone-dependent breast cancer (HDBC) may be more effectively treated by dual inhibition of aromatase and steroid sulfatase (STS). The aromatase inhibitory pharmacophore was thus introduced into a known biphenyl STS inhibitor to give a series of novel dual aromatase-sulfatase inhibitors (DASIs). Several compounds are good aromatase or STS inhibitors and DASI 20 (IC(50): aromatase, 2.0 nM; STS, 35 nM) and its chlorinated congener 23 (IC(50): aromatase, 0.5 nM; STS, 5.5 nM) are examples that show exceptional dual potency in JEG-3 cells. Both biphenyls share a para-sulfamate-containing ring B and a ring A, which contains a triazol-1-ylmethyl meta to the biphenyl bridge and para to a nitrile. At 1 mg/kg po, 20 and 23 reduced plasma estradiol levels strongly and inhibited liver STS activity potently in vivo. 23 is nonestrogenic and potently inhibits carbonic anhydrase II (IC(50) 86 nM). A complex was crystallized and its structure was solved by X-ray crystallography. This class of DASI should encourage further development toward multitargeted therapeutic intervention in HDBC.

  1. Electrostatic Binding of Electroactive and Non-Electroactive Anions in a Surface-Confined, Electroactive Polymer: Selectivity of Binding Measured by Auger Spectroscopy and Cyclic Voltammetry.

    DTIC Science & Technology

    1981-09-15

    reverse side it necessary and Identify I block nuimber) * --, surface confined polymers, electrostatic binding, Auger spectroscopy, cyclic voltammetry .... 4...chemically reversible redox reaction when bound to the polymer, as determined by cyclic voltammetry . Such electroactive anions can be bound in the (PQ 2+)n...polymer for prolonged periods (>1 h) in the presence of 0.1 M KCI. Cyclic voltammetry of electrodes having variable amounts of IrCl6 3- *2+ 2 +3- 2

  2. Development of Atmospheric Monitoring System for Auger North

    NASA Astrophysics Data System (ADS)

    Claus, John; Allen, Clint; Botts, Adam; Carande, Bryce; Calhoun, Mike; Emmert, Lucas; Hamilton, Levi; Heid, T. J.; Koop, John; Morgan, Sarah; Robinson, Shay; Sherman, John; Wiencke, Lawrence

    2009-10-01

    The Pierre Auger Northern Fluorescence Detector will measure air-showers over distances of 40 km. Vertical Aerosol profile of the atmosphere at the Pierre Auger Northern site will be measured using the side-scatter method over the 40 km baseline. An atmospheric monitoring telescope (AMT) will use a 3.5 m^2 mirror optimized for UV reflection to focus light from a laser onto a cluster of phototmultiplier tubes. The AMT has been built and final testing and modifications are being carried out before its installation later this year. A remotely programmed, 355 nm YAG laser with a final beam energy of 5 mJ is being used. The automation of the laser and the AMT is controlled via a single board computer (SBC). This talk will present an overview of this R&D program.

  3. Biaryl ethers as potent allosteric inhibitors of reverse transcriptase and its key mutant viruses: aryl substituted pyrazole as a surrogate for the pyrazolopyridine motif.

    PubMed

    Su, Dai-Shi; Lim, John J; Tinney, Elizabeth; Tucker, Thomas J; Saggar, Sandeep; Sisko, John T; Wan, Bang-Lin; Young, Mary Beth; Anderson, Kenneth D; Rudd, Deanne; Munshi, Vandna; Bahnck, Carolyn; Felock, Peter J; Lu, Meiquing; Lai, Ming-Tain; Touch, Sinoeun; Moyer, Gregory; Distefano, Daniel J; Flynn, Jessica A; Liang, Yuexia; Sanchez, Rosa; Perlow-Poehnelt, Rebecca; Miller, Mike; Vacca, Joe P; Williams, Theresa M; Anthony, Neville J

    2010-08-01

    Biaryl ethers were recently reported as potent NNRTIs. Herein, we disclose a detailed effort to modify the previously reported compound 1. We have designed and synthesized a series of novel pyrazole derivatives as a surrogate for pyrazolopyridine motif that were potent inhibitors of HIV-1 RT with nanomolar intrinsic activity on the WT and key mutant enzymes and potent antiviral activity in infected cells.

  4. Rice Bran Protein as a Potent Source of Antimelanogenic Peptides with Tyrosinase Inhibitory Activity.

    PubMed

    Ochiai, Akihito; Tanaka, Seiya; Tanaka, Takaaki; Taniguchi, Masayuki

    2016-10-28

    Rice (Oryza sativa) is consumed as a staple food globally, and rice bran, the byproduct, is an unused biomass that is ultimately discarded as waste. Thus, in the present study, a technique for producing tyrosinase inhibitory peptides from rice bran protein (RBP) was developed. Simultaneous treatment of RBP with chymotrypsin and trypsin produced numerous peptides. Subsequently, six tyrosinase inhibitory peptides were isolated from the hydrolysate fractions in a multistep purification protocol, and their amino acid sequences were determined. Three of these peptides had a C-terminal tyrosine residue and exhibited significant inhibitory effects against tyrosinase-mediated monophenolase reactions. Furthermore, peptide CT-2 (Leu-Gln-Pro-Ser-His-Tyr) potently inhibited melanogenesis in mouse B16 melanoma cells without causing cytotoxicity, suggesting the potential of CT-2 as an agent for melanin-related skin disorder treatment. The present data indicate that RBP is a potent source of tyrosinase inhibitory peptides and that simultaneous treatment of RBP with chymotrypsin and trypsin efficiently produces these peptides.

  5. Identification of a potent immunostimulatory oligodeoxynucleotide from Streptococcus thermophilus lacZ.

    PubMed

    Shimosato, Takeshi; Tohno, Masanori; Sato, Takashi; Nishimura, Junko; Kawai, Yasushi; Saito, Tadao; Kitazawa, Haruki

    2009-10-01

    Immunostimulatory sequences of oligodeoxynucleotides (ODNs), such as CpG ODNs, are potent stimulators of innate immunity. Here, we identified a strong immunostimulatory CpG ODN, which we named MsST, from the lac Z gene of Streptococcus (S.) thermophilus ATCC19258, and we evaluated its immune functions. In in vitro studies, MsST had a similar ability as the murine prototype CpG ODN 1555 to induce inflammatory cytokine production and cell proliferation. In mouse splenocytes, MsST increased the number of CD80+CD11c+and CD86+CD11c+ dendritic cells and CD4+CD25+ regulatory T cells. We also analyzed the effects of MsST on the expression of regulatory cytokines by real-time quantitative PCR. MsST was more potent at inducing interleukin-10 expression than the ODN control 1612, indicating that MsST can augment the regulatory T cell response via Toll-like receptor 9, which plays an important role in suppressing T helper type 2 responses. These results suggest that S. thermophilus, whose genes include a strong Immunostimulatory sequence-ODN, is a good candidate for a starter culture to develop new physiologically functional foods and feeds.

  6. Relativistic Radiative and Auger Rates for Fe XXIV

    NASA Technical Reports Server (NTRS)

    Bautista, M. A.; Mendoza, C.; Kallman, T. R.; Palmeri, P.; White, Nicholas E. (Technical Monitor)

    2002-01-01

    As part of a project to compute improved atomic data for the spectral modeling of iron K lines, we report extensive calculations and comparisons of radiative and Auger rates for transitions involving the K-vacancy states in Fe XXIV. By making use of several computational codes, a detailed study is carried out of orbital representation, configuration interaction, relativistic corrections, cancellation effects, and fine tuning. It is shown that a formal treatment of the Breit interaction is essential to render the important magnetic correlations that take part in the decay pathways of this ion. As a result, the accuracy of the present A-values is firmly ranked at better than 10% while that of the Auger rates at only 15%.

  7. Auger recombination in long-wave infrared InAs/InAsSb type-II superlattices

    SciTech Connect

    Olson, B. V.; Grein, C. H.; Kim, J. K.; Kadlec, E. A.; Klem, J. F.; Hawkins, S. D.; Shaner, E. A.

    2015-12-29

    The Auger lifetime is a critical intrinsic parameter for infrared photodetectors as it determines the longest potential minority carrier lifetime and consequently the fundamental limitations to their performance. Here, Auger recombination is characterized in a long-wave infrared InAs/InAsSb type-II superlattice. Auger coefficients as small as 7.1×10–26 cm6/s are experimentally measured using carrier lifetime data at temperatures in the range of 20 K–80 K. The data are compared to Auger-1 coefficients predicted using a 14-band K•p electronic structure model and to coefficients calculated for HgCdTe of the same bandgap. In conclusion, the experimental superlattice Auger coefficients are found to be an order-of-magnitude smaller than HgCdTe.

  8. Auger recombination in long-wave infrared InAs/InAsSb type-II superlattices

    DOE PAGES

    Olson, B. V.; Grein, C. H.; Kim, J. K.; ...

    2015-12-29

    The Auger lifetime is a critical intrinsic parameter for infrared photodetectors as it determines the longest potential minority carrier lifetime and consequently the fundamental limitations to their performance. Here, Auger recombination is characterized in a long-wave infrared InAs/InAsSb type-II superlattice. Auger coefficients as small as 7.1×10–26 cm6/s are experimentally measured using carrier lifetime data at temperatures in the range of 20 K–80 K. The data are compared to Auger-1 coefficients predicted using a 14-band K•p electronic structure model and to coefficients calculated for HgCdTe of the same bandgap. In conclusion, the experimental superlattice Auger coefficients are found to be anmore » order-of-magnitude smaller than HgCdTe.« less

  9. Prokaryotic expression of a constitutively expressed Tephrosia villosa defensin and its potent antifungal activity.

    PubMed

    Vijayan, S; Guruprasad, Lalitha; Kirti, P B

    2008-10-01

    Plant defensins are small, highly stable, cysteine-rich antimicrobial peptides produced by the plants for inhibiting a broad-spectrum of microbial pathogens. Some of the well-characterized plant defensins exhibit potent antifungal activity on certain pathogenic fungal species only. We characterized a defensin, TvD1 from a weedy leguminous herb, Tephrosia villosa. The open reading frame of the cDNA was 228 bp, which codes for a peptide with 75 amino acids. Expression analyses indicated that this defensin is expressed constitutively in T. villosa with leaf, stem, root, and seed showing almost similar levels of high expression. The recombinant peptide (rTvD1), expressed in the Escherichia coli expression system, exhibited potent in vitro antifungal activity against several filamentous soil-borne fungal pathogens. The purified peptide also showed significant inhibition of root elongation in Arabidopsis seedlings, subsequently affecting the extension of growing root hairs indicating that it has the potential to disturb the plant growth and development.

  10. Pentobra: A potent antibiotic with multiple layers of selective antimicrobial mechanisms against Propionibacterium acnes

    PubMed Central

    Schmidt, Nathan W.; Agak, George W.; Deshayes, Stephanie; Yu, Yang; Blacker, Alyssa; Champer, Jackson; Xian, Wujing; Kasko, Andrea M.; Kim, Jenny; Wong, Gerard C. L.

    2015-01-01

    Although antibiotics are a common treatment for acne, the difficulties inherent to effective antimicrobial penetration in sebum and selective antimicrobial action in skin are compounded by increasing resistance of Propionibacterium acnes clinical isolates. To address these problems, we engineered Pentobra, a peptide-aminoglycoside molecule which has multiple mechanisms of antibacterial action, and investigated whether it can be a potential candidate for the treatment of acne. Pentobra combines the potent ribosomal activity of aminoglycosides with the bacteria-selective membrane-permeabilizing abilities of antimicrobial peptides (AMPs). Pentobra demonstrated potent and selective killing of P. acnes, but not against human skin cells in vitro. In direct comparison, Pentobra demonstrated bactericidal activity and drastically outperformed free tobramycin (by 5–7 logs) against multiple P. acnes clinical strains. Moreover, EM studies showed that Pentobra had robust membrane activity, as treatment with Pentobra killed P. acnes cells and caused leakage of intracellular contents. Pentobra may also have potential anti-inflammatory effects as demonstrated by suppression of some P. acnes-induced chemokines. Importantly, the killing activity was maintained in sebaceous environments as Pentobra was bactericidal against clinical isolates in comedones extracts isolated from human donors. Our work demonstrates that equipping aminoglycosides with selective membrane activity is a viable approach for developing antibiotics against P. acnes that are effective in cutaneous environments. PMID:25668237

  11. B7-Dc, a New Dendritic Cell Molecule with Potent Costimulatory Properties for T Cells

    PubMed Central

    Tseng, Su-Yi; Otsuji, Mizuto; Gorski, Kevin; Huang, Xin; Slansky, Jill E.; Pai, Sara I.; Shalabi, Ahmed; Shin, Tahiro; Pardoll, Drew M.; Tsuchiya, Haruo

    2001-01-01

    Dendritic cells (DCs), unique antigen-presenting cells (APCs) with potent T cell stimulatory capacity, direct the activation and differentiation of T cells by providing costimulatory signals. As such, they are critical regulators of both natural and vaccine-induced immune responses. A new B7 family member, B7-DC, whose expression is highly restricted to DCs, was identified among a library of genes differentially expressed between DCs and activated macrophages. B7-DC fails to bind the B7.1/2 receptors CD28 and cytotoxic T lymphocyte–associated antigen (CTLA)-4, but does bind PD-1, a receptor for B7-H1/PD-L1. B7-DC costimulates T cell proliferation more efficiently than B7.1 and induces a distinct pattern of lymphokine secretion. In particular, B7-DC strongly costimulates interferon γ but not interleukin (IL)-4 or IL-10 production from isolated naive T cells. These properties of B7-DC may account for some of the unique activity of DCs, such as their ability to initiate potent T helper cell type 1 responses. PMID:11283156

  12. Spectrum of energy depositions in the Auger Water Cherenkov Detector

    NASA Astrophysics Data System (ADS)

    Salazar, Humberto

    1999-08-01

    The measured spectrum of energy depositions in a Water Cherenkov Detector (WCD) prototype for the Pierre Auger Observatory is presented. A WCD (area 10 m2 )is located in the Puebla University campus at a depth of 800 g/cm2 (2200 m above sea level). Differential and integral spectra in a wide energy deposition range (0.5 - 150 of vertical equivalent muons) are presented. The problem of the WCD "self calibration" procedure (by rate of the muon events) is discussed. The characteristic change of the slopes of the differential spectrum at the transition from single muon signals to EAS signals is also discussed. The measured energy deposition spectrum at extreme signals is used to estimate the linearity of the response of the WCD PMTs. Key words: Auger array, water Cherenkov detector, extensive air showers

  13. BU74, a complex oripavine derivative with potent kappa opioid receptor agonism and delayed opioid antagonism.

    PubMed

    Husbands, Stephen M; Neilan, Claire L; Broadbear, Jillian; Grundt, Peter; Breeden, Simon; Aceto, Mario D; Woods, James H; Lewis, John W; Traynor, John R

    2005-02-21

    In the search for opioid agonists with delayed antagonist actions as potential treatments for substance abuse, the bridged morphinan BU74 (17-cyclopropylmethyl-3-hydroxy-[5beta,7beta,3',5']-pyrrolidino-2'[S]-phenyl-7alpha-methyl-6,14-endoetheno morphinan) (3f) was synthesized. In isolated tissue and [35S]GTPgammaS opioid receptor functional assays BU74 was shown to be a potent long-lasting kappa opioid receptor agonist, delta opioid receptor partial agonist and mu opioid receptor antagonist. In antinociceptive tests in the mouse, BU74 showed high efficacy and potent kappa opioid receptor agonism. When its agonist action had waned BU74 became an antagonist of kappa and mu opioid receptor agonists in the tail flick assay and of delta, kappa and mu opioid receptor agonists in the acetic acid writhing assay. The slow onset, long-duration kappa opioid receptor agonist effects of BU74 suggests that it could be a lead compound for the discovery of a treatment for cocaine abuse.

  14. A novel peptide with potent and broad-spectrum antiviral activities against multiple respiratory viruses

    PubMed Central

    Zhao, Hanjun; Zhou, Jie; Zhang, Ke; Chu, Hin; Liu, Dabin; Poon, Vincent Kwok-Man; Chan, Chris Chung-Sing; Leung, Ho-Chuen; Fai, Ng; Lin, Yong-Ping; Zhang, Anna Jin-Xia; Jin, Dong-Yan; Yuen, Kwok-Yung; Zheng, Bo-Jian

    2016-01-01

    A safe, potent and broad-spectrum antiviral is urgently needed to combat emerging respiratory viruses. In light of the broad antiviral activity of β-defensins, we tested the antiviral activity of 11 peptides derived from mouse β-defensin-4 and found that a short peptide, P9, exhibited potent and broad-spectrum antiviral effects against multiple respiratory viruses in vitro and in vivo, including influenza A virus H1N1, H3N2, H5N1, H7N7, H7N9, SARS-CoV and MERS-CoV. The antiviral activity of P9 was attributed to its high-affinity binding to viral glycoproteins, as well as the abundance of basic amino acids in its composition. After binding viral particles through viral surface glycoproteins, P9 entered into cells together with the viruses via endocytosis and prevented endosomal acidification, which blocked membrane fusion and subsequent viral RNA release. This study has paved the avenue for developing new prophylactic and therapeutic agents with broad-spectrum antiviral activities. PMID:26911565

  15. JMV641: a potent bombesin receptor antagonist that inhibits Swiss 3T3 cell proliferation.

    PubMed

    Azay, J; Gagne, D; Devin, C; Llinares, M; Fehrentz, J A; Martinez, J

    1996-08-27

    The peptides of the bombesin family are involved in stimulation of mitogenesis in various cell lines, including cancerous cell lines. Bombesin receptor antagonists are of great interest to inhibit this proliferation. We have synthesized a potent bombesin receptor antagonist, e.g., compound JMV641 [H-DPhe-Gln-Trp-Ala-Val-Gly-His-NH-*CH[CH2-CH(CH3)2]-**CHOH- (CH2)3-CH3 [*(S); **92% of (S) isomer], in which a pseudopeptide bond mimicking the transition state analogue replaced the peptide bond between the two C-terminal residues. This compound was highly potent to dose-dependently inhibit binding of 125I-GRP to Swiss 3T3 cells (IC50 = 0.85 +/- 0.15 nM) and bombesin-stimulated Swiss 3T3 proliferation (pA2 = 8.78). However, compound JMV641 can inhibit bombesin-induced AP-1 regulated genes that are nuclear messengers mediating the actions of signal transduction pathways stimulated by growth factors.

  16. The hybrid performance of the Pierre Auger Observatory

    SciTech Connect

    Mostafa, Miguel, A.; /New Mexico U.

    2005-08-01

    The Pierre Auger Observatory detects ultra-high energy cosmic rays by implementing two complementary air-shower techniques. The combination of a large ground array and fluorescence detectors, known as the hybrid concept, means that a rich variety of measurements can be made on a single shower, providing much improved information over what is possible with either detector alone. In this paper the hybrid reconstruction approach and its performance are described.

  17. Comment on mesic-atom Auger-rate calculation

    NASA Astrophysics Data System (ADS)

    Altman, A.; Fried, Z.

    1983-07-01

    Auger rates for a mesic atom consisting of a lithium nucleus and two electrons are presented. It is shown that the results are sensitive to the screening of the initial and final state of the ejected electron by the spectator electron. These results are compared to transition rates one would obtain by following the procedure used by Burbridge and de Borde, which neglect screening of one electron by the others. Our results show a 40% reduction in transition rates.

  18. Synthesis of a novel series of 2-alkylthio substituted naphthoquinones as potent acyl-CoA: cholesterol acyltransferase (ACAT) inhibitors.

    PubMed

    Lee, Kyeong; Cho, Soo Hyun; Lee, Jee Hyun; Goo, Jail; Lee, Sung Yoon; Boovanahalli, Shanthaveerappa K; Yeo, Siok Koon; Lee, Sung-Joon; Kim, Young Kook; Kim, Dong Hee; Choi, Yongseok; Song, Gyu-Yong

    2013-04-01

    We report a new series of naphthoquinone derivatives as potent ACAT inhibitors, which were obtained through structural variations of previously disclosed lead 1. Several analogs represented by 3i-l, 4k-m, 6a-n, 7a, and 7i demonstrated potent human macrophage ACAT inhibitory activity by a cell-based reporter assay with human HepG2 cell lines. In particular, compounds 4l and 6j emerged as highly potent inhibitors, exhibiting significantly high inhibitory potencies with IC50 values of 0.44 μM and 0.6 μM, respectively. Moreover, compound 4l significantly reduced the accumulation of cellular cholesterol in HepG2 cell lines.

  19. Natural fatty acid synthase inhibitors as potent therapeutic agents for cancers: A review.

    PubMed

    Zhang, Jia-Sui; Lei, Jie-Ping; Wei, Guo-Qing; Chen, Hui; Ma, Chao-Ying; Jiang, He-Zhong

    2016-09-01

    Context Fatty acid synthase (FAS) is the only mammalian enzyme to catalyse the synthesis of fatty acid. The expression level of FAS is related to cancer progression, aggressiveness and metastasis. In recent years, research on natural FAS inhibitors with significant bioactivities and low side effects has increasingly become a new trend. Herein, we present recent research progress on natural fatty acid synthase inhibitors as potent therapeutic agents. Objective This paper is a mini overview of the typical natural FAS inhibitors and their possible mechanism of action in the past 10 years (2004-2014). Method The information was collected and compiled through major databases including Web of Science, PubMed, and CNKI. Results Many natural products induce cancer cells apoptosis by inhibiting FAS expression, with fewer side effects than synthetic inhibitors. Conclusion Natural FAS inhibitors are widely distributed in plants (especially in herbs and foods). Some natural products (mainly phenolics) possessing potent biological activities and stable structures are available as lead compounds to synthesise promising FAS inhibitors.

  20. Neuroprotective Effects of the Triterpenoid, CDDO Methyl Amide, a Potent Inducer of Nrf2-Mediated Transcription

    PubMed Central

    Yang, Lichuan; Calingasan, Noel Y.; Thomas, Bobby; Chaturvedi, Rajnish K.; Kiaei, Mahmoud; Wille, Elizabeth J.; Liby, Karen T.; Williams, Charlotte; Royce, Darlene; Risingsong, Renee; Musiek, Eric S.; Morrow, Jason D.; Sporn, Michael; Beal, M. Flint

    2009-01-01

    The NF-E2-related factor-2 (Nrf2)/antioxidant response element (ARE) signaling pathway regulates phase 2 detoxification genes, including a variety of antioxidative enzymes. We tested neuroprotective effects of the synthetic triterpenoid CDDO-MA, a potent activator of the Nrf2/ARE signaling. CDDO-MA treatment of neuroblastoma SH-SY5Y cells resulted in Nrf2 upregulation and translocation from cytosol to nucleus and subsequent activation of ARE pathway genes. CDDO-MA blocked t-butylhydroperoxide-induced production of reactive oxygen species (ROS) by activation of ARE genes only in wild type, but not Nrf2 knockout mouse embryonic fibroblasts. Oral administration of CDDO-MA resulted in significant protection against MPTP-induced nigrostriatal dopaminergic neurodegeneration, pathological alpha-synuclein accumulation and oxidative damage in mice. Additionally, CDDO-MA treatment in rats produced significant rescue against striatal lesions caused by the neurotoxin 3-NP, and associated increases in the oxidative damage markers malondialdehyde, F2-Isoprostanes, 8-hydroxy-2-deoxyguanosine, 3-nitrotyrosine, and impaired glutathione homeostasis. Our results indicate that the CDDO-MA renders its neuroprotective effects through its potent activation of the Nrf2/ARE pathway, and suggest that triterpenoids may be beneficial for the treatment of neurodegenerative diseases like Parkinson's disease and Huntington's disease. PMID:19484125

  1. Fusogenic oncolytic herpes simplex viruses as a potent and personalized cancer vaccine.

    PubMed

    Li, Qi-Xiang; Liu, Guohong; Zhang, Xiaoliu

    2012-07-01

    The recent FDA approval of Sipuleucel-T for the treatment of prostate cancer represents an important milestone of cancer immunotherapy, which, for the first time, validates the concept of bringing true clinical benefit to cancer patients by stimulating patients' own anti-tumor immunity. Among the different experimental cancer immunotherapies, oncolytic virotherapy may represent a low-cost yet potent and personalized cancer vaccine for the treatment of solid tumors. This review describes the constructions of several human herpes simplex virus (HSV)-derived oncolytic viruses as candidate cancer vaccines, which induce specific and potent anti-tumor immunity in pre-clinical models, and thus resulting in stronger overall anti-tumor efficacy as compared to oncolytic effect alone. This article also describes the approaches to enhance the antitumor immunity of oncolytic HSVs, and in particular, the key role played by integrating membrane-fusion activity into these viruses. Additionally, this article reviews the potential effect of certain chemotherapeutic agents (e.g. cyclophosphamide) in boosting antitumor immunity induced by oncolytic HSV, and the mechanisms behind it. In summary, all the preclinical and clinical data have suggested that HSV-based oncolytic virotherapies could likely be developed as a new generation of cancer vaccines for the treatment of solid tumors.

  2. Bis(1,8-anilinonaphthalenesulfonate). A novel and potent inhibitor of microtubule assembly.

    PubMed

    Horowitz, P; Prasad, V; Luduena, R F

    1984-12-10

    Two related compounds, 1,8-anilinonaphthalenesulfonate (1,8-ANS) and bis(1,8-anilinonaphthalenesulfonate) (Bis-ANS), are useful fluorescent probes for hydrophobic areas on protein molecules. Using fluorescence, we examined the binding of these compounds to bovine brain tubulin and found that Bis-ANS and 1,8-ANS bound to tubulin with Ki values of 2 and 25 microM, respectively. Bis-ANS potently inhibited the polymerization of tubulin into microtubules in vitro. In the presence of microtubule-associated protein 2, half-maximal inhibition of assembly was obtained at 3 microM Bis-ANS. In the presence of tau protein, half-maximal inhibition was obtained at 15 microM Bis-ANS. Surprisingly, 1,8-ANS, even at 200 microM, did not inhibit assembly. Scatchard analysis indicated one binding site for Bis-ANS on tubulin. Previous reports of 1,8-ANS binding to tubulin may have been influenced by the presence of Bis-ANS which until recently was a common contaminant of commercial supplies. Because of its intense fluorescence in addition to its potent inhibitory effects, Bis-ANS appears to be a useful probe to study microtubule assembly and other interactions involving tubulin.

  3. Cloning, sequencing and characterization of the biosynthetic gene cluster of sanglifehrin A, a potent cyclophilin inhibitor.

    PubMed

    Qu, Xudong; Jiang, Nan; Xu, Fei; Shao, Lei; Tang, Gongli; Wilkinson, Barrie; Liu, Wen

    2011-03-01

    Sanglifehrin A (SFA), a potent cyclophilin inhibitor produced by Streptomyces flaveolus DSM 9954, bears a unique [5.5] spirolactam moiety conjugated with a 22-membered, highly functionalized macrolide through a linear carbon chain. SFA displays a diverse range of biological activities and offers significant therapeutic potential. However, the structural complexity of SFA poses a tremendous challenge for new analogue development via chemical synthesis. Based on a rational prediction of its biosynthetic origin, herein we report the cloning, sequencing and characterization of the gene cluster responsible for SFA biosynthesis. Analysis of the 92 776 bp contiguous DNA region reveals a mixed polyketide synthase (PKS)/non-ribosomal peptide synthetase (NRPS) pathway which includes a variety of unique features for unusual PKS and NRPS building block formation. Our findings suggest that SFA biosynthesis requires a crotonyl-CoA reductase/carboxylase (CCR) for generation of the putative unusual PKS starter unit (2R)-2-ethylmalonamyl-CoA, an iterative type I PKS for the putative atypical extender unit (2S)-2-(2-oxo-butyl)malonyl-CoA and a phenylalanine hydroxylase for the NRPS extender unit (2S)-m-tyrosine. A spontaneous ketalization of significant note, may trigger spirolactam formation in a stereo-selective manner. This study provides a framework for the application of combinatorial biosynthesis methods in order to expand the structural diversity of SFA.

  4. Some strategies for quantitative scanning Auger electron microscopy

    NASA Technical Reports Server (NTRS)

    Browning, R.; Peacock, D. C.; Prutton, M.

    1985-01-01

    The general applicability of power law forms of the background in electron spectra is pointed out and exploited for background removal from under Auger peaks. This form of B(E) is found to be extremely sensitive to instrumental alignment and to fault-free construction - an observation which can be used to set up analyser configurations in an accurate way. Also, differences between N(E) and B(E) can be used to derive a spectrometer transmission function T(E). The questions of information density in an energy-analysing spatially-resolving instrument are addressed after reliable instrumental characterization has been established. Strategies involving ratio histograms, showing the population distribution of the ratio of a pair of Auger peak heights, composition scatter diagrams and windowed imaging are discussed and illustrated.

  5. Atmospheric aerosol monitoring at the Pierre Auger Observatory

    SciTech Connect

    Cester, R.; Chiosso, M.; Chirin, J.; Clay, R.; Dawson, B.; Fick, B.; Filipcic, A.; Garcia, B.; Grillo, A.; Horvat, M.; Iarlori, M.; Malek, M.; Matthews, J.; Matthews, J.A.J.; Melo, D.; Meyhandan, R.; Mostafa, M.; Mussa, R.; Prouza, M.; Raefert, B.; Rizi, V.

    2005-07-01

    For a ground based cosmic-ray observatory the atmosphere is an integral part of the detector. Air fluorescence detectors (FDs) are particularly sensitive to the presence of aerosols in the atmosphere. These aerosols, consisting mainly of clouds and dust, can strongly affect the propagation of fluorescence and Cherenkov light from cosmic-ray induced extensive air showers. The Pierre Auger Observatory has a comprehensive program to monitor the aerosols within the atmospheric volume of the detector. In this paper the aerosol parameters that affect FD reconstruction will be discussed. The aerosol monitoring systems that have been deployed at the Pierre Auger Observatory will be briefly described along with some measurements from these systems.

  6. Synthesis and characterization of phosphocitric acid, a potent inhibitor of hydroxylapatite crystal growth.

    PubMed

    Tew, W P; Mahle, C; Benavides, J; Howard, J E; Lehninger, A L

    1980-04-29

    Human urine and extracts of rat liver mitochondria contain apparently identical agents capable of inhibiting the precipitation or crystallization of calcium phosphate. Its general properties, as well as 1H NMR and mass spectra, have suggested that the agent is phosphocitric acid. This paper reports the synthesis of phosphocitric acid via the phosphorylation of triethyl citrate with o-phenylene phosphochloridate, hydrogenolysis of the product to yield triethyl phosphocitrate, hydrolytic removal of the blocking ethyl groups and also chromatographic purification. An enzymatic assay of phosphocitrate is described. Synthetic phosphocitrate was found to be an exceedingly potent inhibitor of the growth of hydroxylapatite seed crystals in a medium supersaturated with respect to Ca2+ and phosphate. Comparative assays showed phosphocitrate to be much more potent than the most active precipitation-crystallization inhibitors previously reported, which include pyrophosphate and ATP. 14C-Labeled phosphocitrate was bound very tightly to hydroxylapatite crystals. Such binding appeared to be essential for its inhibitory activity on crystal growth. Citrate added before but not after, phosphocitrate greatly enhanced the inhibitory potency of the latter. This enhancement effect was not given by other tricarboxylic acids. The monoethyl ester of phosphocitrate had no inhibitory effect on hydroxylapatite crystal growth.

  7. A potent 1,4-dihydropyridine L-type calcium channel blocker, benidipine, promotes osteoblast differentiation.

    PubMed

    Nishiya, Y; Kosaka, N; Uchii, M; Sugimoto, S

    2002-01-01

    During their differentiation, osteoblasts sequentially express type I collagen, alkaline phosphatase (ALP), and osteocalcin, and then undergo mineral deposition. Among dihydropyridine-type calcium channel blockers, only benidipine stimulated ALP activity of osteoblastic cells derived from neonatal mouse calvaria. To identify the molecular target of benidipine and elucidate the mechanism of action of the drug in osteoblasts, the mouse osteoblastic cell line MC3T3-E1 was used. Benidipine prompted ALP activity and ALP transcription induced by ascorbic acid, and mineral deposition by ascorbic acid and b-glycerophosphate. Benidipine, however, did not change collagen accumulation. MC3T3-E1 cells expressed the L-type Ca channel a1C subunit throughout the differentiation process, and Ca influx by potassium ions and Bay K 8644, an agonist, was strongly attenuated by benidipine. Each one of three structurally different classes of Ca channel blockers, nifedipine, verapamil, and diltiazem stimulated ALP activity, although at much higher concentrations of ca. 100 nM than benidipine, 1 pM. These results suggest that benidipine directly exerts its effect on osteoblasts and promotes osteoblast differentiation after the step of collagen accumulation by blocking the L-type Ca channel. Since benidipine blocked Ca influx more potently than the three other Ca channel blockers, the unique and potent osteoblast differentiating ability of benidipine may be due to its high affinity for Ca channel together with its high membrane retaining ability, as has been previously reported.

  8. Study of the Auger line shape of polyethylene and diamond

    NASA Technical Reports Server (NTRS)

    Dayan, M.; Pepper, S. V.

    1984-01-01

    The KVV Auger electron line shapes of carbon in polyethylene and diamond have been studied. The spectra were obtained in derivative form by electron beam excitation. They were treated by background subtraction, integration and deconvolution to produce the intrinsic Auger line shape. Electron energy loss spectra provided the response function in the deconvolution procedure. The line shape from polyethylene is compared with spectra from linear alkanes and with a previous spectrum of Kelber et al. Both spectra are compared with the self-convolution of their full valence band densities of states and of their p-projected densities. The experimental spectra could not be understood in terms of existing theories. This is so even when correlation effects are qualitatively taken into account account to the theories of Cini and Sawatzky and Lenselink.

  9. Photonic crystal enhancement of auger-suppressed infrared photodetectors

    NASA Astrophysics Data System (ADS)

    Djurić, Zoran; Jakšić, Zoran; Ehrfeld, Wolfgang; Schmidt, Andreas; Matić, Milan; Popović, Mirjana

    2001-04-01

    We examine theoretically and experimentally the possibilities to reach room-temperature background-limited operation of narrow-bandgap compound semiconductor photodetectors in (3-14) micrometer infrared wavelength range. To this purpose we consider the combination of non-equilibrium Auger suppression with photonic crystal enhancement (PCE). This means that Auger generation-recombination processes are suppressed utilizing exclusion, extraction or magnetoconcentration effects or their combination. The residual radiative recombination is removed by immersing the detector active area into a photonic crystal and using the benefits of re-absorption (photon recycling) to effectively increase the radiative lifetime. In this manner the total generation-recombination noise is strongly quenched in sufficiently defect-free device materials. It is concluded that the operation of thus enhanced photonic detectors could even approach signal fluctuation limit.

  10. Ramsey interferometry for resonant Auger decay through core-excited states

    NASA Astrophysics Data System (ADS)

    Chatterjee, Souvik; Nakajima, Takashi

    2016-08-01

    We theoretically investigate the electron dynamics in Ne atoms involving core-excited states through the Ramsey scheme with a pair of time-delayed x-ray pulses. Irradiation of Ne atoms by the ˜1 femtosecond x-ray pulse simultaneously populates two core-excited states, and an identical but time-delayed x-ray pulse probes the dynamics of the core-excited electron wave packet which is subject to the resonant Auger decay. The energy-integrated total Auger electron yield and energy-resolved Auger electron spectra in the time domain show periodic structures due to the temporal evolution of the wave packet, from which we can obtain the counterpart in the frequency domain through the Fourier transformation. The Auger electron energy spectra in the time as well as frequency domains show the interference patterns between the two Auger electron wave packets released into the continuum from the superposition of two core-excited states at different times. These spectra are important to clarify the individual contribution of the different Auger decay channels upon core excitation by the x-ray pulse.

  11. The Past, Present, and Future of Auger Lineshape Analysis

    DTIC Science & Technology

    1991-01-01

    Availability Codei Avail and/or Dist Special Technical Report No. 55 Wf The Past, Present, And Future of Auger Lineshape Analysis By DAVID E. RAMAKER Prepared...interaction on the 0 atom. Values from 4 to 14 have been reported (see reference Ramhtsc2 for a summary of the theoretical and experimental estimates). The 0...public releas \\ ,, distributibin unlimited ) 4 4. PERFORMING ORGANIZATION REPORT NUMBERCS) S. MONITORING- ORGANIZATION REPOR T NUMBER(S) - Technical

  12. Potent inhibition by star fruit of human cytochrome P450 3A (CYP3A) activity.

    PubMed

    Hidaka, Muneaki; Fujita, Ken-ichi; Ogikubo, Tetsuya; Yamasaki, Keishi; Iwakiri, Tomomi; Okumura, Manabu; Kodama, Hirofumi; Arimori, Kazuhiko

    2004-06-01

    There has been very limited information on the capacities of tropical fruits to inhibit human cytochrome P450 3A (CYP3A) activity. Thus, the inhibitory effects of tropical fruits on midazolam 1'-hydroxylase activity of CYP3A in human liver microsomes were evaluated. Eight tropical fruits such as common papaw, dragon fruit, kiwi fruit, mango, passion fruit, pomegranate, rambutan, and star fruit were tested. We also examined the inhibition of CYP3A activity by grapefruit (white) and Valencia orange as controls. The juice of star fruit showed the most potent inhibition of CYP3A. The addition of a star fruit juice (5.0%, v/v) resulted in the almost complete inhibition of midazolam 1'-hydroxylase activity (residual activity of 0.1%). In the case of grape-fruit, the residual activity was 14.7%. The inhibition depended on the amount of fruit juice added to the incubation mixture (0.2-6.0%, v/v). The elongation of the preincubation period of a juice from star fruit (1.25 or 2.5%, v/v) with the microsomal fraction did not alter the CYP3A inhibition, suggesting that the star fruit did not contain a mechanism-based inhibitor. Thus, we discovered filtered extracts of star fruit juice to be inhibitors of human CYP3A activity in vitro.

  13. Laser enabled Auger decay in argon atoms and dimers

    NASA Astrophysics Data System (ADS)

    Ranitovic, Predrag; Tong, Xiao-Min; Hogle, Craig W.; Toshima, N.; Murnane, M. M.; Kapteyn, H. C.

    2011-05-01

    In rare-gas atoms, Auger decay in which an inner-valence shell ns hole is filled is normally not energetically allowed. However, in the presence of a strong laser field, a new laser-enabled Auger decay channel can open up to increase the double-ionization yield. This process is efficient at high laser intensities, and an ns hole can be filled within a few femtoseconds of its creation. This novel laser-enabled Auger decay (LEAD) process is of fundamental importance for controlling electron dynamics in atoms, molecules, and materials. We then use LEAD to investigate charge transfer in a Coulomb exploding Ar dimer. We can selectively double-ionize either the Ar dimer (threshold ~ 36 eV) or Ar atoms (threshold ~ 43.5 eV) using combined laser (1.5 eV) and XUV photons (36 eV) in a time-resolved fashion, and then comparing the kinetic energy releases. The Ar dimer can be double ionized when the 3s hole is filled by a 3p electron from either one of the two Ar atoms through LEAD. Theoretical calculation will support data taken using COLTRIMS and HHG.

  14. Activation of TRPM3 by a potent synthetic ligand reveals a role in peptide release.

    PubMed

    Held, Katharina; Kichko, Tatjana; De Clercq, Katrien; Klaassen, Hugo; Van Bree, Rieta; Vanherck, Jean-Christophe; Marchand, Arnaud; Reeh, Peter W; Chaltin, Patrick; Voets, Thomas; Vriens, Joris

    2015-03-17

    Transient receptor potential (TRP) cation channel subfamily M member 3 (TRPM3), a member of the TRP channel superfamily, was recently identified as a nociceptor channel in the somatosensory system, where it is involved in the detection of noxious heat; however, owing to the lack of potent and selective agonists, little is known about other potential physiological consequences of the opening of TRPM3. Here we identify and characterize a synthetic TRPM3 activator, CIM0216, whose potency and apparent affinity greatly exceeds that of the canonical TRPM3 agonist, pregnenolone sulfate (PS). In particular, a single application of CIM0216 causes opening of both the central calcium-conducting pore and the alternative cation permeation pathway in a membrane-delimited manner. CIM0216 evoked robust calcium influx in TRPM3-expressing somatosensory neurons, and intradermal injection of the compound induced a TRPM3-dependent nocifensive behavior. Moreover, CIM0216 elicited the release of the peptides calcitonin gene-related peptide (CGRP) from sensory nerve terminals and insulin from isolated pancreatic islets in a TRPM3-dependent manner. These experiments identify CIM0216 as a powerful tool for use in investigating the physiological roles of TRPM3, and indicate that TRPM3 activation in sensory nerve endings can contribute to neurogenic inflammation.

  15. Development of a recombinant antithrombin variant as a potent antidote to fondaparinux and other heparin derivatives.

    PubMed

    Bianchini, Elsa P; Fazavana, Judicael; Picard, Veronique; Borgel, Delphine

    2011-02-10

    Heparin derivative-based therapy has evolved from unfractionated heparin (UFH) to low-molecular-weight heparins (LMWHs) and now fondaparinux, a synthetic pentasaccharide. Contrary to UFH or LMWHs, fondaparinux is not neutralized by protamine sulfate, and no antidote is available to counteract bleeding disorders associated with overdosing. To make the use of fondaparinux safer, we developed an antithrombin (AT) variant as a potent antidote to heparin derivatives. This variant (AT-N135Q-Pro394) combines 2 mutations: substitution of Asn135 by a Gln to remove a glycosylation site and increase affinity for heparins, and the insertion of a Pro between Arg393 and Ser394 to abolish its anticoagulant activity. As expected, AT-N135Q-Pro394 anticoagulant activity was almost abolished, and it exhibited a 3-fold increase in fondaparinux affinity. AT-N135Q-Pro394 was shown to reverse fondaparinux overdosing in vitro in a dose-dependent manner through a competitive process with plasma AT for fondaparinux binding. This antidote effect was also observed in vivo: administration of AT-N135Q-Pro394 in 2.5-fold molar excess versus plasma AT neutralized 86% of the anti-Xa activity within 5 minutes in mice treated with fondaparinux. These results clearly demonstrate that AT-N135Q-Pro394 can reverse the anticoagulant activity of fondaparinux and thus could be used as an antidote for this drug.

  16. Isocombretastatins A: 1,1-diarylethenes as potent inhibitors of tubulin polymerization and cytotoxic compounds.

    PubMed

    Alvarez, Raquel; Alvarez, Concepción; Mollinedo, Faustino; Sierra, Beatriz G; Medarde, Manuel; Peláez, Rafael

    2009-09-01

    Isocombretastatins A are 1,1-diarylethene isomers of combretastatins A. We have synthesized the isomers of combretastatin A-4, deoxycombretastatin A-4, 3-amino-deoxycombretastatin A-4 (AVE-8063), naphthylcombretastatin and the N-methyl- and N-ethyl-5-indolyl analogues of combretastatin A-4. Analogues with a 2,3,4-trimethoxyphenyl ring instead of the 3,4,5-trimethoxyphenyl ring have also been prepared. The isocombretastatins A strongly inhibit tubulin polymerization and are potent cytotoxic compounds, some of them with IC(50)s in the nanomolar range. This new family of tubulin inhibitors shows higher or comparable potency when compared to phenstatin or combretastatin analogues. These results suggest that one carbon bridges with a geminal diaryl substitution can successfully replace the two carbon bridge of combretastatins and that the carbonyl group of phenstatins is not essential for high potency.

  17. Total synthesis of periploside A, a unique pregnane hexasaccharide with potent immunosuppressive effects

    PubMed Central

    Zhang, Xiaheng; Zhou, Yu; Zuo, Jianping; Yu, Biao

    2015-01-01

    Periploside A is a pregnane hexasaccharide identified from the Chinese medicinal plant Periploca sepium, which features a unique seven-membered formyl acetal bridged orthoester (FABO) motif and potent immunosuppressive activities. Here, we show the synthesis of this molecule in a total of 76 steps with the longest linear sequence of 29 steps and 9.2% overall yield. The FABO motif is constructed via a combination of Sinaÿ’s and Crich’s protocol for the formation of orthoester and acetal glycosides, respectively. The 2-deoxy-β-glycosidic linkages are assembled stereoselectively with judicious choice of the glycosylation methods. The epimer at the spiro-quaternary carbon in the FABO motif has also been elaborated in a stereo-controlled manner. This epimer, as well as the synthetic analogues bearing the FABO motif, retain largely the inhibitory activities of periploside A against the proliferation of T-lymphocyte, indicating the importance of the chemical connection of the FABO motif to their immunosuppressive activity. PMID:25600477

  18. Aurora-A Kinase: A Potent Oncogene and Target for Cancer Therapy.

    PubMed

    Yan, Min; Wang, Chunli; He, Bin; Yang, Mengying; Tong, Mengying; Long, Zijie; Liu, Bing; Peng, Fei; Xu, Lingzhi; Zhang, Yan; Liang, Dapeng; Lei, Haixin; Subrata, Sen; Kelley, Keith W; Lam, Eric W-F; Jin, Bilian; Liu, Quentin

    2016-11-01

    The Aurora kinase family is comprised of three serine/threonine kinases, Aurora-A, Aurora-B, and Aurora-C. Among these, Aurora-A and Aurora-B play central roles in mitosis, whereas Aurora-C executes unique roles in meiosis. Overexpression or gene amplification of Aurora kinases has been reported in a broad range of human malignancies, pointing to their role as potent oncogenes in tumorigenesis. Aurora kinases therefore represent promising targets for anticancer therapeutics. A number of Aurora kinase inhibitors (AKIs) have been generated; some of which are currently undergoing clinical evaluation. Recent studies have unveiled novel unexpected functions of Aurora kinases during cancer development and the mechanisms underlying the anticancer actions of AKIs. In this review, we discuss the most recent advances in Aurora-A kinase research and targeted cancer therapy, focusing on the oncogenic roles and signaling pathways of Aurora-A kinases in promoting tumorigenesis, the recent preclinical and clinical AKI data, and potential alternative routes for Aurora-A kinase inhibition.

  19. Chemoproteomics-Enabled Discovery of a Potent and Selective Inhibitor of the DNA Repair Protein MGMT.

    PubMed

    Wang, Chao; Abegg, Daniel; Hoch, Dominic G; Adibekian, Alexander

    2016-02-18

    We present a novel chemical scaffold for cysteine-reactive covalent inhibitors. Chloromethyl triazoles (CMTs) are readily accessed in only two chemical steps, thus enabling the rapid optimization of the pharmacological properties of these inhibitors. We demonstrate the tunability of the CMTs towards a specific biological target by synthesizing AA-CW236 as the first potent non-pseudosubstrate inhibitor of the O(6) -alkylguanine DNA methyltransferase (MGMT), a protein of major clinical significance for the treatment of several severe cancer forms. Using quantitative proteomics profiling techniques, we show that AA-CW236 exhibits a high degree of selectivity towards MGMT. Finally, we validate the effectiveness of our MGMT inhibitor in combination with the DNA alkylating drug temozolomide in breast and colon cancer cells by fluorescence imaging and a cell-viability assay. Our results may open a new avenue towards the development of a clinically approved MGMT inhibitor.

  20. Evaluation of NHS Carbamates as a Potent and Selective Class of Endocannabinoid Hydrolase Inhibitors

    PubMed Central

    2013-01-01

    Monoacylglycerol lipase (MAGL) is a principal metabolic enzyme responsible for hydrolyzing the endogenous cannabinoid (endocannabinoid) 2-arachidonoylglycerol (2-AG). Selective inhibitors of MAGL offer valuable probes to further understand the enzyme’s function in biological systems and may lead to drugs for treating a variety of diseases, including psychiatric disorders, neuroinflammation, and pain. N-Hydroxysuccinimidyl (NHS) carbamates have recently been identified as a promising class of serine hydrolase inhibitors that shows minimal cross-reactivity with other proteins in the proteome. Here, we explore NHS carbamates more broadly and demonstrate their potential as inhibitors of endocannabinoid hydrolases and additional enzymes from the serine hydrolase class. We extensively characterize an NHS carbamate 1a (MJN110) as a potent, selective, and in-vivo-active MAGL inhibitor. Finally, we demonstrate that MJN110 alleviates mechanical allodynia in a rat model of diabetic neuropathy, marking NHS carbamates as a promising class of MAGL inhibitors. PMID:23731016

  1. Identification of potent Yes1 kinase inhibitors using a library screening approach.

    PubMed

    Patel, Paresma R; Sun, Hongmao; Li, Samuel Q; Shen, Min; Khan, Javed; Thomas, Craig J; Davis, Mindy I

    2013-08-01

    Yes1 kinase has been implicated as a potential therapeutic target in a number of cancers including melanomas, breast cancers, and rhabdomyosarcomas. Described here is the development of a robust and miniaturized biochemical assay for Yes1 kinase that was applied in a high throughput screen (HTS) of kinase-focused small molecule libraries. The HTS provided 144 (17% hit rate) small molecule compounds with IC₅₀ values in the sub-micromolar range. Three of the most potent Yes1 inhibitors were then examined in a cell-based assay for inhibition of cell survival in rhabdomyosarcoma cell lines. Homology models of Yes1 were generated in active and inactive conformations, and docking of inhibitors supports binding to the active conformation (DFG-in) of Yes1. This is the first report of a large high throughput enzymatic activity screen for identification of Yes1 kinase inhibitors, thereby elucidating the polypharmacology of a variety of small molecules and clinical candidates.

  2. Resonant Auger Effect at High X-Ray Intensity

    SciTech Connect

    Rohringer, N; Santra, R

    2008-03-27

    The resonant Auger effect of atomic neon exposed to high-intensity x-ray radiation in resonance with the 1s {yields} 3p transition is discussed. High intensity here means that the x-ray peak intensity is sufficient ({approx} 10{sup 18} W/cm{sup 2}) to induce Rabi oscillations between the neon ground state and the 1s{sup -1}3p ({sup 1}P) state within the relaxation lifetime of the inner-shell vacancy. For the numerical analysis presented, an effective two-level model, including a description of the resonant Auger decay process, is employed. Both coherent and chaotic x-ray pulses are treated. The latter are used to simulate radiation from x-ray free-electron lasers based on the principle of self-amplified spontaneous emission. Observing x-ray-driven atomic population dynamics in the time domain is challenging for chaotic pulse ensembles. A more practical option for experiments using x-ray free-electron lasers is to measure the line profiles in the kinetic energy distribution of the resonant Auger electron. This provides information on both atomic population dynamics and x-ray pulse properties.

  3. Intergroup boundaries and attitudes: the power of a single potent link.

    PubMed

    Gulker, Jill E; Monteith, Margo J

    2013-07-01

    Many prejudice reduction strategies involve linking the self to outgroup members. We tested the novel question of whether establishing a potent link with a single outgroup member can reduce explicit and implicit prejudice toward the outgroup as a whole. White participants completed a mock adoption procedure where they "adopted" a baby from another country. Three experiments showed that this single link fostered perceived overlap between the self and the ethnic outgroup. This overlap mediated the effect of the adoption manipulation on explicit prejudice, which was significantly reduced. Whereas the single link was insufficient to reduce implicit prejudice significantly when the self-outgroup member link was not practiced, repeatedly practicing this connection reduced prejudice significantly in comparison with a control group that had no connection to the outgroup member. Furthermore, unlike explicit attitudes, this effect was direct.

  4. Aurones: A Promising Heterocyclic Scaffold for the Development of Potent Antileishmanial Agents

    PubMed Central

    Roussaki, Marina; Costa Lima, Sofia; Kypreou, Anna-Maria; Kefalas, Panagiotis; Cordeiro da Silva, Anabela; Detsi, Anastasia

    2012-01-01

    A series of (Z)-2-benzylidenebenzofuran-3-(2H)-ones (aurones) bearing a variety of substituents on rings A and B were synthesized and evaluated for their antiparasitic activity against the intracellular amastigote form of Leishmania infantum and their cytotoxicity against human THP1-differentiated macrophages. In general, aurones bearing no substituents on ring A (compounds 4a–4f) exhibit higher toxicity than aurones with 4,6-dimethoxy substitution (compounds 4g–4l). Among the latter, two aurones possessing a 2′-methoxy or a 2′-methyl group (compounds 4i and 4j) exhibit potent antileishmanial activity (IC50 = 1.3 ± 0.1 μM and IC50 = 1.6 ± 0.2 μM, resp.), comparable to the activity of the reference drug Amphotericin B, whereas they present significantly lower cytotoxicity than Amphotericin B as deduced by the higher selectivity index. PMID:25374683

  5. Biochemical characterization and structure determination of a potent, selective antibody inhibitor of human MMP9.

    PubMed

    Appleby, Todd C; Greenstein, Andrew E; Hung, Magdeleine; Liclican, Albert; Velasquez, Maile; Villaseñor, Armando G; Wang, Ruth; Wong, Melanie H; Liu, Xiaohong; Papalia, Giuseppe A; Schultz, Brian E; Sakowicz, Roman; Smith, Victoria; Kwon, Hyock Joo

    2017-02-24

    Matrix metalloproteinase 9 (MMP9) is a key regulator of the extracellular matrix (ECM), involved in the degradation of various ECM proteins. MMP9 is a member of a large family of proteases that are secreted as inactive zymogens. MMP9 plays a pathological role in a variety of inflammatory and oncology disorders and has long been considered an attractive therapeutic target. GS-5745 is a potent, highly selective humanized monoclonal antibody inhibitor of MMP9 that has shown promise in treating ulcerative colitis and gastric cancer. Here we describe the crystal structure of GS-5745:MMP9 complex and biochemical studies to elucidate the mechanism of GS-5745 inhibition of MMP9. GS-5745 binds MMP9 distal to the active site, near the junction between the prodomain and catalytic domain. GS-5745 inhibits MMP9 by two mechanisms: binding to active MMP9 allosterically inhibits MMP9 activity and binding to pro-MMP9 prevents MMP9 activation.

  6. Cefsulodin Inspired Potent and Selective Inhibitors of mPTPB, a Virulent Phosphatase from Mycobacterium tuberculosis

    PubMed Central

    2015-01-01

    mPTPB is a virulent phosphatase from Mycobacterium tuberculosis and a promising therapeutic target for tuberculosis. To facilitate mPTPB-based drug discovery, we identified α-sulfophenylacetic amide (SPAA) from cefsulodin, a third generation β-lactam cephalosporin antibiotic, as a novel pTyr pharmacophore for mPTPB. Structure-guided and fragment-based optimization of SPAA led to the most potent and selective mPTPB inhibitor 9, with a Ki of 7.9 nM and more than 10,000-fold preference for mPTPB over a large panel of 25 phosphatases. Compound 9 also exhibited excellent cellular activity and specificity in blocking mPTPB function in macrophage. Given its novel structure, modest molecular mass, and extremely high ligand efficiency (0.46), compound 9 represents an outstanding lead compound for anti-TB drug discovery targeting mPTPB. PMID:26713110

  7. Discovery of Potent, Selective, and Structurally Novel Dot1L Inhibitors by a Fragment Linking Approach.

    PubMed

    Möbitz, Henrik; Machauer, Rainer; Holzer, Philipp; Vaupel, Andrea; Stauffer, Frédéric; Ragot, Christian; Caravatti, Giorgio; Scheufler, Clemens; Fernandez, Cesar; Hommel, Ulrich; Tiedt, Ralph; Beyer, Kim S; Chen, Chao; Zhu, Hugh; Gaul, Christoph

    2017-03-09

    Misdirected catalytic activity of histone methyltransferase Dot1L is believed to be causative for a subset of highly aggressive acute leukemias. Targeting the catalytic domain of Dot1L represents a potential therapeutic approach for these leukemias. In the context of a comprehensive Dot1L hit finding strategy, a knowledge-based virtual screen of the Dot1L SAM binding pocket led to the discovery of 2, a non-nucleoside fragment mimicking key interactions of SAM bound to Dot1L. Fragment linking of 2 and 3, an induced back pocket binder identified in earlier studies, followed by careful ligand optimization led to the identification of 7, a highly potent, selective and structurally novel Dot1L inhibitor.

  8. Observation of the Auger resonant Raman effect

    SciTech Connect

    Brown, G.S.; Chen, M.H.; Crasemann, B.; Ice, G.E.

    1980-11-01

    Monochromatized synchrotron radiation near the photoionization threshold was used to produce the (2p/sub 3/2/) vacancy state in atomic Xe. Deexcitation of the state through L/sub 3/-M/sub 4/M/sub 5/(/sup 1/G/sub 4/) Auger-electron emission was measured. The 5d spectator-electron Auger satellite was observed. The satellite energy exhibits linear dispersion. The observed width of the /sup 1/G diagram line decreases by approx. 40% when the exciting photon energy reaches the vicinity of the Xe L/sub 3/ binding energy. This radiationless process can thus be construed as the Auger analog of the x-ray resonant Raman effect. The /sup 1/G diagram line is shifted by -+3 eV due to post-collision interaction; this shift varies with excitation energy.

  9. Ficus racemosa Stem Bark Extract: A Potent Antioxidant and a Probable Natural Radioprotector

    PubMed Central

    Veerapur, V. P.; Prabhakar, K. R.; Parihar, Vipan kumar; Kandadi, Machendar Reddy; Ramakrishana, S.; Mishra, B.; Satish Rao, B. S.; Srinivasan, K. K.; Priyadarsini, K. I.

    2009-01-01

    Ethanol extract (FRE) and water extract (FRW) of Ficus racemosa (family: Moraceae) were subjected to free radical scavenging both by steady state and time resolved methods such as nanosecond pulse radiolysis and stopped-flow spectrophotometric analyses. FRE exhibited significantly higher steady state antioxidant activity than FRW. FRE exhibited concentration dependent DPPH, ABTS•−, hydroxyl radical and superoxide radical scavenging and inhibition of lipid peroxidation with IC50 comparable with tested standard compounds. In vitro radioprotective potential of FRE was studied using micronucleus assay in irradiated Chinese hamster lung fibroblast cells (V79). Pretreatment with different doses of FRE 1h prior to 2 Gy γ-radiation resulted in a significant (P < 0.001) decrease in the percentage of micronucleated binuclear V79 cells. Maximum radioprotection was observed at 20 μg/ml of FRE. The radioprotection was found to be significant (P < 0.01) when cells were treated with optimum dose of FRE (20 μg/ml) 1 h prior to 0.5, 1, 2, 3 and 4 Gy γ-irradiation compared to the respective radiation controls. The cytokinesis-block proliferative index indicated that FRE does not alter radiation induced cell cycle delay. Based on all these results we conclude that the ethanol extract of F. racemosa acts as a potent antioxidant and a probable radioprotector. PMID:18955240

  10. A rapid and potent DNA vaccination strategy defined by in vivo monitoring of antigen expression.

    PubMed

    Bins, Adriaan D; Jorritsma, Annelies; Wolkers, Monika C; Hung, Chien-Fu; Wu, T-C; Schumacher, Ton N M; Haanen, John B A G

    2005-08-01

    Induction of immunity after DNA vaccination is generally considered a slow process. Here we show that DNA delivery to the skin results in a highly transient pulse of antigen expression. Based on this information, we developed a new rapid and potent intradermal DNA vaccination method. By short-interval intradermal DNA delivery, robust T-cell responses, of a magnitude sufficient to reject established subcutaneous tumors, are generated within 12 d. Moreover, this vaccination strategy confers protecting humoral immunity against influenza A infection within 2 weeks after the start of vaccination. The strength and speed of this newly developed strategy will be beneficial in situations in which immunity is required in the shortest possible time.

  11. Identification of a potent phytoestrogen in hops (Humulus lupulus L.) and beer.

    PubMed

    Milligan, S R; Kalita, J C; Heyerick, A; Rong, H; De Cooman, L; De Keukeleire, D

    1999-06-01

    The female flowers of the hop plant are used as a preservative and as a flavoring agent in beer. However, a recurring suggestion has been that hops have a powerful estrogenic activity and that beer may also be estrogenic. In this study, sensitive and specific in vitro bioassays for estrogens were used for an activity-guided fractionation of hops via selective solvent extraction and appropriate HPLC separation. We have identified a potent phytoestrogen in hops, 8-prenylnaringenin, which has an activity greater than other established plant estrogens. The estrogenic activity of this compound was reflected in its relative binding affinity to estrogen receptors from rat uteri. The presence of 8-prenylnaringenin in hops may provide an explanation for the accounts of menstrual disturbances in female hop workers. This phytoestrogen can also be detected in beer, but the levels are low and should not pose any cause for concern.

  12. Is matching ruthenium with dithiocarbamato ligands a potent chemotherapeutic weapon in oncology?

    PubMed

    Nardon, Chiara; Brustolin, Leonardo; Fregona, Dolores

    2016-01-01

    In the last years, several metal-based compounds have been designed and biologically investigated worldwide in order to obtain chemotherapeutics with a better toxicological profile and comparable or higher antiblastic activity than the clinically-established platinum-based drugs. In this context, researchers have addressed their attention to alternative nonplatinum derivatives able to maximize the anticancer activity of the new drugs and to minimize the side effects. Among them, a number of ruthenium complexes have been developed, including the compounds NAMI-A and KP1019, now in clinical trials. Here, we report the results collected so far for a particular class of ruthenium complexes - the ruthenium(II/III)-dithiocarbamates - which proved more potent than cisplatin in vitro, even at nanomolar concentrations, against a wide panel of human tumor cell lines.

  13. High-speed helicopter rotor noise - Shock waves as a potent source of sound

    NASA Technical Reports Server (NTRS)

    Farassat, F.; Lee, Yung-Jang; Tadghighi, H.; Holz, R.

    1991-01-01

    In this paper we discuss the problem of high speed rotor noise prediction. In particular, we propose that from the point of view of the acoustic analogy, shocks around rotating blades are sources of sound. We show that, although for a wing at uniform steady rectilinear motion with shocks the volume quadrupole and shock sources cancel in the far field to the order of 1/r, this cannot happen for rotating blades. In this case, some cancellation between volume quadrupoles and shock sources occurs, yet the remaining shock noise contribution is still potent. A formula for shock noise prediction is presented based on mapping the deformable shock surface to a time independent region. The resulting equation is similar to Formulation 1A of Langley. Shock noise prediction for a hovering model rotor for which experimental noise data exist is presented. The comparison of measured and predicted acoustic data shows good agreement.

  14. Discovery of highly selective and potent p38 inhibitors based on a phthalazine scaffold.

    PubMed

    Herberich, Brad; Cao, Guo-Qiang; Chakrabarti, Partha P; Falsey, James R; Pettus, Liping; Rzasa, Robert M; Reed, Anthony B; Reichelt, Andreas; Sham, Kelvin; Thaman, Maya; Wurz, Ryan P; Xu, Shimin; Zhang, Dawei; Hsieh, Faye; Lee, Matthew R; Syed, Rashid; Li, Vivian; Grosfeld, David; Plant, Matthew H; Henkle, Bradley; Sherman, Lisa; Middleton, Scot; Wong, Lu Min; Tasker, Andrew S

    2008-10-23

    Investigations into the structure-activity relationships (SAR) of a series of phthalazine-based inhibitors of p38 are described. These efforts originated from quinazoline 1 and through rational design led to the development of a series of orally bioavailable, potent, and selective inhibitors. Kinase selectivity was achieved by exploiting a collection of interactions with p38alpha including close contact to Ala157, occupation of the hydrophobic gatekeeper pocket, and a residue flip with Gly110. Substitutions on the phthalazine influenced the pharmacokinetic properties, of which compound 16 displayed the most desirable profile. Oral dosing (0.03 mg/kg) of 16 in rats 1 h prior to LPS challenge gave a >50% decrease in TNFalpha production.

  15. Building a better dynasore: the dyngo compounds potently inhibit dynamin and endocytosis.

    PubMed

    McCluskey, Adam; Daniel, James A; Hadzic, Gordana; Chau, Ngoc; Clayton, Emma L; Mariana, Anna; Whiting, Ainslie; Gorgani, Nick N; Lloyd, Jonathan; Quan, Annie; Moshkanbaryans, Lia; Krishnan, Sai; Perera, Swetha; Chircop, Megan; von Kleist, Lisa; McGeachie, Andrew B; Howes, Mark T; Parton, Robert G; Campbell, Michael; Sakoff, Jennette A; Wang, Xuefeng; Sun, Jian-Yuan; Robertson, Mark J; Deane, Fiona M; Nguyen, Tam H; Meunier, Frederic A; Cousin, Michael A; Robinson, Phillip J

    2013-12-01

    Dynamin GTPase activity increases when it oligomerizes either into helices in the presence of lipid templates or into rings in the presence of SH3 domain proteins. Dynasore is a dynamin inhibitor of moderate potency (IC₅₀ ~ 15 μM in vitro). We show that dynasore binds stoichiometrically to detergents used for in vitro drug screening, drastically reducing its potency (IC₅₀ = 479 μM) and research tool utility. We synthesized a focused set of dihydroxyl and trihydroxyl dynasore analogs called the Dyngo™ compounds, five of which had improved potency, reduced detergent binding and reduced cytotoxicity, conferred by changes in the position and/or number of hydroxyl substituents. The Dyngo compound 4a was the most potent compound, exhibiting a 37-fold improvement in potency over dynasore for liposome-stimulated helical dynamin activity. In contrast, while dynasore about equally inhibited dynamin assembled in its helical or ring states, 4a and 6a exhibited >36-fold reduced activity against rings, suggesting that they can discriminate between helical or ring oligomerization states. 4a and 6a inhibited dynamin-dependent endocytosis of transferrin in multiple cell types (IC₅₀ of 5.7 and 5.8 μM, respectively), at least sixfold more potently than dynasore, but had no effect on dynamin-independent endocytosis of cholera toxin. 4a also reduced synaptic vesicle endocytosis and activity-dependent bulk endocytosis in cultured neurons and synaptosomes. Overall, 4a and 6a are improved and versatile helical dynamin and endocytosis inhibitors in terms of potency, non-specific binding and cytotoxicity. The data further suggest that the ring oligomerization state of dynamin is not required for clathrin-mediated endocytosis.

  16. Potent anti-inflammatory activity of betulinic acid treatment in a model of lethal endotoxemia.

    PubMed

    Costa, José Fernando Oliveira; Barbosa-Filho, José Maria; Maia, Gabriela Lemos de Azevedo; Guimarães, Elisalva Teixeira; Meira, Cássio Santana; Ribeiro-dos-Santos, Ricardo; de Carvalho, Lain Carlos Pontes; Soares, Milena Botelho Pereira

    2014-12-01

    Betulinic acid (BA) is a lupane-type triterpene with a number of biological activities already reported. While potent anti-HIV and antitumoral activities were attributed to BA, it is considered to have a moderate anti-inflammatory activity. Here we evaluated the effects of BA in a mouse model of endotoxic shock. Endotoxemia was induced through intraperitoneally LPS administration, nitric oxide (NO) and cytokines were assessed by Griess method and ELISA, respectively. Treatment of BALB/c mice with BA at 67 mg/kg caused a 100% survival against a lethal dose of lipopolysaccharide (LPS). BA treatment caused a reduction in TNF-α production induced by LPS but did not alter IL-6 production. Moreover, BA treatment increased significantly the serum levels of IL-10 compared to vehicle-treated, LPS-challenged mice. To investigate the role of IL-10 in BA-induced protection, wild-type and IL-10(-/-) mice were studied. In contrast to the observations in IL-10(+/+) mice, BA did not protect IL-10(-/-) mice against a lethal LPS challenge. Addition of BA inhibited the production of pro-inflammatory mediators by macrophages stimulated with LPS, while promoting a significant increase in IL-10 production. BA-treated peritoneal exudate macrophages produced lower concentrations of TNF-α and NO and higher concentrations of IL-10 upon LPS stimulation. Similarly, macrophages obtained from BA-treated mice produced less pro-inflammatory mediators and increased IL-10 when compared to non-stimulated macrophages obtained from vehicle-treated mice. In conclusion, we have shown that BA has a potent anti-inflammatory activity in vivo, protecting mice against LPS by modulating TNF-α production by macrophages in vivo through a mechanism dependent on IL-10.

  17. A potent antimalarial benzoxaborole targets a Plasmodium falciparum cleavage and polyadenylation specificity factor homologue.

    PubMed

    Sonoiki, Ebere; Ng, Caroline L; Lee, Marcus C S; Guo, Denghui; Zhang, Yong-Kang; Zhou, Yasheen; Alley, M R K; Ahyong, Vida; Sanz, Laura M; Lafuente-Monasterio, Maria Jose; Dong, Chen; Schupp, Patrick G; Gut, Jiri; Legac, Jenny; Cooper, Roland A; Gamo, Francisco-Javier; DeRisi, Joseph; Freund, Yvonne R; Fidock, David A; Rosenthal, Philip J

    2017-03-06

    Benzoxaboroles are effective against bacterial, fungal and protozoan pathogens. We report potent activity of the benzoxaborole AN3661 against Plasmodium falciparum laboratory-adapted strains (mean IC50 32 nM), Ugandan field isolates (mean ex vivo IC50 64 nM), and murine P. berghei and P. falciparum infections (day 4 ED90 0.34 and 0.57 mg kg(-1), respectively). Multiple P. falciparum lines selected in vitro for resistance to AN3661 harboured point mutations in pfcpsf3, which encodes a homologue of mammalian cleavage and polyadenylation specificity factor subunit 3 (CPSF-73 or CPSF3). CRISPR-Cas9-mediated introduction of pfcpsf3 mutations into parental lines recapitulated AN3661 resistance. PfCPSF3 homology models placed these mutations in the active site, where AN3661 is predicted to bind. Transcripts for three trophozoite-expressed genes were lost in AN3661-treated trophozoites, which was not observed in parasites selected or engineered for AN3661 resistance. Our results identify the pre-mRNA processing factor PfCPSF3 as a promising antimalarial drug target.

  18. A potent antimalarial benzoxaborole targets a Plasmodium falciparum cleavage and polyadenylation specificity factor homologue

    PubMed Central

    Sonoiki, Ebere; Ng, Caroline L.; Lee, Marcus C. S.; Guo, Denghui; Zhang, Yong-Kang; Zhou, Yasheen; Alley, M. R. K.; Ahyong, Vida; Sanz, Laura M.; Lafuente-Monasterio, Maria Jose; Dong, Chen; Schupp, Patrick G.; Gut, Jiri; Legac, Jenny; Cooper, Roland A.; Gamo, Francisco-Javier; DeRisi, Joseph; Freund, Yvonne R.; Fidock, David A.; Rosenthal, Philip J.

    2017-01-01

    Benzoxaboroles are effective against bacterial, fungal and protozoan pathogens. We report potent activity of the benzoxaborole AN3661 against Plasmodium falciparum laboratory-adapted strains (mean IC50 32 nM), Ugandan field isolates (mean ex vivo IC50 64 nM), and murine P. berghei and P. falciparum infections (day 4 ED90 0.34 and 0.57 mg kg−1, respectively). Multiple P. falciparum lines selected in vitro for resistance to AN3661 harboured point mutations in pfcpsf3, which encodes a homologue of mammalian cleavage and polyadenylation specificity factor subunit 3 (CPSF-73 or CPSF3). CRISPR-Cas9-mediated introduction of pfcpsf3 mutations into parental lines recapitulated AN3661 resistance. PfCPSF3 homology models placed these mutations in the active site, where AN3661 is predicted to bind. Transcripts for three trophozoite-expressed genes were lost in AN3661-treated trophozoites, which was not observed in parasites selected or engineered for AN3661 resistance. Our results identify the pre-mRNA processing factor PfCPSF3 as a promising antimalarial drug target. PMID:28262680

  19. In silico reconstruction of the viral evolutionary lineage yields a potent gene therapy vector

    PubMed Central

    Zinn, Eric; Pacouret, Simon; Khaychuk, Vadim; Turunen, Heikki T.; Carvalho, Livia S.; Andres-Mateos, Eva; Shah, Samiksha; Shelke, Rajani; Maurer, Anna C.; Plovie, Eva; Xiao, Ru; Vandenberghe, Luk H.

    2015-01-01

    SUMMARY Adeno-associated viral vectors (AAV) have emerged as a gene delivery platform with demonstrated safety and efficacy in a handful of clinical trials for monogenic disorders. However, limitations of the current generation vectors often prevent broader application of AAV gene therapy. Efforts to engineer AAV have been hampered by a limited understanding of the structure-function relationship of the complex multimeric icosahedral architecture of the particle. To develop additional reagents pertinent to further our insight into AAV, we inferred evolutionary intermediates of the viral capsid using ancestral sequence reconstruction. In silico derived sequences were synthesized de novo and characterized for biological properties relevant to clinical applications. This effort led to the generation of 9 functional putative ancestral AAVs and the identification of Anc80, the predicted ancestor of the widely studied AAV serotypes 1, 2, 8 and 9 as a highly potent in vivo gene therapy vector for targeting liver, muscle, and retina. PMID:26235624

  20. (R)-2-Phenylpyrrolidine Substituted Imidazopyridazines: A New Class of Potent and Selective Pan-TRK Inhibitors

    PubMed Central

    2015-01-01

    Deregulated kinase activities of tropomyosin receptor kinase (TRK) family members have been shown to be associated with tumorigenesis and poor prognosis in a variety of cancer types. In particular, several chromosomal rearrangements involving TRKA have been reported in colorectal, papillary thyroid, glioblastoma, melanoma, and lung tissue that are believed to be the key oncogenic driver in these tumors. By screening the Novartis compound collection, a novel imidazopyridazine TRK inhibitor was identified that served as a launching point for drug optimization. Structure guided drug design led to the identification of (R)-2-phenylpyrrolidine substituted imidazopyridazines as a series of potent, selective, orally bioavailable pan-TRK inhibitors achieving tumor regression in rats bearing KM12 xenografts. From this work the (R)-2-phenylpyrrolidine has emerged as an ideal moiety to incorporate in bicyclic TRK inhibitors by virtue of its shape complementarity to the hydrophobic pocket of TRKs. PMID:26005534

  1. A novel bispecific antibody, S-Fab, induces potent cancer cell killing.

    PubMed

    Li, Li; He, Ping; Zhou, Changhua; Jing, Li; Dong, Bin; Chen, Siqi; Zhang, Ning; Liu, Yawei; Miao, Ji; Wang, Zhong; Li, Qing

    2015-01-01

    Bispecific antibodies that engage immune cells to kill cancer cells have been actively studied in cancer immunotherapy. In this study, we present a novel bispecific format, S-Fab, fabricated by linking a single-domain anti-carcinoembryonic antigen VHH to a conventional anti-CD3 Fab. In contrast to most bispecific antibodies, the S-Fab bispecific antibody can be efficiently expressed and purified from bacteria. The purified S-Fab is stable in serum and is able to recruit T cells to drive potent cancer cell killing. In xenograft models, the S-Fab antibody suppresses tumor growth in the presence of human immune cells. Our study suggested that the bispecific S-Fab format can be applied to a wide range of immunotherapies.

  2. Discovery and refinement of a new structural class of potent peptide deformylase inhibitors.

    PubMed

    Boularot, Adrien; Giglione, Carmela; Petit, Sylvain; Duroc, Yann; Alves de Sousa, Rodolphe; Larue, Valéry; Cresteil, Thierry; Dardel, Frédéric; Artaud, Isabelle; Meinnel, Thierry

    2007-01-11

    New classes of antibiotics are urgently needed to counter increasing levels of pathogen resistance. Peptide deformylase (PDF) was originally selected as a specific bacterial target, but a human homologue, the inhibition of which causes cell death, was recently discovered. We developed a dual-screening strategy for selecting highly effective compounds with low inhibition effect against human PDF. We selected a new scaffold in vitro that discriminated between human and bacterial PDFs. Analyses of structure-activity relationships identified potent antibiotics such as 2-(5-bromo-1H-indol-3-yl)-N-hydroxyacetamide (6b) with the same mode of action in vivo as previously identified PDF inhibitors but without the apoptotic effects of these inhibitors in human cells.

  3. The noni anthraquinone damnacanthal is a multi-kinase inhibitor with potent anti-angiogenic effects.

    PubMed

    García-Vilas, Javier A; Pino-Ángeles, Almudena; Martínez-Poveda, Beatriz; Quesada, Ana R; Medina, Miguel Ángel

    2017-01-28

    The natural bioactive compound damnacanthal inhibits several tyrosine kinases. Herein, we show that -in fact- damancanthal is a multi kinase inhibitor. A docking and molecular dynamics simulation approach allows getting further insight on the inhibitory effect of damnacanthal on three different kinases: vascular endothelial growth factor receptor-2, c-Met and focal adhesion kinase. Several of the kinases targeted and inhibited by damnacanthal are involved in angiogenesis. Ex vivo and in vivo experiments clearly demonstrate that, indeed, damnacanthal is a very potent inhibitor of angiogenesis. A number of in vitro assays contribute to determine the specific effects of damnacanthal on each of the steps of the angiogenic process, including inhibition of tubulogenesis, endothelial cell proliferation, survival, migration and production of extracellular matrix remodeling enzyme. Taken altogether, these results suggest that damancanthal could have potential interest for the treatment of cancer and other angiogenesis-dependent diseases.

  4. Potent anti-proliferative actions of a non-diuretic glucosamine derivative of ethacrynic acid.

    PubMed

    Punganuru, Surendra R; Mostofa, A G M; Madala, Hanumantha Rao; Basak, Debasish; Srivenugopal, Kalkunte S

    2016-06-15

    Ethacrynic acid (EA), a known inhibitor of the neoplastic marker glutathione S-transferase P1 and other GSTs, exerts a weak antiproliferative activity against human cancer cells. The clinical use of EA (Edecrin) as an anticancer drug is limited by its potent loop diuretic activity. In this study, we developed a non-diuretic 2-amino-2-deoxy-d-glucose conjugated EA (EAG) to target tumors cells via the highly expressed glucose transporter 1 (GLUT1). Cell survival assays revealed that EAG had little effect on normal cells, but was cytotoxic 3 to 4.5-fold greater than EA. Mechanistically, the EAG induced selective cell death in cancer cells by inhibiting GSTP1 and generating abundant reactive oxygen species. Furthermore, EAG induced p21(cip1) expression and a G2/M cell cycle block irrespective of the p53 gene status in tumor cells. These data encourage the development of new EA analogs.

  5. Discriminative stimulus effects of S(-)-methcathinone (CAT): a potent stimulant drug of abuse.

    PubMed

    Young, R; Glennon, R A

    1998-12-01

    Methcathinone ("CAT") is a CNS stimulant that is a very significant drug of abuse in the former Soviet Union. It has also appeared on the clandestine market in the United States and has been recently classified as a Schedule I substance. In the present study, S(-)-methcathinone [S(-)-CAT, 0.50 mg/kg, IP] was employed as the training drug in a two-lever drug discrimination task in rats. Once established, the S(-)-CAT stimulus was shown to have a rapid onset to action (within 5 min) and a duration of effect of approximately 60-90 min. In tests of stimulus generalization (substitution), the S(-)-CAT (ED50 = 0.11 mg/kg) stimulus generalized to S(+)-methamphetamine (ED5 = 0.17 mg/kg), S(-)-cathinone (ED50 = 0.19 mg/kg), S(+)-amphetamine (ED50 = 0.23 mg/kg), aminorex (ED50 = 0.27 mg/kg), (+/-)-CAT (ED50 = 0.25 mg/kg), (+/-)-cathinone (ED50 = 0.41 mg/kg), R(+)-CAT (ED50 = 0.43 mg/kg), cis-4-methylaminorex (ED50 = 0.49 mg/kg), methylphenidate (ED50 = 0.83 mg/kg), and cocaine (ED50= 1.47 mg/kg). S(-)-CAT-stimulus generalization did not occur to fenfluramine, a structurally related nonstimulant anorectic. Lastly, haloperidol (AD50 = 0.18 mg/kg), a dopamine receptor antagonist, potently antagonized the S(-)-CAT stimulus. It is concluded that S(-)-methcathinone is a very potent CNS stimulant, which appears to produce its stimulus effect, at least in part, via a dopaminergic mechanism.

  6. Discovery and Characterization of a Potent Interleukin-6 Binding Peptide with Neutralizing Activity In Vivo

    PubMed Central

    Ranganath, Sheila; Bhandari, Ashok; Avitahl-Curtis, Nicole; McMahon, Jaimee; Wachtel, Derek; Zhang, Jenny; Leitheiser, Christopher; Bernier, Sylvie G.; Liu, Guang; Tran, Tran T.; Celino, Herodion; Tobin, Jenny; Jung, Joon; Zhao, Hong; Glen, Katie E.; Graul, Chris; Griffin, Aliesha; Schairer, Wayne C.; Higgins, Carolyn; Reza, Tammi L.; Mowe, Eva; Rivers, Sam; Scott, Sonya; Monreal, Alex; Shea, Courtney; Bourne, Greg; Coons, Casey; Smith, Adaline; Tang, Kim; Mandyam, Ramya A.; Masferrer, Jaime; Liu, David; Patel, Dinesh V.; Fretzen, Angelika; Murphy, Craig A.; Milne, G. Todd; Smythe, Mark L.; Carlson, Kenneth E.

    2015-01-01

    Interleukin-6 (IL-6) is an important member of the cytokine superfamily, exerting pleiotropic actions on many physiological processes. Over-production of IL-6 is a hallmark of immune-mediated inflammatory diseases such as Castleman’s Disease (CD) and rheumatoid arthritis (RA). Antagonism of the interleukin IL-6/IL-6 receptor (IL-6R)/gp130 signaling complex continues to show promise as a therapeutic target. Monoclonal antibodies (mAbs) directed against components of this complex have been approved as therapeutics for both CD and RA. To potentially provide an additional modality to antagonize IL-6 induced pathophysiology, a peptide-based antagonist approach was undertaken. Using a combination of molecular design, phage-display, and medicinal chemistry, disulfide-rich peptides (DRPs) directed against IL-6 were developed with low nanomolar potency in inhibiting IL-6-induced pSTAT3 in U937 monocytic cells. Targeted PEGylation of IL-6 binding peptides resulted in molecules that retained their potency against IL-6 and had a prolongation of their pharmacokinetic (PK) profiles in rodents and monkeys. One such peptide, PN-2921, contained a 40 kDa polyethylene glycol (PEG) moiety and inhibited IL-6-induced pSTAT3 in U937 cells with sub-nM potency and possessed 23, 36, and 59 h PK half-life values in mice, rats, and cynomolgus monkeys, respectively. Parenteral administration of PN-2921 to mice and cynomolgus monkeys potently inhibited IL-6-induced biomarker responses, with significant reductions in the acute inflammatory phase proteins, serum amyloid A (SAA) and C-reactive protein (CRP). This potent, PEGylated IL-6 binding peptide offers a new approach to antagonize IL-6-induced signaling and associated pathophysiology. PMID:26555695

  7. Repositioning tolcapone as a potent inhibitor of transthyretin amyloidogenesis and associated cellular toxicity

    PubMed Central

    Sant'Anna, Ricardo; Gallego, Pablo; Robinson, Lei Z.; Pereira-Henriques, Alda; Ferreira, Nelson; Pinheiro, Francisca; Esperante, Sebastian; Pallares, Irantzu; Huertas, Oscar; Rosário Almeida, Maria; Reixach, Natàlia; Insa, Raul; Velazquez-Campoy, Adrian; Reverter, David; Reig, Núria; Ventura, Salvador

    2016-01-01

    Transthyretin (TTR) is a plasma homotetrameric protein implicated in fatal systemic amyloidoses. TTR tetramer dissociation precedes pathological TTR aggregation. Native state stabilizers are promising drugs to treat TTR amyloidoses. Here we repurpose tolcapone, an FDA-approved molecule for Parkinson's disease, as a potent TTR aggregation inhibitor. Tolcapone binds specifically to TTR in human plasma, stabilizes the native tetramer in vivo in mice and humans and inhibits TTR cytotoxicity. Crystal structures of tolcapone bound to wild-type TTR and to the V122I cardiomyopathy-associated variant show that it docks better into the TTR T4 pocket than tafamidis, so far the only drug on the market to treat TTR amyloidoses. These data indicate that tolcapone, already in clinical trials for familial amyloid polyneuropathy, is a strong candidate for therapeutic intervention in these diseases, including those affecting the central nervous system, for which no small-molecule therapy exists. PMID:26902880

  8. Flavaglines: potent anticancer drugs that target prohibitins and the helicase eIF4A.

    PubMed

    Basmadjian, Christine; Thuaud, Frédéric; Ribeiro, Nigel; Désaubry, Laurent

    2013-12-01

    Flavaglines are complex natural products that are found in several medicinal plants of Southeast Asia in the genus Aglaia; these compounds have shown exceptional anticancer and cytoprotective activities. This review describes the significance of flavaglines as a new class of pharmacological agents and presents recent developments in their synthesis, structure-activity relationships, identification of their molecular targets and modes of action. Flavaglines display a unique profile of anticancer activities that are mediated by two classes of unrelated proteins: prohibitins and the translation initiation factor eIF4A. The identification of these molecular targets is expected to accelerate advancement toward clinical studies. The selectivity of cytotoxicity towards cancer cells has been shown to be due to an inhibition of the transcription factor HSF1 and an upregulation of the tumor suppressor TXNIP. In addition, flavaglines display potent anti-inflammatory, cardioprotective and neuroprotective activities; however, the mechanisms underlying these activities are yet to be elucidated.

  9. Isolation of potent neutralizing antibodies from a survivor of the 2014 Ebola virus outbreak

    PubMed Central

    Bornholdt, Zachary A.; Turner, Hannah L.; Murin, Charles D.; Li, Wen; Sok, Devin; Souders, Colby A.; Piper, Ashley E.; Goff, Arthur; Shamblin, Joshua D.; Wollen, Suzanne E.; Sprague, Thomas R.; Fusco, Marnie L.; Pommert, Kathleen B.J.; Cavacini, Lisa A.; Smith, Heidi L.; Klempner, Mark; Reimann, Keith A.; Krauland, Eric; Gerngross, Tillman U.; Wittrup, Dane K.; Saphire, Erica Ollmann; Burton, Dennis R.; Glass, Pamela J.; Ward, Andrew B.; Walker, Laura M.

    2016-01-01

    Antibodies targeting the Ebola virus surface glycoprotein (EBOV GP) are implicated in protection against lethal disease, but the characteristics of the human antibody response to EBOV GP remain poorly understood. Here we isolated and characterized 349 GP-specific monoclonal antibodies (mAbs) from the peripheral B cells of a convalescent donor who survived the 2014 EBOV Zaire outbreak. Remarkably, 77% of the mAbs neutralize live EBOV and several mAbs exhibit unprecedented potency. Structures of selected mAbs in complex with GP reveal a site of vulnerability located in the GP stalk region proximal to the viral membrane. Neutralizing antibodies (NAbs) targeting this site show potent therapeutic efficacy against lethal EBOV challenge in mice. The results provide a framework for the design of new EBOV vaccine candidates and immunotherapies. PMID:26912366

  10. Restoring visual function to the blind retina with a potent, safe and long-lasting photoswitch.

    PubMed

    Tochitsky, Ivan; Trautman, Jay; Gallerani, Nicholas; Malis, Jonatan G; Kramer, Richard H

    2017-04-13

    Photoswitch compounds such as DENAQ confer light-sensitivity on endogenous neuronal ion channels, enabling photocontrol of neuronal activity without genetic manipulation. DENAQ treatment restores both retinal light responses and visual behaviors in rodent models of Retinitis pigmentosa. However, retinal photosensitization requires a high dose of DENAQ and disappears within several days after treatment. Here we report that BENAQ, an improved photoswitch, is 20-fold more potent than DENAQ and persists in restoring visual responses to the retina for almost 1 month after a single intraocular injection. Studies on mice and rabbits show that BENAQ is non-toxic at concentrations 10-fold higher than required to impart light-sensitivity. These favorable properties make BENAQ a potential drug candidate for vision restoration in patients with degenerative blinding diseases.

  11. Virtual ligand screening of α-glucosidase: Identification of a novel potent noncarbohydrate mimetic inhibitor.

    PubMed

    Hakamata, Wataru; Ishikawa, Ryosuke; Ushijima, Yoriko; Tsukagoshi, Takumi; Tamura, Saori; Hirano, Takako; Nishio, Toshiyuki

    2012-01-01

    5-Thiazoleacetamide derivatives of AR122 and AR125 were screened as α-glucosidase inhibitors by in silico high-throughput screening from commercial drug-like small compound libraries. Inhibition of α-glucosidase with AR122 and AR125 is time dependent: with no preincubation, AR122 and AR125 are relatively moderate inhibitors, but interestingly, after a 120 min incubation, they were 50-fold more potent (AR122: IC(50)=2.47 μM and AR125: IC(50)=27.1 μM). Plots of ln [residual α-glucosidase activity %] versus preincubation time show a pseudo-first order kinetics for both inhibitors. Through dialysis of enzyme-inhibitor complexes, no activity recovery was shown. These results suggest that AR122 and AR125 constitute a new class of noncarbohydrate mimetic inhibitor with an irreversible mechanism.

  12. Hit-to-Lead Optimization of a Novel Class of Potent, Broad-Spectrum Trypanosomacides.

    PubMed

    Russell, Stephanie; Rahmani, Raphaël; Jones, Amy J; Newson, Harriet L; Neilde, Kevin; Cotillo, Ignacio; Rahmani Khajouei, Marzieh; Ferrins, Lori; Qureishi, Sana; Nguyen, Nghi; Martinez-Martinez, Maria S; Weaver, Donald F; Kaiser, Marcel; Riley, Jennifer; Thomas, John; De Rycker, Manu; Read, Kevin D; Flematti, Gavin R; Ryan, Eileen; Tanghe, Scott; Rodriguez, Ana; Charman, Susan A; Kessler, Albane; Avery, Vicky M; Baell, Jonathan B; Piggott, Matthew J

    2016-11-10

    The parasitic trypanosomes Trypanosoma brucei and T. cruzi are responsible for significant human suffering in the form of human African trypanosomiasis (HAT) and Chagas disease. Drugs currently available to treat these neglected diseases leave much to be desired. Herein we report optimization of a novel class of N-(2-(2-phenylthiazol-4-yl)ethyl)amides, carbamates, and ureas, which rapidly, selectively, and potently kill both species of trypanosome. The mode of action of these compounds is unknown but does not involve CYP51 inhibition. They do, however, exhibit clear structure-activity relationships, consistent across both trypanosome species. Favorable physicochemical parameters place the best compounds in CNS drug-like chemical space but, as a class, they exhibit poor metabolic stability. One of the best compounds (64a) cleared all signs of T. cruzi infection in mice when CYP metabolism was inhibited, with sterile cure achieved in one mouse. This family of compounds thus shows significant promise for trypanosomiasis drug discovery.

  13. DNA Recognition by a Novel Bis-Intercalator, Potent Anticancer Drug XR5944

    PubMed Central

    Lin, Clement; Yang, Danzhou

    2016-01-01

    XR5944 is a potent anticancer drug with a novel DNA binding mode: DNA bis-intercalationg with major groove binding. XR5944 can bind the estrogen response element (ERE) sequence to block ER-ERE binding and inhibit ERα activities, which may be useful for overcoming drug resistance to currently available antiestrogen treatments. This review discusses the progress relating to the structure and function studies of specific DNA recognition of XR5944. The sites of intercalation within a native promoter sequence appear to be different from the ideal binding site and are context- and sequence- dependent. The structural information may provide insights for rational design of improved ERE-specific XR5944 derivatives, as well as of DNA bis-intercalators in general. PMID:25866279

  14. A Potent, Selective and Cell-active Inhibitor of Human Type I Protein Arginine Methyltransferases

    PubMed Central

    Wu, Hong; Senisterra, Guillermo; Li, Fengling; Butler, Kyle V.; Kaniskan, H. Ümit; Speed, Brandon A.; dela Seña, Carlo; Dong, Aiping; Zeng, Hong; Schapira, Matthieu; Brown, Peter J.; Arrowsmith, Cheryl H.; Barsyte-Lovejoy, Dalia; Liu, Jing; Vedadi, Masoud; Jin, Jian

    2015-01-01

    Protein arginine methyltransferases (PRMTs) play a crucial role in a variety of biological processes. Overexpression of PRMTs has been implicated in various human diseases including cancer. Consequently, selective small-molecule inhibitors of PRMTs have been pursued by both academia and pharmaceutical industry as chemical tools for testing biological and therapeutic hypotheses. PRMTs are divided into three categories: type I PRMTs which catalyze mono- and asymmetric dimethylation of arginine residues, type II PRMTs which catalyze mono- and symmetric dimethylation of arginine residues, and type III PRMT which catalyzes only monomethylation of arginine residues. Here, we report the discovery of a potent, selective and cell-active inhibitor of human type I PRMTs, MS023, and characterization of this inhibitor in a battery of biochemical, biophysical and cellular assays. MS023 displayed high potency for type I PRMTs including PRMT1, 3, 4, 6 and 8, but was completely inactive against type II and type III PRMTs, protein lysine methyltransferases and DNA methyltransferases. A crystal structure of PRMT6 in complex with MS023 revealed that MS023 binds the substrate binding site. MS023 potently decreased cellular levels of histone arginine asymmetric dimethylation. It also reduced global levels of arginine asymmetric dimethylation and concurrently increased levels of arginine monomethylation and symmetric dimethylation in cells. We also developed MS094, a close analog of MS023, which was inactive in biochemical and cellular assays, as a negative control for chemical biology studies. MS023 and MS094 are useful chemical tools for investigating the role of type I PRMTs in health and disease. PMID:26598975

  15. Identification of resveratrol analogs as potent anti-dengue agents using a cell-based assay.

    PubMed

    Han, Ying-Shan; Penthala, Narsimha Reddy; Oliveira, Maureen; Mesplède, Thibault; Xu, Hongtao; Quan, Yudong; Crooks, Peter A; Wainberg, Mark A

    2017-03-01

    Dengue virus (DENV) causes a variety of difficult-to-treat diseases that threaten almost half of the world's population. Currently, no effective vaccine or antiviral therapy is available. We have examined a series of synthetic resveratrol analogs to identify potential anti-DENV agents. Here, we demonstrate that two resveratrol analogs, PNR-4-44 and PNR-5-02, possess potent anti-DENV activity with EC50 values in the low nanomolar range. These two resveratrol analogs were shown to mainly target viral RNA translation and viral replication, but PNR-5-02 is also likely to target cellular factors inside host cells. Although the precise molecular mechanism(s) mediating anti-DENV activities have not been elucidated, further structure-guided design might lead to the development of newer improved resveratrol derivatives that might have therapeutic value. J. Med. Virol. 89:397-407, 2017. © 2016 Wiley Periodicals, Inc.

  16. 30 CFR 819.17 - Auger mining: Subsidence protection.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 30 Mineral Resources 3 2014-07-01 2014-07-01 false Auger mining: Subsidence protection. 819.17 Section 819.17 Mineral Resources OFFICE OF SURFACE MINING RECLAMATION AND ENFORCEMENT, DEPARTMENT OF THE... MINING § 819.17 Auger mining: Subsidence protection. Auger mining shall be conducted in accordance...

  17. 30 CFR 819.17 - Auger mining: Subsidence protection.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 3 2010-07-01 2010-07-01 false Auger mining: Subsidence protection. 819.17 Section 819.17 Mineral Resources OFFICE OF SURFACE MINING RECLAMATION AND ENFORCEMENT, DEPARTMENT OF THE... MINING § 819.17 Auger mining: Subsidence protection. Auger mining shall be conducted in accordance...

  18. 30 CFR 819.17 - Auger mining: Subsidence protection.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 30 Mineral Resources 3 2013-07-01 2013-07-01 false Auger mining: Subsidence protection. 819.17 Section 819.17 Mineral Resources OFFICE OF SURFACE MINING RECLAMATION AND ENFORCEMENT, DEPARTMENT OF THE... MINING § 819.17 Auger mining: Subsidence protection. Auger mining shall be conducted in accordance...

  19. 30 CFR 819.17 - Auger mining: Subsidence protection.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 30 Mineral Resources 3 2012-07-01 2012-07-01 false Auger mining: Subsidence protection. 819.17 Section 819.17 Mineral Resources OFFICE OF SURFACE MINING RECLAMATION AND ENFORCEMENT, DEPARTMENT OF THE... MINING § 819.17 Auger mining: Subsidence protection. Auger mining shall be conducted in accordance...

  20. 30 CFR 819.17 - Auger mining: Subsidence protection.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 30 Mineral Resources 3 2011-07-01 2011-07-01 false Auger mining: Subsidence protection. 819.17 Section 819.17 Mineral Resources OFFICE OF SURFACE MINING RECLAMATION AND ENFORCEMENT, DEPARTMENT OF THE... MINING § 819.17 Auger mining: Subsidence protection. Auger mining shall be conducted in accordance...

  1. Binding ability of impromidine, a potent H2 agonist of histamine

    NASA Astrophysics Data System (ADS)

    Anouar, A.; Lhadi, E.; Decock, P.; Kozlowskyinst4, H.

    1999-09-01

    Impromidine (fig.1) is a potent and selective histamine H2 receptor agonist and its structure comprises a strongly basic guanidine group containing two different imidazole-containing side chains. The present work deals with the study of coordination equilibria between impromidine and Cu(II) and Ni(II) in aqueous solution at 25 circC. Potentiometric, UV-Visible and EPR studies on Cu(II) complexes with impromidine have shown that this anti-ulcerogenic drug is a very potent chelating agent. This drug is found to be a very effective ligand for Ni(II) ions also. The effective coordination of impromidine to metal ions may have significant biological implications. L'impromidine est un agoniste H2 de l'histamine, sa structure possède un groupement guanidinique de forte basicité et dont l'environne ment des deux groupements imidazoliques est différent. Le présent travail consiste en l'étude de la coordination de l'impromidine avec le Cu(II) et le Ni(II) en milieu aqueux à 25 circC. La potentiométrie, LíUV-Visible et la RPE montrent que le cuivre se coordine très fortement avec l'impromidine. Nous avons trouvé que ce médicament se coordine aussi fortement avec le nickel(II). La coordination de l'impromidine avec les métaux pourrait avoir des applications importantes en médecine.

  2. Potent analgesic effects of a store-operated calcium channel inhibitor

    PubMed Central

    Xia, Jingsheng; Tian, Yuzhen; Barrett, James E.; Dai, Yue; Hu, Huijuan

    2013-01-01

    Chronic pain often accompanies immune responses and immune cells are known to be involved in chronic pain. Store-operated calcium (SOC) channels are calcium-selective cation channels and play an important role in the immune system. YM-58483, a potent SOC channel inhibitor, has been shown to inhibit cytokine production from immune cells and attenuate antigen-induced hypersensitivity reactions. Here, we report that YM-58483 has analgesic actions in chronic pain and produces antinociceptive effects in acute pain and prevents the development of chronic pain in mice. Oral administration of 10 mg/kg or 30 mg/kg YM-58483 dramatically attenuated Complete Freund's adjuvant (CFA)-induced thermal hyperalgesia and prevented the development of thermal and mechanical hypersensitivity in a dose-dependent manner. Analgesic effects were observed when YM-58483 administered systemically, intrathecally, and also intraplantarly. YM-58483 decreased spared nerve injury (SNI)-induced thermal and mechanical hypersensitivity and prevented the development of SNI-induced pain hypersensitivity. Pretreatment with YM-58483 strongly reduced both the first and second phases of formalin-induced spontaneous nocifensive behavior dose-dependently. YM-58483 produced antinociception in acute pain induced by heat or chemical or mechanical stimuli at the dose of 30 mg/kg. YM-58483 diminished CFA-induced paw edema, and reduced production of TNF-α, IL-1β and PGE2 in the CFA-injected paw. In vitro, SOC entry in nociceptors was more robust than in nonnociceptors, and the inhibition of SOC entry by YM-58483 in nociceptors was much greater than in non-nociceptors. Our findings indicate that YM-58483 is a potent analgesic and suggest that SOC channel inhibitors may represent a novel class of therapeutics for pain. PMID:23778292

  3. Discovery of TAK-272: A Novel, Potent, and Orally Active Renin Inhibitor.

    PubMed

    Imaeda, Yasuhiro; Tokuhara, Hidekazu; Fukase, Yoshiyuki; Kanagawa, Ray; Kajimoto, Yumiko; Kusumoto, Keiji; Kondo, Mitsuyo; Snell, Gyorgy; Behnke, Craig A; Kuroita, Takanobu

    2016-10-13

    The aspartic proteinase renin is an attractive target for the treatment of hypertension and cardiovascular/renal disease such as chronic kidney disease and heart failure. We introduced an S1' site binder into the lead compound 1 guided by structure-based drug design (SBDD), and further optimization of physicochemical properties led to the discovery of benzimidazole derivative 10 (1-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-yl)carbonylpiperidin-3-yl]-1H-benzimidazole-2-carboxamide hydrochloride, TAK-272) as a highly potent and orally active renin inhibitor. Compound 10 demonstrated good oral bioavailability (BA) and long-lasting efficacy in rats. Compound 10 is currently in clinical trials.

  4. Adrenomedullary progenitor cells: Isolation and characterization of a multi-potent progenitor cell population.

    PubMed

    Vukicevic, Vladimir; Rubin de Celis, Maria Fernandez; Pellegata, Natalia S; Bornstein, Stefan R; Androutsellis-Theotokis, Andreas; Ehrhart-Bornstein, Monika

    2015-06-15

    The adrenal is a highly plastic organ with the ability to adjust to physiological needs by adapting hormone production but also by generating and regenerating both adrenocortical and adrenomedullary tissue. It is now apparent that many adult tissues maintain stem and progenitor cells that contribute to their maintenance and adaptation. Research from the last years has proven the existence of stem and progenitor cells also in the adult adrenal medulla throughout life. These cells maintain some neural crest properties and have the potential to differentiate to the endocrine and neural lineages. In this article, we discuss the evidence for the existence of adrenomedullary multi potent progenitor cells, their isolation and characterization, their differentiation potential as well as their clinical potential in transplantation therapies but also in pathophysiology.

  5. A new class of potent centrally acting muscle relaxants: pharmacology of oxazolidinones in rat decerebrate rigidity.

    PubMed Central

    Masaki, M.; Shinozaki, H.

    1986-01-01

    The severity of anaemic decerebrate rigidity was quantitatively determined by measuring the frequency of electromyographic potentials in the rat. Some oxazolidinones markedly reduced the severity of this decerebrate rigidity in a dose-dependent manner, (4S,5R)-4-(2-methylpropyl)-3- [3-(perhydroazepin-1-yl)propyl]-5-phenyl-1,3-oxazolidin-2-on e (MLV-6976) being the most potent. In addition to the oxazolidinones, an aminoalcohol derivative, (1RS,2SR)-5-methyl-1-phenyl-2-(3-piperidinopropylamino )hexan-1-ol (MLV-5860) also reduced the rat decerebrate rigidity. In the oxazolidinone series, the optical isomers with absolute configuration (S) at the 4-position were more potent than the corresponding (4R)-isomers, while there was no significant difference in their LD50 values. Normal rats and mice receiving MLV-6976 at doses which reduced decerebrate rigidity showed no behavioural changes, impairment of motor coordination only appearing at extremely high doses. MLV-6976 and its derivatives did not affect spinal reflex potentials in cats. MLV-6976 reduced the severity of harmaline-induced tremor in mice in a dose-dependent manner, but slightly augmented tremorine-induced tremor. The frequency of the spike discharges induced by iontophoretically applied glutamate was reduced by MLV-6976 in a dose-dependent manner in rat cortical neurones. The amplitude of miniature endplate potentials of the rat diaphragm was decreased by MLV-6976 only at concentrations greater than 0.1 mM. It is concluded that MLV-6976 acts on the brainstem or/and higher levels of the brain rather than on the spinal cord or the peripheral nervous system to reduce the excessive activities of the nervous system. PMID:2879590

  6. Taurine is a potent activator of extrasynaptic GABA(A) receptors in the thalamus.

    PubMed

    Jia, Fan; Yue, Minerva; Chandra, Dev; Keramidas, Angelo; Goldstein, Peter A; Homanics, Gregg E; Harrison, Neil L

    2008-01-02

    Taurine is one of the most abundant free amino acids in the brain. In a number of studies, taurine has been reported to activate glycine receptors (Gly-Rs) at moderate concentrations (> or = 100 microM), and to be a weak agonist at GABA(A) receptors (GABA(A)-Rs), which are usually activated at high concentrations (> or = 1 mM). In this study, we show that taurine reduced the excitability of thalamocortical relay neurons and activated both extrasynaptic GABA(A)-Rs and Gly-Rs in neurons in the mouse ventrobasal (VB) thalamus. Low concentrations of taurine (10-100 microM) decreased neuronal input resistance and firing frequency, and elicited a steady outward current under voltage clamp, but had no effects on fast inhibitory synaptic currents. Currents elicited by 50 microM taurine were abolished by gabazine, insensitive to midazolam, and partially blocked by 20 microM Zn2+, consistent with the pharmacological properties of extrasynaptic GABA(A)-Rs (alpha4beta2delta subtype) involved in tonic inhibition in the thalamus. Tonic inhibition was enhanced by an inhibitor of taurine transport, suggesting that taurine can act as an endogenous activator of these receptors. Taurine-evoked currents were absent in relay neurons from GABA(A)-R alpha4 subunit knock-out mice. The amplitude of the taurine current was larger in neurons from adult mice than juvenile mice. Taurine was a more potent agonist at recombinant alpha4beta2delta GABA(A)-Rs than at alpha1beta2gamma2 GABA(A)-Rs. We conclude that physiological concentrations of taurine can inhibit VB neurons via activation of extrasynaptic GABA(A)-Rs and that taurine may function as an endogenous regulator of excitability and network activity in the thalamus.

  7. Neuropeptide gamma: a mammalian tachykinin endowed with potent antidipsogenic action in rats.

    PubMed

    Polidori, C; Staffinati, G; Perfumi, M C; de Caro, G; Massi, M

    1995-09-01

    Neuropeptide gamma (NP gamma) is a 21 aminoacid peptide belonging to the tachykinin (TK) family and including neurokinin A (NKA) in its C-terminal sequence. NP gamma possesses higher affinity than NKA for central NK-2 receptors; it shows lower affinity for NK-1 receptors, however, it potently stimulates salivary secretion, which is mediated by NK-1 receptor activation. Pulse intracerebroventricular (pICV) injection of TKs selectively inhibits water intake in rats. Our studies have suggested that NK-1 receptors may mediate the inhibition of angiotensin II-induced drinking, while NK-2 receptors that of drinking induced by cell dehydration. The present study evaluated the effect of pICV injections of NP gamma on water intake in rats. The injection of NP gamma, 8-250 ng/rat, markedly inhibited angiotensin II-induced drinking, and its effect was blocked by the NK-1 receptor antagonist WIN 62577. NP gamma potently inhibited also drinking induced by SC hypertonic NaCl load or water deprivation. The threshold dose for these effects was 31 ng/rat. Also carbachol-induced drinking was inhibited, but at higher doses. On the other hand, NP gamma did not modify food intake in food deprived rats or 0.1% saccharin intake in water and food sated rats, at the same doses effective on drinking. Present findings support the idea that TKs selectively inhibit water intake in rats and are in keeping with our hypothesis that NK-1 and NK-2 receptors mediate, respectively, inhibition of angiotensin II- and cell dehydration-induced drinking.(ABSTRACT TRUNCATED AT 250 WORDS)

  8. Cloning and rational mutagenesis of kexstatin I, a potent proteinaceous inhibitor of Kex2 proteinase.

    PubMed Central

    Oda, K; Oyama, H; Ito, S; Fukiharu, M; Miyagawa, Y; Takahashi, S; Hirose, M; Kikuchi, N; Nakayama, T; Shibano, Y

    2001-01-01

    Kexstatin I is a potent proteinaceous inhibitor of Kex2 proteinase (EC 3.4.21.61). In the present study we show the molecular cloning, primary structure determination and expression of the gene encoding kexstatin I. We also demonstrate its enhanced activity and specificity for Kex2 proteinase inhibition by rational mutagenesis. The cloned kexstatin I gene encoded a protein of 145 amino acid residues, including the 35-residue signal sequence for secretion. The amino acid sequence showed 52% identity with those of the Streptomyces subtilisin inhibitors (SSIs). Thus kexstatin I is the first SSI-family member that can inhibit Kex2 proteinase. The reactive site of the inhibitor was determined to be -Thr(69)-Lys(70) downward arrowGlu(71)-, where downward arrow indicates the reactive site. Because Kex2 proteinase generally shows the highest affinity for substrates with basic amino acid residues at the P(1) and P(2) sites, conversion of the Thr(69)-Lys(70) segment of the inhibitor into dibasic motifs was expected to result in enhanced inhibitory activities. Thus we constructed kexstatin I mutants, in which the Thr(69)-Lys(70) sequence was replaced by the Thr(69)-Arg(70), Lys(69)-Lys(70) and Lys(69)-Arg(70) sequences using PCR-based mutagenesis, and analysed them kinetically. Among these mutants, the Lys(69)-Arg(70) mutant was the most potent inhibitor. The K(i) for Kex2 proteinase was 3.2x10(-10) M, which was 140-fold lower than that of the inhibitor with the Thr(69)-Lys(70) sequence. Although kexstatin I could also inhibit subtilisin, the enhancement of inhibitory activity upon such mutations was specific for Kex2 proteinase inhibition. PMID:11284720

  9. Bisphenol A Is More Potent than Phthalate Metabolites in Reducing Pancreatic β-Cell Function

    PubMed Central

    Weldingh, Nina Mickelson; Jørgensen-Kaur, Lena; Holme, Jørn A.

    2017-01-01

    Bisphenol A (BPA) and phthalates are common environmental contaminants that have been proposed to influence incidence and development of types 1 and 2 diabetes. Thus, effects of BPA and three phthalate metabolites (monoisobutyl phthalate (MiBP), mono-n-butyl phthalate (MnBP), and mono-(2-ethylhexyl) phthalate (MEHP)) were studied in the pancreatic β-cell line INS-1E, after 2–72 h of exposure to 5–500 μM. Three endpoints relevant to accelerated development of types 1 or 2 diabetes were investigated: β-cell viability, glucose-induced insulin secretion, and β-cell susceptibility to cytokine-induced cell death. BPA and the phthalate metabolites reduced cellular viability after 72 h of exposure, with BPA as the most potent chemical. Moreover, BPA, MEHP, and MnBP increased insulin secretion after 2 h of simultaneous exposure to chemicals and glucose, with potency BPA > MEHP > MnBP. Longer chemical exposures (24–72 h) showed no consistent effects on glucose-induced insulin secretion, and none of the environmental chemicals affected susceptibility to cytokine-induced cell death. Overall, BPA was more potent than the investigated phthalate metabolites in affecting insulin secretion and viability in the INS-1E pancreatic β-cells. In contrast to recent literature, concentrations with relevance to human exposures (1–500 nM) did not affect the investigated endpoints, suggesting that this experimental model displayed relatively low sensitivity to environmental chemical exposure. PMID:28286763

  10. SCR7 is neither a selective nor a potent inhibitor of human DNA ligase IV.

    PubMed

    Greco, George E; Matsumoto, Yoshihiro; Brooks, Rhys C; Lu, Zhengfei; Lieber, Michael R; Tomkinson, Alan E

    2016-07-01

    DNA ligases are attractive therapeutics because of their involvement in completing the repair of almost all types of DNA damage. A series of DNA ligase inhibitors with differing selectivity for the three human DNA ligases were identified using a structure-based approach with one of these inhibitors being used to inhibit abnormal DNA ligase IIIα-dependent repair of DNA double-strand breaks (DSB)s in breast cancer, neuroblastoma and leukemia cell lines. Raghavan and colleagues reported the characterization of a derivative of one of the previously identified DNA ligase inhibitors, which they called SCR7 (designated SCR7-R in our experiments using SCR7). SCR7 appeared to show increased selectivity for DNA ligase IV, inhibit the repair of DSBs by the DNA ligase IV-dependent non-homologous end-joining (NHEJ) pathway, reduce tumor growth, and increase the efficacy of DSB-inducing therapeutic modalities in mouse xenografts. In attempting to synthesize SCR7, we encountered problems with the synthesis procedures and discovered discrepancies in its reported structure. We determined the structure of a sample of SCR7 and a related compound, SCR7-G, that is the major product generated by the published synthesis procedure for SCR7. We also found that SCR7-G has the same structure as the compound (SCR7-X) available from a commercial vendor (XcessBio). The various SCR7 preparations had similar activity in DNA ligation assay assays, exhibiting greater activity against DNA ligases I and III than DNA ligase IV. Furthermore, SCR7-R failed to inhibit DNA ligase IV-dependent V(D)J recombination in a cell-based assay. Based on our results, we conclude that SCR7 and the SCR7 derivatives are neither selective nor potent inhibitors of DNA ligase IV.

  11. A Method to Obtain Auger Recombination Coefficient in an InGaN-Based Blue Light-Emitting Diode

    NASA Astrophysics Data System (ADS)

    Wang, Lai; Meng, Xiao; Song, Jung-Hoon; Kim, Tae-Soo; Lim, Seung-Young; Hao, Zhi-Biao; Luo, Yi; Sun, Chang-Zheng; Han, Yan-Jun; Xiong, Bing; Wang, Jian; Li, Hong-Tao

    2017-01-01

    Not Available Supported by the National Key Research and Development Program of China under Grant No 2016YFB0400102, the National Basic Research Program of China under Grant Nos 2012CB3155605, 2013CB632804, 2014CB340002 and 2015CB351900, the National Natural Science Foundation of China under Grant Nos 61574082, 61210014, 61321004, 61307024, and 51561165012, the High-Technology Research and Development Program of China under Grant No 2015AA017101, the Tsinghua University Initiative Scientific Research Program under Grant Nos 2013023Z09N and 2015THZ02-3, the Open Fund of the State Key Laboratory on Integrated Optoelectronics under Grant No IOSKL2015KF10, the CAEP Microsystem and THz Science and Technology Foundation under Grant No CAEPMT201505, the Science Challenge Project under Grant No JCKY2016212A503, and the Guangdong Province Science and Technology Program under Grant No 2014B010121004.

  12. Pseudopyronine B: A Potent Antimicrobial and Anticancer Molecule Isolated from a Pseudomonas mosselii

    PubMed Central

    Nishanth Kumar, S.; Aravind, S. R.; Jacob, Jubi; Gopinath, Geethu; Lankalapalli, Ravi S.; Sreelekha, T.T.; Dileep Kumar, B.S.

    2016-01-01

    In continuation of our search for new bioactive compounds from soil microbes, a fluorescent Pseudomonas strain isolated from paddy field soil of Kuttanad, Kerala, India was screened for the production of bioactive secondary metabolites. This strain was identified as Pseudomonas mosselii through 16S rDNA gene sequencing followed by BLAST analysis and the bioactive metabolites produced were purified by column chromatography (silica gel) and a pure bioactive secondary metabolite was isolated. This bioactive compound was identified as Pseudopyronine B by NMR and HR-ESI-MS. Pseudopyronine B recorded significant antimicrobial activity especially against Gram-positive bacteria and agriculturally important fungi. MTT assay was used for finding cell proliferation inhibition, and Pseudopyronine B recorded significant antitumor activity against non-small cell lung cancer cell (A549), and mouse melanoma cell (B16F10). The preliminary MTT assay results revealed that Pseudopyronine B recorded both dose- and time-dependent inhibition of the growth of test cancer cell lines. Pseudopyronine B induced apoptotic cell death in cancer cells as evidenced by Acridine orange/ethidium bromide and Hoechst staining, and this was further confirmed by flow cytometry analysis using Annexin V. Cell cycle analysis also supports apoptosis by inducing G2/M accumulation in both A549 and B16F10 cells. Pseudopyronine B treated cells recorded significant up-regulation of caspase 3 activity. Moreover, this compound recorded immunomodulatory activity by enhancing the proliferation of lymphocytes. The production of Pseudopyronine B by P. mosselii and its anticancer activity in A549 and B16F10 cell lines is reported here for the first time. The present study has a substantial influence on the information of Pseudopyronine B from P. mosselii as potential sources of novel drug molecule for the pharmaceutical companies, especially as potent antimicrobial and anticancer agent. PMID:27617005

  13. A novel vitamin D analog with two double bonds in its side chain. A potent inducer of osteoblastic cell differentiation.

    PubMed

    Mahonen, A; Jääskeläinen, T; Mäenpää, P H

    1996-04-12

    EB 1089 (1 alpha,25-dihydroxy-22,24-diene-24,26,27-trihomovitamin D3) is a novel, synthetic analog of calcitriol, characterized by two extra double bonds in its side chain. It is less potent than calcitriol in its calcemic action, but is an order of magnitude more potent in its antiproliferative action. The aim of this study was to determine the ability of EB 1089 to induce the well-known biological effects of calcitriol in MG-63 human osteosarcoma cells (i.e. by inhibiting cell proliferation and by induction of differentiation). Both calcitriol and EB 1089 significantly decreased cell growth after 2 days in culture. At 5 days, however, Eb 1089 was more potent than the natural hormone in inhibiting the proliferation of MG-63 cells. Potent effects of EB 1089 on cell differentiation were also seen in the stimulation of alkaline phosphatase activity, cellular vitamin D receptor mRNA levels, and medium osteocalcin synthesis. EB 1089 was clearly more effective than calcitriol in stimulating alkaline phosphatase activity and osteocalcin synthesis. In gel shift assays, the binding of vitamin D receptor to the composite AP-1 plus vitamin-D responsive promoter region of the human osteocalcin gene after EB 1089 treatment was stronger and longer-lasting than after calcitriol treatment.

  14. Potent Cells

    ERIC Educational Resources Information Center

    Liu, Dennis

    2007-01-01

    It seems hard to believe that Dolly the cloned sheep was born 10 years ago, kindling furious arguments over the prospects and ethics of cloning a human. Today, the controversy over cloning is entwined, often confused, with concerns over the use of human embryonic stem cells. Most people are unclear what cloning is, and they know even less when it…

  15. A lectin isolated from bananas is a potent inhibitor of HIV replication.

    PubMed

    Swanson, Michael D; Winter, Harry C; Goldstein, Irwin J; Markovitz, David M

    2010-03-19

    BanLec is a jacalin-related lectin isolated from the fruit of bananas, Musa acuminata. This lectin binds to high mannose carbohydrate structures, including those found on viruses containing glycosylated envelope proteins such as human immunodeficiency virus type-1 (HIV-1). Therefore, we hypothesized that BanLec might inhibit HIV-1 through binding of the glycosylated HIV-1 envelope protein, gp120. We determined that BanLec inhibits primary and laboratory-adapted HIV-1 isolates of different tropisms and subtypes. BanLec possesses potent anti-HIV activity, with IC(50) values in the low nanomolar to picomolar range. The mechanism for BanLec-mediated antiviral activity was investigated by determining if this lectin can directly bind the HIV-1 envelope protein and block entry of the virus into the cell. An enzyme-linked immunosorbent assay confirmed direct binding of BanLec to gp120 and indicated that BanLec can recognize the high mannose structures that are recognized by the monoclonal antibody 2G12. Furthermore, BanLec is able to block HIV-1 cellular entry as indicated by temperature-sensitive viral entry studies and by the decreased levels of the strong-stop product of early reverse transcription seen in the presence of BanLec. Thus, our data indicate that BanLec inhibits HIV-1 infection by binding to the glycosylated viral envelope and blocking cellular entry. The relative anti-HIV activity of BanLec compared favorably to other anti-HIV lectins, such as snowdrop lectin and Griffithsin, and to T-20 and maraviroc, two anti-HIV drugs currently in clinical use. Based on these results, BanLec is a potential component for an anti-viral microbicide that could be used to prevent the sexual transmission of HIV-1.

  16. Fenugreek, A Potent Hypoglycaemic Herb Can Cause Central Hypothyroidism Via Leptin - A Threat To Diabetes Phytotherapy.

    PubMed

    Majumdar, Jayjeet; Chakraborty, Pratip; Mitra, Analava; Sarkar, Nirmal Kumar; Sarkar, Supriti

    2017-04-13

    Fenugreek (Trigonella foenum graecum), a medicinal herb with potent antihyperglycaemic and hypoglycaemic effects, is used to treat diabetes. This study is aimed to explore the interaction of fenugreek seed extract (FSE) and HPT (hypothalamic-pituitary-thyroid) axis in context of leptin secretion which have important role in normal and type-1 diabetic subjects. FSE (confirmed to contain trigonelline, diosgenin, 4 hydroxyisoleucine) was gavaged (0.25 gm/kg body weight/day) to normal and alloxan-induced type-1 diabetic rats for 4 weeks. Expression of hypothalamic prepro-TRH (Thyrotropin releasing hormone) mRNA, serum levels of TRH, TSH (Thyroid stimulating hormone), fT3, fT4, insulin, leptin, glucose; thyroperoxidase activity and growth of thyroid gland, food intake, adiposity index were also studied FSE significantly down regulated prepro-TRH mRNA expression; decreased serum TRH, TSH, fT3, fT4 levels, and regressed thyroid gland in FSE-fed normal and diabetic rats than those observed in normal diet-fed control and diabetic rats. FSE decreased (p<0.005-0.001) adiposity index and leptin secretion, increased food intake and body weight in all FSE-fed rats. FSE improved insulin secretion, decreased glucose level but impaired HPT axis in diabetic rats, indicating insulin-independent central hypothyroidism. Results suggested that the dominant signal to hypothalamus suppressing HPT axis is the fall in leptin level which i resulted from decreased adiposity index following FSE feeding. Fenugreek simultaneously having hypoglycaemic and hypothyroidal actions raises questions whether it can be safely used to treat diabetes and/or hyperthyroidism as was suggested by many workers.

  17. Evaluation of the Transport, In Vitro Metabolism and Pharmacokinetics of Salvinorin A, a Potent Hallucinogen

    PubMed Central

    Teksin, Zeynep S.; Lee, Insong J.; Nemieboka, Noble N.; Othman, Ahmed A.; Upreti, Vijay V.; Hassan, Hazem E.; Syed, Shariq S.; Prisinzano, Thomas E.; Eddington, Natalie D.

    2009-01-01

    Salvinorin A is an unregulated potent hallucinogen isolated from the leaves of Salvia divinorum. It is the only known non-nitrogenous kappa-opioid selective agonist and rivals synthetic lysergic acid diethylamide (LSD) in potency. This objective of this study was to characterize the in vitro transport, in vitro metabolism, and pharmacokinetic properties of Salvinorin A. The transport characteristics of Salvinorin A were assessed using MDCK-MDR1 cell monolayers. The P-glycoprotein (P-gp) affinity status was assessed by the P-gp ATPase assay. In vitro metabolism studies were performed with various specific human CYP450 isoforms and UGT2B7 to assess the metabolic characteristics of Salvinorin A. Cohorts (n=3) of male Sprague Dawley rats were used to evaluate the pharmacokinetics and brain distribution of Salvinorin A (10 mg/kg, intraperitonal (i.p.) over a 240 min period. A validated UV-HPLC and LC/MS/MS method was used to quantify the hallucinogen concentrations obtained from the in vitro and in vivo studies, respectively. Salvinorin A displayed a high secretory transport in the MDCK-MDR1 cells (4.07±1.34 × 10-5 cm/s). Salvinorin A also stimulated the P-gp ATPase activity in a concentration (5-10 μm) dependent manner, suggesting that it may be a substrate of P-gp. A significant decrease in Salvinorin A concentration ranging from 14.7±0.80 % to 31.1±1.20 % was observed after incubation with CYP2D6, CYP1A1, CYP2C18, and CYP2E1, respectively. A significant decrease was also observed after incubation with UGT2B7. These results suggest that Salvinorin A may be a substrate of UGT2B7, CYP2D6, CYP1A1, CYP2E1 and CYP2C18. The in vivo pharmacokinetic study showed a relatively fast elimination with a half-life (t1/2) of 75 min and a clearance (Cl/F) of 26 L/h/kg. The distribution was extensive (Vd of 47.1 L/kg), however the brain to plasma ratio was 0.050. Accordingly, the brain half life was relatively short, 36 min. Salvinorin A is rapidly eliminated after i.p. dosing

  18. Evaluation of the transport, in vitro metabolism and pharmacokinetics of Salvinorin A, a potent hallucinogen.

    PubMed

    Teksin, Zeynep S; Lee, Insong J; Nemieboka, Noble N; Othman, Ahmed A; Upreti, Vijay V; Hassan, Hazem E; Syed, Shariq S; Prisinzano, Thomas E; Eddington, Natalie D

    2009-06-01

    Salvinorin A is an unregulated potent hallucinogen isolated from the leaves of Salvia divinorum. It is the only known non-nitrogenous kappa-opioid selective agonist, and rivals synthetic lysergic acid diethylamide (LSD) in potency. The objective of this study was to characterize the in vitro transport, in vitro metabolism, and pharmacokinetic properties of Salvinorin A. The transport characteristics of Salvinorin A were assessed using MDCK-MDR1 cell monolayers. The P-glycoprotein (P-gp) affinity status was assessed by the P-gp ATPase assay. In vitro metabolism studies were performed with various specific human CYP450 isoforms and UGT2B7 to assess the metabolic characteristics of Salvinorin A. Cohorts (n = 3) of male Sprague Dawley rats were used to evaluate the pharmacokinetics and brain distribution of Salvinorin A (10 mg/kg, intraperitoneal (i.p.) over a 240-min period. A validated UV-HPLC and LC/MS/MS method was used to quantify the hallucinogen concentrations obtained from the in vitro and in vivo studies, respectively. Salvinorin A displayed a high secretory transport in the MDCK-MDR1 cells (4.07 +/- 1.34 x 10(-)5 cm/s). Salvinorin A also stimulated the P-gp ATPase activity in a concentration (5 and 10 microM)-dependent manner, suggesting that it may be a substrate of (P-gp). A significant decrease in Salvinorin A concentration ranging from 14.7 +/- 0.80% to 31.1 +/- 1.20% was observed after incubation with CYP2D6, CYP1A1, CYP2C18, and CYP2E1, respectively. A significant decrease was also observed after incubation with UGT2B7. These results suggest that Salvinorin A maybe a substrate of UGT2B7, CYP2D6, CYP1A1, CYP2E1, and CYP2C18. The in vivo pharmacokinetic study showed a relatively fast elimination with a half-life (t1/2) of 75 min and a clearance (Cl/F) of 26 L/h/kg. The distribution was extensive (Vd of 47.1 L/kg); however, the brain to plasma ratio was 0.050. Accordingly, the brain half-life was relatively short, 36 min. Salvinorin A is rapidly eliminated

  19. The discovery of potent antitumor agent C11-deoxypsymberin/irciniastatin A: total synthesis and biology of advanced psymberin analogs.

    PubMed

    Huang, Xianhai; Shao, Ning; Huryk, Robert; Palani, Anandan; Aslanian, Robert; Seidel-Dugan, Cynthia

    2009-02-19

    Structure-activity relationship (SAR) studies by modification of the unsaturated side chain of potent anticancer marine natural product psymberin/irciniastatin A (1) suggest that substitution at C4 and C5 is important for the cytotoxicity of psymberin, but the terminal double bond is not essential for activity. An aryl group is a good replacement for the olefin. The total synthesis of structurally simplified C11-deoxypsymberin (29) was completed, and its activity is consistently more potent than the natural product which provides a unique opportunity for further SAR studies in the psymberin and pederin family. Preliminary mechanism studies suggest the mode of action of psymberin is through cell apoptosis.

  20. Novel phospholipase A2 inhibitors from python serum are potent peptide antibiotics.

    PubMed

    Samy, Ramar Perumal; Thwin, Maung Maung; Stiles, Brad G; Satyanarayana-Jois, Seetharama; Chinnathambi, Arunachalam; Zayed, M E; Alharbi, Sulaiman Ali; Siveen, Kodappully Sivaraman; Sikka, Sakshi; Kumar, Alan Prem; Sethi, Gautam; Lim, Lina Hsiu Kim

    2015-04-01

    Antimicrobial peptides (AMPs) play a vital role in defense against resistant bacteria. In this study, eight different AMPs synthesized from Python reticulatus serum protein were tested for bactericidal activity against various Gram-positive and Gram-negative bacteria (Staphylococcus aureus, Burkholderia pseudomallei (KHW and TES strains), and Proteus vulgaris) using a disc-diffusion method (20 μg/disc). Among the tested peptides, phospholipase A2 inhibitory peptide (PIP)-18[59-76], β-Asp65-PIP[59-67], D-Ala66-PNT.II, and D60,65E-PIP[59-67] displayed the most potent bactericidal activity against all tested pathogens in a dose-dependent manner (100-6.8 μg/ml), with a remarkable activity noted against S. aureus at 6.8 μg/ml dose within 6 h of incubation. Determination of minimum inhibitory concentrations (MICs) by a micro-broth dilution method at 100-3.125 μg/ml revealed that PIP-18[59-76], β-Asp65-PIP[59-67] and D-Ala66-PNT.II peptides exerted a potent inhibitory effect against S. aureus and B. pseudomallei (KHW) (MICs 3.125 μg/ml), while a much less inhibitory potency (MICs 12.5 μg/ml) was noted for β-Asp65-PIP[59-67] and D-Ala66-PNT.II peptides against B. pseudomallei (TES). Higher doses of peptides had no effect on the other two strains (i.e., Klebsiella pneumoniae and Streptococcus pneumoniae). Overall, PIP-18[59-76] possessed higher antimicrobial activity than that of chloramphenicol (CHL), ceftazidime (CF) and streptomycin (ST) (30 μg/disc). When the two most active peptides, PIP-18[59-76] and β-Asp65-PIP[59-67], were applied topically at a 150 mg/kg dose for testing wound healing activity in a mouse model of S. aureus infection, the former accelerates faster wound healing than the latter peptide at 14 days post-treatment. The western blot data suggest that the topical application of peptides (PIP-18[59-67] and β-Asp65-PIP[59-67]) modulates NF-kB mediated wound repair in mice with relatively little haemolytic (100-1.56 μg/ml) and cytotoxic (1000

  1. Otilonium: a potent blocker of neuronal nicotinic ACh receptors in bovine chromaffin cells.

    PubMed Central

    Gandía, L.; Villarroya, M.; Lara, B.; Olmos, V.; Gilabert, J. A.; López, M. G.; Martínez-Sierra, R.; Borges, R.; García, A. G.

    1996-01-01

    1. Otilonium, a clinically useful spasmolytic, behaves as a potent blocker of neuronal nicotinic acetylcholine receptors (AChR) as well as a mild wide-spectrum Ca2+ channel blocker in bovine adrenal chromaffin cells. 2. 45Ca2+ uptake into chromaffin cells stimulated with high K+ (70 mM, 1 min) was blocked by otilonium with an IC50 of 7.6 microM. The drug inhibited the 45Ca2+ uptake stimulated by the nicotinic AChR agonist, dimethylphenylpiperazinium (DMPP) with a 79 fold higher potency (IC50 = 0.096 microM). 3. Whole-cell Ba2+ currents (IBa) through Ca2+ channels of voltage-clamped chromaffin cells were blocked by otilonium with an IC50 of 6.4 microM, very close to that of K(+)-evoked 45Ca2+ uptake. Blockade developed in 10-20 s, almost as a single step and was rapidly and almost fully reversible. 4. Whole-cell nicotinic AChR-mediated currents (250 ms pulses of 100 microM DMPP) applied at 30 s intervals were blocked by otilonium in a concentration-dependent manner, showing an IC50 of 0.36 microM. Blockade was induced in a step-wise manner. Wash out of otilonium allowed a slow recovery of the current, also in discrete steps. 5. In experiments with recordings in the same cells of whole-cell IDMPP, Na+ currents (INa) and Ca2+ currents (ICa), 1 microM otilonium blocked 87% IDMPP, 7% INa and 13% ICa. 6. Otilonium inhibited the K(+)-evoked catecholamine secretory response of superfused bovine chromaffin cells with an IC50 of 10 microM, very close to the IC50 for blockade of K(+)-induced 45Ca2+ uptake and IBa. 7. Otilonium inhibited the secretory responses induced by 10 s pulses of 50 microM DMPP with an IC50 of 7.4 nM. Hexamethonium blocked the DMPP-evoked responses with an IC50 of 29.8 microM, 4,000 fold higher than that of otilonium. 8. In conclusion, otilonium is a potent blocker of nicotinic AChR-mediated responses. The drugs also blocked various subtypes of neuronal voltage-dependent Ca2+ channels at a considerably lower potency. Na+ channels were unaffected by

  2. Potent Anticancer Effects of Bioactive Mushroom Extracts (Phellinus linteus) on a Variety of Human Cancer Cells

    PubMed Central

    Konno, Sensuke; Chu, Kevin; Feuer, Nicholas; Phillips, John; Choudhury, Muhammad

    2015-01-01

    Background Although several therapeutic options are currently available for patients with various cancers, the outcomes are often disappointing and a more effective modality needs to be promptly established. We have been exploring an alternative approach using natural agents and two bioactive mushroom extracts isolated from Phellinus linteus (PL), namely PL-ES and PL-I-ES, were of our interest. As anticancer effects of similar extracts have been reported in several cancers, we investigated whether PL-ES and PL-I-ES might have such anticancer activities on a variety of human cancer cells in vitro. Methods Ten different types of human cancer cell lines, including three metastatic prostate, bladder, kidney, lung, breast, stomach, liver, and brain cancer cells, were employed and tested with PL-ES or PL-I-ES. Cell growth/viability, exertion of oxidative stress, and induction of apoptosis were assessed by MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide) assay, lipid peroxidation (LPO) assay, and specific enzymatic assay, respectively. Results PL-ES (100 µg/mL) exhibited potent anticancer activity, resulting in a significant (40-80%) growth reduction in all 10 cancer cells at 72 hours. PL-I-ES (100 µg/mL) was effective on only four cancer cells but its higher concentration at 250 µg/mL led to a significant (25-90%) growth reduction in seven cancer cells. LPO assays indicated that such a significant growth reduction by PL-ES (100 µg/mL) or PL-I-ES (100 or 250 µg/mL) could result from cell death due to a cytotoxic effect of oxidative stress (through free radicals). Moreover, enzymatic assays for caspase-3 (Csp-3) and caspase-9 (Csp-9), the pro-apoptotic regulators, showed that both enzymes were significantly activated by PL-ES or PL-I-ES, indicating that cell death due to oxidative stress was more likely associated with apoptosis. Conclusions The present study shows that both PL-ES and PL-I-ES indeed have anticancer effects on a variety of cancer

  3. Kappa opioid mediation of cannabinoid effects of the potent hallucinogen, salvinorin A, in rodents

    PubMed Central

    Walentiny, D. Matthew; Vann, Robert E.; Warner, Jonathan A.; King, Lindsey S.; Seltzman, Herbert H.; Navarro, Hernán A.; Twine, Charles E.; Thomas, Brian F.; Gilliam, Anne F.; Gilmour, Brian P.; Carroll, F. Ivy

    2010-01-01

    Rationale Salvinorin A, the primary psychoactive derivative of the hallucinogenic herb Salvia divinorum, is a potent and highly selective kappa-opioid receptor (KOR) agonist. Several recent studies, however, have suggested endocannabinoid system mediation of some of its effects. Objectives This study represents a systematic examination of this hypothesis. Methods Salvinorin A was isolated from S. divinorum and was evaluated in a battery of in vitro and in vivo procedures designed to detect cannabinoid activity, including CB1 receptor radioligand and [35S]GTPγS binding, calcium flux assay, in vivo cannabinoid screening tests, and drug discrimination. Results Salvinorin A did not bind to nor activate CB1 receptors. In vivo salvinorin A produced pronounced hypolocomotion and antinociception (and to a lesser extent, hypothermia). These effects were blocked by the selective KOR antagonist, JDTic, but not by the CB1 receptor antagonist rimonabant. Interestingly, however, rimonabant attenuated KOR activation stimulated by U69,593 in a [35S]GTPγS assay. Salvinorin A did not substitute for Δ9-tetrahydrocannabinol (THC) in mice trained to discriminate THC. Conclusions These findings suggest that similarities in the pharmacological effects of salvinorin A and those of cannabinoids are mediated by its activation of KOR rather than by any direct action of salvinorin A on the endocannabinoid system. Further, the results suggest that rimonabant reversal of salvinorin A effects in previous studies may be explained in part by rimonabant attenuation of KOR activation. PMID:20354680

  4. 5-Chloroindole: a potent allosteric modulator of the 5-HT3 receptor

    PubMed Central

    Newman, Amy S; Batis, Nikolaos; Grafton, Gillian; Caputo, Francesca; Brady, Catherine A; Lambert, Jeremy J; Peters, John A; Gordon, John; Brain, Keith L; Powell, Andrew D; Barnes, Nicholas M

    2013-01-01

    Background and Purpose The 5-HT3 receptor is a ligand-gated ion channel that is modulated allosterically by various compounds including colchicine, alcohols and volatile anaesthetics. However the positive allosteric modulators (PAMs) identified to date have low affinity, which hinders investigation because of non-selective effects at pharmacologically active concentrations. The present study identifies 5-chloroindole (Cl-indole) as a potent PAM of the 5-HT3 receptor. Experimental Approach 5-HT3 receptor function was assessed by the increase in intracellular calcium and single-cell electrophysiological recordings in HEK293 cells stably expressing the h5-HT3A receptor and also the mouse native 5-HT3 receptor that increases neuronal contraction of bladder smooth muscle. Key Results Cl-indole (1–100 μM) potentiated agonist (5-HT) and particularly partial agonist [(S)-zacopride, DDP733, RR210, quipazine, dopamine, 2-methyl-5-HT, SR57227A, meta chlorophenyl biguanide] induced h5-HT3A receptor-mediated responses. This effect of Cl-indole was also apparent at the mouse native 5-HT3 receptor. Radioligand-binding studies identified that Cl-indole induced a small (∼twofold) increase in the apparent affinity of 5-HT for the h5-HT3A receptor, whereas there was no effect upon the affinity of the antagonist, tropisetron. Cl-indole was able to reactivate desensitized 5-HT3 receptors. In contrast to its effect on the 5-HT3 receptor, Cl-indole did not alter human nicotinic α7 receptor responses. Conclusions and Implications The present study identifies Cl-indole as a relatively potent and selective PAM of the 5-HT3 receptor; such compounds will aid investigation of the molecular basis for allosteric modulation of the 5-HT3 receptor and may assist the discovery of novel therapeutic drugs targeting this receptor. Linked Articles Recent reviews on allosteric modulation can be found at: Kenakin, T (2013). New concepts in pharmacological efficacy at 7TM receptors: IUPHAR Review 2

  5. A novel highly potent therapeutic antibody neutralizes multiple human chemokines and mimics viral immune modulation.

    PubMed

    Scalley-Kim, Michelle L; Hess, Bruce W; Kelly, Ryan L; Krostag, Anne-Rachel F; Lustig, Kurt H; Marken, John S; Ovendale, Pamela J; Posey, Aaron R; Smolak, Pamela J; Taylor, Janelle D L; Wood, C L; Bienvenue, David L; Probst, Peter; Salmon, Ruth A; Allison, Daniel S; Foy, Teresa M; Raport, Carol J

    2012-01-01

    Chemokines play a key role in leukocyte recruitment during inflammation and are implicated in the pathogenesis of a number of autoimmune diseases. As such, inhibiting chemokine signaling has been of keen interest for the development of therapeutic agents. This endeavor, however, has been hampered due to complexities in the chemokine system. Many chemokines have been shown to signal through multiple receptors and, conversely, most chemokine receptors bind to more than one chemokine. One approach to overcoming this complexity is to develop a single therapeutic agent that binds and inactivates multiple chemokines, similar to an immune evasion strategy utilized by a number of viruses. Here, we describe the development and characterization of a novel therapeutic antibody that targets a subset of human CC chemokines, specifically CCL3, CCL4, and CCL5, involved in chronic inflammatory diseases. Using a sequential immunization approach, followed by humanization and phage display affinity maturation, a therapeutic antibody was developed that displays high binding affinity towards the three targeted chemokines. In vitro, this antibody potently inhibits chemotaxis and chemokine-mediated signaling through CCR1 and CCR5, primary chemokine receptors for the targeted chemokines. Furthermore, we have demonstrated in vivo efficacy of the antibody in a SCID-hu mouse model of skin leukocyte migration, thus confirming its potential as a novel therapeutic chemokine antagonist. We anticipate that this antibody will have broad therapeutic utility in the treatment of a number of autoimmune diseases due to its ability to simultaneously neutralize multiple chemokines implicated in disease pathogenesis.

  6. Acinetobacter baumannii Outer Membrane Vesicles Elicit a Potent Innate Immune Response via Membrane Proteins

    PubMed Central

    Jun, So Hyun; Lee, Jung Hwa; Kim, Bo Ra; Kim, Seung Il; Park, Tae In

    2013-01-01

    Acinetobacter baumannii is increasingly becoming a major nosocomial pathogen. This opportunistic pathogen secretes outer membrane vesicles (OMVs) that interact with host cells. The aim of this study was to investigate the ability of A. baumannii OMVs to elicit a pro-inflammatory response in vitro and the immunopathology in response to A. baumannii OMVs in vivo. OMVs derived from A. baumannii ATCC 19606T induced expression of pro-inflammatory cytokine genes, interleukin (IL)-1β and IL-6, and chemokine genes, IL-8, macrophage inflammatory protein-1α, and monocyte chemoattractant protein-1, in epithelial cells in a dose-dependent manner. Disintegration of OMV membrane with ethylenediaminetetraacetic acid resulted in low expression of pro-inflammatory cytokine genes, as compared with the response to intact OMVs. In addition, proteinase K-treated A. baumannii OMVs did not induce significant increase in expression of pro-inflammatory cytokine genes above the basal level, suggesting that the surface-exposed membrane proteins in intact OMVs are responsible for pro-inflammatory response. Early inflammatory processes, such as vacuolization and detachment of epithelial cells and neutrophilic infiltration, were clearly observed in lungs of mice injected with A. baumannii OMVs. Our data demonstrate that OMVs produced by A. baumannii elicit a potent innate immune response, which may contribute to immunopathology of the infected host. PMID:23977136

  7. Discovery of a potent, selective, and orally bioavailable pyridinyl-pyrimidine phthalazine aurora kinase inhibitor.

    PubMed

    Cee, Victor J; Schenkel, Laurie B; Hodous, Brian L; Deak, Holly L; Nguyen, Hanh N; Olivieri, Philip R; Romero, Karina; Bak, Annette; Be, Xuhai; Bellon, Steve; Bush, Tammy L; Cheng, Alan C; Chung, Grace; Coats, Steve; Eden, Patrick M; Hanestad, Kelly; Gallant, Paul L; Gu, Yan; Huang, Xin; Kendall, Richard L; Lin, Min-Hwa Jasmine; Morrison, Michael J; Patel, Vinod F; Radinsky, Robert; Rose, Paul E; Ross, Sandra; Sun, Ji-Rong; Tang, Jin; Zhao, Huilin; Payton, Marc; Geuns-Meyer, Stephanie D

    2010-09-09

    The discovery of aurora kinases as essential regulators of cell division has led to intense interest in identifying small molecule aurora kinase inhibitors for the potential treatment of cancer. A high-throughput screening effort identified pyridinyl-pyrimidine 6a as a moderately potent dual inhibitor of aurora kinases -A and -B. Optimization of this hit resulted in an anthranilamide lead (6j) that possessed improved enzyme and cellular activity and exhibited a high level of kinase selectivity. However, this anthranilamide and subsequent analogues suffered from a lack of oral bioavailability. Converting the internally hydrogen-bonded six-membered pseudo-ring of the anthranilamide to a phthalazine (8a-b) led to a dramatic improvement in oral bioavailability (38-61%F) while maintaining the potency and selectivity characteristics of the anthranilamide series. In a COLO 205 tumor pharmacodynamic assay measuring phosphorylation of the aurora-B substrate histone H3 at serine 10 (p-histone H3), oral administration of 8b at 50 mg/kg demonstrated significant reduction in tumor p-histone H3 for at least 6 h.

  8. Characterization of the biological activity of a potent small molecule Hec1 inhibitor TAI-1

    PubMed Central

    2014-01-01

    Background Hec1 (NDC80) is an integral part of the kinetochore and is overexpressed in a variety of human cancers, making it an attractive molecular target for the design of novel anticancer therapeutics. A highly potent first-in-class compound targeting Hec1, TAI-1, was identified and is characterized in this study to determine its potential as an anticancer agent for clinical utility. Methods The in vitro potency, cancer cell specificity, synergy activity, and markers for response of TAI-1 were evaluated with cell lines. Mechanism of action was confirmed with western blotting and immunofluorescent staining. The in vivo potency of TAI-1 was evaluated in three xenograft models in mice. Preliminary toxicity was evaluated in mice. Specificity to the target was tested with a kinase panel. Cardiac safety was evaluated with hERG assay. Clinical correlation was performed with human gene database. Results TAI-1 showed strong potency across a broad spectrum of tumor cells. TAI-1 disrupted Hec1-Nek2 protein interaction, led to Nek2 degradation, induced significant chromosomal misalignment in metaphase, and induced apoptotic cell death. TAI-1 was effective orally in in vivo animal models of triple negative breast cancer, colon cancer and liver cancer. Preliminary toxicity shows no effect on the body weights, organ weights, and blood indices at efficacious doses. TAI-1 shows high specificity to cancer cells and to target and had no effect on the cardiac channel hERG. TAI-1 is synergistic with doxorubicin, topotecan and paclitaxel in leukemia, breast and liver cancer cells. Sensitivity to TAI-1 was associated with the status of RB and P53 gene. Knockdown of RB and P53 in cancer cells increased sensitivity to TAI-1. Hec1-overexpressing molecular subtypes of human lung cancer were identified. Conclusions The excellent potency, safety and synergistic profiles of this potent first-in-class Hec1-targeted small molecule TAI-1 show its potential for clinically utility in anti

  9. Receptor-DNA binding to target auger electrons for cancer therapy. Final report, August 1, 1993--January 31, 1997

    SciTech Connect

    DeSombre, E.R.

    1997-05-01

    The goal of this program was to investigate the principle of receptor-DNA binding as a means to target Auger electron radiation for cancer therapy, and thereby to evaluate the potential of non-covalent, high-affinity, Auger electron-emitting ligands binding to a DNA associated molecule, or DNA itself, for cancer therapy. These studies were intended to assess the ability of Auger-emitting estrogens to kill estrogen receptor-positive tumor cells, determine the mean lethal dose, and determine whether they could be effective in vitro and in vivo.

  10. Biomimetic Design Results in a Potent Allosteric Inhibitor of Dihydrodipicolinate Synthase from Campylobacter jejuni.

    PubMed

    Skovpen, Yulia V; Conly, Cuylar J T; Sanders, David A R; Palmer, David R J

    2016-02-17

    Dihydrodipicolinate synthase (DHDPS), an enzyme required for bacterial peptidoglycan biosynthesis, catalyzes the condensation of pyruvate and β-aspartate semialdehyde (ASA) to form a cyclic product which dehydrates to form dihydrodipicolinate. DHDPS has, for several years, been considered a putative target for novel antibiotics. We have designed the first potent inhibitor of this enzyme by mimicking its natural allosteric regulation by lysine, and obtained a crystal structure of the protein-inhibitor complex at 2.2 Å resolution. This novel inhibitor, which we named "bislysine", resembles two lysine molecules linked by an ethylene bridge between the α-carbon atoms. Bislysine is a mixed partial inhibitor with respect to the first substrate, pyruvate, and a noncompetitive partial inhibitor with respect to ASA, and binds to all forms of the enzyme with a Ki near 200 nM, more than 300 times more tightly than lysine. Hill plots show that the inhibition is cooperative, indicating that the allosteric sites are not independent despite being located on opposite sides of the protein tetramer, separated by approximately 50 Å. A mutant enzyme resistant to lysine inhibition, Y110F, is strongly inhibited by this novel inhibitor, suggesting this may be a promising strategy for antibiotic development.

  11. Discovery of Pyrazolo[1,5-a]pyrimidine TTK Inhibitors: CFI-402257 is a Potent, Selective, Bioavailable Anticancer Agent.

    PubMed

    Liu, Yong; Laufer, Radoslaw; Patel, Narendra Kumar; Ng, Grace; Sampson, Peter B; Li, Sze-Wan; Lang, Yunhui; Feher, Miklos; Brokx, Richard; Beletskaya, Irina; Hodgson, Richard; Plotnikova, Olga; Awrey, Donald E; Qiu, Wei; Chirgadze, Nickolay Y; Mason, Jacqueline M; Wei, Xin; Lin, Dan Chi-Chia; Che, Yi; Kiarash, Reza; Fletcher, Graham C; Mak, Tak W; Bray, Mark R; Pauls, Henry W

    2016-07-14

    This work describes a scaffold hopping exercise that begins with known imidazo[1,2-a]pyrazines, briefly explores pyrazolo[1,5-a][1,3,5]triazines, and ultimately yields pyrazolo[1,5-a]pyrimidines as a novel class of potent TTK inhibitors. An X-ray structure of a representative compound is consistent with 1(1)/2 type inhibition and provides structural insight to aid subsequent optimization of in vitro activity and physicochemical and pharmacokinetic properties. Incorporation of polar moieties in the hydrophobic and solvent accessible regions modulates physicochemical properties while maintaining potency. Compounds with enhanced oral exposure were identified for xenograft studies. The work culminates in the identification of a potent (TTK K i = 0.1 nM), highly selective, orally bioavailable anticancer agent (CFI-402257) for IND enabling studies.

  12. Acetal-linked paclitaxel prodrug micellar nanoparticles as a versatile and potent platform for cancer therapy.

    PubMed

    Gu, Yudan; Zhong, Yinan; Meng, Fenghua; Cheng, Ru; Deng, Chao; Zhong, Zhiyuan

    2013-08-12

    Endosomal pH-activatable paclitaxel (PTX) prodrug micellar nanoparticles were designed and prepared by conjugating PTX onto water-soluble poly(ethylene glycol)-b-poly(acrylic acid) (PEG-PAA) block copolymers via an acid-labile acetal bond to the PAA block and investigated for potent growth inhibition of human cancer cells in vitro. PTX was readily conjugated to PEG-PAA with high drug contents of 21.6, 27.0, and 42.8 wt % (denoted as PTX prodrugs 1, 2, and 3, respectively) using ethyl glycol vinyl ether (EGVE) as a linker. The resulting PTX conjugates had defined molecular weights and self-assembled in phosphate buffer (PB, pH 7.4, 10 mM) into monodisperse micellar nanoparticles with average sizes of 158.3-180.3 nm depending on PTX contents. The in vitro release studies showed that drug release from PTX prodrug nanoparticles was highly pH-dependent, in which ca. 86.9%, 66.4% and 29.0% of PTX was released from PTX prodrug 3 at 37 °C in 48 h at pH 5.0, 6.0, and pH 7.4, respectively. MTT assays showed that these pH-sensitive PTX prodrug nanoparticles exhibited high antitumor effect to KB and HeLa cells (IC(50) = 0.18 and 0.9 μg PTX equiv/mL, respectively) as well as PTX-resistant A549 cells. Notably, folate-decorated PTX prodrug micellar nanoparticles based on PTX prodrug 3 and 20 wt % folate-poly(ethylene glycol)-b-poly(D,L-lactide) (FA-PEG-PLA) displayed apparent targetability to folate receptor-overexpressing KB cells with IC(50) over 12 times lower than nontargeting PTX prodrug 3 under otherwise the same conditions. Furthermore, PTX prodrug nanoparticles could also load doxorubicin (DOX) to simultaneously release PTX and DOX under mildly acidic pH. These acetal-linked PTX prodrug micellar nanoparticles have appeared as a highly versatile and potent platform for cancer therapy.

  13. Discovery of potent and selective sirtuin 2 (SIRT2) inhibitors using a fragment-based approach.

    PubMed

    Cui, Huaqing; Kamal, Zeeshan; Ai, Teng; Xu, Yanli; More, Swati S; Wilson, Daniel J; Chen, Liqiang

    2014-10-23

    Sirtuin 2 (SIRT2) is one of the sirtuins, a family of NAD(+)-dependent deacetylases that act on a variety of histone and non-histone substrates. Accumulating biological functions and potential therapeutic applications have drawn interest in the discovery and development of SIRT2 inhibitors. Herein we report our discovery of novel SIRT2 inhibitors using a fragment-based approach. Inspired by the purported close binding proximity of suramin and nicotinamide, we prepared two sets of fragments, namely, the naphthylamide sulfonic acids and the naphthalene-benzamides and -nicotinamides. Biochemical evaluation of these two series provided structure-activity relationship (SAR) information, which led to the design of (5-benzamidonaphthalen-1/2-yloxy)nicotinamide derivatives. Among these inhibitors, one compound exhibited high anti-SIRT2 activity (48 nM) and excellent selectivity for SIRT2 over SIRT1 and SIRT3. In vitro, it also increased the acetylation level of α-tubulin, a well-established SIRT2 substrate, in both concentration- and time-dependent manners. Further kinetic studies revealed that this compound behaves as a competitive inhibitor against the peptide substrate and most likely as a noncompetitive inhibitor against NAD(+). Taken together, these results indicate that we have discovered a potent and selective SIRT2 inhibitor whose novel structure merits further exploration.

  14. Fellutamide B is a Potent Inhibitor of the Mycobacterium tuberculosis Proteasome

    SciTech Connect

    Lin, G.; Li, D; Chidawanyika, T; Nathan, C; Li, H

    2010-01-01

    Via high-throughput screening of a natural compound library, we have identified a lipopeptide aldehyde, fellutamide B (1), as the most potent inhibitor of the Mycobacterium tuberculosis (Mtb) proteasome tested to date. Kinetic studies reveal that 1 inhibits both Mtb and human proteasomes in a time-dependent manner under steady-state condition. Remarkably, 1 inhibits the Mtb proteasome in a single-step binding mechanism with K{sub i} = 6.8 nM, whereas it inhibits the human proteasome {beta}5 active site following a two-step mechanism with K{sub i} = 11.5 nM and K*{sub i} = 0.93 nM. Co-crystallization of 1 bound to the Mtb proteasome revealed a structural basis for the tight binding of 1 to the active sites of the Mtb proteasome. The hemiacetal group of 1 in the Mtb proteasome takes the (R)-configuration, whereas in the yeast proteasome it takes the (S)-configuration, indicating that the pre-chiral CHO group of 1 binds to the active site Thr1 in a different orientation. Re-examination of the structure of the yeast proteasome in complex with 1 showed significant conformational changes at the substrate-binding cleft along the active site. These structural differences are consistent with the different kinetic mechanisms of 1 against Mtb and human proteasomes.

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

    PubMed

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

    2017-01-03

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

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

    PubMed Central

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

    2017-01-01

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

  17. The EDLL motif: a potent plant transcriptional activation domain from AP2/ERF transcription factors.

    PubMed

    Tiwari, Shiv B; Belachew, Alemu; Ma, Siu Fong; Young, Melinda; Ade, Jules; Shen, Yu; Marion, Colleen M; Holtan, Hans E; Bailey, Adina; Stone, Jeffrey K; Edwards, Leslie; Wallace, Andreah D; Canales, Roger D; Adam, Luc; Ratcliffe, Oliver J; Repetti, Peter P

    2012-06-01

    In plants, the ERF/EREBP family of transcriptional regulators plays a key role in adaptation to various biotic and abiotic stresses. These proteins contain a conserved AP2 DNA-binding domain and several uncharacterized motifs. Here, we describe a short motif, termed 'EDLL', that is present in AtERF98/TDR1 and other clade members from the same AP2 sub-family. We show that the EDLL motif, which has a unique arrangement of acidic amino acids and hydrophobic leucines, functions as a strong activation domain. The motif is transferable to other proteins, and is active at both proximal and distal positions of target promoters. As such, the EDLL motif is able to partly overcome the repression conferred by the AtHB2 transcription factor, which contains an ERF-associated amphiphilic repression (EAR) motif. We further examined the activation potential of EDLL by analysis of the regulation of flowering time by NF-Y (nuclear factor Y) proteins. Genetic evidence indicates that NF-Y protein complexes potentiate the action of CONSTANS in regulation of flowering in Arabidopsis; we show that the transcriptional activation function of CONSTANS can be substituted by direct fusion of the EDLL activation motif to NF-YB subunits. The EDLL motif represents a potent plant activation domain that can be used as a tool to confer transcriptional activation potential to heterologous DNA-binding proteins.

  18. A potent synthetic inorganic antibiotic with activity against drug-resistant pathogens.

    PubMed

    Hubick, Shelby; Jayaraman, Arumugam; McKeen, Alexander; Reid, Shelby; Alcorn, Jane; Stavrinides, John; Sterenberg, Brian T

    2017-02-06

    The acronymously named "ESKAPE" pathogens represent a group of bacteria that continue to pose a serious threat to human health, not only due to their propensity for repeated emergence, but also due to their ability to "eskape" antibiotic treatment. The evolution of multi-drug resistance in these pathogens alone has greatly outpaced the development of new therapeutics, necessitating an alternative strategy for antibiotic development that considers the evolutionary mechanisms driving antibiotic resistance. In this study, we synthesize a novel inorganic antibiotic, phosphopyricin, which has antibiotic activity against the Gram-positive methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VRE). We show that this potent antibiotic is bactericidal, and exhibits low toxicity in an acute dose assay in mice. As a synthetic compound that does not occur naturally, phosphopyricin would be evolutionarily foreign to microbes, thereby slowing the evolution of resistance. In addition, it loses antibiotic activity upon exposure to light, meaning that the active antibiotic will not accumulate in the general environment where strong selective pressures imposed by antibiotic residuals are known to accelerate resistance. Phosphopyricin represents an innovation in antimicrobials, having a synthetic core, and a photosensitive chemical architecture that would reduce accumulation in the environment.

  19. A potent antibrowning agent from pine needles of Cedrus deodara: 2R,3R-dihydromyricetin.

    PubMed

    Liang, Xue; Wu, Yan-Ping; Qiu, Jing-Hong; Zhong, Kai; Gao, Hong

    2014-09-01

    This article focuses on finding the novel antibrowning agents from the pine needles of Cedrus deodara and studying its antibrowning effect. By bioassay guide of tyrosinase inhibitory activity, the main active compound was isolated and purified from 50% methanol extract of pine needles of C. deodara through macroporous resin Diaion HP-20 column chromatography and high-performance liquid chromatography. Based on mass and nuclear magnetic resonance data, the active compound was identified as 2R,3R-dihydromyricetin, which showed the potent monophenolase and diphenolase inhibitory activities. Moreover, 2R,3R-dihydromyricetin exhibited a strong ABTS radical scavenging activity with a dose-dependent manner. The antibrowning efficacy of 2R,3R-dihydromyricetin was evaluated by monitoring the changes of L*, a*, and b* values and total color difference (△E) on fresh-cut apple slices. It was found that 2R,3R-dihydromyricetin was effective in inhibiting the browning of apple slices treated with a concentration as low as 0.05% at 25 °C for 24 h. Its antibrowning effect was significantly better than ascorbic acid (0.5%) alone. Furthermore, 2R,3R-dihydromyricetin showed a good synergistic antibrowning effect with ascorbic acid. This is the first report that 2R,3R-dihydromyricetin from pine needles of C. deodara may be used as a potential antibrowning agent in protecting against food browning.

  20. Thiazole: a promising heterocycle for the development of potent CNS active agents.

    PubMed

    Mishra, Chandra Bhushan; Kumari, Shikha; Tiwari, Manisha

    2015-03-06

    Thiazole is a valuable scaffold in the field of medicinal chemistry and has accounted to display a variety of biological activities. Thiazole and its derivatives have attracted continuing interest to design various novel CNS active agents. In the past few decades, thiazoles have been widely used to develop a variety of therapeutic agents against numerous CNS targets. Thiazole containing drug molecules are currently being used in treatment of various CNS disorders and a number of thiazole derivatives are also presently in clinical trials. A lot of research has been carried out on thiazole and their analogues, which has proved their efficacy to overcome several CNS disorders in rodent as well as primate models. The aim of present review is to highlights diverse CNS activities displayed by thiazole and their derivatives. SAR of this nucleus has also been well discussed. This review covers the recent updates present in literature and will surely provide a greater insight for the designing and development of potent thiazole based CNS active agents in future.

  1. Insulin-like growth factor I/somatomedin C: a potent inducer of oligodendrocyte development

    SciTech Connect

    McMorris, F.A.; Smith, T.M.; DeSalvo, S.; Furlanetto, R.W.

    1986-02-01

    Cell cultures established from cerebrum of 1-day-old rats were used to investigate hormonal regulation of the development of oligodendrocytes, which synthesize myelin in the central nervous system. The number of oligodendrocytes that developed was preferentially increased by insulin, or by insulin-like growth factor I (IGF-I), also known as somatomedin C. High concentrations of insulin were required for substantial induction of oligodendrocyte development, whereas only 3.3 ng of IGF-I per ml was needed for a 2-fold increase in oligodendrocyte numbers. At an IGF-I concentration of 100 ng/ml, oligodendrocyte numbers were increased 6-fold in cultures grown in the presence of 10% fetal bovine serum, or up to 60-fold in cultures maintained in serum-free medium. IGF-I produced less than a 2-fold increase in the number of nonoligodendroglial cells in the same cultures. Type I IGF receptors were identified on oligodendrocytes and on a putative oligodendrocyte precursor cell population identified by using mouse monoclonal antibody A2B5. Radioligand binding assays were done. These results indicate that IGF-I is a potent inducer of oligodendrocyte development and suggest a possible mechanism based on IGF deficiency for the hypomyelination that results from early postnatal malnutrition.

  2. A potent synthetic inorganic antibiotic with activity against drug-resistant pathogens

    PubMed Central

    Hubick, Shelby; Jayaraman, Arumugam; McKeen, Alexander; Reid, Shelby; Alcorn, Jane; Stavrinides, John; Sterenberg, Brian T.

    2017-01-01

    The acronymously named “ESKAPE” pathogens represent a group of bacteria that continue to pose a serious threat to human health, not only due to their propensity for repeated emergence, but also due to their ability to “eskape” antibiotic treatment12. The evolution of multi-drug resistance in these pathogens alone has greatly outpaced the development of new therapeutics, necessitating an alternative strategy for antibiotic development that considers the evolutionary mechanisms driving antibiotic resistance. In this study, we synthesize a novel inorganic antibiotic, phosphopyricin, which has antibiotic activity against the Gram-positive methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VRE). We show that this potent antibiotic is bactericidal, and exhibits low toxicity in an acute dose assay in mice. As a synthetic compound that does not occur naturally, phosphopyricin would be evolutionarily foreign to microbes, thereby slowing the evolution of resistance. In addition, it loses antibiotic activity upon exposure to light, meaning that the active antibiotic will not accumulate in the general environment where strong selective pressures imposed by antibiotic residuals are known to accelerate resistance. Phosphopyricin represents an innovation in antimicrobials, having a synthetic core, and a photosensitive chemical architecture that would reduce accumulation in the environment. PMID:28165020

  3. 45-Day safety screening for Tank 241-B-102 auger samples, riser 1

    SciTech Connect

    Bell, K.E.

    1994-12-01

    This is the 45-Day report for the fiscal year 1994 Tank 241-B-102 auger sampling characterization effort. Only one of the two planned auger samples was received by the 222-S Laboratory, however it was decided to begin the 45-day clock and issue a report based on receipt of the first auger sample. Included are copies of the differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) scans as requested. Also included is a copy of any immediate notification documentation, chain of custody forms, the hot cell work plan, extruded segment [auger] description sheets, and total alpha data. The TGA percent moisture results are below the safety criteria limit of 17% in a subsample taken approximately five minutes after extrusion and a second subsample taken from the lower half of the auger. Verbal and written notifications were made as prescribed. The DSC analysis of all subsamples indicates the presence of fraction exotherms, however the results are a factor of two or more below the notification limit of 523 Joules/gram (J/g). Total alpha results are all below the detection limit. In some cases, the tank characterization plan (TCP) accuracy and precision criteria are not met. If a re-run was not performed when a TCP quality control limit was not met, then reasons for not performing the re-run are provided.

  4. Auger decay and subsequent fragmentation pathways of ethylene following K -shell ionization

    NASA Astrophysics Data System (ADS)

    Gaire, B.; Haxton, D. J.; Sturm, F. P.; Williams, J.; Gatton, A.; Bocharova, I.; Gehrken, N.; Schöffler, M.; Gassert, H.; Zeller, S.; Voigtsberger, J.; Jahnke, T.; Zohrabi, M.; Reedy, D.; Nook, C.; Landers, A. L.; Belkacem, A.; Cocke, C. L.; Ben-Itzhak, I.; Dörner, R.; Weber, Th.

    2015-07-01

    The fragmentation pathways and dynamics of ethylene molecules after core ionization are explored using coincident measurements of the Auger electron and fragment ions by employing the cold target recoil-ion momentum spectroscopy method. The influence of several factors on the dynamics and kinematics of the dissociation is studied. These include propensity rules, ionization mechanisms, symmetry of the orbitals from which the Auger electrons originate, multiple scattering, conical intersections, interference, and possible core-hole localization for the double ionization of this polyatomic molecule. Energy correlation maps allow probing the multidimensional potential energy surfaces and, in combination with our multiconfiguration self-consistent field calculations, identifying the populated electronic states of the dissociating dication. The measured angular distributions of the Auger electrons in the molecular frame further support and augment these assignments. The deprotonation and molecular hydrogen ion elimination channels show a nearly isotropic Auger electron angular distribution with a small elongation along the direction perpendicular to the molecular axis. For the symmetric breakup the angular distributions show a clear influence of multiple scattering on the outgoing electrons. The lowest kinetic energy release feature of the symmetric breakup channel displays a fingerprint of entangled Auger and photoelectron motion in the angular emission pattern identifying this transition as an excellent candidate to probe core-hole localization at a conical intersection of a polyatomic molecule.

  5. Poly[di(carboxylatophenoxy)phosphazene] is a potent adjuvant for intradermal immunization

    PubMed Central

    Andrianov, Alexander K.; DeCollibus, Daniel P.; Gillis, Helice A.; Kha, Henry H.; Marin, Alexander; Prausnitz, Mark R.; Babiuk, Lorne A.; Townsend, Hugh; Mutwiri, George

    2009-01-01

    Intradermal immunization using microfabricated needles represents a potentially powerful technology, which can enhance immune responses and provide antigen sparing. Solid vaccine formulations, which can be coated onto microneedle patches suitable for simple administration, can also potentially offer improved shelf-life. However the approach is not fully compatible with many vaccine adjuvants including alum, the most common adjuvant used in the vaccine market globally. Here, we introduce a polyphosphazene immuno adjuvant as a biologically potent and synergistic constituent of microneedle-based intradermal immunization technology. Poly[di(carboxylatophenoxy)phosphazene], PCPP, functions both as a vaccine adjuvant and as a key microfabrication material. When used as part of an intradermal delivery system for hepatitis B surface antigen, PCPP demonstrates superior activity in pigs compared to intramascular administration and significant antigen sparing potential. It also accelerates the microneedle fabrication process and reduces its dependence on the use of surfactants. In this way, PCPP-coated microneedles may enable effective intradermal vaccination from an adjuvanted patch delivery system. PMID:19864632

  6. A ceramic drug delivery vehicle for oral administration of highly potent opioids.

    PubMed

    Forsgren, Johan; Jämstorp, Erik; Bredenberg, Susanne; Engqvist, Håkan; Strømme, Maria

    2010-01-01

    Pellets composed of the ceramic material Halloysite and microcrystalline cellulose were synthesized with the aim of producing a drug delivery vehicle for sustained release of the opioid Fentanyl with low risk for dose dumping at oral intake of the highly potent drug. Drug release profiles of intact and crushed pellets, to simulate swallowing without or with chewing, in pH 6.8, pH 1, and in 48% ethanol were recorded in order to replicate the conditions in the small intestines, in the stomach, as well as cointake of the drug with alcohol. The drug release was analyzed by employing the Weibull equation, which showed that the release profiles were either governed by fickian diffusion (intact pellets in pH 6.8 and in ethanol) or by diffusion in a fractal or disordered pore network (intact pellets in pH 1 and crushed pellets in all solutions). A sustained release for approximately 3-4 h was obtained in all studied solutions from intact pellets, whereas crushed pellets released the drug content during approximately 2-3 h. The finding that a sustained release profile could be obtained both in alcohol and after crushing of the pellets, shows that the ceramic carrier under investigation, at least to some extent, hampers dose dumping, and may thus be a promising material in future developments of new opioid containing oral dosage forms.

  7. Contact sensitizer 2,4-dinitrochlorobenzene is a highly potent human TRPA1 agonist.

    PubMed

    Saarnilehto, M; Chapman, H; Savinko, T; Lindstedt, K; Lauerma, A I; Koivisto, A

    2014-10-01

    2,4-Dinitrochlorobenzene (DNCB) is widely used in human clinical studies and in experimental animal studies to evoke allergic contact dermatitis. 2,4-Dinitrochlorobenzene is a potent immunogen capable of inducing contact sensitization in all humans exposed. However, the mechanism by which DNCB evokes such symptoms is presently unknown. TRPA1 is a nonselective cation channel that is expressed in peptidergic sensory neurons and fibroblasts. TRPA1 activation was recently implicated in the pathophysiology of atopic dermatitis especially in transducing cutaneous itch signals. Here, we test the hypothesis that DNCB acts as a TRPA1 agonist and thereby evokes allergic symptoms. We found that DNCB activates human TRPA1 dose dependently in FLIPR experiments with an EC50 of 167 nM, an effect that was fully blocked by selective TRPA1 antagonists Chembridge-5861528 and A-967079. Similarly, DNCB activated nonselective TRPA1 current in patch clamp studies. Neutralization of 3 critical cysteines in TRPA1 resulted in a loss of DNCB agonism.

  8. Design, synthesis, and structure-activity relationship studies of a potent PACE4 inhibitor.

    PubMed

    Kwiatkowska, Anna; Couture, Frédéric; Levesque, Christine; Ly, Kévin; Desjardins, Roxane; Beauchemin, Sophie; Prahl, Adam; Lammek, Bernard; Neugebauer, Witold; Dory, Yves L; Day, Robert

    2014-01-09

    PACE4 plays an important role in the progression of prostate cancer and is an attractive target for the development of novel inhibitor-based tumor therapies. We previously reported the design and synthesis of a novel, potent, and relatively selective PACE4 inhibitor known as a Multi-Leu (ML) peptide. In the present work, we examined the ML peptide through detailed structure-activity relationship studies. A variety of ML-peptide analogues modified at the P8-P5 positions with leucine isomers (Nle, DLeu, and DNle) or substituted at the P1 position with arginine mimetics were tested for their inhibitory activity, specificity, stability, and antiproliferative effect. By incorporating d isomers at the P8 position or a decarboxylated arginine mimetic, we obtained analogues with an improved stability profile and excellent antiproliferative properties. The DLeu or DNle residue also has improved specificity toward PACE4, whereas specificity was reduced for a peptide modified with the arginine mimetic, such as 4-amidinobenzylamide.

  9. IPD-196, a novel phosphatidylinositol 3-kinase inhibitor with potent anticancer activity against hepatocellular carcinoma.

    PubMed

    Lee, Ju-Hee; Lee, Hyunseung; Yun, Sun-Mi; Jung, Kyung Hee; Jeong, Yujeong; Yan, Hong Hua; Hong, Sungwoo; Hong, Soon-Sun

    2013-02-01

    As the activation of phosphatidylinositol 3-kinase (PI3K) is associated with a wide variety of human malignancies, it is emerging as an attractive target for cancer treatment. In this study we synthesized a novel PI3Kα inhibitor, IPD-196 [ethyl 6-(5-(2,4-difluorophenylsulfonamido)pyridin-3-yl)imidazo[1,2-a]pyridine-3-carboxylate], and evaluated its anticancer effects on human hepatocellular carcinoma (HCC) cells. IPD-196 effectively inhibited the phosphorylation of downstream PI3K effectors such as Akt, mTOR, p70S6K, and 4E-BP1, and its antiproliferative effect was more potent than that of sorafenib or LY294002. It also induced cell cycle arrest at the G0/G1 phase as well as apoptosis by increasing the proportion of sub-G1 apoptotic cells, and the levels of cleaved PARP, caspase-3, and caspase-9. Furthermore, it decreased the expression of HIF-1α and VEGF in Huh-7 cells, and inhibited tube formation and migration of human umbilical vein endothelial cells, which was confirmed by a Matrigel plug assay in mice. Taken together, IPD-196 exhibited its anticancer activity through disruption of the PI3K/Akt pathway that caused cell cycle arrest, apoptosis induction, and inhibition of angiogenesis in human HCC cells. We therefore suggest that IPD-196 may be a potential candidate drug for targeted HCC therapy.

  10. A novel polypeptide from shark cartilage with potent anti-angiogenic activity.

    PubMed

    Zheng, Lanhong; Ling, Peixue; Wang, Zheng; Niu, Rongli; Hu, Chaoxin; Zhang, Tianmin; Lin, Xiukun

    2007-05-01

    Using guanidine-HCl extraction, acetone precipitation, ultra-filtration and chromatography, a novel polypeptide with potent anti-angiogenic activity was purified from cartilage of the shark, Prionace glauca. N-terminal amino acid sequence analysis and SDS-PAGE revealed that the substance is a novel polypeptide with MW 15500 (PG155). The anti-angiogenic effects of PG155 were evaluated using zebrafish embryos model in vivo. Treatment of the embryos with 20 microg/ml PG155 resulted in a significant reduction in the growth of subintestinal vessels (SIVs). A higher dose resulted in almost complete inhibition of SIV growth, as observed by endogenous alkaline phosphatase (EAP) staining assay. An in vitro transwell experiment revealed that the polypeptide inhibited vascular endothelial growth factor (VEGF) induced migration and tubulogenesis of human umbilical vein endothelial cells (HUVECs). Exposure of HUVECs in 20 microg/ml PG155 significantly decreased the density of migrated cells. Almost complete inhibition of cell migration was found when HUVECs were treated with 40-80 microg/ml PG155. PG155 (20 microg/ml) markedly inhibited the tube formation of HUVECs and a dose-dependent effect was also found when treatment of HUVECs with PG155 at the concentration from 20-160 microg/ml.

  11. Glycosylated enfuvirtide: a long-lasting glycopeptide with potent anti-HIV activity.

    PubMed

    Cheng, Shuihong; Chang, Xuesong; Wang, Yan; Gao, George F; Shao, Yiming; Ma, Liying; Li, Xuebing

    2015-02-12

    Many peptide-based therapeutics have short circulatory half-lives. We report here that the pharmacokinetics of an anti-HIV peptide drug enfuvirtide (ENF) can be dramatically improved by a chemical glycosylation approach. A set of glycosylated ENFs with varying glycosylation sites and glycan structures were synthesized. Among these, a sialic acid-introduced peptide (SL-ENF) demonstrated a 15-fold extended half-life in rats relative to ENF (T1/2: 23.1 vs 1.5 h), and its antiviral potency was comparable to that of ENF (EC50: 2 vs 3 nM). SL-ENF bound to a functional fragment of the HIV fusogenic protein gp41 and formed complexes with high affinity and α-helicity, revealing the mechanism behind its potent antiviral activity. Because it is widely accepted in biology that glycosylation protects proteins from denaturation and proteases, our approach may be useful for the development of novel protein and peptide drugs with enhanced pharmaceutical properties.

  12. Autocrine selection of a GLP-1R G-protein biased agonist with potent antidiabetic effects

    PubMed Central

    Zhang, Hongkai; Sturchler, Emmanuel; Zhu, Jiang; Nieto, Ainhoa; Cistrone, Philip A.; Xie, Jia; He, LinLing; Yea, Kyungmoo; Jones, Teresa; Turn, Rachel; Di Stefano, Peter S.; Griffin, Patrick R.; Dawson, Philip E.; McDonald, Patricia H.; Lerner, Richard A.

    2015-01-01

    Glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) agonists have emerged as treatment options for type 2 diabetes mellitus (T2DM). GLP-1R signals through G-protein-dependent, and G-protein-independent pathways by engaging the scaffold protein β-arrestin; preferential signalling of ligands through one or the other of these branches is known as ‘ligand bias'. Here we report the discovery of the potent and selective GLP-1R G-protein-biased agonist, P5. We identified P5 in a high-throughput autocrine-based screening of large combinatorial peptide libraries, and show that P5 promotes G-protein signalling comparable to GLP-1 and Exendin-4, but exhibited a significantly reduced β-arrestin response. Preclinical studies using different mouse models of T2DM demonstrate that P5 is a weak insulin secretagogue. Nevertheless, chronic treatment of diabetic mice with P5 increased adipogenesis, reduced adipose tissue inflammation as well as hepatic steatosis and was more effective at correcting hyperglycaemia and lowering haemoglobin A1c levels than Exendin-4, suggesting that GLP-1R G-protein-biased agonists may provide a novel therapeutic approach to T2DM. PMID:26621478

  13. Potent inhibition of human immunodeficiency virus by MDL 101028, a novel sulphonic acid polymer.

    PubMed

    Taylor, D L; Brennan, T M; Bridges, C G; Mullins, M J; Tyms, A S; Jackson, R; Cardin, A D

    1995-10-01

    MDL 101028, a novel biphenyl disulphonic acid urea co-polymer was designed and synthesised as a heparin mimetic. This low molecular weight polymer showed potent inhibition of human immunodeficiency virus type 1 (HIV-1) replication in a number of host-cell/virus systems, including primary clinical isolates of the virus cultured in human peripheral blood mononuclear cells (PBMCs). When compared with the heterogeneous polysulphated molecules, heparin and dextran sulphate, this chemically defined compound showed equivalent antiviral activity with 50% inhibitory concentrations (IC50s) in the range 0.27-3.0 micrograms/ml in the host-cell/virus systems tested. MDL 101028 also inhibited the replication of HIV type 2 and the simian immunodeficiency virus (SIV), as well as HIV-1 variants resistant to reverse transcriptase inhibitors. Virus growth was blocked when exposure of T-lymphocytes to MDL 101028 was restricted to the virus absorption stage, or even in whole blood conditions. MDL 101028 did not irreversibly inactivate virions, and in contrast to heparin, did not inhibit the attachment of radiolabelled HIV-1 to CD4+ T-cells. MDL 101028 blocked HIV-induced cell-to-cell fusion and this activity appears to explain the mechanism of its antiviral action. The antiviral evaluation of discrete oligomer molecules of MDL 101028 showed that a polymer chain length of six repeating units had optimal potency. The lack of anticoagulant properties and significant antiviral activity in whole blood may allow the development of MDL 101028 as a treatment of HIV infections.

  14. The 2′-Trifluoromethyl Analogue of Indomethacin Is a Potent and Selective COX-2 Inhibitor

    PubMed Central

    2013-01-01

    Indomethacin is a potent, time-dependent, nonselective inhibitor of the cyclooxygenase enzymes (COX-1 and COX-2). Deletion of the 2′-methyl group of indomethacin produces a weak, reversible COX inhibitor, leading us to explore functionality at that position. Here, we report that substitution of the 2′-methyl group of indomethacin with trifluoromethyl produces CF3–indomethacin, a tight-binding inhibitor with kinetic properties similar to those of indomethacin and unexpected COX-2 selectivity (IC50 mCOX-2 = 267 nM; IC50 oCOX-1 > 100 μM). Studies with site-directed mutants reveal that COX-2 selectivity results from insertion of the CF3 group into a small hydrophobic pocket formed by Ala-527, Val-349, Ser-530, and Leu-531 and projection of the methoxy group toward a side pocket bordered by Val-523. CF3–indomethacin inhibited COX-2 activity in human head and neck squamous cell carcinoma cells and exhibited in vivo anti-inflammatory activity in the carrageenan-induced rat paw edema model with similar potency to that of indomethacin. PMID:23687559

  15. The 2'-Trifluoromethyl Analogue of Indomethacin Is a Potent and Selective COX-2 Inhibitor.

    PubMed

    Blobaum, Anna L; Uddin, Md Jashim; Felts, Andrew S; Crews, Brenda C; Rouzer, Carol A; Marnett, Lawrence J

    2013-05-09

    Indomethacin is a potent, time-dependent, nonselective inhibitor of the cyclooxygenase enzymes (COX-1 and COX-2). Deletion of the 2'-methyl group of indomethacin produces a weak, reversible COX inhibitor, leading us to explore functionality at that position. Here, we report that substitution of the 2'-methyl group of indomethacin with trifluoromethyl produces CF3-indomethacin, a tight-binding inhibitor with kinetic properties similar to those of indomethacin and unexpected COX-2 selectivity (IC50 mCOX-2 = 267 nM; IC50 oCOX-1 > 100 μM). Studies with site-directed mutants reveal that COX-2 selectivity results from insertion of the CF3 group into a small hydrophobic pocket formed by Ala-527, Val-349, Ser-530, and Leu-531 and projection of the methoxy group toward a side pocket bordered by Val-523. CF3-indomethacin inhibited COX-2 activity in human head and neck squamous cell carcinoma cells and exhibited in vivo anti-inflammatory activity in the carrageenan-induced rat paw edema model with similar potency to that of indomethacin.

  16. Selective detection of angular-momentum-polarized Auger electrons by atomic stereography.

    PubMed

    Matsui, Fumihiko; Fujita, Masayoshi; Ohta, Takuya; Maejima, Naoyuki; Matsui, Hirosuke; Nishikawa, Hiroaki; Matsushita, Tomohiro; Daimon, Hiroshi

    2015-01-09

    When a core level is excited by circularly polarized light, the angular momentum of light is transferred to the emitted photoelectron, which can be confirmed by the parallax shift of the forward focusing peak (FFP) direction in a stereograph of atomic arrangement. No angular momentum has been believed to be transferred to normal Auger electrons resulting from the decay process filling core hole after photoelectron ejection. We succeeded in detecting a non-negligible circular dichroism contrast in a normal Auger electron diffraction from a nonmagnetic Cu(001) surface far off from the absorption threshold. Moreover, we detected angular-momentum-polarized Cu L(3)M(4,5)M(4,5) Auger electrons at the L(3) absorption threshold, where the excited core electron is trapped at the conduction band. From the kinetic energy dependence of the Auger electron FFP parallax shift, we found that the angular momentum is transferred to the Auger electron most effectively in the case of the (1)S(0) two-hole creation.

  17. PU.1 is a potent tumor suppressor in classical Hodgkin lymphoma cells.

    PubMed

    Yuki, Hiromichi; Ueno, Shikiko; Tatetsu, Hiro; Niiro, Hiroaki; Iino, Tadafumi; Endo, Shinya; Kawano, Yawara; Komohara, Yoshihiro; Takeya, Motohiro; Hata, Hiroyuki; Okada, Seiji; Watanabe, Toshiki; Akashi, Koichi; Mitsuya, Hiroaki; Okuno, Yutaka

    2013-02-07

    PU.1 has previously been shown to be down-regulated in classical Hodgkin lymphoma (cHL) cells via promoter methylation. We performed bisulfite sequencing and proved that the promoter region and the -17 kb upstream regulatory element of the PU.1 gene were highly methylated. To evaluate whether down-regulation of PU.1 is essential for the growth of cHL cells, we conditionally expressed PU.1 in 2 cHL cell lines, L428 and KM-H2. Overexpression of PU.1 induced complete growth arrest and apoptosis in both cell lines. Furthermore, in a Hodgkin lymphoma tumor xenograft model using L428 and KM-H2 cell lines, overexpression of PU.1 led to tumor regression or stable disease. Lentiviral transduction of PU.1 into primary cHL cells also induced apoptosis. DNA microarray analysis revealed that among genes related to cell cycle and apoptosis, p21 (CDKN1A) was highly up-regulated in L428 cells after PU.1 induction. Stable knockdown of p21 rescued PU.1-induced growth arrest in L428 cells, suggesting that the growth arrest and apoptosis observed are at least partially dependent on p21 up-regulation. These data strongly suggest that PU.1 is a potent tumor suppressor in cHL and that induction of PU.1 with demethylation agents and/or histone deacetylase inhibitors is worth exploring as a possible therapeutic option for patients with cHL.

  18. Endocrinization of FGF1 produces a neomorphic and potent insulin sensitizer

    PubMed Central

    Suh, Jae Myoung; Jonker, Johan W.; Ahmadian, Maryam; Goetz, Regina; Lackey, Denise; Osborn, Olivia; Huang, Zifeng; Liu, Weilin; Yoshihara, Eiji; van Dijk, Theo; Havinga, Rick; Fan, Weiwei; Yin, Yun-Qiang; Yu, Ruth T.; Liddle, Christopher; Atkins, Annette R.; Olefsky, Jerrold M.; Mohammadi, Moosa; Downes, Michael; Evans, Ronald M.

    2014-01-01

    FGF1 is an autocrine/paracrine regulator whose binding to heparan sulfate proteoglycans effectively precludes its circulation 1,2. Though known as a mitogenic factor, FGF1 knockout mice develop insulin resistance when stressed by a high fat diet, suggesting a potential role in nutrient homeostasis 3,4. Here we show that parenteral delivery of a single dose of recombinant FGF1 (rFGF1) results in potent, insulin-dependent glucose lowering in diabetic mice that is dose-dependent, but does not lead to hypoglycemia. Chronic pharmacological rFGF1 treatment increases insulin-dependent glucose uptake in skeletal muscle and suppresses hepatic glucose production to achieve whole-body insulin sensitization. The sustained glucose lowering and insulin sensitization attributed to rFGF1 are not accompanied by the side effects of weight gain, liver steatosis and bone loss associated with current insulin sensitizing therapies. Furthermore, we demonstrate that the glucose lowering activity of FGF1 can be dissociated from its mitogenic activity and is mediated predominantly via FGF receptor 1 (FGFR1) signaling. In summary, we have uncovered an unexpected, neomorphic insulin sensitizing action for exogenous non-mitogenic human FGF1 with therapeutic potential for treatment of insulin resistance and type 2 diabetes. PMID:25043058

  19. Nigericin is a potent inhibitor of the early stage of vaccinia virus replication.

    PubMed

    Myskiw, Chad; Piper, Jessica; Huzarewich, Rhiannon; Booth, Tim F; Cao, Jingxin; He, Runtao

    2010-12-01

    Poxviruses remain a significant public health concern due to their potential use as bioterrorist agents and the spread of animal borne poxviruses, such as monkeypox virus, to humans. Thus, the identification of small molecule inhibitors of poxvirus replication is warranted. Vaccinia virus is the prototypic member of the Orthopoxvirus genus, which also includes variola and monkeypox virus. In this study, we demonstrate that the carboxylic ionophore nigericin is a potent inhibitor of vaccinia virus replication in several human cell lines. In HeLa cells, we found that the 50% inhibitory concentration of nigericin against vaccinia virus was 7.9 nM, with a selectivity index of 1038. We present data demonstrating that nigericin targets vaccinia virus replication at a post-entry stage. While nigericin moderately inhibits both early vaccinia gene transcription and translation, viral DNA replication and intermediate and late gene expression are severely compromised in the presence of nigericin. Our results demonstrate that nigericin has the potential to be further developed into an effective antiviral to treat poxvirus infections.

  20. The marine cytotoxin portimine is a potent and selective inducer of apoptosis.

    PubMed

    Cuddihy, Sarah L; Drake, Sarah; Harwood, D Tim; Selwood, Andrew I; McNabb, Paul S; Hampton, Mark B

    2016-12-01

    Portimine is a recently discovered member of a class of marine micro-algal toxins called cyclic imines. In dramatic contrast to related compounds in this toxin class, portimine has very low acute toxicity to mice but is highly cytotoxic to cultured cells. In this study we show that portimine kills human Jurkat T-lymphoma cells and mouse embryonic fibroblasts (MEFs), with LC50 values of 6 and 2.5 nM respectively. Treated cells displayed rapid caspase activation and phosphatidylserine exposure, indicative of apoptotic cell death. Jurkat cells overexpressing the anti-apoptotic protein Bcl-2 or Bax/Bak knockout MEFs were completely protected from portimine. This protection was apparent even at high concentrations of portimine, with no evidence of necrotic cell death, indicating that portimine is a selective chemical inducer of apoptosis. Treatment of the Bcl-2-overexpressing cells with both portimine and the Bcl-2 inhibitor ABT-737 proved a powerful combination, causing >90 % death. We conclude that portimine is one of the most potent naturally derived inducers of apoptosis to be discovered, and it displays strong selectivity for the induction of apoptotic pathways.

  1. Demethoxycurcumin Is A Potent Inhibitor of P-Type ATPases from Diverse Kingdoms of Life

    PubMed Central

    Dao, Trong Tuan; Sehgal, Pankaj; Tung, Truong Thanh; Møller, Jesper Vuust; Nielsen, John; Palmgren, Michael; Christensen, Søren Brøgger

    2016-01-01

    P-type ATPases catalyze the active transport of cations and phospholipids across biological membranes. Members of this large family are involved in a range of fundamental cellular processes. To date, a substantial number of P-type ATPase inhibitors have been characterized, some of which are used as drugs. In this work a library of natural compounds was screened and we first identified curcuminoids as plasma membrane H+-ATPases inhibitors in plant and fungal cells. We also found that some of the commercial curcumins contain several curcuminoids. Three of these were purified and, among the curcuminoids, demethoxycurcumin was the most potent inhibitor of all tested P-type ATPases from fungal (Pma1p; H+-ATPase), plant (AHA2; H+-ATPase) and animal (SERCA; Ca2+-ATPase) cells. All three curcuminoids acted as non-competitive antagonist to ATP and hence may bind to a highly conserved allosteric site of these pumps. Future research on biological effects of commercial preparations of curcumin should consider the heterogeneity of the material. PMID:27644036

  2. Norpiperidine imidazoazepines as a new class of potent, selective, and nonsedative H1 antihistamines.

    PubMed

    Janssens, Frans; Leenaerts, Jos; Diels, Gaston; De Boeck, Benoît; Megens, Anton; Langlois, Xavier; van Rossem, Koen; Beetens, Johan; Borgers, Marcel

    2005-03-24

    Clinical doses of available H(1) antihistamines are limited mainly by sedative side effects. However, higher doses are often required to obtain optimal therapeutic activity, especially in dermatology. We report the synthesis of three norpiperidine imidazoazepines representative of a new class of selective and nonsedating H(1) antihistamines. The compounds were at least as potent as cetirizine and loratadine as measured by H(1) receptor binding affinity, by protection against compound 48/80- and histamine-induced lethality in rats and guinea pigs, respectively, and by skin reaction tests in rats, guinea pigs, and dogs. The compounds, in particular 3a, were less prone than the reference compounds to penetrate the brain and to occupy central H(1) receptors, suggesting absence of sedative side effects. In vitro and in vivo cardiovascular safety tests showed that 3a had no intrinsic potential to prolong ventricular repolarization or induce cardiac arrhythmias. Compound 3a has been selected for further clinical development, mainly for application in dermatology.

  3. The reprogramming of tumor stroma by HSF1 is a potent enabler of malignancy

    PubMed Central

    Scherz-Shouval, Ruth; Santagata, Sandro; Mendillo, Marc L.; Sholl, Lynette M.; Ben-Aharon, Irit; Beck, Andrew H.; Dias-Santagata, Dora; Koeva, Martina; Stemmer, Salomon M.; Whitesell, Luke; Lindquist, Susan

    2014-01-01

    Summary Stromal cells within the tumor microenvironment are essential for tumor progression and metastasis. Surprisingly little is known about the factors that drive the transcriptional reprogramming of stromal cells within tumors. We report that the transcriptional regulator Heat-Shock Factor 1 (HSF1) is frequently activated in cancer-associated fibroblasts (CAFs), where it is a potent enabler of malignancy. HSF1 drives a transcriptional program in CAFs that complements, yet is completely different from, the program it drives in adjacent cancer cells. This CAF program is uniquely structured to support the malignant potential of cancer cells in a non-cell-autonomous way. Two central stromal signaling molecules—TGFβ and stromal-derived factor 1 (SDF1) – play a critical role. In early stage breast and lung cancer, high stromal HSF1 activation is strongly associated with poor patient outcome. Thus, tumors co-opt the ancient survival functions of HSF1 to orchestrate malignancy in both cell-autonomous and non-cell-autonomous ways, with far-reaching therapeutic implications. PMID:25083868

  4. Polyopes lancifolia Extract, a Potent α-Glucosidase Inhibitor, Alleviates Postprandial Hyperglycemia in Diabetic Mice.

    PubMed

    Min, Seong Won; Han, Ji Sook

    2014-01-01

    This study was designed to investigate the inhibitory effects of Polyopes lancifolia extract (PLE) on α-glucosidase activity, α-amylase activitiy, and postprandial hyperglycemia in streptozotocin (STZ)-induced diabetic mice. The results of this study revealed a marked inhibitory effect of PLE on α-glucosidase and α-amylase activities. The IC50s of PLE against α-glucosidase and α-amylase were 0.20 mg/mL and 0.35 mg/mL, respectively. PLE was a more effective inhibitor of α-glucosidase and α-amylase activities than acarbose, the positive control. The postprandial blood glucose levels of STZ-induced diabetic mice were significantly lower in the PLE treated group than in the control group. Moreover, PLE administration was associated with a decreased area under the curve for the glucose response in diabetic mice. These results indicate that PLE may be a potent inhibitor of α-glucosidase and α-amylase activities and may suppress postprandial hyperglycemia.

  5. 2,4,6-Trichloroanisole is a potent suppressor of olfactory signal transduction

    PubMed Central

    Takeuchi, Hiroko; Kato, Hiroyuki; Kurahashi, Takashi

    2013-01-01

    We investigated the sensitivity of single olfactory receptor cells to 2,4,6-trichloroanisole (TCA), a compound known for causing cork taint in wines. Such off-flavors have been thought to originate from unpleasant odor qualities evoked by contaminants. However, we here show that TCA attenuates olfactory transduction by suppressing cyclic nucleotide-gated channels, without evoking odorant responses. Surprisingly, suppression was observed even at extremely low (i.e., attomolar) TCA concentrations. The high sensitivity to TCA was associated with temporal integration of the suppression effect. We confirmed that potent suppression by TCA and similar compounds was correlated with their lipophilicity, as quantified by the partition coefficient at octanol/water boundary (pH 7.4), suggesting that channel suppression is mediated by a partitioning of TCA into the lipid bilayer of plasma membranes. The rank order of suppression matched human recognition of off-flavors: TCA equivalent to 2,4,6-tribromoanisole, which is much greater than 2,4,6-trichlorophenol. Furthermore, TCA was detected in a wide variety of foods and beverages surveyed for odor losses. Our findings demonstrate a potential molecular mechanism for the reduction of flavor. PMID:24043819

  6. Benzothiazinethione is a potent preclinical candidate for the treatment of drug-resistant tuberculosis

    PubMed Central

    Gao, Chao; Peng, Cuiting; Shi, Yaojie; You, Xinyu; Ran, Kai; Xiong, Lu; Ye, Ting-hong; Zhang, Lidan; Wang, Ningyu; Zhu, Yongxia; Liu, Kun; Zuo, Weiqiong; Yu, Luoting; Wei, Yuquan

    2016-01-01

    New chemotherapeutic compounds are needed to combat multidrug-resistant Mycobacterium tuberculosis (Mtb), which remains a serious public-health challenge. Decaprenylphosphoryl-β-D-ribose 2′-epimerase (DprE1 enzyme) has been characterized as an attractive therapeutic target to address this urgent demand. Herein, we have identified a new class of DprE1 inhibitors benzothiazinethiones as antitubercular agents. Benzothiazinethione analogue SKLB-TB1001 exhibited excellent activity against Mtb in the Microplate Alamar blue assay and intracellular model, meanwhile SKLB-TB1001 was also highly potent against multi-drug resistant extensively and drug resistant clinical isolates. Importantly, no antagonism interaction was found with any two-drug combinations tested in the present study and the combination of SKLB-TB1001 with rifampicin (RMP) was proved to be synergistic. Furthermore, benzothiazinethione showed superb in vivo antitubercular efficacy in an acute Mtb infection mouse model, significantly better than that of BTZ043. These data combined with the bioavailability and safety profiles of benzothiazinethione indicates SKLB-TB1001 is a promising preclinical candidate for the treatment of drug-resistant tuberculosis. PMID:27405961

  7. Discovery of a Potent Dihydrooxadiazole Series of Non-ATP-Competitive MK2 (MAPKAPK2) Inhibitors.

    PubMed

    Qin, Jun; Dhondi, Pawan; Huang, Xianhai; Aslanian, Robert; Fossetta, James; Tian, Fang; Lundell, Daniel; Palani, Anandan

    2012-02-09

    Inhibition of MK2 has been shown to offer advantages over that of p38 MAPK in the development of cures for inflammatory diseases such as arthritis. P38 MAPK knockout in mice was lethal, whereas MK2-null mice demonstrated strong inhibition of disease progression in collagen-induced arthritis and appeared normal and viable. However, it is challenging to develop ATP-competitive MK2 inhibitors due to high ATP binding affinity to the kinase. Non-ATP-competitive MK2 inhibitors interact and bind to the kinase in a mode independent of ATP concentration, which could provide better selectivity and cellular potency. Therefore, it is desirable to identify non-ATP-competitive MK2 inhibitors. Through structure optimization of lead compound 1, a novel series of dihydrooxadiazoles was discovered. Additional structure-activity relationship (SAR) study of this series led to the identification of compound 38 as a non-ATP-competitive MK2 inhibitor with potent enzymatic activity and good cellular potency. The SAR, synthesis, and biological data of dihydrooxadiazole series are discussed.

  8. Na⁺-K⁺-ATPase, a potent neuroprotective modulator against Alzheimer disease.

    PubMed

    Zhang, Li-Nan; Sun, Yong-Jun; Pan, Shuo; Li, Jun-Xia; Qu, Yin-E; Li, Yao; Wang, Yong-Li; Gao, Zi-Bin

    2013-02-01

    Alzheimer disease (AD) is a neurodegenerative disorder clinically characterized by progressive cognitive and memory dysfunction, which is the most common form of dementia. Although the pathogenesis of neuronal injury in AD is not clear, recent evidences suggest that Na⁺-K⁺-ATPase plays an important role in AD, and may be a potent neuroprotective modulator against AD. This review aims to provide readers with an in-depth understanding of Na⁺-K⁺-ATPase in AD through these modulations of some factors that are as follows, which leads to the change of learning and memory in the process of AD. 1. The deficiency in Na⁺, K⁺-ATPase α1, α2 and α3 isoform genes induced learning and memory deficits, and α isoform was evidently changed in AD, revealing that Na⁺, K⁺-ATPase α isoform genes may play an important role in AD. 2. Some factors, such as β-amyloid, cholinergic and oxidative stress, can modulate learning and memory in AD through the mondulation of Na⁺-K⁺-ATPase activity. 3. Some substances, such as Zn, s-Ethyl cysteine, s-propyl cysteine, citicoline, rivastigmine, Vit E, memantine, tea polyphenol, curcumin, caffeine, Alpinia galanga (L.) fractions, and Bacopa monnieri could play a role in improving memory performance and exert protective effects against AD by increasing expression or activity of Na⁺, K⁺-ATPase.

  9. A potent dauer pheromone component in Caenorhabditis elegans that acts synergistically with other components.

    PubMed

    Butcher, Rebecca A; Ragains, Justin R; Kim, Edward; Clardy, Jon

    2008-09-23

    In the model organism Caenorhabditis elegans, the dauer pheromone is the primary cue for entry into the developmentally arrested, dauer larval stage. The dauer is specialized for survival under harsh environmental conditions and is considered "nonaging" because larvae that exit dauer have a normal life span. C. elegans constitutively secretes the dauer pheromone into its environment, enabling it to sense its population density. Several components of the dauer pheromone have been identified as derivatives of the dideoxy sugar ascarylose, but additional unidentified components of the dauer pheromone contribute to its activity. Here, we show that an ascaroside with a 3-hydroxypropionate side chain is a highly potent component of the dauer pheromone that acts synergistically with previously identified components. Furthermore, we show that the active dauer pheromone components that are produced by C. elegans vary depending on cultivation conditions. Identifying the active components of the dauer pheromone, the conditions under which they are produced, and their mechanisms of action will greatly extend our understanding of how chemosensory cues from the environment can influence such fundamental processes as development, metabolism, and aging in nematodes and in higher organisms.

  10. New-to-nature sophorose analog: a potent inducer for gene expression in Trichoderma reesei.

    PubMed

    Huang, Tom Tao; Wages, John M

    2016-04-01

    Controlled hydrolysis of lactonic sophorolipids from Starmerella bombicola yields a previously undescribed sophorose analog that potently induces cellulase in Trichoderma reesei Rut-C30. Acid treatment of natural sophorolipids results in a mixture of monoacetylated, deacetylated, and diacetylated sophorolipids in acidic and lactonic forms. Isolation of the active components of the mixture, followed by structure determination by MS and NMR, reveals a new chemical entity, in which the lactone ring has been opened at the C-1' rather than at the C-4″ position of the sophorose moiety. This sophorose ester is resistant to degradation by the host and is at least 28 times more powerful an inducer than sophorose in shake-flask culture. Even at low concentrations (0.05 mM), the chemically modified sophorolipid effectively induces cellulase. With further improvements, this highly enabling technology can potentially reduce the cost of enzymes produced in T. reesei and can facilitate the rapid deployment of enzyme plants to support the nascent cellulosic biofuels and biochemicals industries.

  11. Lipo-γ-AApeptides as a new class of potent and broad-spectrum antimicrobial agents.

    PubMed

    Niu, Youhong; Padhee, Shruti; Wu, Haifan; Bai, Ge; Qiao, Qiao; Hu, Yaogang; Harrington, Lacey; Burda, Whittney N; Shaw, Lindsey N; Cao, Chuanhai; Cai, Jianfeng

    2012-04-26

    There is increasing demand to develop antimicrobial peptides (AMPs) as next generation antibiotic agents, as they have the potential to circumvent emerging drug resistance against conventional antibiotic treatments. Non-natural antimicrobial peptidomimetics are an ideal example of this, as they have significant potency and in vivo stability. Here we report for the first time the design of lipidated γ-AApeptides as antimicrobial agents. These lipo-γ-AApeptides show potent broad-spectrum activities against fungi and a series of Gram-positive and Gram-negative bacteria, including clinically relevant pathogens that are resistant to most antibiotics. We have analyzed their structure-function relationship and antimicrobial mechanisms using membrane depolarization and fluorescent microscopy assays. Introduction of unsaturated lipid chain significantly decreases hemolytic activity and thereby increases the selectivity. Furthermore, a representative lipo-γ-AApeptide did not induce drug resistance in S. aureus, even after 17 rounds of passaging. These results suggest that the lipo-γ-AApeptides have bactericidal mechanisms analogous to those of AMPs and have strong potential as a new class of novel antibiotic therapeutics.

  12. Fluoroacetic Acid Is a Potent and Specific Inhibitor of Reproduction in the Nematode Caenorhabditis elegans

    PubMed Central

    Middendorf, Paul J.; Dusenbery, David B.

    1993-01-01

    Fluoroacetic acid is known to lead to inhibition of aconitase and block both the Krebs and glyoxylate cycles. In this study, we discovered it to be a potent and specific inhibitor of reproduction in a bioassay using the nematode Caenorhabditis elegans. Fluoroacetic acid added to the growth medium reduced reproduction in the second generation by 50% at concentrations 3,000 times lower than the concentrations that reduced 24-hour survival by 50%. Four concentrations (2, 4, 8, and 17 mM) of fluoroacetic acid were tested thoroughly. At the two lower concentrations, the survival rates were unaffected, and first-generation reproduction was greatly reduced but not completely eliminated. Survival was reduced at the higher concentrations. Malonate, which inhibits the Krebs cycle, and itaconate, which inhibits the glyoxylate cycle, were tested individually and in combination. The combination did not specifically inhibit reproduction, suggesting another mode of action for fluoroacetic acid. Fluoroacetic acid shows promise as a tool in studies requiring age synchrony. PMID:19279811

  13. Fluoroacetic Acid Is a Potent and Specific Inhibitor of Reproduction in the Nematode Caenorhabditis elegans.

    PubMed

    Middendorf, P J; Dusenbery, D B

    1993-12-01

    Fluoroacetic acid is known to lead to inhibition of aconitase and block both the Krebs and glyoxylate cycles. In this study, we discovered it to be a potent and specific inhibitor of reproduction in a bioassay using the nematode Caenorhabditis elegans. Fluoroacetic acid added to the growth medium reduced reproduction in the second generation by 50% at concentrations 3,000 times lower than the concentrations that reduced 24-hour survival by 50%. Four concentrations (2, 4, 8, and 17 mM) of fluoroacetic acid were tested thoroughly. At the two lower concentrations, the survival rates were unaffected, and first-generation reproduction was greatly reduced but not completely eliminated. Survival was reduced at the higher concentrations. Malonate, which inhibits the Krebs cycle, and itaconate, which inhibits the glyoxylate cycle, were tested individually and in combination. The combination did not specifically inhibit reproduction, suggesting another mode of action for fluoroacetic acid. Fluoroacetic acid shows promise as a tool in studies requiring age synchrony.

  14. Cutting assembly including expanding wall segments of auger

    DOEpatents

    Treuhaft, Martin B.; Oser, Michael S.

    1983-01-01

    A mining auger comprises a cutting head carried at one end of a tubular shaft and a plurality of wall segments which in a first position thereof are disposed side by side around said shaft and in a second position thereof are disposed oblique to said shaft. A vane projects outwardly from each wall segment. When the wall segments are in their first position, the vanes together form a substantially continuous helical wall. A cutter is mounted on the peripheral edge of each of the vanes. When the wall segments are in their second position, the cutters on the vanes are disposed radially outward from the perimeter of the cutting head.

  15. 18β-Glycyrrhetinic Acid Derivatives Possessing a Trihydroxylated A Ring Are Potent Gram-Positive Antibacterial Agents.

    PubMed

    Huang, Li-Rong; Hao, Xiao-Jiang; Li, Qi-Ji; Wang, Dao-Ping; Zhang, Jian-Xin; Luo, Heng; Yang, Xiao-Sheng

    2016-04-22

    The oleanane-type triterpene 18β-glycyrrhetinic acid (1) was modified chemically through the introduction of a trihydroxylated A ring and an ester moiety at C-20 to enhance its antibacterial activity. Compounds 22, 23, 25, 28, 29, 31, and 32 showed more potent inhibitory activity against Streptomyces scabies than the positive control, streptomycin. Additionally, the inhibitory activity of the most potent compound, 29, against Bacillus subtilis, Staphylococcus aureus, and methicillin-resistant Staphylococcus aureus was greater than that of the positive controls. The antibacterial mode of action of the active derivatives involved the regulation of the expression of genes associated with peptidoglycans, the respiratory metabolism, and the inherent virulence factors found in bacteria, as determined through a quantitative real-time reverse transcriptase PCR assay.

  16. Education and Public Outreach of the Pierre Auger Cosmic Ray Observatory

    NASA Astrophysics Data System (ADS)

    Snow, Gregory

    2012-03-01

    The scale and scope of the physics studied at the Auger Observatory offer significant opportunities for original outreach work. Education, outreach and public relations of the Auger collaboration are coordinated in a separate task whose goals are to encourage and support a wide range of education and outreach efforts that link schools and the public with the Auger scientists and the science of cosmic rays, particle physics, and associated technologies. The presentation will focus on the impact of the collaboration in Mendoza Province, Argentina, as: the Auger Visitor Center in Malarg"ue that has hosted over 60,000 visitors since 2001 and a third collaboration-sponsored science fair held on the Observatory campus in November 2010. The Rural Schools Program, which is run by Observatory staff and which brings cosmic-ray science and infrastructure improvements to remote schools, will be highlighted. Numerous online resources, video documentaries, and animations of extensive air showers have been created for wide public release. Increasingly, collaborators draw on these resources to develop Auger related displays and outreach events at their institutions and in public settings to disseminate the science and successes of the Observatory worldwide.

  17. Supramolecular assembly of multifunctional maspin-mimetic nanostructures as a potent peptide-based angiogenesis inhibitor

    DOE PAGES

    Zha, R. Helen; Sur, Shantanu; Boekhoven, Job; ...

    2014-11-08

    Aberrant angiogenesis plays a large role in pathologies ranging from tumor growth to macular degeneration. Anti-angiogenic proteins have thus come under scrutiny as versatile, potent therapeutics but face problems with purification and tissue retention. We report here on the synthesis of supramolecular nanostructures that mimic the anti-angiogenic activity of maspin, a class II tumor suppressor protein. These maspin-mimetic nanostructures are formed via self-assembly of small peptide amphiphiles containing the g-helix motif of maspin. Using tubulogenesis assays with human umbilical vein endothelial cells, we demonstrate that maspin-mimetic nanostructures show anti-angiogenic activity at concentrations that are significantly lower than those necessary formore » the g-helix peptide. Furthermore, in vivo assays in the chick chorioallantoic membrane show maspin-mimetic nanostructures to be effective over controls at inhibiting angiogenesis. Thus, in conclusion, the nanostructures investigated here offer an attractive alternative to the use of anti-angiogenic recombinant proteins in the treatment of cancer or other diseases involving abnormal blood vessel formation.« less

  18. Synthesis of giant globular multivalent glycofullerenes as potent inhibitors in a model of Ebola virus infection

    NASA Astrophysics Data System (ADS)

    Muñoz, Antonio; Sigwalt, David; Illescas, Beatriz M.; Luczkowiak, Joanna; Rodríguez-Pérez, Laura; Nierengarten, Iwona; Holler, Michel; Remy, Jean-Serge; Buffet, Kevin; Vincent, Stéphane P.; Rojo, Javier; Delgado, Rafael; Nierengarten, Jean-François; Martín, Nazario

    2016-01-01

    The use of multivalent carbohydrate compounds to block cell-surface lectin receptors is a promising strategy to inhibit the entry of pathogens into cells and could lead to the discovery of novel antiviral agents. One of the main problems with this approach, however, is that it is difficult to make compounds of an adequate size and multivalency to mimic natural systems such as viruses. Hexakis adducts of [60]fullerene are useful building blocks in this regard because they maintain a globular shape at the same time as allowing control over the size and multivalency. Here we report water-soluble tridecafullerenes decorated with 120 peripheral carbohydrate subunits, so-called ‘superballs’, that can be synthesized efficiently from hexakis adducts of [60]fullerene in one step by using copper-catalysed azide-alkyne cycloaddition click chemistry. Infection assays show that these superballs are potent inhibitors of cell infection by an artificial Ebola virus with half-maximum inhibitory concentrations in the subnanomolar range.

  19. Lactate is a potent inhibitor of the capsaicin receptor TRPV1

    PubMed Central

    de la Roche, Jeanne; Walther, Isabella; Leonow, Waleria; Hage, Axel; Eberhardt, Mirjam; Fischer, Martin; Reeh, Peter W.; Sauer, Susanne; Leffler, Andreas

    2016-01-01

    Tissue ischemia results in an accumulation of lactate and local or systemic lactic acidosis. In nociceptive sensory neurons, lactate was reported to sensitize or activate the transient receptor potential ion channel TRPA1 and acid-sensing ion channels (ASICs). However, it is unclear how lactate modulates the TRPV1 regarded as the main sensor for acidosis in sensory neurons. In this study we investigated the effects of lactate (LA) on recombinant and native TRPV1 channels and on TRPV1-mediated release of neuropeptides from mouse nerves. TRPV1-mediated membrane currents evoked by protons, capsaicin or heat are inhibited by LA at concentrations ranging from 3 μM to 100 mM. LA inhibits TRPV1-mediated proton-induced Ca2+-influx in dorsal root ganglion neurons as well as proton-evoked neuropeptide release from mouse nerves. Inhibition of TRPV1 by LA is significantly stronger on inward currents as compared to outward currents since LA affects channel gating, shifting the activation curve towards more positive potentials. The mutation I680A in the pore lower gate displays no LA inhibition. Cell-attached as well as excised inside- and outside-out patches suggest an interaction through an extracellular binding site. In conclusion, our data demonstrate that lactate at physiologically relevant concentrations is a potent endogenous inhibitor of TRPV1. PMID:27827430

  20. Crystal structure of HIV-1 primary receptor CD4 in complex with a potent antiviral antibody.

    PubMed

    Freeman, Michael M; Seaman, Michael S; Rits-Volloch, Sophia; Hong, Xinguo; Kao, Chia-Ying; Ho, David D; Chen, Bing

    2010-12-08

    Ibalizumab is a humanized, anti-CD4 monoclonal antibody. It potently blocks HIV-1 infection and targets an epitope in the second domain of CD4 without interfering with immune functions mediated by interaction of CD4 with major histocompatibility complex (MHC) class II molecules. We report here the crystal structure of ibalizumab Fab fragment in complex with the first two domains (D1-D2) of CD4 at 2.2 Å resolution. Ibalizumab grips CD4 primarily by the BC-loop (residues 121-125) of D2, sitting on the opposite side of gp120 and MHC-II binding sites. No major conformational change in CD4 accompanies binding to ibalizumab. Both monovalent and bivalent forms of ibalizumab effectively block viral infection, suggesting that it does not need to crosslink CD4 to exert antiviral activity. While gp120-induced structural rearrangements in CD4 are probably minimal, CD4 structural rigidity is dispensable for ibalizumab inhibition. These results could guide CD4-based immunogen design and lead to a better understanding of HIV-1 entry.

  1. Crystal structure of HIV-1 primary receptor CD4 in complex with a potent antiviral antibody

    PubMed Central

    Freeman, Michael M.; Seaman, Michael S.; Rits-Volloch, Sophia; Hong, Xinguo; Kao, Chia-Ying; Ho, David D.; Chen, Bing

    2010-01-01

    Summary Ibalizumab is a humanized, anti-CD4 monoclonal antibody. It potently blocks HIV-1 infection and targets an epitope in the second domain of CD4 without interfering with immune functions mediated by interaction of CD4 with major histocompatibility complex (MHC) class II molecules. We report here the crystal structure of ibalizumab Fab fragment in complex with the first two domains (D1-D2) of CD4 at 2.2 Å resolution. Ibalizumab grips CD4 primarily by the BC-loop (residues 121-125) of D2, sitting on the opposite side of gp120 and MHC-II binding sites. No major conformational change in CD4 accompanies binding to ibalizumab. Both monovalent and bivalent forms of ibalizumab effectively block viral infection, suggesting that it does not need to crosslink CD4 to exert antiviral activity. While gp120-induced structural rearrangements in CD4 are probably minimal, CD4 structural rigidity is dispensable for ibalizumab inhibition. These results could guide CD4-based immunogen design and lead to a better understanding of HIV-1 entry. PMID:21134642

  2. Synthesis of conolidine, a potent non-opioid analgesic for tonic and persistent pain

    NASA Astrophysics Data System (ADS)

    Tarselli, Michael A.; Raehal, Kirsten M.; Brasher, Alex K.; Streicher, John M.; Groer, Chad E.; Cameron, Michael D.; Bohn, Laura M.; Micalizio, Glenn C.

    2011-06-01

    Management of chronic pain continues to represent an area of great unmet biomedical need. Although opioid analgesics are typically embraced as the mainstay of pharmaceutical interventions in this area, they suffer from substantial liabilities that include addiction and tolerance, as well as depression of breathing, nausea and chronic constipation. Because of their suboptimal therapeutic profile, the search for non-opioid analgesics to replace these well-established therapeutics is an important pursuit. Conolidine is a rare C5-nor stemmadenine natural product recently isolated from the stem bark of Tabernaemontana divaricata (a tropical flowering plant used in traditional Chinese, Ayurvedic and Thai medicine). Although structurally related alkaloids have been described as opioid analgesics, no therapeutically relevant properties of conolidine have previously been reported. Here, we describe the first de novo synthetic pathway to this exceptionally rare C5-nor stemmadenine natural product, the first asymmetric synthesis of any member of this natural product class, and the discovery that (±)-, (+)- and (-)-conolidine are potent and efficacious non-opioid analgesics in an in vivo model of tonic and persistent pain.

  3. Procyanidins are potent inhibitors of LOX-1: a new player in the French Paradox

    PubMed Central

    NISHIZUKA, Taichi; FUJITA, Yoshiko; SATO, Yuko; NAKANO, Atushi; KAKINO, Akemi; OHSHIMA, Shunji; KANDA, Tomomasa; YOSHIMOTO, Ryo; SAWAMURA, Tatsuya

    2011-01-01

    Lectin-like oxidized LDL receptor-1 (LOX-1) is an endothelial receptor for oxidized LDL (oxLDL) and plays multiple roles in the development of cardiovascular diseases. We screened more than 400 foodstuff extracts for identifying materials that inhibit oxLDL binding to LOX-1. Results showed that 52 extracts inhibited LOX-1 by more than 70% in cell-free assays. Subsequent cell-based assays revealed that a variety of foodstuffs known to be rich in procyanidins such as grape seed extracts and apple polyphenols, potently inhibited oxLDL uptake in Chinese hamster ovary (CHO) cells expressing LOX-1. Indeed, purified procyanidins significantly inhibited oxLDL binding to LOX-1 while other ingredients of apple polyphenols did not. Moreover, chronic administration of oligomeric procyanidins suppressed lipid accumulation in vascular wall in hypertensive rats fed with high fat diet. These results suggest that procyanidins are LOX-1 inhibitors and LOX-1 inhibition might be a possible underlying mechanism of the well-known vascular protective effects of red wine, the French Paradox. PMID:21422743

  4. Preclinical and clinical properties of trimegestone: a potent and selective progestin.

    PubMed

    Sitruk-Ware, Regine; Bossemeyer, Ronald; Bouchard, Phillipe

    2007-06-01

    Trimegestone (TMG) is a novel, 19-norpregnane progestin with potent and selective properties. In preclinical studies, TMG has been shown to provide high endometrial selectivity. Further, TMG has high affinity and selectivity for the progesterone receptor and lacks the agonist effects of other steroid hormones. In clinical studies, TMG has been shown to have high endometrial safety and an improved bleeding profile along with improved tolerability compared with other progestins. In addition, TMG also does not impede the beneficial effects of estrogen, especially on bone, and does not compromise quality of life. The preclinical findings of lack of mineralocorticoid activity of TMG were supported in clinical findings, with neutral effect on body weight. Similarly, the smaller effect of TMG on the GABA-ergic (gamma-aminobutyric acid) system in preclinical studies is consistent with the improvement of central nervous system-related effects on depressed mood and sleep quality in clinical studies. Low-dose estradiol/TMG regimens provide rapid relief from menopausal symptoms, reducing the number and severity of hot flushes as effectively as 2 mg 17beta-estradiol/1 mg norethisterone acetate. Therefore, it may be concluded that TMG provides a clinically proven option in hormone therapy for both clinicians and patients.

  5. Supramolecular assembly of multifunctional maspin-mimetic nanostructures as a potent peptide-based angiogenesis inhibitor

    SciTech Connect

    Zha, R. Helen; Sur, Shantanu; Boekhoven, Job; Shi, Heidi Y.; Zhang, Ming; Stupp, Samuel I.

    2014-11-08

    Aberrant angiogenesis plays a large role in pathologies ranging from tumor growth to macular degeneration. Anti-angiogenic proteins have thus come under scrutiny as versatile, potent therapeutics but face problems with purification and tissue retention. We report here on the synthesis of supramolecular nanostructures that mimic the anti-angiogenic activity of maspin, a class II tumor suppressor protein. These maspin-mimetic nanostructures are formed via self-assembly of small peptide amphiphiles containing the g-helix motif of maspin. Using tubulogenesis assays with human umbilical vein endothelial cells, we demonstrate that maspin-mimetic nanostructures show anti-angiogenic activity at concentrations that are significantly lower than those necessary for the g-helix peptide. Furthermore, in vivo assays in the chick chorioallantoic membrane show maspin-mimetic nanostructures to be effective over controls at inhibiting angiogenesis. Thus, in conclusion, the nanostructures investigated here offer an attractive alternative to the use of anti-angiogenic recombinant proteins in the treatment of cancer or other diseases involving abnormal blood vessel formation.

  6. Immunohistochemical molecular gene expression profile of metastatic brain tumor as a potent personalized medicine.

    PubMed

    Kato, Yasutaka; Nishihara, Hiroshi; Yuzawa, Sayaka; Mohri, Hiromi; Kanno, Hiromi; Hatanaka, Yutaka; Kimura, Taichi; Tanino, Mishie; Tanaka, Shinya

    2013-07-01

    Recent progress in molecule-targeting therapy may yield personalized therapeutic strategies for patients with metastatic brain tumors (MBT), the most frequently encountered intracranial tumors. For this purpose, we investigated the molecular expression profile of MBT to establish the pathological basis for personalized diagnosis. We studied 166 MBT specimens including 70 cases of lung cancer and 34 cases of breast cancer, and performed immunostaining for EGFR, COX-2, and O-6-methylguanine-DNA methyltransferase (MGMT), among others, which could be target molecules for therapeutic agents or enable prediction of drug efficacy. Loss of MGMT expression was observed in approximately 20-40% of MBT derived from lung, breast, and gastrointestinal cancers, indicating the possibility of treatment of MBT patients with temozolomide. In addition, MBT expressed a variety of receptor tyrosine kinases, for example EGFR and HER2, and signal transduction molecules, for example phospho-mTOR and COX-2, irrespective of tumor origin, enabling individualized medication with molecule-targeting drugs. We also identified alteration of molecular expression profile in 4 MBT cases during recurrence. Our results not only reveal the molecular characteristics of MBT but also suggest the possibility of potent personalized medicine for MBT patients.

  7. Discovery of benzoylisoindolines as a novel class of potent, selective and orally active GlyT1 inhibitors.

    PubMed

    Pinard, Emmanuel; Alberati, Daniela; Bender, Markus; Borroni, Edilio; Brom, Virginie; Burner, Serge; Fischer, Holger; Hainzl, Dominik; Halm, Remy; Hauser, Nicole; Jolidon, Synèse; Lengyel, Judith; Marty, Hans-Peter; Meyer, Thierry; Moreau, Jean-Luc; Mory, Roland; Narquizian, Robert; Norcross, Roger D; Schmid, Philipp; Wermuth, Roger; Zimmerli, Daniel

    2010-12-01

    Benzoylisoindolines were discovered as a novel structural class of GlyT1 inhibitors. SAR studies and subsequent lead optimization efforts focused primarily on addressing hERG liability and on improving in vivo efficacy resulted in the identification of potent GlyT1 inhibitors displaying excellent selectivity and in vivo PD and PK profiles.

  8. 7alpha,11beta-Dimethyl-19-nortestosterone: a potent and selective androgen response modulator with prostate-sparing properties.

    PubMed

    Cook, C Edgar; Kepler, John A

    2005-02-15

    7alpha,11beta-Dimethyl-19-nortestosterone, made by 1,6-methyl addition to 17beta-acetoxy-11beta-methylestra-4,6-dien-3-one, was a highly potent and selective androgen response modulator, with enhanced androgen receptor binding, androgenic activity and anabolic:androgenic ratio over its two monomethyl homologs.

  9. 3-Amido-3-aryl-piperidines: A Novel Class of Potent, Selective, and Orally Active GlyT1 Inhibitors.

    PubMed

    Pinard, Emmanuel; Alberati, Daniela; Alvarez-Sanchez, Ruben; Brom, Virginie; Burner, Serge; Fischer, Holger; Hauser, Nicole; Kolczewski, Sabine; Lengyel, Judith; Mory, Roland; Saladin, Christian; Schulz-Gasch, Tanja; Stalder, Henri

    2014-04-10

    3-Amido-3-aryl-piperidines were discovered as a novel structural class of GlyT1 inhibitors. The structure-activity relationship, which was developed, led to the identification of highly potent compounds exhibiting excellent selectivity against the GlyT2 isoform, drug-like properties, and in vivo activity after oral administration.

  10. 3-Amido-3-aryl-piperidines: A Novel Class of Potent, Selective, and Orally Active GlyT1 Inhibitors

    PubMed Central

    2014-01-01

    3-Amido-3-aryl-piperidines were discovered as a novel structural class of GlyT1 inhibitors. The structure–activity relationship, which was developed, led to the identification of highly potent compounds exhibiting excellent selectivity against the GlyT2 isoform, drug-like properties, and in vivo activity after oral administration. PMID:24900853

  11. Collybolide is a novel biased agonist of κ-opioid receptors with potent antipruritic activity

    PubMed Central

    Gupta, Achla; Gomes, Ivone; Bobeck, Erin N.; Fakira, Amanda K.; Massaro, Nicholas P.; Sharma, Indrajeet; Cavé, Adrien; Hamm, Heidi E.; Parello, Joseph

    2016-01-01

    Among the opioid receptors, the κ-opioid receptor (κOR) has been gaining considerable attention as a potential therapeutic target for the treatment of complex CNS disorders including depression, visceral pain, and cocaine addiction. With an interest in discovering novel ligands targeting κOR, we searched natural products for unusual scaffolds and identified collybolide (Colly), a nonnitrogenous sesquiterpene from the mushroom Collybia maculata. This compound has a furyl-δ-lactone core similar to that of Salvinorin A (Sal A), another natural product from the plant Salvia divinorum. Characterization of the molecular pharmacological properties reveals that Colly, like Sal A, is a highly potent and selective κOR agonist. However, the two compounds differ in certain signaling and behavioral properties. Colly exhibits 10- to 50-fold higher potency in activating the mitogen-activated protein kinase pathway compared with Sal A. Taken with the fact that the two compounds are equipotent for inhibiting adenylyl cyclase activity, these results suggest that Colly behaves as a biased agonist of κOR. Behavioral studies also support the biased agonistic activity of Colly in that it exhibits ∼10-fold higher potency in blocking non–histamine-mediated itch compared with Sal A, and this difference is not seen in pain attenuation by these two compounds. These results represent a rare example of functional selectivity by two natural products that act on the same receptor. The biased agonistic activity, along with an easily modifiable structure compared with Sal A, makes Colly an ideal candidate for the development of novel therapeutics targeting κOR with reduced side effects. PMID:27162327

  12. Simultaneous inhibition of multiple oncogenic miRNAs by a multi-potent microRNA sponge.

    PubMed

    Jung, Jaeyun; Yeom, Chanjoo; Choi, Yeon-Sook; Kim, Sinae; Lee, EunJi; Park, Min Ji; Kang, Sang Wook; Kim, Sung Bae; Chang, Suhwan

    2015-08-21

    The roles of oncogenic miRNAs are widely recognized in many cancers. Inhibition of single miRNA using antagomiR can efficiently knock-down a specific miRNA. However, the effect is transient and often results in subtle phenotype, as there are other miRNAs contribute to tumorigenesis. Here we report a multi-potent miRNA sponge inhibiting multiple miRNAs simultaneously. As a model system, we targeted miR-21, miR-155 and miR-221/222, known as oncogenic miRNAs in multiple tumors including breast and pancreatic cancers. To achieve efficient knockdown, we generated perfect and bulged-matched miRNA binding sites (MBS) and introduced multiple copies of MBS, ranging from one to five, in the multi-potent miRNA sponge. Luciferase reporter assay showed the multi-potent miRNA sponge efficiently inhibited 4 miRNAs in breast and pancreatic cancer cells. Furthermore, a stable and inducible version of the multi-potent miRNA sponge cell line showed the miRNA sponge efficiently reduces the level of 4 target miRNAs and increase target protein level of these oncogenic miRNAs. Finally, we showed the miRNA sponge sensitize cells to cancer drug and attenuate cell migratory activity. Altogether, our study demonstrates the multi-potent miRNA sponge is a useful tool to examine the functional impact of simultaneous inhibition of multiple miRNAs and proposes a therapeutic potential.

  13. Surface detector array for the Pierre Auger observatory

    NASA Astrophysics Data System (ADS)

    Salazar, H.; Garipov, G. K.; Khrenov, B. A.; Martínez, O.; Moreno, E.; Villaseñor, L.; Zepeda, A.

    2001-05-01

    The Pierre Auger international collaboration will install two observatories, one in the southern hemisphere and other in the northern hemisphere. Each observatory will consist of two different subsystem: a surface detector array of about 1600 water Cherenkov detectors (WCD) and a set of fluorescence eyes to measure the longitudinal development of air showers. The large area covered by the surface detectors requires efficient calibration and monitoring methods that can be implemented remotely. We present several complementary methods to calibrate and monitor the performance of the individual surface detector stations. We also present some results of the studies made with a full size prototype tank in Puebla, Mexico and in Malargue, Argentina. .

  14. The balanced scorecard: a potent tool for energizing and focusing healthcare organization management.

    PubMed

    Chow, C W; Ganulin, D; Teknika, O; Haddad, K; Williamson, J

    1998-01-01

    The current environment for healthcare organizations contains many forces demanding unprecedented levels of change. These forces include changing demographics, increased customer expectations, increased competition, and intensified governmental pressure. Meeting these challenges will require healthcare organizations to undergo fundamental changes and to continuously seek new ways to create future value. This article provides explanation of a potent new management tool-the balanced scorecard-that can be used by healthcare organizations to meet these challenges. The article also presents the opinions of many high-level healthcare administrators that the balanced scorecard can be highly beneficial to healthcare organizations. It also summarizes these administrators' suggestions regarding the goals and measures that can make up an effective scorecard for a hospital as a whole, as well as for a specific subunit of a hospital. Interestingly, while no published report of balanced scorecard implementations in healthcare organizations exists, a number of administrators stated that they had fully implemented systems similar to the scorecard. These actions can be considered support for the scorecard's potential usefulness; at the same time, they suggest that some sharing of experiences will likely be available in the future. As all administrators are well aware, moving from concept to practice is often difficult. While the article includes some suggestions for scorecard development and implementation, each organization must engage in the full range of activities, from defining its mission to the selection of goals and strategies, and develop its own unique scorecard to assist progress toward the selected goals. As a starting point, Table 3 provides a timeline of some general events that may be common to all organizations during this process.

  15. A NOVEL MULTI-MODAL DRUG REPURPOSING APPROACH FOR IDENTIFICATION OF POTENT ACK1 INHIBITORSǂ

    PubMed Central

    Phatak, Sharangdhar S.; Zhang, Shuxing

    2013-01-01

    Exploiting drug polypharmacology to identify novel modes of actions for drug repurposing has gained significant attentions in the current era of weak drug pipelines. From a serendipitous to systematic or rational ways, a variety of unimodal computational approaches have been developed but the complexity of the problem clearly needs multi-modal approaches for better solutions. In this study, we propose an integrative computational framework based on classical structure-based drug design and chemical-genomic similarity methods, combined with molecular graph theories for this task. Briefly, a pharmacophore modeling method was employed to guide the selection of docked poses resulting from our high-throughput virtual screening. We then evaluated if complementary results (hits missed by docking) can be obtained by using a novel chemo-genomic similarity approach based on chemical/sequence information. Finally, we developed a bipartite-graph based on the extensive data curation of DrugBank, PDB, and UniProt. This drug-target bipartite graph was used to assess similarity of different inhibitors based on their connections to other compounds and targets. The approaches were applied to the repurposing of existing drugs against ACK1, a novel cancer target significantly overexpressed in breast and prostate cancers during their progression. Upon screening of ~1,447 marketed drugs, a final set of 10 hits were selected for experimental testing. Among them, four drugs were identified as potent ACK1 inhibitors. Especially the inhibition of ACK1 by Dasatinib was as strong as IC50=1nM. We anticipate that our novel, integrative strategy can be easily extended to other biological targets with a more comprehensive coverage of known bio-chemical space for repurposing studies. PMID:23424109

  16. Ajulemic acid (CT3): a potent analog of the acid metabolites of THC.

    PubMed

    Burstein, S H

    2000-09-01

    The acid metabolites of THC were discovered almost 30 years ago and were later shown to posses modest analgesic and anti-inflammatory activity in a variety of models. Ajulemic acid (CT3) is a more potent analog of THC-11-oic acid in which a dimethylheptyl side chain is substituted for the pentyl side chain of the naturally occurring metabolite. It produces analgesia in the mouse hot plate, the PPQ writhing, the formalin and the tail clip assays. In the latter, it was equipotent to morphine; however, it showed a much greater duration of action. In the paw edema, subcutaneous air pouch and rat adjuvant-induced arthritis models of inflammation; it showed significant therapeutic activity at a dose of 0.2 mg/kg p.o. In the arthritis model it greatly reduced permanent damage to joints when compared to an indomethacin control as evidenced by an improved joint score over vehicle controls and by histopathological examination. In contrast to the NSAIDs, it was totally nonulcerogenic at therapeutically relevant doses. Moreover, it does not depress respiration, exhibit dependence, induce body weight loss or cause mutagenesis. It shows none of the typical actions in models of the psychotropic actions of cannabinoids suggesting that a good separation of desirable from undesirable effects was achieved. Studies on its mechanism of action are currently underway. The data thus far suggest the existence of a novel receptor for ajulemic acid with possible downstream effects on eicosanoid production, cytokine synthesis and metalloprotease activity. There is also circumstantial evidence for a putative endogenous ajulemic acid, namely, arachidonylglycine.

  17. Time of flight spectrometer for background-free positron annihilation induced Auger electron spectroscopy.

    PubMed

    Mukherjee, S; Shastry, K; Anto, C V; Joglekar, P V; Nadesalingam, M P; Xie, S; Jiang, N; Weiss, A H

    2016-03-01

    We describe a novel spectrometer designed for positron annihilation induced Auger electron spectroscopy employing a time-of-flight spectrometer. The spectrometer's new configuration enables us to implant monoenergetic positrons with kinetic energies as low as 1.5 eV on the sample while simultaneously allowing for the detection of electrons emitted from the sample surface at kinetic energies ranging from ∼500 eV to 0 eV. The spectrometer's unique characteristics made it possible to perform (a) first experiments demonstrating the direct transition of a positron from an unbound scattering state to a bound surface state and (b) the first experiments demonstrating that Auger electron spectra can be obtained down to 0 eV without the beam induced secondary electron background obscuring the low energy part of the spectra. Data are presented which show alternative means of estimating positron surface state binding energy and background-free Auger spectra.

  18. 4th generation of the 1st level surface detector trigger in the Pierre Auger Observator

    NASA Astrophysics Data System (ADS)

    Szadkowski, Z.

    The proposal of a new 4th generation of the Front-End with the advanced 1st level triggers for the Infill Array of the Pierre Auger Observatory and for the Auger North is described. Newest FPGA chips offer much higher capacity of logic registers and memories, as well as DSP blocks. The calibration channel, previously supported by an external dual-port RAM, has been fully implemented into FPGA chip, through a large internal memory. In turn DSP blocks allowed on implementation of much more sophisticated spectral trigger algorithms. A single chip simplified board design, newer architecture of FPGA reduced resouces utilization and power consumption. Higher sampling in the new Front- End in comparison with previous 40 MHz designs as well as free resources for new detection algotithms can be a good platform for CR radio detection technique at Auger enhancing a duty cycle for the detection of UHECR’s.

  19. Characterization of GSK′963: a structurally distinct, potent and selective inhibitor of RIP1 kinase

    PubMed Central

    Berger, SB; Harris, P; Nagilla, R; Kasparcova, V; Hoffman, S; Swift, B; Dare, L; Schaeffer, M; Capriotti, C; Ouellette, M; King, BW; Wisnoski, D; Cox, J; Reilly, M; Marquis, RW; Bertin, J; Gough, PJ

    2015-01-01

    Necroptosis and signaling regulated by RIP1 kinase activity is emerging as a key driver of inflammation in a variety of disease settings. A significant amount has been learned about how RIP1 regulates necrotic cell death through the use of the RIP1 kinase inhibitor Necrostatin-1 (Nec-1). Nec-1 has been a transformational tool for exploring the function of RIP1 kinase activity; however, its utility is somewhat limited by moderate potency, off-target activity against indoleamine-2,3-dioxygenase (IDO), and poor pharmacokinetic properties. These limitations of Nec-1 have driven an effort to identify next-generation tools to study RIP1 function, and have led to the identification of 7-Cl-O-Nec-1 (Nec-1s), which has improved pharmacokinetic properties and lacks IDO inhibitory activity. Here we describe the characterization of GSK′963, a chiral small-molecule inhibitor of RIP1 kinase that is chemically distinct from both Nec-1 and Nec-1s. GSK′963 is significantly more potent than Nec-1 in both biochemical and cellular assays, inhibiting RIP1-dependent cell death with an IC50 of between 1 and 4 nM in human and murine cells. GSK′963 is >10 000-fold selective for RIP1 over 339 other kinases, lacks measurable activity against IDO and has an inactive enantiomer, GSK′962, which can be used to confirm on-target effects. The increased in vitro potency of GSK′963 also translates in vivo, where GSK′963 provides much greater protection from hypothermia at matched doses to Nec-1, in a model of TNF-induced sterile shock. Together, we believe GSK′963 represents a next-generation tool for examining the function of RIP1 in vitro and in vivo, and should help to clarify our current understanding of the role of RIP1 in contributing to disease pathogenesis. PMID:27551444

  20. TrxR1 as a Potent Regulator of the Nrf2-Keap1 Response System

    PubMed Central

    Cebula, Marcus; Schmidt, Edward E.

    2015-01-01

    Abstract Significance: All cells must maintain a balance between oxidants and reductants, while allowing for fluctuations in redox states triggered by signaling, altered metabolic flow, or extracellular stimuli. Furthermore, they must be able to rapidly sense and react to various challenges that would disrupt the redox homeostasis. Recent Advances: Many studies have identified Keap1 as a key sensor for oxidative or electrophilic stress, with modification of Keap1 by oxidation or electrophiles triggering Nrf2-mediated transcriptional induction of enzymes supporting reductive and detoxification pathways. However, additional mechanisms for Nrf2 regulation are likely to exist upstream of, or in parallel with, Keap1. Critical Issues: Here, we propose that the mammalian selenoprotein thioredoxin reductase 1 (TrxR1) is a potent regulator of Nrf2. A high chemical reactivity of TrxR1 and its vital role for the thioredoxin (Trx) system distinguishes TrxR1 as a prime target for electrophilic challenges. Chemical modification of the selenocysteine (Sec) in TrxR1 by electrophiles leads to rapid inhibition of thioredoxin disulfide reductase activity, often combined with induction of NADPH oxidase activity of the derivatized enzyme, thereby affecting many downstream redox pathways. The notion of TrxR1 as a regulator of Nrf2 is supported by many publications on effects in human cells of selenium deficiency, oxidative stress or electrophile exposure, as well as the phenotypes of genetic mouse models. Future Directions: Investigation of the role of TrxR1 as a regulator of Nrf2 activation will facilitate further studies of redox control in diverse cells and tissues of mammals, and possibly also in animals of other classes. Antioxid. Redox Signal. 23, 823–853. PMID:26058897

  1. Green synthesis of graphene-silver nanocomposites and its application as a potent marine antifouling agent.

    PubMed

    Yee, Maxine Swee-Li; Khiew, Poi-Sim; Chiu, Wee Siong; Tan, Yuen Fen; Kok, Yih-Yih; Leong, Chee-Onn

    2016-12-01

    Fouling of marine surfaces has been a perpetual problem ever since the days of the early sailors. The tenacious attachment of seaweed and invertebrates to man-made surfaces, notably on ship hulls, has incurred undesirable economic losses. Graphene receives great attention in the materials world for its unique combination of physical and chemical properties. Herein, we present a novel 2-step synthesis method of graphene-silver nanocomposites which bypasses the formation of graphene oxide (GO), and produces silver nanoparticles supported on graphene sheets through a mild hydrothermal reduction process. The graphene-Ag (GAg) nanocomposite combines the antimicrobial property of silver nanoparticles and the unique structure of graphene as a support material, with potent marine antifouling properties. The GAg nanocomposite was composed of micron-scaled graphene flakes with clusters of silver nanoparticles. The silver nanoparticles were estimated to be between 72 and 86nm (SEM observations) while the crystallite size of the silver nanoparticles (AgNPs) was estimated between 1 and 5nm. The nanocomposite also exhibited the SERS effect. GAg was able to inhibit Halomonas pacifica, a model biofilm-causing microbe, from forming biofilms with as little as 1.3wt.% loading of Ag. All GAg samples displayed significant biofilm inhibition property, with the sample recording the highest Ag loading (4.9wt.% Ag) associated with a biofilm inhibition of 99.6%. Moreover, GAg displayed antiproliferative effects on marine microalgae, Dunaliella tertiolecta and Isochrysis sp. and inhibited the growth of the organisms by more than 80% after 96h. The marine antifouling properties of GAg were a synergy of the biocidal AgNPs anchored on the stable yet flexible graphene sheets, providing maximum active contact surface areas to the target organisms.

  2. Observatorio Pierre Auger: motivación y estado actual

    NASA Astrophysics Data System (ADS)

    Rovero, A. C.; Etchegoyen, A.; García, B.

    The Pierre Auger Observatory is aiming to understand the origin, nature and acceleration mechanisms of the most energetic cosmic rays (E>10 E18 eV). It will consist of one hybrid detector in each hemisphere, giving a total acceptance of 14200 km2 sr. The southern observatory is being constructed in Malargue, Mendoza, Argentina, and will be finished in 2006. No final statement can be made so far about any feature in the most energetic part of the spectrum. However, good candidate events were observed to have a primary energy of about 10 E20 eV.

  3. C-phycocyanin, a very potent and novel platelet aggregation inhibitor from Spirulina platensis.

    PubMed

    Hsiao, George; Chou, Po-Hsiu; Shen, Ming-Yi; Chou, Duen-Suey; Lin, Chien-Huang; Sheu, Joen-Rong

    2005-10-05

    The aim of this study was to systematically examine the inhibitory mechanisms of C-phycocyanin (C-PC), one of the major phycobiliproteins of Spirulina platensis (a blue-green alga), in platelet activation. In this study, C-PC concentration-dependently (0.5-10 nM) inhibited platelet aggregation stimulated by agonists. C-PC (4 and 8 nM) inhibited intracellular Ca2+ mobilization and thromboxane A2 formation but not phosphoinositide breakdown stimulated by collagen (1 microg/mL) in human platelets. In addition, C-PC (4 and 8 nM) markedly increased levels of cyclic GMP and cyclic GMP-induced vasodilator-stimulated phosphoprotein (VASP) Ser(157) phosphorylation. Rapid phosphorylation of a platelet protein of Mw 47,000 (P47), a marker of protein kinase C activation, was triggered by phorbol-12,13-dibutyrate (150 nM). This phosphorylation was markedly inhibited by C-PC (4 and 8 nM). In addition, C-PC (4 and 8 nM) markedly reduced the electron spin resonance (ESR) signal intensity of hydroxyl radicals in collagen (1 microg/mL)-activated platelets. The present study reports on a novel and very potent (in nanomolar concentrations) antiplatelet agent, C-PC, which is involved in the following inhibitory pathways: (1) C-phycocyanin increases cyclic GMP/VASP Ser157 phosphorylation and subsequently inhibits protein kinase C activity, resulting in inhibition of both P47 phosphorylation and intracellular Ca2+ mobilization, and (2) C-PC may inhibit free radicals (such as hydroxyl radicals) released from activated platelets, which ultimately inhibits platelet aggregation. These results strongly indicate that C-PC appears to represent a novel and potential antiplatelet agent for treatment of arterial thromboembolism.

  4. A chalcone with potent inhibiting activity against biofilm formation by nontypeable Haemophilus influenzae.

    PubMed

    Kunthalert, Duangkamol; Baothong, Sudarat; Khetkam, Pichit; Chokchaisiri, Suwadee; Suksamrarn, Apichart

    2014-10-01

    Nontypeable Haemophilus influenzae (NTHi), an important human respiratory pathogen, frequently causes biofilm infections. Currently, resistance of bacteria within the biofilm to conventional antimicrobials poses a major obstacle to effective medical treatment on a global scale. Novel agents that are effective against NTHi biofilm are therefore urgently required. In this study, a series of natural and synthetic chalcones with various chemical substituents were evaluated in vitro for their antibiofilm activities against strong biofilm-forming strains of NTHi. Of the test chalcones, 3-hydroxychalcone (chalcone 8) exhibited the most potent inhibitory activity, its mean minimum biofilm inhibitory concentration (MBIC50 ) being 16 μg/mL (71.35 μM), or approximately sixfold more active than the reference drug, azithromycin (MBIC50 419.68 μM). The inhibitory activity of chalcone 8, which is a chemically modified chalcone, appeared to be superior to those of the natural chalcones tested. Significantly, chalcone 8 inhibited biofilm formation by all studied NTHi strains, indicating that the antibiofilm activities of this compound occur across multiple strong-biofilm forming NTHi isolates of different clinical origins. According to antimicrobial and growth curve assays, chalcone 8 at concentrations that decreased biofilm formation did not affect growth of NTHi, suggesting the biofilm inhibitory effect of chalcone 8 is non-antimicrobial. In terms of structure-activity relationship, the possible substituent on the chalcone backbone required for antibiofilm activity is discussed. These findings indicate that 3-hydroxychalcone (chalcone 8) has powerful antibiofilm activity and suggest the potential application of chalcone 8 as a new therapeutic agent for control of NTHi biofilm-associated infections.

  5. High-Content Screening in Zebrafish Embryos Identifies Butafenacil as a Potent Inducer of Anemia

    PubMed Central

    Leet, Jessica K.; Lindberg, Casey D.; Bassett, Luke A.; Isales, Gregory M.; Yozzo, Krystle L.; Raftery, Tara D.; Volz, David C.

    2014-01-01

    Using transgenic zebrafish (fli1:egfp) that stably express enhanced green fluorescent protein (eGFP) within vascular endothelial cells, we recently developed and optimized a 384-well high-content screening (HCS) assay that enables us to screen and identify chemicals affecting cardiovascular development and function at non-teratogenic concentrations. Within this assay, automated image acquisition procedures and custom image analysis protocols are used to quantify body length, heart rate, circulation, pericardial area, and intersegmental vessel area within individual live embryos exposed from 5 to 72 hours post-fertilization. After ranking developmental toxicity data generated from the U.S. Environmental Protection Agency's (EPA's) zebrafish teratogenesis assay, we screened 26 of the most acutely toxic chemicals within EPA's ToxCast Phase-I library in concentration-response format (0.05–50 µM) using this HCS assay. Based on this screen, we identified butafenacil as a potent inducer of anemia, as exposure from 0.39 to 3.125 µM butafenacil completely abolished arterial circulation in the absence of effects on all other endpoints evaluated. Butafenacil is an herbicide that inhibits protoporphyrinogen oxidase (PPO) – an enzyme necessary for heme production in vertebrates. Using o-dianisidine staining, we then revealed that severe butafenacil-induced anemia in zebrafish was due to a complete loss of hemoglobin following exposure during early development. Therefore, six additional PPO inhibitors within the ToxCast Phase-I library were screened to determine whether anemia represents a common adverse outcome for these herbicides. Embryonic exposure to only one of these PPO inhibitors – flumioxazin – resulted in a similar phenotype as butafenacil, albeit not as severe as butafenacil. Overall, this study highlights the potential utility of this assay for (1) screening chemicals for cardiovascular toxicity and (2) prioritizing chemicals for future hypothesis

  6. Disentangling atomic-layer-specific x-ray absorption spectra by Auger electron diffraction spectroscopy

    NASA Astrophysics Data System (ADS)

    Matsui, Fumihiko; Matsushita, Tomohiro; Kato, Yukako; Hashimoto, Mie; Daimon, Hiroshi

    2009-11-01

    In order to investigate the electronic and magnetic structures of each atomic layer at subsurface, we have proposed a new method, Auger electron diffraction spectroscopy, which is the combination of x-ray absorption spectroscopy (XAS) and Auger electron diffraction (AED) techniques. We have measured a series of Ni LMM AED patterns of the Ni film grown on Cu(001) surface for various thicknesses. Then we deduced a set of atomic-layer-specific AED patterns in a numerical way. Furthermore, we developed an algorithm to disentangle XANES spectra from different atomic layers using these atomic-layer-specific AED patterns. Surface and subsurface core level shift were determined for each atomic layer.

  7. Valorisation of forestry waste by pyrolysis in an auger reactor

    SciTech Connect

    Puy, Neus; Murillo, Ramon; Navarro, Maria V.; Lopez, Jose M.; Rieradevall, Joan; Fowler, G.; Aranguren, Ignacio; Garcia, Tomas; Bartroli, Jordi; Mastral, Ana M.

    2011-06-15

    Pyrolysis of forestry waste has been carried out in an auger reactor to study the influence of operational variables on the reactor performance and the properties of the related products. Pine woodchips were used for the first time as raw material and fed continuously into the reactor. Ten experiments were carried out under inert atmosphere at: (i) different reaction temperature (1073, 973, 873, 823 and 773 K); (ii) different solid residence time (5, 3, 2 and 1.5 min); and (iii) different biomass flow rate (3.9, 4.8 and 6.9 kg/h). Results show that the greatest yields for liquid production (59%) and optimum product characterisation were obtained at the lowest temperature studied (773 K) and applying solid residence times longer than 2 min. Regarding bio-oil properties, GC/MS qualitative identification show that the most abundant compounds are volatile polar compounds, phenols and benzenediols; and very few differences can be observed among the samples regardless of the pyrolysis operating conditions. On the whole, experimental results demonstrate that complete reaction of forest woodchips can be achieved in an auger reactor in most of the experimental conditions tested. Moreover, this study presents the initial steps for the future scaling up of the auger reactor with the aim of converting it into a mobile plant which will be able to remotely process biomass such as energy crops, forestry and agricultural wastes to obtain bio-oil that, in turn, can be used as energy vector to avoid high transport costs.

  8. Valorisation of forestry waste by pyrolysis in an auger reactor.

    PubMed

    Puy, Neus; Murillo, Ramón; Navarro, María V; López, José M; Rieradevall, Joan; Fowler, G; Aranguren, Ignacio; García, Tomás; Bartrolí, Jordi; Mastral, Ana M

    2011-06-01

    Pyrolysis of forestry waste has been carried out in an auger reactor to study the influence of operational variables on the reactor performance and the properties of the related products. Pine woodchips were used for the first time as raw material and fed continuously into the reactor. Ten experiments were carried out under inert atmosphere at: (i) different reaction temperature (1073, 973, 873, 823 and 773 K); (ii) different solid residence time (5, 3, 2 and 1.5 min); and (iii) different biomass flow rate (3.9, 4.8 and 6.9 kg/h). Results show that the greatest yields for liquid production (59%) and optimum product characterisation were obtained at the lowest temperature studied (773 K) and applying solid residence times longer than 2 min. Regarding bio-oil properties, GC/MS qualitative identification show that the most abundant compounds are volatile polar compounds, phenols and benzenediols; and very few differences can be observed among the samples regardless of the pyrolysis operating conditions. On the whole, experimental results demonstrate that complete reaction of forest woodchips can be achieved in an auger reactor in most of the experimental conditions tested. Moreover, this study presents the initial steps for the future scaling up of the auger reactor with the aim of converting it into a mobile plant which will be able to remotely process biomass such as energy crops, forestry and agricultural wastes to obtain bio-oil that, in turn, can be used as energy vector to avoid high transport costs.

  9. A three monoclonal antibody combination potently neutralizes multiple botulinum neurotoxin serotype F subtypes

    PubMed Central

    Fan, Yongfeng; Garcia-Rodriguez, Consuelo; Lou, Jianlong; Wen, Weihua; Conrad, Fraser; Zhai, Wenwu; Smith, Theresa J.; Smith, Leonard A.

    2017-01-01

    Human botulism is primarily caused by botulinum neurotoxin (BoNT) serotypes A, B and E, with around 1% caused by serotype F (BoNT/F). BoNT/F comprises at least seven different subtypes with the amino acid sequence difference between subtypes as high as 36%. The sequence differences present a significant challenge for generating monoclonal antibodies (mAbs) that can bind, detect and neutralize all BoNT/F subtypes. We used repertoire cloning of immune mouse antibody variable (V) regions and yeast display to generate a panel of 33 lead single chain Fv (scFv) mAbs that bound one or more BoNT/F subtypes with a median equilibrium dissociation constant (KD) of 4.06 × 10−9 M. By diversifying the V-regions of the lead mAbs and selecting for cross reactivity we generated five mAbs that bound each of the seven subtypes. Three scFv binding non-overlapping epitopes were converted to IgG that had KD for the different BoNT/F subtypes ranging from 2.2×10−8 M to 1.47×10−12 pM. An equimolar combination of the mAbs was able to potently neutralize BoNT/F1, F2, F4 and F7 in the mouse neutralization assay. The mAbs have potential utility as diagnostics capable of recognizing the known BoNT/F subtypes and could be developed as antitoxins to prevent and treat type F botulism. PMID:28323873

  10. Systemically active human opiorphin is a potent yet non-addictive analgesic without drug tolerance effects.

    PubMed

    Rougeot, C; Robert, F; Menz, L; Bisson, J-F; Messaoudi, M

    2010-08-01

    Human opiorphin QRFSR-peptide protects enkephalins from degradation by human neutral endopeptidase (hNEP) and aminopeptidase-N (hAP-N) and inhibits pain perception in a behavioral model of mechanical acute pain (1). Here, using two other pain rat models, the tail-flick and the formalin tests, we assess the potency and duration of the antinociceptive action of opiorphin with reference to morphine. The occurrence of adverse effects with emphasis on the side-effect profile at equi-analgesic doses was compared. We demonstrate that opiorphin elicits minimal adverse morphine-associated effects, at doses (1-2 mg/kg, i.v.) that produce a comparable analgesic potency in both spinally controlled thermal-induced acute and peripheral chemical-induced tonic nociception. The analgesic response induced by opiorphin in the formalin-induced pain model preferentially requires activation of endogenous mu-opioid pathways. However, in contrast to exogenous mu-opioid agonists such as morphine, opiorphin, does not develop significant abuse liability or antinociceptive drug tolerance after subchronic treatment. In addition, anti-peristaltism was not observed. We conclude that opiorphin, by inhibiting the destruction of endogenous enkephalins, which are released according to the painful stimulus, activates restricted opioid pathways specifically involved in pain control, thus contributing to a greater balance between analgesia and side-effects than found with morphine. Therefore, opiorphin could give rise to new analgesics endowed with potencies similar to morphine but with fewer adverse effects than opioid agonists. Its chemical optimization, to generate functional derivatives endowed with better bioavailability properties than the native peptide, could lead to a potent class of physiological type analgesics.

  11. Melatonin: a potent candidate in the regulation of fish oocyte growth and maturation.

    PubMed

    Maitra, Saumen Kumar; Chattoraj, Asamanja; Mukherjee, Sourav; Moniruzzaman, Mahammed

    2013-01-15

    Recent studies on several fish species, especially carp, implicated pineal hormone melatonin (N-acetyl-5-methoxytryptamine) as a potent candidate in the regulatory mechanism of seasonal reproduction. Under natural conditions, the temporal pattern of serum melatonin varied with daily light-dark cycle and the reproductive status of the fish as well. Carefully controlled study revealed that exogenous administration of melatonin may result in stimulation or inhibition or no influences at all on the gonadal functions depending on the reproductive status of fish. Cross-talk between the melatonin and ovarian steroid has been evident from in vitro study, in which melatonin accelerated the action of 17α,20β-dihydroxy-4-pregnen-3-one or maturation inducing hormone (MIH) on meiotic cell cycle resumption in carp oocytes by formation of maturation promoting factor (MPF) - a complex of two proteins, cyclin B and cyclin dependant kinase Cdk1. While several lines of evidence suggest melatonin effects on hypothalamo-hypophyseal-gonadal axis, localization and dynamics of a 37-kDa melatonin receptor protein in carp oocytes argued in favor of extra-hypothalamic direct action of melatonin on fish reproduction. A recent study in carp indicated that influences of an identical regimen of photoperiods in different parts of annual cycle on ovarian functions vary in relation to the profiles of serum melatonin, but not to any rhythm parameters of MT1 or MT2 receptors on the gonad or brain. The purpose of this short review is to bring together the current knowledge on the biological effects of melatonin on fish reproduction mainly focusing the recent findings on carp.

  12. Molecular mechanism of viral resistance to a potent non-nucleoside inhibitor unveiled by molecular simulations.

    PubMed

    Asthana, Shailendra; Shukla, Saumya; Ruggerone, Paolo; Vargiu, Attilio V

    2014-11-11

    Recently, we reported on a potent benzimidazole derivative (227G) that inhibits the growth of the bovine viral diarrhea virus (BVDV) in cell-based and enzyme assays at nanomolar concentrations. The target of 227G is the viral RNA-dependent RNA polymerase (RdRp), and the I261M mutation located in motif I of the RdRp finger domain was found to induce drug resistance. Here we propose a molecular mechanism for the retained functionality of the enzyme in the presence of the inhibitor, on the basis of a thorough computational study of the apo and holo forms of the BVDV RdRp either in the wild type (wt) or in the form carrying the I261M mutation. Our study shows that although the mutation affects to some extent the structure of the apoenzyme, the functional dynamics of the protein appear to be largely maintained, which is consistent with the retained functionality of this natural mutant. Despite the binding site of 227G not collapsing or undergoing drastic structural changes upon introduction of the I261M substitution, these alterations reflect crucially on the binding mode of 227G, which is significantly different from that found in wt RdRp. In particular, while in the wt system the four loops lining the template entrance site embrace 227G and close the template passageway, in the I261M variant the template entrance is only marginally occluded, allowing in principle the translocation of the template to the interior of the enzyme. In addition, the mutated enzyme in the presence of 227G retains several characteristics of the wt apoprotein. Our work provides an original molecular picture of a resistance mechanism that is consistent with published experimental data.

  13. A three monoclonal antibody combination potently neutralizes multiple botulinum neurotoxin serotype F subtypes.

    PubMed

    Fan, Yongfeng; Garcia-Rodriguez, Consuelo; Lou, Jianlong; Wen, Weihua; Conrad, Fraser; Zhai, Wenwu; Smith, Theresa J; Smith, Leonard A; Marks, James D

    2017-01-01

    Human botulism is primarily caused by botulinum neurotoxin (BoNT) serotypes A, B and E, with around 1% caused by serotype F (BoNT/F). BoNT/F comprises at least seven different subtypes with the amino acid sequence difference between subtypes as high as 36%. The sequence differences present a significant challenge for generating monoclonal antibodies (mAbs) that can bind, detect and neutralize all BoNT/F subtypes. We used repertoire cloning of immune mouse antibody variable (V) regions and yeast display to generate a panel of 33 lead single chain Fv (scFv) mAbs that bound one or more BoNT/F subtypes with a median equilibrium dissociation constant (KD) of 4.06 × 10-9 M. By diversifying the V-regions of the lead mAbs and selecting for cross reactivity we generated five mAbs that bound each of the seven subtypes. Three scFv binding non-overlapping epitopes were converted to IgG that had KD for the different BoNT/F subtypes ranging from 2.2×10-8 M to 1.47×10-12 pM. An equimolar combination of the mAbs was able to potently neutralize BoNT/F1, F2, F4 and F7 in the mouse neutralization assay. The mAbs have potential utility as diagnostics capable of recognizing the known BoNT/F subtypes and could be developed as antitoxins to prevent and treat type F botulism.

  14. Deoxyarbutin Possesses a Potent Skin-Lightening Capacity with No Discernible Cytotoxicity against Melanosomes

    PubMed Central

    Fan, Zhi-Feng; Jiang, Shan; Xu, Shi-Zheng; Lei, Tie-Chi

    2016-01-01

    Safe and effective ingredients capable of removing undesired hyperpigmentation from facial skin are urgently needed for both pharmaceutical and cosmetic purposes. Deoxyarbutin (4-[(tetrahydro-2H-pyran-2-yl) oxy] phenol, D-Arb) is a glucoside derivative of hydroquinone. Here, we investigated the toxicity and efficacy of D-Arb at the sub-cellular level (directly on melanosomes) and skin pigmentation using in vivo and in vitro models to compare with its parent compound hydroquinone (1,4-benzenediol, HQ). At first, we examined the ultrastructural changes of melanosomes in hyperpigmented guinea pig skin induced by 308-nm monochromatic excimer lightand/or treated with HQ and D-Arb using transmission electron microscopy. The results showed that prominent changes in the melanosomal membrane, such as bulb-like structure and even complete rupture of the outer membranes, were found in the skin after topical application of 5% HQ for 10 days. These changes were barely observed in the skin treated with D-Arb. To further clarify whether membrane toxicity of HQ was a direct result of the compound treatment, we also examinedultrastructural changes of individual melanosomes purified from MNT1 human melanoma cells. Similar observations were obtained from the naked melanosome model in vitro. Finally, we determined the effects of melanosomal fractions exposed to HQ or D-Arb on hydroxyl radical generation in the Fenton reaction utilizing an electron spin resonance assay. D-Arb-treated melanosomesexhibit a moderate hydroxyl radical-scavenging activity, whereas HQ-treated melanosomessignificantly generate more hydroxyl free radicals. This study suggests that D-Arb possesses a potent ability in skin lightening and antioxidation with less melanosome cytotoxicity. PMID:27776184

  15. Labeling of SR 46349B, a potent and selective 5-HT{sub 2} receptor antagonist

    SciTech Connect

    Tan, P.; Fowler, J.S.; Ding, Y.S.

    1995-05-01

    SR 46349B is a potent and selective 5-HT{sub 2} receptor antagonist (Kd =1.2 nM) which is currently being evaluated as an antidepressant. We labeled SR46349B with F-18 for PET studies via the nitro-for-fluorine exchange reaction. Among the five nitro-precursors (o-nitroacetophenone) examined for nucleophilic aromatic substitution ({sup 18}F{sup {minus}}, K{sub 2}CO{sub 3}, kryptofix-222, 120{degrees}C, 6 min), only phenol protected ether proceeded well and gave 36.4 {plus_minus} 14.3%(n=19) yield of which was directly hydrolyzed (Hcl, 90{degrees}C, 10 min) to afford. Removal of the nitro-precursor, which was generated in situ during hydrolysis was critical in the purification of the final product and was accomplished using a combination of C-18 Sep-Pak and silica gel column chromatography. The condensation of {sup 18}F- ketone with Me{sub 2}NCH{sub 2}CH{sub 2}ONH{sub 2}HCl in 2-(2{prime}-methoxyethoxy)ethanol (p-TsOH, 165{degrees}C, 10 min) gave a mixture of [{sup 18}F]SR 46349B and its geometric isomer with ca 1:1 ratio in quantitative yield. [{sup 18}F]SR 46349B was separated from its geometric isomer and other by-products by HPLC [Econosil C-18 semi-prep column, MeOH:MeCN:0.1 MK{sub 2}HPO{sub 4}(27.5:27.5:45), 5 ml/min]. The three step hot synthesis required 170 min and gave a specific activity of 1.14 Ci/{mu}mol, 5% radiochemical yield (EOB) and 96% radiochemical purity.

  16. Resonant Auger decay of Xe{sup *} 4d{sub 5/2}{sup -1}6p: A contribution to the complete experiment from fluorescence polarization studies

    SciTech Connect

    O'Keeffe, P.; Aloiese, S.; Meyer, M.; Lohmann, B.; Kleiman, U.; Grum-Grzhimailo, A. N.

    2004-07-01

    Fluorescence polarimetry has been used to determine the relative partial-wave Auger decay widths for transitions to states of the Xe II 5p{sup 4}6p multiplet after photoexcitation of the Xe{sup *} 4d{sub 5/2}{sup -1}6p(J{sup *}=1) resonance by linearly and circularly polarized synchrotron radiation. Combination with data on the angular distribution and spin polarization of the Auger electrons, providing information on the relative phases of the amplitudes, constitutes the complete experiment on the Auger decay. Multiconfiguration relativistic calculations of the amplitudes have been performed and compared to the measurements.

  17. Angle-resolved Auger electron spectra induced by neon ion impact on aluminum

    NASA Technical Reports Server (NTRS)

    Pepper, S. V.; Aron, P. R.

    1986-01-01

    Auger electron emission from aluminum bombarded with 1 to 5 keV neon ions was studied by angle-resolved electron spectroscopy. The position and shape of the spectral features depended on the incident ion energy, angle of ion incidence, and electron take-off angle with respect to the aluminum surface. These spectral dependencies were interpreted in terms of the Doppler shift given to the Auger electron velocity by the excited atom ejected into the vacuum. For oblique ion incidence it is concluded that a flux of high energy atoms are ejected in a direction close to the projection of the ion beam on the target surface. In addition, a new spectral feature was found and identified as due to Auger emission from excited neon in the aluminum matrix.

  18. Search for multiple-electron emission in Auger transition processes in solids

    NASA Astrophysics Data System (ADS)

    Kalaskar, S.; Hulbert, S. L.; Dong, Q.; Bartynski, B. A.; Weiss, A. H.

    2010-03-01

    We present electron-electron coincidence measurements from Ag(100) taken using a synchrotron radiation photon beam of 465eV energy (which is just above the Ag 3d threshold), with one electron energy analyzer fixed at 175 eV kinetic energy and the other scanned from 150 to 200 eV. The data show a pronounced step at 175 eV consistent with processes in which the energy associated with the filling of the M core hole is shared with two or more correlated electrons that are emitted in an Auger transition accompanied by multiple-electron emission. These results provide direct evidence for the existence of these multiple-electron Auger processes, first posited to explain the origin of the large low energy tail characteristic of Auger spectra from solids.footnotetextE. Jensen, R. A. Bartynski, R. F. Garrett, S. L. Hulbert, E. D. Johnson, and C.-C., Phys. Rev. B 45, 13636 (1992)

  19. 27. MASCOT BRICK AUGER AND No 1 COMBINATION CUTTING TABLE ...

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

    27. MASCOT BRICK AUGER AND No 1 COMBINATION CUTTING TABLE MANUFACTURED BY THE AMERICAN CLAY MACHINERY CO. OF BUCYRUS, OHIO. IT WAS PURCHASED IN 1903. AND USED AT THE FIRST MORAVIAN POTTERY AND TILE WORKS BEFORE BEING MOVED TO ITS PRESENT LOCATION IN 1912. IT IS USED TO SCREEN STONES FROM RAW CLAY AND INCORPORATE WATER TO A PROPER WORKING CONSISTENCY. IT IS NOW POWERED BY AN ELECTRIC MOTOR INSTALLED IN 1990. - Moravian Pottery & Tile Works, Southwest side of State Route 313 (Swamp Road), Northwest of East Court Street, Doylestown, Bucks County, PA

  20. Aperture calculation of the Pierre Auger Observatory surface detector

    SciTech Connect

    Allard, D.; Allekotte, I.; Armengaud, E.; Aublin, J.; Bertou, Xavier; Chou, A.; Ghia, P.L.; Gomez Berisso, M.; Hamilton, J.C.; Lhenry-Yvon, I.; Medina, C.; Navarra, G.; Parizot, E.; Tripathi, A.

    2005-08-01

    We determine the instantaneous aperture and integrated exposure of the surface detector of the Pierre Auger Observatory, taking into account the trigger efficiency as a function of the energy, arrival direction (with zenith angle lower than 60 degrees) and nature of the primary cosmic-ray. We make use of the so-called Lateral Trigger Probability function (or LTP) associated with an extensive air shower, which summarizes all the relevant information about the physics of the shower, the water tank Cherenkov detector, and the triggers.