Science.gov

Sample records for reduced e2 transition

  1. 8 Be Anomalous Internal Pair Production: Possible E2 Transitions

    NASA Astrophysics Data System (ADS)

    Ward, Thomas; Koltick, David; Wang, Haoyu

    2017-01-01

    Significant enhancement of 8 Be internal pair production at 16.7 MeV with large angle correlations from the 18.150 MeV (Jπ =1+) level have been interpreted as a possible dark matter candidate, a light (Jπ =1+) neutral boson or a fifth-force vector gauge boson. We present a conventional alternative interpretation, unseen E2 transitions from the Jπ =2+ levels at 16.626 MeV and 16.922 MeV populated in the decay of the 18.150 MeV (Jπ =1+) level. The calculated E2 transition probabilities agree well with the measured pair production intensity in the back angle correlation where one expects the E2 gamma-ray correlation to peak. Work partially funded under auspices of USDOE-NE Contract DE-DT0004091.

  2. Generalized seniority and E 2 transitions in the tin isotopes

    NASA Astrophysics Data System (ADS)

    Morales, Irving O.; Van Isacker, P.; Talmi, I.

    2011-09-01

    Recently, a shallow minimum was discovered in B(E2) values in even Sn isotopes around the middle of the neutron major shell. A peak in that region was expected according to calculations using generalized seniority. In a model calculation we show that the observed shape is consistent with generalized seniority. It seems to be due to the order of filling of j-orbits.

  3. E1, M1, E2 transition energies and probabilities of W54+ ions

    NASA Astrophysics Data System (ADS)

    Ding, Xiao-bin; Sun, Rui; Liu, Jia-xin; Koike, Fumihiro; Murakami, Izumi; Kato, Daiji; Sakaue, Hiroyuki A.; Nakamura, Nobuyuki; Dong, Chen-zhong

    2017-02-01

    A comprehensive theoretical study of the E1, M1, E2 transitions of a Ca-like tungsten ion is presented. Using the multi-configuration Dirac–Fock (MCDF) method with a restricted active space treatment, the wavelengths and probabilities of the M1 and E2 transitions between the multiplets of the ground state configuration ([Ne]3s23p63d2) and of the E1 transitions between [Ne]3s23p53d3 and [Ne]3s23p63d2 have been calculated. The results are in reasonable agreement with available experimental data. The present E1 and M1 calculations are compared with previous theoretical values. For E2 transitions, the importance of electron correlation from 3s and 3p orbitals is pointed out. Several strong E1 transitions are predicted, which have potential advantages for plasma diagnostics.

  4. E2 transition probabilities for decays of isomers observed in neutron-rich odd Sn isotopes

    SciTech Connect

    Iskra, Ł. W.; Broda, R.; Janssens, R. V.F.; Wrzesiński, J.; Chiara, C. J.; Carpenter, M. P.; Fornal, B.; Hoteling, N.; Kondev, F. G.; Królas, W.; Lauritsen, T.; Pawłat, T.; Seweryniak, D.; Stefanescu, I.; Walters, W. B.; Zhu, S.

    2015-01-01

    High-spin states were investigated with gamma coincidence techniques in neutron-rich Sn isotopes produced in fission processes following ⁴⁸Ca + ²⁰⁸Pb, ⁴⁸Ca + ²³⁸U, and ⁶⁴Ni + ²³⁸U reactions. By exploiting delayed and cross-coincidence techniques, level schemes have been delineated in odd ¹¹⁹⁻¹²⁵Sn isotopes. Particular attention was paid to the occurrence of 19/2⁺ and 23/2⁺ isomeric states for which the available information has now been significantly extended. Reduced transition probabilities, B(E2), extracted from the measured half-lives and the established details of the isomeric decays exhibit a striking regularity. This behavior was compared with the previously observed regularity of the B(E2) amplitudes for the seniority ν = 2 and 3, 10⁺ and 27/2⁻ isomers in even- and odd-Sn isotopes, respectively.

  5. E2 transition probabilities for decays of isomers observed in neutron-rich odd Sn isotopes

    DOE PAGES

    Iskra, Ł. W.; Broda, R.; Janssens, R. V.F.; ...

    2015-01-01

    High-spin states were investigated with gamma coincidence techniques in neutron-rich Sn isotopes produced in fission processes following ⁴⁸Ca + ²⁰⁸Pb, ⁴⁸Ca + ²³⁸U, and ⁶⁴Ni + ²³⁸U reactions. By exploiting delayed and cross-coincidence techniques, level schemes have been delineated in odd ¹¹⁹⁻¹²⁵Sn isotopes. Particular attention was paid to the occurrence of 19/2⁺ and 23/2⁺ isomeric states for which the available information has now been significantly extended. Reduced transition probabilities, B(E2), extracted from the measured half-lives and the established details of the isomeric decays exhibit a striking regularity. This behavior was compared with the previously observed regularity of the B(E2) amplitudesmore » for the seniority ν = 2 and 3, 10⁺ and 27/2⁻ isomers in even- and odd-Sn isotopes, respectively.« less

  6. Surface phases of the transition-metal dichalcogenide IrT e2

    NASA Astrophysics Data System (ADS)

    Chen, Chen; Kim, Jisun; Yang, Yifan; Cao, Guixin; Jin, Rongying; Plummer, E. W.

    2017-03-01

    Transition-metal dichalcogenide IrT e2 has attracted attention because of its striped lattice, charge ordering, and superconductivity. We have investigated the surface structure of IrT e2 , using low-energy electron diffraction and scanning tunneling microscopy. A complex striped lattice modulation as a function of temperature is observed, which shows hysteresis between cooling and warming. While the bulk 5 × 1 and 8 × 1 phases appear at high temperatures, the surface ground state has the 6 × 1 phase, not seen in the bulk, and the surface transition temperatures are distinct from the bulk. The broken symmetry at the surface creates a quite different phase diagram, with the coexistence of several periodicities resembling devil's staircase behavior.

  7. E2 transitions between excited single-phonon states: Role of ground-state correlations

    NASA Astrophysics Data System (ADS)

    Kamerdzhiev, S. P.; Voitenkov, D. A.

    2016-11-01

    The probabilities for E2 transitions between low-lying excited 3- and 5- single-phonon states in the 208Pb and 132Sn magic nuclei are estimated on the basis of the theory of finite Fermi systems. The approach used involves a new type of ground-state correlations, that which originates from integration of three (rather than two, as in the random-phase approximation) single-particle Green's functions. These correlations are shown to make a significant contribution to the probabilities for the aforementioned transitions.

  8. Electrical anisotropy and coexistence of structural transitions and superconductivity in IrT e2

    NASA Astrophysics Data System (ADS)

    Cao, Guixin; Xie, Weiwei; Phelan, W. Adam; DiTusa, J. F.; Jin, Rongying

    2017-01-01

    We report experimental investigations of the electrical transport, magnetic, and thermodynamic properties of IrT e2 single crystals. The resistivity, magnetization, and specific heat display anomalies at TS 1≈283 K ,TS 2≈167 K , and Tc≈2.5 K , corresponding to two structural and one superconducting phase transitions, respectively, demonstrating the coexistence of all of these transitions in high-quality stoichiometric samples. While there is little magnetic anisotropy, a large a b -plane (ρab) and c -axis (ρc) electrical resistivity ratio (ρc/ρab≈730 at T =4 K ) is observed. This two-dimensional (2D) electronic character is further reflected in the disparate temperature dependences of ρab and ρc, with ρab exhibiting a Fermi-liquid-like T2 dependence below ˜25 K , while ρc deviates significantly from this standard metallic behavior. In contrast, the magnetization is almost isotropic and negative over a wide temperature range. This can be explained by larger diamagnetism induced by electronic structure reconstruction as probed by the Hall effect and smaller positive contribution from itinerant electrons due to a low density of states (DOS) at the Fermi level. A small electronic specific heat coefficient with γ ≈1.8 mJ /mol K2 confirms this assertion. This implies that IrT e2 is a weakly coupled superconductor. The connection between the superconductivity and the two structural transitions is discussed.

  9. Measurement of absolute E2 transition strengths in 176W: Signatures for a rapid shape change

    NASA Astrophysics Data System (ADS)

    Fransen, Ch.; Dewald, A.; Friessner, G.; Hackstein, M.; Jolie, J.; Möller, O.; Pissulla, T.; Rother, W.; Zell, K.-O.

    2011-10-01

    The X(5) symmetry describes nuclei at the critical point of the shape phase transition from axially deformed rotor nuclei to spherical vibrators. 150Nd, 152Sm, and 154Gd were the first nuclei where the predicted charateristics of the X(5) symmetry were observed. Later it was shown that also 176,178,180Os can be successfully described with the X(5) symmetry. In the close vicinity of shape phase transitions one expects strongly changing nuclear shapes. In the X(5) region around A = 150 this was observed for nuclei with different neutron numbers, whereas in the X(5) region around A = 180 this is to be expected for different proton numbers. The aim of the work presented here is the confirmation of a rapid shape change for nuclei close to 178Os. Besides the knowledge on the level scheme of the nuclei of interest, especially absolute E2 transition strengths are crucial for the interpretation of nuclear structure. Prolate deformation is expected for 176W. Thus we performed a recoil distance Doppler shift (RDDS) measurement on 176W to measure E2 transition strengths from level lifetimes. The experiment was performed at the Cologne FN TANDEM accelerator with the Cologne coincidence plunger with the reaction 169Dy(16O,4n)176W and a beam energy of 80 MeV. We will present our experimental results and relate them to data on the neighboring nuclei 178Os and 182Pt. The results will be discussed in the framework of nuclear shape transitions in this mass region and compared to calculations with both the Interacting Boson Model (IBM) and the GCM.

  10. Multiple Methanol Transitions Detected in W51-E2 from the Arecibo Galactic Chemistry Survey

    NASA Astrophysics Data System (ADS)

    Minchin, Robert F.; Harrington, Kevin; Ghosh, Tapasi; Salter, Christopher J.; Araya, Esteban; Arce, Hector G.; Lebron Santos, Mayra E.; De Vries, Christopher H.

    2015-01-01

    Two major components of the star-forming region W51 have been observed with the Arecibo 305-m telescope as a part of the Arecibo Galactic Chemistry Survey. Located at a distance of ~6 kpc towards the Sagittarius Arm, W51 is one of the most luminous and massive (upper 5-10% by mass and upper 1% by size of all Giant Molecular Clouds in our Galaxy; Carpenter & Sanders, 1998). The infrared source, IRS1, was observed over 1.1 - 10 GHz from 2010 through 2012, and the angularly nearby compact component, E2, over 4.3 - 4.9 GHz and 8.0 - 10.2 GHz in 2014. Methanol (CH3OH) transitions at 8.34-GHz (4(1,3)-4(1,4)-+), 9.94-GHz (9(-1,9)-8(-2,7)), 9.98-GHz (4(3,2)-5(2,3)++), and 10.06-GHz (4(3,1)-5(2,4)--) were detected towards W51-E2 for the first time, some showing a mixture of emission and absorption. The peak emission ratios for the 9.94- to 9.98-GHz, and the 9.94- to 10.06-GHz transitions are consistent with the predictions of Slysh, Kalenskii & Val'tts (1993). All three 6-cm wavelength hydroxyl (OH) transitions were also detected, with the 4.66-GHz satellite line masing strongly. In IRS1, the intense methanol maser at 6.67 GHz (Araya et al. 2013) was observed to have a flux density of > 200 Jy, with the 4.66-GHz OH maser having an intensity of ~1 Jy. In IRS1, we also detected the methanol 9.94-GHz transition featuring emission with multiple components. Additionally, a total of over 60 H, 30 He, and 8 C radio recombination lines (RRLs) were identified in E2 over the two frequency ranges observed. This includes the highest frequency spectral line yet detected at Arecibo, namely the He(86)α RRL at 10.17 GHz. Over 120 H, 70 He, and 40 C recombination lines were identified in IRS1 over the frequency range of 4 - 10 GHz.

  11. Rates of E1, E2, M1, and M2 transitions in Ni II

    NASA Astrophysics Data System (ADS)

    Cassidy, C. M.; Hibbert, A.; Ramsbottom, C. A.

    2016-03-01

    Aims: We present rates for all E1, E2, M1, and M2 transitions among the 295 fine-structure levels of the configurations 3d9, 3d84s, 3d74s2, 3d84p, and 3d74s4p, determined through an extensive configuration interaction calculation. Methods: The CIV3 code developed by Hibbert and coworkers is used to determine for these levels configuration interaction wave functions with relativistic effects introduced through the Breit-Pauli approximation. Results: Two different sets of calculations have been undertaken with different 3d and 4d functions to ascertain the effect of such variation. The main body of the text includes a representative selection of data, chosen so that key points can be discussed. Some analysis to assess the accuracy of the present data has been undertaken, including comparison with earlier calculations and the more limited range of experimental determinations. The full set of transition data is given in the supplementary material as it is very extensive. Conclusions: We believe that the present transition data are the best currently available. Full Table 4 and Tables 5-8 are only available at the CDS via anonymous ftp to http://cdsarc.u-strasbg.fr (ftp://130.79.128.5) or via http://cdsarc.u-strasbg.fr/viz-bin/qcat?J/A+A/587/A107

  12. E1, E2 and M1 transition parameters for some levels over ionization limit of Ne III

    NASA Astrophysics Data System (ADS)

    Eser, Selda; Özdemir, Leyla

    2016-07-01

    We have reported the level energies and radiative transition ( E1 , E2 and M1 parameters, such as wavelengths, transition rates, oscillator strengths and line strengths for some levels over the ionization limit of Ne III (oxygen-like). The calculations have been performed using the general-purpose relativistic atomic structure package (GRASP) based on the fully relativistic multiconfiguration Dirac-Fock (MCDF) method. The results obtained have been compared with the available theoretical and experimental values in the literature.

  13. Excited states and reduced transition probabilities in 168Os

    NASA Astrophysics Data System (ADS)

    Grahn, T.; Stolze, S.; Joss, D. T.; Page, R. D.; Sayǧı, B.; O'Donnell, D.; Akmali, M.; Andgren, K.; Bianco, L.; Cullen, D. M.; Dewald, A.; Greenlees, P. T.; Heyde, K.; Iwasaki, H.; Jakobsson, U.; Jones, P.; Judson, D. S.; Julin, R.; Juutinen, S.; Ketelhut, S.; Leino, M.; Lumley, N.; Mason, P. J. R.; Möller, O.; Nomura, K.; Nyman, M.; Petts, A.; Peura, P.; Pietralla, N.; Pissulla, Th.; Rahkila, P.; Sapple, P. J.; Sarén, J.; Scholey, C.; Simpson, J.; Sorri, J.; Stevenson, P. D.; Uusitalo, J.; Watkins, H. V.; Wood, J. L.

    2016-10-01

    The level scheme of the neutron-deficient nuclide 168Os has been extended and mean lifetimes of excited states have been measured by the recoil distance Doppler-shift method using the JUROGAM γ -ray spectrometer in conjunction with the IKP Köln plunger device. The 168Osγ rays were measured in delayed coincidence with recoiling fusion-evaporation residues detected at the focal plane of the RITU gas-filled separator. The ratio of reduced transition probabilities B (E 2 ;41+→21+) /B (E 2 ;21+→01+) is measured to be 0.34(18), which is very unusual for collective band structures and cannot be reproduced by interacting boson model (IBM-2) calculations based on the SkM* energy-density functional.

  14. Radiative rates for forbidden M1 and E2 transitions of astrophysical interest in doubly ionized iron-peak elements

    NASA Astrophysics Data System (ADS)

    Fivet, V.; Quinet, P.; Bautista, M. A.

    2016-01-01

    Aims: Accurate and reliable atomic data for lowly ionized Fe-peak species (Sc, Ti, V, Cr, Mn, Fe, Co, and Ni) are of paramount importance for analyzing the high-resolution astrophysical spectra currently available. The third spectra of several iron group elements have been observed in different galactic sources, such as Herbig-Haro objects in the Orion Nebula and stars like Eta Carinae. However, forbidden M1 and E2 transitions between low-lying metastable levels of doubly charged iron-peak ions have been investigated very little so far, and radiative rates for those lines remain sparse or nonexistent. We attempt to fill that gap and provide transition probabilities for the most important forbidden lines of all doubly ionized iron-peak elements. Methods: We carried out a systematic study of the electronic structure of doubly ionized Fe-peak species. The magnetic dipole (M1) and electric quadrupole (E2) transition probabilities were computed using the pseudo-relativistic Hartree-Fock (HFR) code of Cowan and the central Thomas-Fermi-Dirac-Amaldi potential approximation implemented in AUTOSTRUCTURE. This multiplatform approach allowed for consistency checks and intercomparison and has proven very useful in many previous works for estimating the uncertainties affecting the radiative data. Results: We present transition probabilities for the M1 and E2 forbidden lines depopulating the metastable even levels belonging to the 3dk and 3dk-14s configurations in Sc III (k = 1), Ti III (k = 2), V III (k = 3), Cr III (k = 4), Mn III (k = 5), Fe III (k = 6), Co III (k = 7), and Ni III (k = 8).

  15. Gait transitions in simulated reduced gravity.

    PubMed

    Ivanenko, Yuri P; Labini, Francesca Sylos; Cappellini, Germana; Macellari, Velio; McIntyre, Joseph; Lacquaniti, Francesco

    2011-03-01

    Gravity has a strong effect on gait and the speed of gait transitions. A gait has been defined as a pattern of locomotion that changes discontinuously at the transition to another gait. On Earth, during gradual speed changes, humans exhibit a sudden discontinuous switch from walking to running at a specific speed. To study the effects of altered gravity on both the stance and swing legs, we developed a novel unloading exoskeleton that allows a person to step in simulated reduced gravity by tilting the body relative to the vertical. Using different simulation techniques, we confirmed that at lower gravity levels the transition speed is slower (in accordance with the previously reported Froude number ∼0.5). Surprisingly, however, we found that at lower levels of simulated gravity the transition between walking and running was generally gradual, without any noticeable abrupt change in gait parameters. This was associated with a significant prolongation of the swing phase, whose duration became virtually equal to that of stance in the vicinity of the walk-run transition speed, and with a gradual shift from inverted-pendulum gait (walking) to bouncing gait (running).

  16. Measurement of absolute E2 transition strengths in {sup 176}W: Signatures for a rapid shape change

    SciTech Connect

    Fransen, Ch.; Dewald, A.; Friessner, G.; Hackstein, M.; Jolie, J.; Pissulla, T.; Rother, W.; Zell, K.-O.; Moeller, O.

    2011-10-28

    The X(5) symmetry describes nuclei at the critical point of the shape phase transition from axially deformed rotor nuclei to spherical vibrators. {sup 150}Nd, {sup 152}Sm, and {sup 154}Gd were the first nuclei where the predicted characteristics of the X(5) symmetry were observed. Later it was shown that also {sup 176,178,180}Os can be successfully described with the X(5) symmetry.In the close vicinity of shape phase transitions one expects strongly changing nuclear shapes. In the X(5) region around A = 150 this was observed for nuclei with different neutron numbers, whereas in the X(5) region around A = 180 this is to be expected for different proton numbers. The aim of the work presented here is the confirmation of a rapid shape change for nuclei close to {sup 178}Os. Besides the knowledge on the level scheme of the nuclei of interest, especially absolute E2 transition strengths are crucial for the interpretation of nuclear structure. Prolate deformation is expected for {sup 176}W. Thus we performed a recoil distance Doppler shift (RDDS) measurement on {sup 176}W to measure E2 transition strengths from level lifetimes. The experiment was performed at the Cologne FN TANDEM accelerator with the Cologne coincidence plunger with the reaction {sup 169}Dy({sup 16}O,4n){sup 176}W and a beam energy of 80 MeV. We will present our experimental results and relate them to data on the neighboring nuclei {sup 178}Os and {sup 182}Pt. The results will be discussed in the framework of nuclear shape transitions in this mass region and compared to calculations with both the Interacting Boson Model (IBM) and the GCM.

  17. E2→E1 transition and Rb(+) release induced by Na(+) in the Na(+)/K(+)-ATPase. Vanadate as a tool to investigate the interaction between Rb(+) and E2.

    PubMed

    Montes, Mónica R; Monti, José L E; Rossi, Rolando C

    2012-09-01

    This work presents a detailed kinetic study that shows the coupling between the E2→E1 transition and Rb(+) deocclusion stimulated by Na(+) in pig-kidney purified Na,K-ATPase. Using rapid mixing techniques, we measured in parallel experiments the decrease in concentration of occluded Rb(+) and the increase in eosin fluorescence (the formation of E1) as a function of time. The E2→E1 transition and Rb(+) deocclusion are described by the sum of two exponential functions with equal amplitudes, whose rate coefficients decreased with increasing [Rb(+)]. The rate coefficient values of the E2→E1 transition were very similar to those of Rb(+)-deocclusion, indicating that both processes are simultaneous. Our results suggest that, when ATP is absent, the mechanism of Na(+)-stimulated Rb(+) deocclusion would require the release of at least one Rb(+) ion through the extracellular access prior to the E2→E1 transition. Using vanadate to stabilize E2, we measured occluded Rb(+) in equilibrium conditions. Results show that, while Mg(2+) decreases the affinity for Rb(+), addition of vanadate offsets this effect, increasing the affinity for Rb(+). In transient experiments, we investigated the exchange of Rb(+) between the E2-vanadate complex and the medium. Results show that, in the absence of ATP, vanadate prevents the E2→E1 transition caused by Na(+) without significantly affecting the rate of Rb(+) deocclusion. On the other hand, we found the first evidence of a very low rate of Rb(+) occlusion in the enzyme-vanadate complex, suggesting that this complex would require a change to an open conformation in order to bind and occlude Rb(+).

  18. Na(+) transport, and the E(1)P-E(2)P conformational transition of the Na(+)/K(+)-ATPase.

    PubMed Central

    Babes, A; Fendler, K

    2000-01-01

    We have used admittance analysis together with the black lipid membrane technique to analyze electrogenic reactions within the Na(+) branch of the reaction cycle of the Na(+)/K(+)-ATPase. ATP release by flash photolysis of caged ATP induced changes in the admittance of the compound membrane system that are associated with partial reactions of the Na(+)/K(+)-ATPase. Frequency spectra and the Na(+) dependence of the capacitive signal are consistent with an electrogenic or electroneutral E(1)P <--> E(2)P conformational transition which is rate limiting for a faster electrogenic Na(+) dissociation reaction. We determine the relaxation rate of the rate-limiting reaction and the equilibrium constants for both reactions at pH 6.2-8.5. The relaxation rate has a maximum value at pH 7.4 (approximately 320 s(-1)), which drops to acidic (approximately 190 s(-1)) and basic (approximately 110 s(-1)) pH. The E(1)P <--> E(2)P equilibrium is approximately at a midpoint position at pH 6.2 (equilibrium constant approximately 0.8) but moves more to the E(1)P side at basic pH 8.5 (equilibrium constant approximately 0.4). The Na(+) affinity at the extracellular binding site decreases from approximately 900 mM at pH 6.2 to approximately 200 mM at pH 8.5. The results suggest that during Na(+) transport the free energy supplied by the hydrolysis of ATP is mainly used for the generation of a low-affinity extracellular Na(+) discharge site. Ionic strength and lyotropic anions both decrease the relaxation rate. However, while ionic strength does not change the position of the conformational equilibrium E(1)P <--> E(2)P, lyotropic anions shift it to E(1)P. PMID:11053130

  19. Structural and electronic transitions in G e2S b2T e5 induced by ion irradiation damage

    NASA Astrophysics Data System (ADS)

    Privitera, S. M. S.; Mio, A. M.; Smecca, E.; Alberti, A.; Zhang, W.; Mazzarello, R.; Benke, J.; Persch, C.; La Via, F.; Rimini, E.

    2016-09-01

    G e2S b2T e5 polycrystalline films either in the trigonal stable phase or in the metastable rock-salt structure have been irradiated with 150 keV Ar+ ions. The effects of disorder are studied by electrical, optical, and structural measurements and density functional theory (DFT) simulations. In the metastable structure, the main effect of ion irradiation is a progressive amorphization, with an optical threshold at a fluence of 3 ×1013c m-2 . For the trigonal structure, a metal-insulator transition and a crystalline transition to rock-salt structure occur prior to amorphization, which requires a fluence of 8 ×1013c m-2 . The bonds of Te atoms close to the van der Waals gaps, present in the trigonal phase and identified by Raman spectroscopy, change as a function of the disorder induced by the irradiation. Comparison with DFT simulations shows that ion irradiation leads to the gradual filling of the van der Waals gaps with displaced Ge and Sb lattice atoms, giving rise first to a metal-insulator transition (9 % of displaced atoms) correlated to the modification of the Te bonds and then induces a structural transition to the metastable rock-salt phase (15 % of displaced atoms). The data presented here not only show the possibility to tune the degree of order, and therefore the electrical properties and the structure of phase change materials by ion irradiation, but also underline the importance of the van der Waals gaps in determining the transport mechanisms and the stability of the crystalline structure.

  20. Energy levels, wavelengths, and transition rates of multipole transitions (E1, E2, M1, M2) in Au{sup 67+} and Au{sup 66+} ions

    SciTech Connect

    Hamasha, Safeia

    2013-11-15

    The fully relativistic configuration interaction method of the FAC code is used to calculate atomic data for multipole transitions in Mg-like Au (Au{sup 67+}) and Al-like Au (Au{sup 66+}) ions. Generated atomic data are important in the modeling of M-shell spectra for heavy Au ions and Au plasma diagnostics. Energy levels, oscillator strengths and transition rates are calculated for electric-dipole (E1), electric quadrupole (E2), magnetic dipole (M1), and magnetic quadrupole (M2) for transitions between excited and ground states 3l−nl{sup ′}, such that n=4,5,6,7. The local central potential is derived using the Dirac–Fock–Slater method. Correlation effects to all orders are considered by the configuration interaction expansion. All relativistic effects are included in the calculations. Calculated energy levels are compared against published values that were calculated using the multi-reference many body perturbation theory, which includes higher order QED effects. Favorable agreement was observed, with less than 0.15% difference.

  1. Prostaglandin E2 reduces radiation-induced epithelial apoptosis through a mechanism involving AKT activation and bax translocation.

    PubMed

    Tessner, Teresa G; Muhale, Filipe; Riehl, Terrence E; Anant, Shrikant; Stenson, William F

    2004-12-01

    Prostaglandin E2 (PGE2) synthesis modulates the response to radiation injury in the mouse intestinal epithelium through effects on crypt survival and apoptosis; however, the downstream signaling events have not been elucidated. WT mice receiving 16,16-dimethyl PGE2 (dmPGE2) had fewer apoptotic cells per crypt than untreated mice. Apoptosis in Bax(-/-) mice receiving 12 Gy was approximately 50% less than in WT mice, and the ability of dmPGE2 to attenuate apoptosis was lost in Bax(-/-) mice. Positional analysis revealed that apoptosis in the Bax(-/-) mice was diminished only in the bax-expressing cells of the lower crypts and that in WT mice, dmPGE2 decreased apoptosis only in the bax-expressing cells. The HCT-116 intestinal cell line and Bax(-/-) HCT-116 recapitulated the apoptotic response of the mouse small intestine with regard to irradiation and dmPGE2. Irradiation of HCT-116 cells resulted in phosphorylation of AKT that was enhanced by dmPGE2 through transactivation of the EGFR. Inhibition of AKT phosphorylation prevented the reduction of apoptosis by dmPGE2 following radiation. Transfection of HCT-116 cells with a constitutively active AKT reduced apoptosis in irradiated cells to the same extent as in nontransfected cells treated with dmPGE2. Treatment with dmPGE2 did not alter bax or bcl-x expression but suppressed bax translocation to the mitochondrial membrane. Our in vivo studies indicate that there are bax-dependent and bax-independent radiation-induced apoptosis in the intestine but that only the bax-dependent apoptosis is reduced by dmPGE2. The in vitro studies indicate that dmPGE2, most likely by signaling through the E prostaglandin receptor EP2, reduces radiation-induced apoptosis through transactivation of the EGFR and enhanced activation of AKT and that this results in reduced bax translocation to the mitochondria.

  2. Thymoquinone suppresses migration of LoVo human colon cancer cells by reducing prostaglandin E2 induced COX-2 activation

    PubMed Central

    Hsu, Hsi-Hsien; Chen, Ming-Cheng; Day, Cecilia Hsuan; Lin, Yueh-Min; Li, Shin-Yi; Tu, Chuan-Chou; Padma, Viswanadha Vijaya; Shih, Hui-Nung; Kuo, Wei-Wen; Huang, Chih-Yang

    2017-01-01

    AIM To identify potential anti-cancer constituents in natural extracts that inhibit cancer cell growth and migration. METHODS Our experiments used high dose thymoquinone (TQ) as an inhibitor to arrest LoVo (a human colon adenocarcinoma cell line) cancer cell growth, which was detected by cell proliferation assay and immunoblotting assay. Low dose TQ did not significantly reduce LoVo cancer cell growth. Cyclooxygenase 2 (COX-2) is an enzyme that is involved in the conversion of arachidonic acid into prostaglandin E2 (PGE2) in humans. PGE2 can promote COX-2 protein expression and tumor cell proliferation and was used as a control. RESULTS Our results showed that 20 μmol/L TQ significantly reduced human LoVo colon cancer cell proliferation. TQ treatment reduced the levels of p-PI3K, p-Akt, p-GSK3β, and β-catenin and thereby inhibited the downstream COX-2 expression. Results also showed that the reduction in COX-2 expression resulted in a reduction in PGE2 levels and the suppression of EP2 and EP4 activation. Further analysis showed that TG treatment inhibited the nuclear translocation of β-catenin in LoVo cancer cells. The levels of the cofactors LEF-1 and TCF-4 were also decreased in the nucleus following TQ treatment in a dose-dependent manner. Treatment with low dose TQ inhibited the COX-2 expression at the transcriptional level and the regulation of COX-2 expression efficiently reduced LoVo cell migration. The results were further verified in vivo by confirming the effects of TQ and/or PGE2 using tumor xenografts in nude mice. CONCLUSION TQ inhibits LoVo cancer cell growth and migration, and this result highlights the therapeutic advantage of using TQ in combination therapy against colorectal cancer. PMID:28275297

  3. E2F1 Coregulates Cell Cycle Genes and Chromatin Components during the Transition of Oligodendrocyte Progenitors from Proliferation to Differentiation

    PubMed Central

    Magri, Laura; Swiss, Victoria A.; Jablonska, Beata; Lei, Liang; Pedre, Xiomara; Walsh, Martin; Zhang, Weijia; Gallo, Vittorio; Canoll, Peter

    2014-01-01

    Cell cycle exit is an obligatory step for the differentiation of oligodendrocyte progenitor cells (OPCs) into myelinating cells. A key regulator of the transition from proliferation to quiescence is the E2F/Rb pathway, whose activity is highly regulated in physiological conditions and deregulated in tumors. In this paper we report a lineage-specific decline of nuclear E2F1 during differentiation of rodent OPC into oligodendrocytes (OLs) in developing white matter tracts and in cultured cells. Using chromatin immunoprecipitation (ChIP) and deep-sequencing in mouse and rat OPCs, we identified cell cycle genes (i.e., Cdc2) and chromatin components (i.e., Hmgn1, Hmgn2), including those modulating DNA methylation (i.e., Uhrf1), as E2F1 targets. Binding of E2F1 to chromatin on the gene targets was validated and their expression assessed in developing white matter tracts and cultured OPCs. Increased expression of E2F1 gene targets was also detected in mouse gliomas (that were induced by retroviral transformation of OPCs) compared with normal brain. Together, these data identify E2F1 as a key transcription factor modulating the expression of chromatin components in OPC during the transition from proliferation to differentiation. PMID:24453336

  4. Tables of E2 transition probabilities from the first 2+ states in even-even nuclei [B(E2) evaluation for 0+1 → 2+1 transitions in even-even nuclei

    DOE PAGES

    Pritychenko, B.; Birch, M.; Singh, B.; ...

    2015-11-03

    A complete B(E2)↑ evaluation and compilation for even-even nuclei has been presented. The present paper is a continuation of P.H. Stelson and L. Grodzins, and S. Raman et al. nuclear data evaluations and was motivated by a large number of new measurements. It extends the list of evaluated nuclides from 328 to 452, includes an extended list of nuclear reaction kinematics parameters and comprehensive shell model analysis. Evaluation policies for analysis of experimental data have been discussed and conclusions are given. Moreover, future plans for B(E2)↑ systematics and experimental technique analyses of even-even nuclei are outlined.

  5. The reduced transition probabilities for excited states of rare-earths and actinide even-even nuclei

    SciTech Connect

    Ghumman, S. S.

    2015-08-28

    The theoretical B(E2) ratios have been calculated on DF, DR and Krutov models. A simple method based on the work of Arima and Iachello is used to calculate the reduced transition probabilities within SU(3) limit of IBA-I framework. The reduced E2 transition probabilities from second excited states of rare-earths and actinide even–even nuclei calculated from experimental energies and intensities from recent data, have been found to compare better with those calculated on the Krutov model and the SU(3) limit of IBA than the DR and DF models.

  6. Phonon density of states of single-crystal SrF e2A s2 across the collapsed phase transition at high pressure

    NASA Astrophysics Data System (ADS)

    Wang, Y. Q.; Lu, P. C.; Wu, J. J.; Liu, J.; Wang, X. C.; Zhao, J. Y.; Bi, W.; Alp, E. E.; Park, C. Y.; Popov, D.; Jin, C. Q.; Sun, J.; Lin, J. F.

    2016-07-01

    To help our understanding of the structural and superconducting transitions in ferropnictides, partial phonon density of states (PDOS) of iron in a single-crystal SrF e2A s2 pnictide have been investigated from both out-of-plane and in-plane polarizations with respect to the basal plane of the crystal structure using nuclear resonant inelastic x-ray scattering in a high-pressure diamond anvil cell at ambient temperature. The partial PDOS of iron in the pnictide crystal changes dramatically at approximately 8 GPa, which can be associated with the tetragonal (T) to collapsed tetragonal (CT) isostructural transition as evidenced in high-pressure x-ray diffraction measurements and theoretical calculations. Across the T-CT phase transition, analysis of the PDOS spectra shows a rapid stiffening of the optical phonon modes and a dramatic increase of the Lamb-Mössbauer factor (fLM) and mean force constant which can be associated with the rapid decrease of the c axis and the anomalous expansion of the a axis. Theoretically calculated Fe partial PDOS and lattice parameters of SrF e2A s2 further reveal the strong correlation between the lattice parameters and phonons. Our results show that the T-CT transition can induce significant changes in the vibrational, elastic, and thermodynamic properties of SrF e2A s2 single crystal at high pressure.

  7. Momentum injection in tokamak plasmas and transitions to reduced transport.

    PubMed

    Parra, F I; Barnes, M; Highcock, E G; Schekochihin, A A; Cowley, S C

    2011-03-18

    The effect of momentum injection on the temperature gradient in tokamak plasmas is studied. A plausible scenario for transitions to reduced transport regimes is proposed. The transition happens when there is sufficient momentum input so that the velocity shear can suppress or reduce the turbulence. However, it is possible to drive too much velocity shear and rekindle the turbulent transport. The optimal level of momentum injection is determined. The reduction in transport is maximized in the regions of low or zero magnetic shear.

  8. Momentum Injection in Tokamak Plasmas and Transitions to Reduced Transport

    SciTech Connect

    Parra, F. I.; Highcock, E. G.; Schekochihin, A. A.; Barnes, M.

    2011-03-18

    The effect of momentum injection on the temperature gradient in tokamak plasmas is studied. A plausible scenario for transitions to reduced transport regimes is proposed. The transition happens when there is sufficient momentum input so that the velocity shear can suppress or reduce the turbulence. However, it is possible to drive too much velocity shear and rekindle the turbulent transport. The optimal level of momentum injection is determined. The reduction in transport is maximized in the regions of low or zero magnetic shear.

  9. The over expression of long non-coding RNA ANRIL promotes epithelial-mesenchymal transition by activating the ATM-E2F1 signaling pathway in pancreatic cancer: an in vivo and in vitro study.

    PubMed

    Chen, Shi; Zhang, Jia-Qiang; Chen, Jiang-Zhi; Chen, Hui-Xing; Qiu, Fu-Nan; Yan, Mao-Lin; Chen, Yan-Ling; Peng, Cheng-Hong; Tian, Yi-Feng; Wang, Yao-Dong

    2017-03-23

    This study aims to investigate the roles of lncRNA ANRIL in epithelial-mesenchymal transition (EMT) by regulating the ATM-E2F1 signaling pathway in pancreatic cancer (PC). PC rat models were established and ANRIL overexpression and interference plasmids were transfected. The expression of ANRIL, EMT markers (E-cadherin, N-cadherin and Vimentin) and ATM-E2F1 signaling pathway-related proteins (ATM, E2F1, INK4A, INK4B and ARF) were detected. Small molecule drugs were applied to activate and inhibit the ATM-E2F1 signaling pathway. Transwell assay and the scratch test were adopted to detect cell invasion and migration abilities. ANRIL expression in the PC cells was higher than in normal pancreatic duct epithelial cells. In the PC rat models and PC cells, ANRIL interference promoted the expressions of INK4B, INK4A, ARF and E-cadherin, while reduced N-cadherin and Vimentin expression. Over-expressed ANRIL decreased the expression of INK4B, INK4A, ARF and E-cadherin, but raised N-cadherin and Vimentin expressions. By inhibiting the ATM-E2F1 signaling pathway in PC cells, E-cadherin expression increased but N-cadherin and Vimentin expressions decreased. After ANRIL was silenced or the ATM-E2F1 signaling pathway inhibited, PC cell migration and invasion abilities were decreased. In conclusion, over-expression of lncRNA ANRIL can promote EMT of PC cells by activating the ATM-E2F1 signaling pathway.

  10. The impact of substituents on the transition states of SN2 and E2 reactions in aliphatic and vinylic systems: remarkably facile vinylic eliminations.

    PubMed

    Nettey, Samuel; Swift, Christopher A; Joviliano, Renan; Noin, Diogo O; Gronert, Scott

    2012-06-06

    For a series of α and β substituted haloethanes and haloethenes, gas-phase experiments and computational modeling have been used to characterize their nucleophilic substitution and elimination reactions. Despite being less thermodynamically favorable, the vinylic eliminations have rate constants and computed barriers that are similar to those of analogous aliphatic eliminations. This is the result of the vinylic systems shifting to more E1(cb)-like transition states and exploiting the inherent greater acidity of vinylic hydrogens. In general, the α-substituents have a greater impact on the S(N)2 pathways and stabilize the transition states via field and polarizability effects. Substantial stabilization is also provided to the E2 transition states by the α-substituents, but they have surprisingly little impact on the geometries of the transition states of either pathway. The β-substituents generally lead to a strong bias toward elimination and greatly affect the synchronicity of the elimination (more E1(cb)-like) as well as its location on the reaction coordinate (early). The experimental and computational data are in good accord, and the full data set provides a comprehensive picture of substituent effects on solvent-free S(N)2 and E2 processes.

  11. Effective theory for the nonrigid rotor in an electromagnetic field: Toward accurate and precise calculations of E2 transitions in deformed nuclei

    DOE PAGES

    Coello Pérez, Eduardo A.; Papenbrock, Thomas F.

    2015-07-27

    In this paper, we present a model-independent approach to electric quadrupole transitions of deformed nuclei. Based on an effective theory for axially symmetric systems, the leading interactions with electromagnetic fields enter as minimal couplings to gauge potentials, while subleading corrections employ gauge-invariant nonminimal couplings. This approach yields transition operators that are consistent with the Hamiltonian, and the power counting of the effective theory provides us with theoretical uncertainty estimates. We successfully test the effective theory in homonuclear molecules that exhibit a large separation of scales. For ground-state band transitions of rotational nuclei, the effective theory describes data well within theoreticalmore » uncertainties at leading order. To probe the theory at subleading order, data with higher precision would be valuable. For transitional nuclei, next-to-leading-order calculations and the high-precision data are consistent within the theoretical uncertainty estimates. In addition, we study the faint interband transitions within the effective theory and focus on the E2 transitions from the 02+ band (the “β band”) to the ground-state band. Here the predictions from the effective theory are consistent with data for several nuclei, thereby proposing a solution to a long-standing challenge.« less

  12. Effective theory for the nonrigid rotor in an electromagnetic field: Toward accurate and precise calculations of E2 transitions in deformed nuclei

    SciTech Connect

    Coello Pérez, Eduardo A.; Papenbrock, Thomas F.

    2015-07-27

    In this paper, we present a model-independent approach to electric quadrupole transitions of deformed nuclei. Based on an effective theory for axially symmetric systems, the leading interactions with electromagnetic fields enter as minimal couplings to gauge potentials, while subleading corrections employ gauge-invariant nonminimal couplings. This approach yields transition operators that are consistent with the Hamiltonian, and the power counting of the effective theory provides us with theoretical uncertainty estimates. We successfully test the effective theory in homonuclear molecules that exhibit a large separation of scales. For ground-state band transitions of rotational nuclei, the effective theory describes data well within theoretical uncertainties at leading order. To probe the theory at subleading order, data with higher precision would be valuable. For transitional nuclei, next-to-leading-order calculations and the high-precision data are consistent within the theoretical uncertainty estimates. In addition, we study the faint interband transitions within the effective theory and focus on the E2 transitions from the 02+ band (the “β band”) to the ground-state band. Here the predictions from the effective theory are consistent with data for several nuclei, thereby proposing a solution to a long-standing challenge.

  13. Transitional care management reimbursement to reduce COPD readmission.

    PubMed

    Kangovi, Shreya; Grande, David

    2014-01-01

    Reducing preventable readmissions for COPD is an important national health policy goal. Thus far, Centers for Medicare & Medicaid Services (CMS) policies focused on incentivizing improvements in inpatient quality have had variable success. In its 2013 physician-payment rule, CMS announced new payments that reimburse ambulatory care providers for timely posthospital visits and transitional care management services. CMS hopes that posthospital transitional care and services will substitute for readmission, but the evidence supporting this hypothesis is mixed. In this article, we discuss ways for ambulatory pulmonologists to leverage transitional care management payments to enhance access for their patients with COPD while minimizing the risk of a paradoxic increase in readmission rates.

  14. Transition matrices and orbitals from reduced density matrix theory

    SciTech Connect

    Etienne, Thibaud

    2015-06-28

    In this contribution, we report two different methodologies for characterizing the electronic structure reorganization occurring when a chromophore undergoes an electronic transition. For the first method, we start by setting the theoretical background necessary to the reinterpretation through simple tensor analysis of (i) the transition density matrix and (ii) the natural transition orbitals in the scope of reduced density matrix theory. This novel interpretation is made more clear thanks to a short compendium of the one-particle reduced density matrix theory in a Fock space. The formalism is further applied to two different classes of excited states calculation methods, both requiring a single-determinant reference, that express an excited state as a hole-particle mono-excited configurations expansion, to which particle-hole correlation is coupled (time-dependent Hartree-Fock/time-dependent density functional theory) or not (configuration interaction single/Tamm-Dancoff approximation). For the second methodology presented in this paper, we introduce a novel and complementary concept related to electronic transitions with the canonical transition density matrix and the canonical transition orbitals. Their expression actually reflects the electronic cloud polarisation in the orbital space with a decomposition based on the actual contribution of one-particle excitations from occupied canonical orbitals to virtual ones. This approach validates our novel interpretation of the transition density matrix elements in terms of the Euclidean norm of elementary transition vectors in a linear tensor space. A proper use of these new concepts leads to the conclusion that despite the different principles underlying their construction, they provide two equivalent excited states topological analyses. This connexion is evidenced through simple illustrations of (in)organic dyes electronic transitions analysis.

  15. On transition strengths of E1, E2, & E3 in the regions of mixed quadrupole-octupole collectivity

    NASA Astrophysics Data System (ADS)

    Rasmussen, John; Luo, Y. X.; Hamilton, Joseph; Ramayya, A. V.; Donangelo, Raul

    2010-11-01

    We review the main highlights of experiment and theory for the lowest three electric multipolarities, B(E1), B(E2), and B(E3), for nuclei where quadrupole and octupole collectivity may both occur. The principal regions of interest are around 6 to 12 protons and 6 to 12 neutrons beyond the doubly-closed shell nuclei ^132Sn and ^208Pb. We examine microscopic theoretical calculationsootnotetextW. Zhang et al., Phys. Rev. C 81, 034302 (2010) and references therein. in which deformations are driven by Nilsson orbitals near the Fermi energy. We also focus attention on recent experimentalootnotetextP.E. Garrett et al., Phys. Rev. Letts. 103, 062501 (2009) studies of ^152Sm, where the ground band and associated K=1^- band are mirrored by another 0^+ and 1^- band about 0.7 MeV higher in energy. We suggest that a monopole pairing force alone is insufficient to cause this mirroring, and monopole-plus-quadrupole pairing or a more realistic nucleon-nucleon force is needed.

  16. First row transition metal complexes of (E)-2-(2-(2-hydroxybenzylidene) hydrazinyl)-2-oxo-N-phenylacetamide complexes

    NASA Astrophysics Data System (ADS)

    Yousef, T. A.; Abu El-Reash, G. M.; Rakha, T. H.; El-Ayaan, Usama

    2011-12-01

    Manganese(II), iron(II), cobalt(II), nickel(II), copper(II), and chromium(III) complexes of (E)-2-(2-(2-hydroxybenzylidene)hydrazinyl)-2-oxo-N-phenylacetamide were synthesized and characterized by elemental and thermal (TG and DTA) analyses, IR, UV-vis and 1H NMR spectra as well as magnetic moment. Mononuclear complexes are obtained with 1:1 molar ratio except [Mn(HOS) 2(H 2O) 2] and [Co(OS) 2](H 2O) 2 complexes which are obtained with 1:2 molar ratios. The IR spectra of ligand and metal complexes reveal various modes of chelation. The ligand behaves as a monobasic bidentate one and coordination occurs via the enolic oxygen atom and azomethine nitrogen atom. The ligand behaves also as a monobasic tridentate one and coordination occurs through the carbonyl oxygen atom, azomethine nitrogen atom and the hydroxyl oxygen. Moreover, the ligand behaves as a dibasic tridentate and coordination occurs via the enolic oxygen, azomethine nitrogen and the hydroxyl oxygen atoms. The electronic spectra and magnetic moment measurements reveal that all complexes possess octahedral geometry except the copper complexes possesses a square planar geometry. From the modeling studies, the bond length, bond angle, HOMO, LUMO and dipole moment had been calculated to confirm the geometry of the ligands and their investigated complexes. The thermal studies showed the type of water molecules involved in metal complexes as well as the thermal decomposition of some metal complexes. The protonation constant of the ligand and the stability constant of metal complexes were determined pH-metrically in 50% (v/v) dioxane-water mixture at 298 K and found to be consistent with Irving-Williams order. Moreover, the minimal inhibitory concentration (MIC) of these compounds against Staphylococcus aureus, Escherechia coli and Candida albicans were determined.

  17. MicroRNA-10b inhibition reduces E2F1-mediated transcription and miR-15/16 activity in glioblastoma

    PubMed Central

    Teplyuk, Nadiya M.; Uhlmann, Erik J.; Wong, Andus Hon-Kit; Karmali, Priya; Basu, Meenakshi; Gabriely, Galina; Jain, Anant; Wang, Yang; Chiocca, E. Antonio; Stephens, Robert; Marcusson, Eric; Yi, Ming; Krichevsky, Anna M.

    2015-01-01

    MicroRNA-10b (miR-10b) is commonly elevated in glioblastoma (GBM), while not expressed in normal brain tissues. Targeted inhibition of miR-10b has pleiotropic effects on GBM derived cell lines, it reduces GBM growth in animal models, but does not affect normal neurons and astrocytes. This data raises the possibility of developing miR-10b-targeting GBM therapy. However, the mechanisms contributing to miR-10b-mediated glioma cell survival and proliferation are unexplored. We found that inhibition of miR-10b has distinct effects on specific glioma cell lines. In cells expressing high levels of tumor suppressor p21WAF1/Cip1, it represses E2F1-mediated transcription, leading to down-regulation of multiple E2F1 target genes encoding for S-phase specific proteins, epigenetic modulators, and miRNAs (e.g. miR-15/16), and thereby stalling progression through the S-phase of cell cycle. Subsequently, miR-15/16 activities are reduced and many of their direct targets are de-repressed, including ubiquitin ligase FBXW7 that destabilizes Cyclin E. Conversely, GBM cells expressing low p21 level, or after p21 knock-down, exhibit weaker or no E2F1 response to miR-10b inhibition. Comparative analysis of The Cancer Genome Atlas revealed a strong correlation between miR-10b and multiple E2F target genes in GBM and low-grade glioma. Taken together, these findings indicate that miR-10b regulates E2F1-mediated transcription in GBM, in a p21-dependent fashion. PMID:25738367

  18. A universal reduced glass transition temperature for liquids

    NASA Technical Reports Server (NTRS)

    Fedors, R. F.

    1979-01-01

    Data on the dependence of the glass transition temperature on the molecular structure for low-molecular-weight liquids are analyzed in order to determine whether Boyer's reduced glass transition temperature (1952) is a universal constant as proposed. It is shown that the Boyer ratio varies widely depending on the chemical nature of the molecule. It is pointed out that a characteristic temperature ratio, defined by the ratio of the sum of the melting temperature and the boiling temperature to the sum of the glass transition temperature and the boiling temperature, is a universal constant independent of the molecular structure of the liquid. The average value of the ratio obtained from data for 65 liquids is 1.15.

  19. Reducing transit bus emissions: Alternative fuels or traffic operations?

    NASA Astrophysics Data System (ADS)

    Alam, Ahsan; Hatzopoulou, Marianne

    2014-06-01

    In this study, we simulated the operations and greenhouse gas (GHG) emissions of transit buses along a busy corridor and quantified the effects of two different fuels (conventional diesel and compressed natural gas) as well as a set of driving conditions on emissions. Results indicate that compressed natural gas (CNG) reduces GHG emissions by 8-12% compared to conventional diesel, this reduction could increase to 16% with high levels of traffic congestion. However, the benefits of switching from conventional diesel to CNG are less apparent when the road network is uncongested. We also investigated the effects of bus operations on emissions by applying several strategies such as transit signal priority (TSP), queue jumper lanes, and relocation of bus stops. Results show that in congested conditions, TSP alone can reduce GHG emissions by 14% and when combined with improved technology; a reduction of 23% is achieved. The reduction benefits are even more apparent when other transit operational improvements are combined with TSP. Finally a sensitivity analysis was performed to investigate the effect of operational improvements on emissions under varying levels of network congestion. We observe that under “extreme congestion”, the benefits of TSP decrease.

  20. Reducing youth exposure to alcohol ads: targeting public transit.

    PubMed

    Simon, Michele

    2008-07-01

    Underage drinking is a major public health problem. Youth drink more heavily than adults and are more vulnerable to the adverse effects of alcohol. Previous research has demonstrated the connection between alcohol advertising and underage drinking. Restricting outdoor advertising in general and transit ads in particular, represents an important opportunity to reduce youth exposure. To address this problem, the Marin Institute, an alcohol industry watchdog group in Northern California, conducted a survey of alcohol ads on San Francisco bus shelters. The survey received sufficient media attention to lead the billboard company, CBS Outdoor, into taking down the ads. Marin Institute also surveyed the 25 largest transit agencies; results showed that 75 percent of responding agencies currently have policies that ban alcohol advertising. However, as the experience in San Francisco demonstrated, having a policy on paper does not necessarily mean it is being followed. Communities must be diligent in holding accountable government officials, the alcohol industry, and the media companies through which advertising occurs.

  1. Menoprogen, a TCM Herbal Formula for Menopause, Increases Endogenous E2 in an Aged Rat Model of Menopause by Reducing Ovarian Granulosa Cell Apoptosis

    PubMed Central

    Li, Yu; Ma, Hong; Lu, Ye; Tan, B. J.; Xu, L.; Lawal, Temitope O.; Mahady, Gail B.; Liu, Daniel

    2016-01-01

    The effect of Menoprogen (MPG) on ovarian granulosa cell (GC) apoptosis was investigated in vitro and in vivo in an aged rat model of menopause. Intragastric administration of Menoprogen or estradiol valerate to 14-month-old senile female rats for eight weeks increased plasma E2 levels, as well as the weight of both ovarian and uterine tissues. Flow cytometric (FCM) analysis of isolated GCs from MPG-treated aged rats showed reductions in the G0/G1 ratio and apoptotic peaks. Isolated GCs also exhibited an increase in cell size and the number of cytoplastic organelles and intracellular gap junctions, the reappearance of secretory granules, and a lack of apoptotic bodies as determined by TEM. Results from a TdT-mediated dUTP nick end-labeling (TUNEL) assay revealed a reduction in TUNEL-positive GCs after MPG treatment. Immunohistochemical analysis showed a downregulation of proapoptotic Bax proteins and an upregulation of antiapoptotic Bcl-2 proteins. The addition of MPG-medicated serum to the media of cultured GCs also reduced cadmium chloride-induced apoptosis and downregulated caspase-3 protein expression. This work demonstrates that Menoprogen inhibits GC apoptosis in aged female rats and thereby increases E2 production. This represents a novel mechanism of action for this herbal medicine in the treatment of menopausal symptoms. PMID:26981526

  2. Age-associated increase of skin fibroblast-derived prostaglandin E2 contributes to reduced collagen levels in elderly human skin

    PubMed Central

    Li, Yong; Lei, Dan; Swindell, William R; Xia, Wei; Weng, Shinuo; Fu, Jianping; Worthen, Christal A; Okubo, Toru; Johnston, Andrew; Gudjonsson, Johann E; Voorhees, John J; Fisher, Gary J

    2015-01-01

    Production of type I collagen declines during aging, leading to skin thinning and impaired function. Prostaglandin E2 (PGE2) is a pleiotropic lipid mediator that is synthesized from arachidonic acid by the sequential actions of cyclooxygenases (COX) and PGE synthases (PTGES). PGE2 inhibits collagen production by fibroblasts in vitro. We report that PTGES1 and COX2 progressively increase with aging in sun-protected human skin. PTGES1 and COX2 mRNA was increased 3.4-fold and 2.7-fold, respectively, in the dermis of elderly (>80 years) versus young (21-30 years) individuals. Fibroblasts were the major cell source of both enzymes. PGE2 levels were increased 70% in elderly skin. Fibroblasts in aged skin display reduced spreading due to collagen fibril fragmentation. To investigate the relationship between spreading and PGE2 synthesis, fibroblasts were cultured on micropost arrays or hydrogels of varying mechanical compliance. Reduced spreading/mechanical force resulted in increased expression of both PTGES1 and COX2 and elevated levels of PGE2. Inhibition of PGE2 synthesis by diclofenac enhanced collagen production in skin organ cultures. These data suggest that reduced spreading/mechanical force of fibroblasts in aged skin elevates PGE2 production, contributing to reduced collagen production. Inhibition of PGE2 production may be therapeutically beneficial for combating age-associated collagen deficit in human skin. PMID:25905589

  3. Host knockout of E-prostanoid 2 receptors reduces tumor growth and causes major alterations of gene expression in prostaglandin E2-producing tumors

    PubMed Central

    Asting, Annika Gustafsson; Iresjö, Britt-Marie; Nilsberth, Camilla; Smedh, Ulrika; Lundholm, Kent

    2017-01-01

    Prostaglandin E2 (PGE2) is elevated in a variety of malignant tumors and has been shown to affect several hallmarks of cancer. Accordingly, the PGE2 receptor, E-prostanoid 2 (EP2), has been reported to be associated with patient survival and reduced tumor growth in EP2-knockout mice. Thus, the aim of the present study was to screen for major gene expression alterations in tumor tissue growing in EP2-knockout mice. EP2-knockout mice were bred and implanted with EP2 receptor-expressing and PGE2-producing epithelial-like tumors. Tumor tissue and plasma were collected and used for analyses with gene expression microarrays and multiplex enzyme-linked immunosorbent assays. Tumor growth, acute phase reactions/systemic inflammation and the expression of interleukin-6 were reduced in EP2-knockout tumor-bearing mice. Several hundreds of genes displayed major changes of expression in the tumor tissue when grown in EP2-knockout mice. Such gene alterations involved several different cellular functions, including stemness, migration and cell signaling. Besides gene expression, several long non-coding RNAs were downregulated in the tumors from the EP2-knockout mice. Overall, PGE2 signaling via host EP2 receptors affected a large number of different genes involved in tumor progression based on signaling between host stroma and tumor cells, which caused reduced tumor growth. PMID:28123585

  4. E2F transcription factor-1 deficiency reduces pathophysiology in the mouse model of Duchenne muscular dystrophy through increased muscle oxidative metabolism.

    PubMed

    Blanchet, Emilie; Annicotte, Jean-Sébastien; Pradelli, Ludivine A; Hugon, Gérald; Matecki, Stéfan; Mornet, Dominique; Rivier, François; Fajas, Lluis

    2012-09-01

    E2F1 deletion leads to increased mitochondrial number and function, increased body temperature in response to cold and increased resistance to fatigue with exercise. Since E2f1-/- mice show increased muscle performance, we examined the effect of E2f1 genetic inactivation in the mdx background, a mouse model of Duchenne muscular dystrophy (DMD). E2f1-/-;mdx mice demonstrated a strong reduction of physiopathological signs of DMD, including preservation of muscle structure, decreased inflammatory profile, increased utrophin expression, resulting in better endurance and muscle contractile parameters, comparable to normal mdx mice. E2f1 deficiency in the mdx genetic background increased the oxidative metabolic gene program, mitochondrial activity and improved muscle functions. Interestingly, we observed increased E2F1 protein levels in DMD patients, suggesting that E2F1 might represent a promising target for the treatment of DMD.

  5. Reducing Youth Exposure to Alcohol Ads: Targeting Public Transit

    PubMed Central

    2008-01-01

    Underage drinking is a major public health problem. Youth drink more heavily than adults and are more vulnerable to the adverse effects of alcohol. Previous research has demonstrated the connection between alcohol advertising and underage drinking. Restricting outdoor advertising in general and transit ads in particular, represents an important opportunity to reduce youth exposure. To address this problem, the Marin Institute, an alcohol industry watchdog group in Northern California, conducted a survey of alcohol ads on San Francisco bus shelters. The survey received sufficient media attention to lead the billboard company, CBS Outdoor, into taking down the ads. Marin Institute also surveyed the 25 largest transit agencies; results showed that 75 percent of responding agencies currently have policies that ban alcohol advertising. However, as the experience in San Francisco demonstrated, having a policy on paper does not necessarily mean it is being followed. Communities must be diligent in holding accountable government officials, the alcohol industry, and the media companies through which advertising occurs. PMID:18389374

  6. The Agrobacterium tumefaciens Ti Plasmid Virulence Gene virE2 Reduces Sri Lankan Cassava Mosaic Virus Infection in Transgenic Nicotiana benthamiana Plants

    PubMed Central

    Resmi, Thulasi Raveendrannair; Hohn, Thomas; Hohn, Barbara; Veluthambi, Karuppannan

    2015-01-01

    Cassava mosaic disease is a major constraint to cassava cultivation worldwide. In India, the disease is caused by Indian cassava mosaic virus (ICMV) and Sri Lankan cassava mosaic virus (SLCMV). The Agrobacterium Ti plasmid virulence gene virE2, encoding a nuclear-localized, single-stranded DNA binding protein, was introduced into Nicotiana benthamiana to develop tolerance against SLCMV. Leaf discs of transgenic N. benthamiana plants, harboring the virE2 gene, complemented a virE2 mutation in A. tumefaciens and produced tumours. Three tested virE2 transgenic plants displayed reduction in disease symptoms upon agroinoculation with SLCMV DNA A and DNA B partial dimers. A pronounced reduction in viral DNA accumulation was observed in all three virE2 transgenic plants. Thus, virE2 is an effective candidate gene to develop tolerance against the cassava mosaic disease and possibly other DNA virus diseases. PMID:26008704

  7. Prostaglandin E2 Reduces the Release and Infectivity of New Cell-Free Virions and Cell-To-Cell HIV-1 Transfer

    PubMed Central

    Serramía, María Jesús; Martínez-Bonet, Marta; Muñoz-Fernández, María Ángeles

    2014-01-01

    Background The course of human immunodeficiency virus type-1 (HIV-1) infection is influenced by a complex interplay between viral and host factors. HIV infection stimulates several proinflammatory genes, such as cyclooxigense-2 (COX-2), which leads to an increase in prostaglandin (PG) levels in the plasma of HIV-1-infected patients. These genes play an indeterminate role in HIV replication and pathogenesis. The effect of prostaglandin E2 (PGE2) on HIV infection is quite controversial and even contradictory, so we sought to determine the role of PGE2 and the signal transduction pathways involved in HIV infection to elucidate possible new targets for antiretrovirals. Results Our results suggest that PGE2 post-infection treatment acts in the late stages of the viral cycle to reduce HIV replication. Interestingly, viral protein synthesis was not affected, but a loss of progeny virus production was observed. No modulation of CD4 CXCR4 and CCR5 receptor expression, cell proliferation, or activation after PGE2 treatment was detected. Moreover, PGE2 induced an increase in intracellular cAMP (cyclic AMP) levels through the EP2/EP4 receptors. PGE2 effects were mimicked by dbcAMP and by a specific Epac (exchange protein directly activated by cyclic AMP) agonist, 8-Cpt-cAMP. Treatment with PGE2 increased Rap1 activity, decreased RhoA activity and subsequently reduced the polymerization of actin by approximately 30% compared with untreated cells. In connection with this finding, polarized viral assembly platforms enriched in Gag were disrupted, altering HIV cell-to-cell transfer and the infectivity of new virions. Conclusions Our results demonstrate that PGE2, through Epac and Rap activation, alters the transport of newly synthesized HIV-1 components to the assembly site, reducing the release and infectivity of new cell-free virions and cell-to-cell HIV-1 transfer. PMID:24586238

  8. Curcumin reduces prostaglandin E2, matrix metalloproteinase-3 and proteoglycan release in the secretome of interleukin 1β-treated articular cartilage

    PubMed Central

    Mobasheri, Ali

    2013-01-01

    Objective: Curcumin (diferuloylmethane) is a phytochemical with potent anti-inflammatory and anti-oxidant properties, and has therapeutic potential for the treatment of a range of inflammatory diseases, including osteoarthritis (OA). The aim of this study was to determine whether non-toxic concentrations of curcumin can reduce interleukin-1beta (IL-1β)-stimulated inflammation and catabolism in an explant model of cartilage inflammation. Methods: Articular cartilage explants and primary chondrocytes were obtained from equine metacarpophalangeal joints. Curcumin was added to monolayer cultured primary chondrocytes and cartilage explants in concentrations ranging from 3μM-100μM. Prostaglandin E 2 (PGE 2) and matrix metalloproteinase (MMP)-3 release into the secretome of IL-1β-stimulated explants was measured using a competitive ELISA and western blotting respectively. Proteoglycan (PG) release in the secretome was measured using the 1,9-dimethylmethylene blue (DMMB) assay. Cytotoxicity was assessed with a live/dead assay in monolayer cultures after 24 hours, 48 hours and five days, and in explants after five days. Results: Curcumin induced chondrocyte death in primary cultures (50μM p<0.001 and 100μM p<0.001) after 24 hours. After 48 hours and five days, curcumin (≥25μM) significantly increased cell death ( p<0.001 both time points). In explants, curcumin toxicity was not observed at concentrations up to and including 25μM after five days. Curcumin (≥3μM) significantly reduced IL-1β-stimulated PG ( p<0.05) and PGE 2 release ( p<0.001) from explants, whilst curcumin (≥12μM) significantly reduced MMP-3 release ( p<0.01). Conclusion: Non-cytotoxic concentrations of curcumin exert anti-catabolic and anti-inflammatory effects in cartilage explants. PMID:24555068

  9. Noninvasive observations on eyes of cats after long-term maintenance of reduced intraocular pressure by topical application of prostaglandin E2.

    PubMed

    Bito, L Z; Srinivasan, B D; Baroody, R A; Schubert, H

    1983-03-01

    Daily or twice daily prostaglandin E2 (PGE2) application to cat eyes was shown to maintain a reduced intraocular pressure (IOP) for several months without causing substantial flare or cellular response. We report now on detailed ophthalmic examinations performed on these cats after 5-9 months of such treatment (ie, after 150 to 250 unilateral PGE2 applications; 100 micrograms/treatment per eye). A comparison of the treated and contralateral control eyes revealed no differences in the axial length of ocular compartments, in the biomicroscopic appearance of the lens, vitreous, retina, or optic nerve head, in the rate of light-induced pupillary constriction or in the wave form of the electroretinogram. The cell density of the corneal endothelium was not decreased, but the endothelial surface did contain a few small "dark spots." A slight iridial heterochromia was generally apparent. In three of the cats PGE2 application had a sialagogic effect that became a conditioned reflex. Cats tended to keep their lids closed after each treatment; lid closure was more prolonged in the PGE2-treated eye than in the contralateral eye that received the same volume (50 microliters) of vehicle solution. It is concluded that daily treatment with PGE2, in doses sufficient to cause a maintained reduction in IOP, does have some side effects. However, none of these side effects are of sufficient importance to exclude the use of eicosanoids as potential anti-glaucoma agents.

  10. Prostaglandin E2 EP2 activation reduces memory decline in R6/1 mouse model of Huntington's disease by the induction of BDNF-dependent synaptic plasticity.

    PubMed

    Anglada-Huguet, Marta; Vidal-Sancho, Laura; Giralt, Albert; García-Díaz Barriga, Gerardo; Xifró, Xavier; Alberch, Jordi

    2016-11-01

    Huntington's disease (HD) patients and mouse models show learning and memory impairment even before the onset of motor symptoms. Deficits in hippocampal synaptic plasticity have been involved in the HD memory impairment. Several studies show that prostaglandin E2 (PGE2) EP2 receptor stimulates synaptic plasticity and memory formation. However, this role was not explored in neurodegenerative diseases. Here, we investigated the capacity of PGE2 EP2 receptor to promote synaptic plasticity and memory improvements in a model of HD, the R6/1 mice, by administration of the agonist misoprostol. We found that misoprostol increases dendritic branching in cultured hippocampal neurons in a brain-derived neurotrophic factor (BDNF)-dependent manner. Then, we implanted an osmotic mini-pump system to chronically administrate misoprostol to R6/1 mice from 14 to 18weeks of age. We observed that misoprostol treatment ameliorates the R6/1 long-term memory deficits as analyzed by the T-maze spontaneous alternation task and the novel object recognition test. Importantly, administration of misoprostol promoted the expression of hippocampal BDNF. Moreover, the treatment with misoprostol in R6/1 mice blocked the reduction in the number of PSD-95 and VGluT-1 positive particles observed in hippocampus of vehicle-R6/1 mice. In addition, we observed an increase of cAMP levels in the dentate ` of WT and R6/1 mice treated with misoprostol. Accordingly, we showed a reduction in the number of mutant huntingtin nuclear inclusions in the dentate gyrus of R6/1 mice. Altogether, these results suggest a putative therapeutic effect of PGE2 EP2 receptor in reducing cognitive deficits in HD.

  11. Prostaglandin E2 reduces swine myocardial ischemia reperfusion injury via increased endothelial nitric oxide synthase and vascular endothelial growth factor expression levels

    PubMed Central

    Zhou, Ying; Yang, Peng; Li, Aili; Ye, Xiaojun; Ren, Shiyan; Li, Xianlun

    2017-01-01

    Prostaglandin E2 (PGE2) has been demonstrated to attenuate cardiac ischemia-reperfusion (I/R) injury. However, the underlying mechanism of PGE2 in cardiac I/R injury remains unknown. Upregulated expression levels of vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS) were reported in acute myocardial infarction (AMI), and were demonstrated to diminish I/R injury. In the current study the involvement of VEGF and eNOS in the myocardial protective effect of PGE2 were investigated in a catheter-based porcine model of AMI. Twenty-two Chinese miniature pigs were randomized into sham-surgery (n=6), control (n=8) and PGE2 (n=8) groups. PGE2 (1 µg/kg) was injected from 10 min prior to left anterior descending occlusion up to 1 h after reperfusion in the PGE2 group. Subsequently, the hemodynamic parameters were evaluated. Thioflavin-S and Evans Blue double staining were performed to evaluate the extent of the myocardial reperfusion area (RA) and no-reflow area (NRA). Immunohistochemical and western blot analysis were used to evaluate protein expression levels of VEGF and eNOS. Left ventricular (LV) systolic pressure significantly improved and LV end-diastolic pressure significantly decreased in the PGE2 group when compared with the control group 2 h after occlusion and 3 h after reperfusion (P<0.05, respectively). The RA and NRA were smaller in the PGE2 group than in the control group (P<0.05, respectively). Furthermore, PGE2 treatment increased the myocardial content of VEGF and eNOS when compared with the control group (P<0.05, respectively). Thus, the results of the present study demonstrate the cardio-protective mechanisms of PGE2, which may protect the heart from I/R injury via enhancement of VEGF and eNOS expression levels. PMID:28357071

  12. Tables of E2 transition probabilities from the first 2+ states in even-even nuclei [B(E2) evaluation for 0+1 → 2+1 transitions in even-even nuclei

    SciTech Connect

    Pritychenko, B.; Birch, M.; Singh, B.; Horoi, M.

    2015-11-03

    A complete B(E2)↑ evaluation and compilation for even-even nuclei has been presented. The present paper is a continuation of P.H. Stelson and L. Grodzins, and S. Raman et al. nuclear data evaluations and was motivated by a large number of new measurements. It extends the list of evaluated nuclides from 328 to 452, includes an extended list of nuclear reaction kinematics parameters and comprehensive shell model analysis. Evaluation policies for analysis of experimental data have been discussed and conclusions are given. Moreover, future plans for B(E2)↑ systematics and experimental technique analyses of even-even nuclei are outlined.

  13. A minocycline derivative reduces nerve injury-induced allodynia, LPS-induced prostaglandin E2 microglial production and signaling via toll-like receptors 2 and 4

    PubMed Central

    Bastos, Leandro F. S.; Godin, Adriana M.; Zhang, Yingning; Jarussophon, Suwatchai; Ferreira, Bruno C. S.; Machado, Renes R.; Maier, Steven F.; Konishi, Yasuo; de Freitas, Rossimiriam P.; Fiebich, Bernd L.; Watkins, Linda R.; Coelho, Márcio M.; Moraes, Márcio F. D.

    2013-01-01

    Many studies have shown that minocycline, an antibacterial tetracycline, suppresses experimental pain. While minocycline’s positive effects on pain resolution suggest that clinical use of such drugs may prove beneficial, minocycline’s antibiotic actions and divalent cation (Ca2+; Mg2+) chelating effects detract from its potential utility. Thus, we tested the antiallodynic effect induced by a non-antibacterial, non-chelating minocycline derivative in a model of neuropathic pain and performed an initial investigation of its anti-inflammatory effects in vitro. Intraperitoneal minocycline (100 mg/kg) and 12S-hydroxy-1,12-pyrazolinominocycline (PMIN; 23.75, 47.50 or 95.00 mg/kg) reduce the mechanical allodynia induced by chronic constriction injury of mouse sciatic nerve. PMIN reduces the LPS-induced production of PGE2 by primary microglial cell cultures. Human embryonic kidney cells were transfected to express human toll-like receptors 2 and 4, and the signaling via both receptors stimulated with PAM3CSK4 or LPS (respectively) was affected either by minocycline or PMIN. Importantly, these treatments did not affect the cell viability, as assessed by MTT test. Altogether, these results reinforce the evidence that the anti-inflammatory and experimental pain suppressive effects induced by tetracyclines are neither necessarily linked to antibacterial nor to Ca2+ chelating activities. This study supports the evaluation of the potential usefulness of PMIN in the management of neuropathic pain, as its lack of antibacterial and Ca2+ chelating activities might confer greater safety over conventional tetracyclines. PMID:23523650

  14. A minocycline derivative reduces nerve injury-induced allodynia, LPS-induced prostaglandin E2 microglial production and signaling via toll-like receptors 2 and 4.

    PubMed

    Bastos, Leandro F S; Godin, Adriana M; Zhang, Yingning; Jarussophon, Suwatchai; Ferreira, Bruno C S; Machado, Renes R; Maier, Steven F; Konishi, Yasuo; de Freitas, Rossimiriam P; Fiebich, Bernd L; Watkins, Linda R; Coelho, Márcio M; Moraes, Márcio F D

    2013-05-24

    Many studies have shown that minocycline, an antibacterial tetracycline, suppresses experimental pain. While minocycline's positive effects on pain resolution suggest that clinical use of such drugs may prove beneficial, minocycline's antibiotic actions and divalent cation (Ca(2+); Mg(2+)) chelating effects detract from its potential utility. Thus, we tested the antiallodynic effect induced by a non-antibacterial, non-chelating minocycline derivative in a model of neuropathic pain and performed an initial investigation of its anti-inflammatory effects in vitro. Intraperitoneal minocycline (100mg/kg) and 12S-hydroxy-1,12-pyrazolinominocycline (PMIN; 23.75 mg/kg, 47.50mg/kg or 95.00 mg/kg) reduce the mechanical allodynia induced by chronic constriction injury of mouse sciatic nerve. PMIN reduces the LPS-induced production of PGE2 by primary microglial cell cultures. Human embryonic kidney cells were transfected to express human toll-like receptors 2 and 4, and the signaling via both receptors stimulated with PAM3CSK4 or LPS (respectively) was affected either by minocycline or PMIN. Importantly, these treatments did not affect the cell viability, as assessed by MTT test. Altogether, these results reinforce the evidence that the anti-inflammatory and experimental pain suppressive effects induced by tetracyclines are neither necessarily linked to antibacterial nor to Ca(2+) chelating activities. This study supports the evaluation of the potential usefulness of PMIN in the management of neuropathic pain, as its lack of antibacterial and Ca(2+) chelating activities might confer greater safety over conventional tetracyclines.

  15. Analysis of Low Excitation HDO Transitions toward the High-mass Star-forming Regions G34.26+0.15, W51e1/e2, and W49N

    NASA Astrophysics Data System (ADS)

    Kulczak-Jastrzȩbska, Magda

    2017-02-01

    We present observations of the ground state 10,1–00,0 rotational transition of HDO at 464.925 GHz and the 11,0–10,1 transition at 509.292 GHz, toward three high-mass star-forming regions: G34.26+0.15, W49N, and W51e1/e2, carried out with the Caltech Submillimeter Observatory. For the first time, the latter transition is observed from the ground. The spectra are modeled, together with observations of higher-energy HDO transitions, as well as submillimeter dust continuum fluxes from the literature, using a spherically symmetric radiative transfer model to derive the radial distribution of the HDO abundance in the target sources. The abundance profile is divided into an inner hot core region, with kinetic temperatures higher than 100 K, and a cold outer envelope with lower kinetic temperatures. The derived HDO abundance with respect to H2 is (0.3–3.7) × 10‑8 in the hot inner region (T > 100 K) and (7.0–10.0) × 10‑11 in the cold outer envelope. We also used two {{{H}}}218{{O}} fundamental transitions to constrain the H2O abundances in the outer envelopes. The HDO/H2O ratios in these cold regions are found to be (1.8–3.1) × 10‑3 and consequently are higher than in the hot inner regions of these sources.

  16. Reduced transition strengths of low-lying yrast states in chromium isotopes in the vicinity of N =40

    NASA Astrophysics Data System (ADS)

    Braunroth, Thomas; Dewald, A.; Iwasaki, H.; Lenzi, S. M.; Albers, M.; Bader, V. M.; Baugher, T.; Baumann, T.; Bazin, D.; Berryman, J. S.; Fransen, C.; Gade, A.; Ginter, T.; Gottardo, A.; Hackstein, M.; Jolie, J.; Lemasson, A.; Litzinger, J.; Lunardi, S.; Marchi, T.; Modamio, V.; Morse, C.; Napoli, D. R.; Nichols, A.; Recchia, F.; Stroberg, S. R.; Wadsworth, R.; Weisshaar, D.; Whitmore, K.; Wimmer, K.

    2015-09-01

    Background: In neutron-rich nuclei around N =40 rapid changes in nuclear structure can be observed. While 68Ni exhibits signatures of a doubly magic nucleus, experimental data along the isotopic chains in even more exotic Fe and Cr isotopes—such as excitation energies and transition strengths—suggest a sudden rise in collectivity toward N =40 . Purpose: Reduced quadrupole transition strengths for low-lying transitions in neutron-rich 58,60,62Cr are investigated. This gives quantitative new insights into the evolution of quadrupole collectivity in the neutron-rich region close to N =40 . Method: The recoil distance Doppler-shift (RDDS) technique was applied to measure lifetimes of low-lying states in 58,60,62>Cr. The experiment was carried out at the National Superconducting Cyclotron Laboratory (NSCL) with the SeGA array in a plunger configuration coupled to the S800 magnetic spectrograph. The states of interest were populated by means of one-proton knockout reactions. Results: Data reveal a rapid increase in quadrupole collectivity for 58,60,62>Cr toward N =40 and point to stronger quadrupole deformations compared to neighboring Fe isotopes. The experimental B (E 2 ) values are reproduced well with state-of-the-art shell-model calculations using the LNPS effective interaction. A consideration of intrinsic quadrupole moments and B42 ratios suggest an evolution toward a rotational nature of the collective structures in Cr,6260. Compared to 58Cr, experimental B42 and B62 values for 60Cr are in better agreement with the E (5 ) limit. Conclusion: Our results indicate that collective excitations in neutron-rich Cr isotopes saturate at N =38 , which is in agreement with theoretical predictions. More detailed experimental data of excited structures and interband transitions are needed for a comprehensive understanding of quadrupole collectivity close to N =40 . This calls for additional measurements in neutron-rich Cr and neighboring Ti and Fe nuclei.

  17. Pressure-induced structural evaluation and insulator-metal transition in the mixed spinel ferrite Z n0.2M g0.8F e2O4

    NASA Astrophysics Data System (ADS)

    Rahman, S.; Samanta, Sudeshna; Errandonea, D.; Yan, Shuai; Yang, Ke; Lu, Junling; Wang, Lin

    2017-01-01

    The effect of pressure on the electronic properties and crystal structure in a mixed spinel ferrite Z n0.2M g0.8F e2O4 was studied for the first time up to 48 GPa at room temperature using x-ray diffraction, Raman spectroscopy, and electrical transport measurements. The sample was cubic (spinel-type F d 3 ¯m ) at ambient pressure and underwent a pressure-induced structural transition to an orthorhombic phase (CaT i2O4-type B b m m ) at 21 GPa. This structural transformation corresponded to a first-order phase transition that involved 7.5% molar volume shrinkage. The onset of the Mott insulator-metal transition (IMT) around 20 GPa was due to a spin crossover mechanism that led to the F e3 + magnetic moment collapse. All the Raman modes disappeared at high pressures, which supported metallization. Analysis of structural and electrical transport measurements showed a simultaneous volume collapse and sharp IMT within a narrow pressure range. The orthorhombic high-pressure phase was found to have a higher conductivity than the cubic phase. The pressure dependence of the conductivity supported the metallic behavior of the high-pressure phase.

  18. Nuclear localization of γ-tubulin affects E2F transcriptional activity and S-phase progression

    PubMed Central

    Höög, Greta; Zarrizi, Reihaneh; von Stedingk, Kristoffer; Jonsson, Kristina; Alvarado-Kristensson, Maria

    2011-01-01

    We show that the centrosome- and microtubule-regulating protein γ-tubulin interacts with E2 promoter binding factors (E2Fs) to modulate E2F transcriptional activity and thereby control cell cycle progression. γ-Tubulin contains a C-terminal signal that results in its translocation to the nucleus during late G1 to early S phase. γ-Tubulin mutants showed that the C terminus interacts with the transcription factor E2F1 and that the E2F1–γ-tubulin complex is formed during the G1/S transition, when E2F1 is transcriptionally active. Furthermore, E2F transcriptional activity is altered by reduced expression of γ-tubulin or by complex formation between γ-tubulin and E2F1, E2F2, or E2F3, but not E2F6. In addition, the γ-tubulin C terminus encodes a DNA-binding domain that interacts with E2F-regulated promoters, resulting in γ-tubulin-mediated transient activation of E2Fs. Thus, we report a novel mechanism regulating the activity of E2Fs, which can help explain how these proteins affect cell cycle progression in mammalian cells.—Höög, G., Zarrizi, R., von Stedingk, K., Jonsson, K., Alvarado-Kristensson, M. Nuclear localization of γ-tubulin affects E2F transcriptional activity and S-phase progression. PMID:21788450

  19. Reduced linewidth enhancement factor due to excited state transition of quantum dot lasers.

    PubMed

    Xu, Peng-Fei; Ji, Hai-Ming; Xiao, Jin-Long; Gu, Yong-Xian; Huang, Yong-Zhen; Yang, Tao

    2012-04-15

    The carrier induced refractive index change and linewidth enhancement factor α due to ground-state (GS) and excited-state (ES) transitions have been compared by measuring the optical gain spectra from an InAs/GaAs quantum dot (QD) laser structure. It is shown that the ES transition exhibits a reduced α-factor compared to the value due to the GS transition. This result can be explained by the α-factor due to the ES transition having a smaller increase from the non-resonant carriers in the combined state of the wetting layer and InGaAs strain reducing layer than the α-factor increase due to the GS transition, since the relaxation time for carriers from the combined state of the wetting layer and InGaAs strain reducing layer to the ES is shorter than to the GS. The result reported here shows another advantage of using ES QD lasers for optical communication, in addition to their higher modulation speed.

  20. Approaches for reducing the insulator-metal transition pressure in hydrogen

    NASA Technical Reports Server (NTRS)

    Carlsson, A. E.; Ashcroft, N. W.

    1983-01-01

    Two possible techniques for reducing the external pressure required to induce the insulator-metal transition in solid hydrogen are described. One uses impurities to lower the energy of the metallic phase relative to that of the insulating phase. The other utilizes a negative pressure induced in the insulating phase by electron-hole pairs, created either with laser irradiation or pulsed synchrotron sources.

  1. A multi coding technique to reduce transition activity in VLSI circuits

    NASA Astrophysics Data System (ADS)

    Vithyalakshmi, N.; Rajaram, M.

    2014-02-01

    Advances in VLSI technology have enabled the implementation of complex digital circuits in a single chip, reducing system size and power consumption. In deep submicron low power CMOS VLSI design, the main cause of energy dissipation is charging and discharging of internal node capacitances due to transition activity. Transition activity is one of the major factors that also affect the dynamic power dissipation. This paper proposes power reduction analyzed through algorithm and logic circuit levels. In algorithm level the key aspect of reducing power dissipation is by minimizing transition activity and is achieved by introducing a data coding technique. So a novel multi coding technique is introduced to improve the efficiency of transition activity up to 52.3% on the bus lines, which will automatically reduce the dynamic power dissipation. In addition, 1 bit full adders are introduced in the Hamming distance estimator block, which reduces the device count. This coding method is implemented using Verilog HDL. The overall performance is analyzed by using Modelsim and Xilinx Tools. In total 38.2% power saving capability is achieved compared to other existing methods.

  2. E2F-4 and E2F-5, two members of the E2F family, are expressed in the early phases of the cell cycle.

    PubMed Central

    Sardet, C; Vidal, M; Cobrinik, D; Geng, Y; Onufryk, C; Chen, A; Weinberg, R A

    1995-01-01

    The E2F transcription factors play a role in regulating the expression of genes required for cell proliferation. Their activity appears to be regulated by association with the retinoblastoma protein (pRb) and the pRb-related proteins p107 and p130. In vivo, pRb is found in complex with a subset of E2F components--namely, E2F-1, E2F-2, and E2F-3. Here we describe the characterization of cDNAs encoding two unusual E2Fs, E2F-4 and E2F-5, each identified by the ability of their gene product to interact with p130 in a yeast two-hybrid system. E2F-4 and -5 share common sequences with E2F-1, E2F-2, and E2F-3 and, like these other E2Fs, the ability to heterodimerize with DP-1, thereby acquiring the ability to bind an E2F DNA recognition sequence with high affinity. However, in contrast to E2F-1, E2F-4 and E2F-5 fail to bind pRb in a two-hybrid assay. Moreover, they show a unique pattern of expression in synchronized human keratinocytes: E2F-4 and E2F-5 mRNA expression is maximal in mid-G1 phase before E2F-1 expression is detectable. These findings suggest that E2F-4 and E2F-5 may contribute to the regulation of early G1 events including the G0/G1 transition. Images Fig. 2 Fig. 3 Fig. 4 PMID:7892279

  3. Effect of reduced gravity on the preferred walk-run transition speed

    NASA Technical Reports Server (NTRS)

    Kram, R.; Domingo, A.; Ferris, D. P.

    1997-01-01

    We investigated the effect of reduced gravity on the human walk-run gait transition speed and interpreted the results using an inverted-pendulum mechanical model. We simulated reduced gravity using an apparatus that applied a nearly constant upward force at the center of mass, and the subjects walked and ran on a motorized treadmill. In the inverted pendulum model for walking, gravity provides the centripetal force needed to keep the pendulum in contact with the ground. The ratio of the centripetal and gravitational forces (mv2/L)/(mg) reduces to the dimensionless Froude number (v2/gL). Applying this model to a walking human, m is body mass, v is forward velocity, L is leg length and g is gravity. In normal gravity, humans and other bipeds with different leg lengths all choose to switch from a walk to a run at different absolute speeds but at approximately the same Froude number (0.5). We found that, at lower levels of gravity, the walk-run transition occurred at progressively slower absolute speeds but at approximately the same Froude number. This supports the hypothesis that the walk-run transition is triggered by the dynamics of an inverted-pendulum system.

  4. Effect of reduced gravity on the preferred walk-run transition speed.

    PubMed

    Kram, R; Domingo, A; Ferris, D P

    1997-02-01

    We investigated the effect of reduced gravity on the human walk-run gait transition speed and interpreted the results using an inverted-pendulum mechanical model. We simulated reduced gravity using an apparatus that applied a nearly constant upward force at the center of mass, and the subjects walked and ran on a motorized treadmill. In the inverted pendulum model for walking, gravity provides the centripetal force needed to keep the pendulum in contact with the ground. The ratio of the centripetal and gravitational forces (mv2/L)/(mg) reduces to the dimensionless Froude number (v2/gL). Applying this model to a walking human, m is body mass, v is forward velocity, L is leg length and g is gravity. In normal gravity, humans and other bipeds with different leg lengths all choose to switch from a walk to a run at different absolute speeds but at approximately the same Froude number (0.5). We found that, at lower levels of gravity, the walk-run transition occurred at progressively slower absolute speeds but at approximately the same Froude number. This supports the hypothesis that the walk-run transition is triggered by the dynamics of an inverted-pendulum system.

  5. A mutation in the E2 subunit of the mitochondrial pyruvate dehydrogenase complex in Arabidopsis reduces plant organ size and enhances the accumulation of amino acids and intermediate products of the TCA cycle.

    PubMed

    Yu, Hailan; Du, Xiaoqiu; Zhang, Fengxia; Zhang, Fang; Hu, Yong; Liu, Shichang; Jiang, Xiangning; Wang, Guodong; Liu, Dong

    2012-08-01

    The mitochondrial pyruvate dehydrogenase complex (mtPDC) plays a pivotal role in controlling the entry of carbon into the tricarboxylic acid (TCA) cycle for energy production. This multi-enzyme complex consists of three components: E1, E2, and E3. In Arabidopsis, there are three genes, mtE2-1, mtE2-2, and mtE2-3, which encode the putative mtPDC E2 subunit but how each of them contributes to the total mtPDC activity remains unknown. In this work, we characterized an Arabidopsis mutant, m132, that has abnormal small organs. Molecular cloning indicated that the phenotype of m132 is caused by a mutation in the mtE2-1 gene, which results in a truncation of 109 amino acids at the C-terminus of the encoded protein. In m132, mtPDC activity is only 30% of the WT and ATP production is severely impaired. The mutation in the mtE2-1 gene also leads to the over-accumulation of most intermediate products of the TCA cycle and of all the amino acids for protein synthesis. Our results suggest that, among the three mtE2 genes, mtE2-1 is a major contributor to the function of Arabidopsis mtPDC and that the functional disruption of mtE2-1 profoundly affects plant growth and development, as well as its metabolism.

  6. Skin Injuries Reduce Survival and Modulate Corticosterone, C-Reactive Protein, Complement Component 3, IgM, and Prostaglandin E2 after Whole-Body Reactor-Produced Mixed Field (n + γ-Photons) Irradiation

    PubMed Central

    Kiang, Juliann G.; Ledney, G. David

    2013-01-01

    Skin injuries such as wounds or burns following whole-body γ-irradiation (radiation combined injury (RCI)) increase mortality more than whole-body γ-irradiation alone. Wound-induced decreases in survival after irradiation are triggered by sustained activation of inducible nitric oxide synthase pathways, persistent alteration of cytokine homeostasis, and increased susceptibility to systemic bacterial infection. Among these factors, radiation-induced increases in interleukin-6 (IL-6) concentrations in serum were amplified by skin wound trauma. Herein, the IL-6-induced stress proteins including C-reactive protein (CRP), complement 3 (C3), immunoglobulin M (IgM), and prostaglandin E2 (PGE2) were evaluated after skin injuries given following a mixed radiation environment that might be found after a nuclear incident. In this report, mice received 3 Gy of reactor-produced mixed field (n + γ-photons) radiations at 0.38 Gy/min followed by nonlethal skin wounding or burning. Both wounds and burns reduced survival and increased CRP, C3, and PGE2 in serum after radiation. Decreased IgM production along with an early rise in corticosterone followed by a subsequent decrease was noted for each RCI situation. These results suggest that RCI-induced alterations of corticosterone, CRP, C3, IgM, and PGE2 cause homeostatic imbalance and may contribute to reduced survival. Agents inhibiting these responses may prove to be therapeutic for RCI and improve related survival. PMID:24175013

  7. The Papillomavirus E2 proteins

    SciTech Connect

    McBride, Alison A.

    2013-10-15

    The papillomavirus E2 proteins are pivotal to the viral life cycle and have well characterized functions in transcriptional regulation, initiation of DNA replication and partitioning the viral genome. The E2 proteins also function in vegetative DNA replication, post-transcriptional processes and possibly packaging. This review describes structural and functional aspects of the E2 proteins and their binding sites on the viral genome. It is intended to be a reference guide to this viral protein. - Highlights: • Overview of E2 protein functions. • Structural domains of the papillomavirus E2 proteins. • Analysis of E2 binding sites in different genera of papillomaviruses. • Compilation of E2 associated proteins. • Comparison of key mutations in distinct E2 functions.

  8. On reducible nonlinear time-delayed stochastic systems: fluctuation dissipation relations, transitions to bistability, and secondary transitions to non-stationarity

    NASA Astrophysics Data System (ADS)

    Patanarapeelert, K.; Frank, T. D.; Friedrich, R.; Tang, I. M.

    2005-12-01

    We show the conditions under which nonlinear time-delayed dynamical systems with multiplicative noise sources can be transformed into linear time-delayed systems with additive noise sources. We show that, for such reducible systems, analytical expressions for stationary distributions can be obtained. We demonstrate that fluctuation-dissipation relations of reducible systems become trivial and we show that reducible systems may exhibit delay- and noise-induced transitions to bistability and secondary transitions to non-stationarity. Our general findings are exemplified for three models: a Gompertz model, a Hongler model and a model involving a 1 - x2 noise amplitude.

  9. Robustness of reduced-order observer-based controllers in transitional 2D Blasius boundary layers

    NASA Astrophysics Data System (ADS)

    Belson, Brandt; Semeraro, Onofrio; Rowley, Clarence; Pralits, Jan; Henningson, Dan

    2011-11-01

    In this work, we seek to delay transition in the Blasius boundary layer. We trip the flow with an upstream disturbance and dampen the growth of the resulting structures downstream. The observer-based controllers use a single sensor and a single localized body force near the wall. To formulate the controllers, we first find a reduced-order model of the system via the Eigensystem Realization Algorithm (ERA), then find the H2 optimal controller for this reduced-order system. We find the resulting controllers are effective only when the sensor is upstream of the actuator (in a feedforward configuration), but as is expected, are sensitive to model uncertainty. When the sensor is downstream of the actuator (in a feedback configuration), the reduced-order observer-based controllers are not robust and ineffective on the full system. In order to investigate the robustness properties of the system, an iterative technique called the adjoint of the direct adjoint (ADA) is employed to find a full-dimensional H2 optimal controller. This avoids the reduced-order modelling step and serves as a reference point. ADA is promising for investigating the lack of robustness previously mentioned.

  10. E-2D Advanced Hawkeye Aircraft (E-2D AHE)

    DTIC Science & Technology

    2015-12-01

    Selected Acquisition Report (SAR) RCS: DD-A&T(Q&A)823-364 E-2D Advanced Hawkeye Aircraft (E-2D AHE) As of FY 2017 President’s Budget Defense...Office Estimate RDT&E - Research, Development, Test, and Evaluation SAR - Selected Acquisition Report SCP - Service Cost Position TBD - To Be Determined

  11. E1-E2 interactions in ubiquitin and Nedd8 ligation pathways.

    PubMed

    Tokgöz, Zeynep; Siepmann, Thomas J; Streich, Frederick; Kumar, Brajesh; Klein, Jennifer M; Haas, Arthur L

    2012-01-02

    Initial rates of E1-catalyzed E2 transthiolation have been used as a reporter function to probe the mechanism of 125I-ubiquitin transfer between activation and ligation half-reactions of ubiquitin conjugation. A functional survey of 11 representative human E2 paralogs reveals similar Km for binding to human Uba1 ternary complex (Km(ave)=121±72 nm) and kcat for ubiquitin transfer (kcat(ave)=4.0±1.2 s(-1)), suggesting that they possess a conserved binding site and transition state geometry and that they compete for charging through differences in intracellular concentration. Sequence analysis and mutagenesis localize this binding motif to three basic residues within Helix 1 of the E2 core domain, confirmed by transthiolation kinetics. Partial conservation of the motif among E2 paralogs not recognized by Uba1 suggests that another factor(s) account for the absolute specificity of cognate E2 binding. Truncation of the Uba1 carboxyl-terminal β-grasp domain reduces cognate Ubc2b binding by 31-fold and kcat by 3.5×10(4)-fold, indicating contributions to E2 binding and transition state stabilization. Truncation of the paralogous domain from the Nedd8 activating enzyme has negligible effect on cognate Ubc12 transthiolation but abrogates E2 specificity toward non-cognate carrier proteins. Exchange of the β-grasp domains between ubiquitin and Nedd8 activating enzymes fails to reverse the effect of truncation. Thus, the conserved Helix 1 binding motif and the β-grasp domain direct general E2 binding, whereas the latter additionally serves as a specificity filter to exclude charging of non-cognate E2 paralogs in order to maintain the fidelity of downstream signaling.

  12. Share of mass transit miles traveled and reduced motor vehicle fatalities in major cities of the United States.

    PubMed

    Stimpson, Jim P; Wilson, Fernando A; Araz, Ozgur M; Pagan, Jose A

    2014-12-01

    The USA leads the developed world in motor vehicle fatalities, presenting a critical public health threat. We examined whether an increasing share of mass transit use, relative to vehicle miles traveled on public roads, was associated with reduced motor vehicle fatalities. We used annual city-level data for the USA from 1982-2010 provided by the Fatality Accident Reporting System, the Texas A&M Transportation Institute, the Census Bureau, and the National Oceanic and Atmospheric Administration to estimate a structural equation model of the factors associated with mass transit miles and motor vehicle fatalities. The final analytic data included 2,900 observations from 100 cities over 29 years. After accounting for climate, year, and the economic costs of driving, an increasing share of mass transit miles traveled per capita was associated with reduced motor vehicle fatalities. The costs of congestion to the average commuter and gas prices were positively associated with increasing the share of mass transit miles traveled. The economic costs of driving increased over time, while both the fatality rate and the share of mass transit miles traveled decreased over time. Increasing the share of mass transit miles traveled may be associated with fewer motor vehicle miles traveled. Increasing mass transit uptake may be an effective public health intervention to reduce motor vehicle fatalities in cities.

  13. Two-phase modeling of deflagration-to-detonation transition in granular materials: Reduced equations

    NASA Astrophysics Data System (ADS)

    Kapila, A. K.; Menikoff, R.; Bdzil, J. B.; Son, S. F.; Stewart, D. S.

    2001-10-01

    Of the two-phase mixture models used to study deflagration-to-detonation transition in granular explosives, the Baer-Nunziato model is the most highly developed. It allows for unequal phase velocities and phase pressures, and includes source terms for drag and compaction that strive to erase velocity and pressure disequilibria. Since typical time scales associated with the equilibrating processes are small, source terms are stiff. This stiffness motivates the present work where we derive two reduced models in sequence, one with a single velocity and the other with both a single velocity and a single pressure. These reductions constitute outer solutions in the sense of matched asymptotic expansions, with the corresponding inner layers being just the partly dispersed shocks of the full model. The reduced models are hyperbolic and are mechanically as well as thermodynamically consistent with the parent model. However, they cannot be expressed in conservation form and hence require a regularization in order to fully specify the jump conditions across shock waves. Analysis of the inner layers of the full model provides one such regularization [Kapila et al., Phys. Fluids 9, 3885 (1997)], although other choices are also possible. Dissipation associated with degrees of freedom that have been eliminated is restricted to the thin layers and is accounted for by the jump conditions.

  14. Role of Physical Therapists in Reducing Hospital Readmissions: Optimizing Outcomes for Older Adults During Care Transitions From Hospital to Community

    PubMed Central

    Burke, Robert E.; Malone, Daniel; Ridgeway, Kyle J.; McManus, Beth M.; Stevens-Lapsley, Jennifer E.

    2016-01-01

    Hospital readmissions in older adult populations are an emerging quality indicator for acute care hospitals. Recent evidence has linked functional decline during and after hospitalization with an elevated risk of hospital readmission. However, models of care that have been developed to reduce hospital readmission rates do not adequately address functional deficits. Physical therapists, as experts in optimizing physical function, have a strong opportunity to contribute meaningfully to care transition models and demonstrate the value of physical therapy interventions in reducing readmissions. Thus, the purposes of this perspective article are: (1) to describe the need for physical therapist input during care transitions for older adults and (2) to outline strategies for expanding physical therapy participation in care transitions for older adults, with an overall goal of reducing avoidable 30-day hospital readmissions. PMID:26939601

  15. Reducing VMTs through Transit-On-Demand with GPS and satellite communications

    SciTech Connect

    Wipke, K.B.

    1996-10-01

    As a partial solution to the problem of increasing foreign petroleum imports,urban congestion, and air pollution from automobiles, NREL researchers have successfully demonstrated a transportation concept called Transit-On-Demand (TOD). TOD uses the global positioning system (GPS) to locate all vehicles in a fleet, two-way communications between the vehicles and a central computer-server, and advanced dispatching and routing software to control the movement of vehicles within the fleet. Reducing the vehicle-miles-travelled (VMTs) through implementing efficient transportation systems such as TOD, results in less energy being required for transportation and a decrease in the amount of required imported petroleum. Through development of an advanced world wide web site and use of the new Java{trademark} Internet programming language, the demonstration allows visitors to the web site to see updates of vehicle position on a map every 20 seconds,while effectively minimizing the internet bandwidth required. The project demonstrates how a fixed-route, fixed- schedule shuttle can be converted to be demand-responsive to more effectively move people from where they are to where they want to be at the time they want to travel.

  16. Reduced Glass Transition Temperatures in Thin Polymer Films: Surface Effect or Artifact?

    NASA Astrophysics Data System (ADS)

    Bäumchen, O.; McGraw, J. D.; Forrest, J. A.; Dalnoki-Veress, K.

    2012-08-01

    We have examined the direct effect of manipulating the number of free surfaces on the measured glass transition temperature Tg of thin polystyrene films. Thin films in the range 35nmreduced from that of the bulk. The exact same films are then transferred to a Si substrate and the Tg of the resulting supported film was determined. The Tg values of the now supported films are the same as the bulk value and the same as previous reports of similar supported films. These experiments unambiguously show that free interfaces are the dominant cause of the Tg reductions for the film thicknesses studied.

  17. Terbium-Doped VO2 Thin Films: Reduced Phase Transition Temperature and Largely Enhanced Luminous Transmittance.

    PubMed

    Wang, Ning; Duchamp, Martial; Dunin-Borkowski, Rafal E; Liu, Shiyu; Zeng, XianTing; Cao, Xun; Long, Yi

    2016-01-26

    Vanadium dioxide (VO2) is a well-known thermochromic material with large IR modulating ability, promising for energy-saving smart windows. The main drawbacks of VO2 are its high phase transition temperature (τ(c) = 68°C), low luminous transmission (T(lum)), and weak solar modulating ability (ΔT(sol)). In this paper, the terbium cation (Tb(3+)) doping was first reported to reduce τ(c) and increase T(lum) of VO2 thin films. Compared with pristine VO2, 2 at. % doping level gives both enhanced T(lum) and ΔT(sol) from 45.8% to 54.0% and 7.7% to 8.3%, respectively. The T(lum) increases with continuous Tb(3+) doping and reaches 79.4% at 6 at. % doping level, representing ∼73.4% relative increment compared with pure VO2. This has surpassed the best reported doped VO2 thin films. The enhanced thermochromic properties is meaningful for smart window applications of VO2 materials.

  18. Conditions for making direct reduced iron, transition direct reduced iron and pig iron nuggets in a laboratory furnace - Temperature-time transformations

    SciTech Connect

    Anameric, B.; Kawatra, S.K.

    2007-02-15

    The pig iron nugget process is gaining in importance as an alternative to the traditional blast furnace. Throughout the process, self-reducing-fluxing dried greenballs composed of iron ore concentrate, reducing-carburizing agent (coal), flux (limestone) and binder (bentonite) are heat-treated. During the heat treatment, dried greenballs are first transformed into direct reduced iron (DRI), then to transition direct reduced iron (TDRI) and finally to pig iron nuggets. The furnace temperature and/or residence time and the corresponding levels of carburization, reduction and metallization dictate these transformations. This study involved the determination of threshold furnace temperatures and residence times for completion of all of the transformation reactions and pig iron nugget production. The experiments involved the heat treatment of self-reducing-fluxing dried greenballs at various furnace temperatures and residence times. The products of these heat treatments were identified by utilizing optical microscopy, apparent density and microhardness measurements.

  19. Inhibitors of the mitochondrial permeability transition reduce ammonia-induced cell swelling in cultured astrocytes.

    PubMed

    Reddy, Pichili V B; Rama Rao, Kakulavarapu V; Norenberg, Michael D

    2009-09-01

    Ammonia is the principal neurotoxin implicated in the pathogenesis of hepatic encephalopathy, and astrocytes are the neural cells predominantly affected in this condition. Astrocyte swelling (cytotoxic edema) represents a critical component of the brain edema in acute form of hepatic encephalopathy (acute liver failure, ALF). Although mechanisms of astrocyte swelling by ammonia are not completely understood, cultured astrocytes exposed to pathophysiological levels of ammonia develop the mitochondrial permeability transition (mPT), a process that was shown to result in astrocyte swelling. Cyclosporin A (CsA), a traditional inhibitor of the mPT, was previously shown to completely block ammonia-induced astrocyte swelling in culture. However, the efficacy of CsA to protect cytotoxic brain edema in ALF is problematic because it poorly crosses the blood-brain barrier, which is relatively intact in ALF. We therefore examined the effect of agents that block the mPT but are also known to cross the blood-brain barrier, including pyruvate, magnesium, minocycline, and trifluoperazine on the ammonia-induced mPT, as well as cell swelling. Cultured astrocytes exposed to ammonia for 24 hr displayed the mPT as demonstrated by a CsA-sensitive dissipation of the mitochondrial inner membrane potential. Pyruvate, minocycline, magnesium, and trifluoperazine significantly blocked the ammonia-induced mPT. Ammonia resulted in a significant increase in cell volume, which was blocked by the above-mentioned agents to a variable degree. A regression analysis indicated a high correlation between the effectiveness of reducing the mPT and cell swelling. Our data suggest that all these agents have therapeutic potential in mitigating brain edema in ALF.

  20. Transition.

    ERIC Educational Resources Information Center

    Thompson, Sandy, Ed.; And Others

    1990-01-01

    This "feature issue" focuses on transition from school to adult life for persons with disabilities. Included are "success stories," brief program descriptions, and a list of resources. Individual articles include the following titles and authors: "Transition: An Energizing Concept" (Paul Bates); "Transition…

  1. A systematic review of transitional-care strategies to reduce rehospitalization in patients with heart failure.

    PubMed

    Albert, Nancy M

    2016-01-01

    The objective of this review was to evaluate existing transition-of-care models and identify common themes that may minimize exacerbation and rehospitalization, and improve quality of life for patients with heart failure (HF). HF is a significant burden in the United States and a common reason for recurrent hospitalizations. When multidisciplinary health care providers function as liaisons and educators during transition from hospital to home, they help prepare patients for life with chronic HF and mitigate the need for readmission. Systematic literature searches were performed to identify research papers relevant to transition-of-care themes in HF. Eight common themes were identified that can be applied to patients with HF to improve long-term outcomes. This paper emphasizes ways in which health care providers can implement theme-based transitional care, including providing patients and caregivers with practical skills and services that promote knowledge and engagement in self-care and stimulate active communication with health care providers.

  2. E2f4 and E2f5 are essential for the development of the male reproductive system.

    PubMed

    Danielian, Paul S; Hess, Rex A; Lees, Jacqueline A

    2016-01-01

    The E2F transcription factors are primarily implicated in the regulation of entry and exit from the cell cycle. However, in vivo studies have established additional roles for E2Fs during organ development and homeostasis. With the goal of addressing the intestinal requirements of E2f4 and E2f5, we crossed mice carrying Vil-cre, E2f4 conditional and E2f5 germline alleles. E2f4 deletion had no detectable effect on intestinal development. However, E2f4f/f;E2f5+/-;Vil-cre males, but not E2f4f/f;Vil-cre littermates, were unexpectedly sterile. This defect was not due to defective spermatogenesis. Instead, the seminiferous tubules and rete testes showed significant dilation, and spermatozoa accumulated aberrantly in the rete testis and efferent ducts. Our data show that these problems result from defective efferent ducts, a tissue whose primary function is to concentrate sperm through fluid absorption. First, Vil-cre expression, and consequent E2F4 loss, was specific to the efferent ducts and not other reproductive tract tissues. Second, the E2f4f/f;E2f5+/-;Vil-cre efferent ducts had completely lost multiciliated cells and greatly reduced levels of critical absorptive cell proteins: aquaporin1, a water channel protein, and clusterin, an endocytic marker. Collectively, the observed testis phenotypes suggest a fluid flux defect. Remarkably, we observed rete testis dilation prior to the normal time of seminiferous fluid production, arguing that the efferent duct defects promote excessive secretory activity within the reproductive tract. Finally, we also detect key aspects of these testis defects in E2f5-/- mice. Thus, we conclude that E2f4 and E2f5 display overlapping roles in controlling the normal development of the male reproductive system.

  3. E2f4 and E2f5 are essential for the development of the male reproductive system

    PubMed Central

    Danielian, Paul S.; Hess, Rex A.; Lees, Jacqueline A.

    2016-01-01

    ABSTRACT The E2F transcription factors are primarily implicated in the regulation of entry and exit from the cell cycle. However, in vivo studies have established additional roles for E2Fs during organ development and homeostasis. With the goal of addressing the intestinal requirements of E2f4 and E2f5, we crossed mice carrying Vil-cre, E2f4 conditional and E2f5 germline alleles. E2f4 deletion had no detectable effect on intestinal development. However, E2f4f/f;E2f5+/−;Vil-cre males, but not E2f4f/f;Vil-cre littermates, were unexpectedly sterile. This defect was not due to defective spermatogenesis. Instead, the seminiferous tubules and rete testes showed significant dilation, and spermatozoa accumulated aberrantly in the rete testis and efferent ducts. Our data show that these problems result from defective efferent ducts, a tissue whose primary function is to concentrate sperm through fluid absorption. First, Vil-cre expression, and consequent E2F4 loss, was specific to the efferent ducts and not other reproductive tract tissues. Second, the E2f4f/f;E2f5+/−;Vil-cre efferent ducts had completely lost multiciliated cells and greatly reduced levels of critical absorptive cell proteins: aquaporin1, a water channel protein, and clusterin, an endocytic marker. Collectively, the observed testis phenotypes suggest a fluid flux defect. Remarkably, we observed rete testis dilation prior to the normal time of seminiferous fluid production, arguing that the efferent duct defects promote excessive secretory activity within the reproductive tract. Finally, we also detect key aspects of these testis defects in E2f5−/− mice. Thus, we conclude that E2f4 and E2f5 display overlapping roles in controlling the normal development of the male reproductive system. PMID:26825228

  4. Interdependent Networks: Reducing the Coupling Strength Leads to a Change from a First to Second Order Percolation Transition

    NASA Astrophysics Data System (ADS)

    Parshani, Roni; Buldyrev, Sergey V.; Havlin, Shlomo

    2010-07-01

    We study a system composed from two interdependent networks A and B, where a fraction of the nodes in network A depends on nodes of network B and a fraction of the nodes in network B depends on nodes of network A. Because of the coupling between the networks, when nodes in one network fail they cause dependent nodes in the other network to also fail. This invokes an iterative cascade of failures in both networks. When a critical fraction of nodes fail, the iterative process results in a percolation phase transition that completely fragments both networks. We show both analytically and numerically that reducing the coupling between the networks leads to a change from a first order percolation phase transition to a second order percolation transition at a critical point. The scaling of the percolation order parameter near the critical point is characterized by the critical exponent β=1.

  5. Synthesis characterization and antimicrobial activity studies of some transition metal complexes derived from 3-chloro-N'-[(1E)-(2-hydroxy phenyl)methylene]-6-methoxy-1-benzothiophene-2-carbohydrazide.

    PubMed

    Biradar, Vivekanand D; Mruthyunjayaswamy, B H M

    2013-01-01

    A series of new coordination complexes of Cu(II), Co(II), Ni(II), Zn(II), Hg(II), Mn(II), and Fe(III) with the Schiff base 3-chloro-N'-[(1E)-(2-hydroxy phenyl)methylene]-6-methoxy-1-benzothiophene-2-carbohydrazide (HL) have been synthesized and characterized by elemental analysis, electrical conductivity measurements, IR spectra, (1)H NMR, mass spectral data, electronic spectra, magnetic susceptibility, ESR spectra, TGA, and Powder XRD data. The Schiff base behaves as tridentate ONO donor ligand and forms the complexes of the type ML2 (metal-ligand) stoichiometry for Cu(II), Co(II), Ni(II), and Mn(II) complexes and ML stoichiometry for Zn(II), Hg(II), and Fe(III) complexes. All the complexes are colored and nonelectrolytes. It is found that Cu(II), Co(II), Ni(II), Mn(II) and Fe(III) complexes have exhibited octahedral geometry whereas Zn(II) and Hg(II) complexes exhibited tetrahedral geometry. The ligand and its metal complexes have been screened for their antibacterial activity against E. coli and S. aureus and antifungal activity against A. niger and A. flavus.

  6. Synthesis Characterization and Antimicrobial Activity Studies of Some Transition Metal Complexes Derived from 3-Chloro-N′-[(1E)-(2-hydroxy phenyl)methylene]-6-methoxy-1-benzothiophene-2-carbohydrazide

    PubMed Central

    Biradar, Vivekanand D.; Mruthyunjayaswamy, B. H. M.

    2013-01-01

    A series of new coordination complexes of Cu(II), Co(II), Ni(II), Zn(II), Hg(II), Mn(II), and Fe(III) with the Schiff base 3-chloro-N′-[(1E)-(2-hydroxy phenyl)methylene]-6-methoxy-1-benzothiophene-2-carbohydrazide (HL) have been synthesized and characterized by elemental analysis, electrical conductivity measurements, IR spectra, 1H NMR, mass spectral data, electronic spectra, magnetic susceptibility, ESR spectra, TGA, and Powder XRD data. The Schiff base behaves as tridentate ONO donor ligand and forms the complexes of the type ML2 (metal-ligand) stoichiometry for Cu(II), Co(II), Ni(II), and Mn(II) complexes and ML stoichiometry for Zn(II), Hg(II), and Fe(III) complexes. All the complexes are colored and nonelectrolytes. It is found that Cu(II), Co(II), Ni(II), Mn(II) and Fe(III) complexes have exhibited octahedral geometry whereas Zn(II) and Hg(II) complexes exhibited tetrahedral geometry. The ligand and its metal complexes have been screened for their antibacterial activity against E. coli and S. aureus and antifungal activity against A. niger and A. flavus. PMID:24453851

  7. Energies and E1, M1, E2, M2 transition rates for states of the 2s{sup 2}2p, 2s2p{sup 2}, and 2p{sup 3} configurations in boron-like ions between N III and Zn XXVI

    SciTech Connect

    Rynkun, P.; Joensson, P.; Gaigalas, G.; Froese Fischer, C.

    2012-07-15

    Energies, E1, M1, E2, M2 transition rates, line strengths, oscillator strengths, and lifetimes from relativistic configuration interaction calculations are reported for the states of the (1s{sup 2})2s{sup 2}2p, 2s2p{sup 2}, and 2p{sup 3} configurations in all boron-like ions between N III and Zn XXVI. Valence, core-valence, and core-core correlation effects were accounted for through single-double multireference (SD-MR) expansions to increasing sets of active orbitals.

  8. Infrastructure and automobile shifts: positioning transit to reduce life-cycle environmental impacts for urban sustainability goals

    NASA Astrophysics Data System (ADS)

    Chester, Mikhail; Pincetl, Stephanie; Elizabeth, Zoe; Eisenstein, William; Matute, Juan

    2013-03-01

    Public transportation systems are often part of strategies to reduce urban environmental impacts from passenger transportation, yet comprehensive energy and environmental life-cycle measures, including upfront infrastructure effects and indirect and supply chain processes, are rarely considered. Using the new bus rapid transit and light rail lines in Los Angeles, near-term and long-term life-cycle impact assessments are developed, including consideration of reduced automobile travel. Energy consumption and emissions of greenhouse gases and criteria pollutants are assessed, as well the potential for smog and respiratory impacts. Results show that life-cycle infrastructure, vehicle, and energy production components significantly increase the footprint of each mode (by 48-100% for energy and greenhouse gases, and up to 6200% for environmental impacts), and emerging technologies and renewable electricity standards will significantly reduce impacts. Life-cycle results are identified as either local (in Los Angeles) or remote, and show how the decision to build and operate a transit system in a city produces environmental impacts far outside of geopolitical boundaries. Ensuring shifts of between 20-30% of transit riders from automobiles will result in passenger transportation greenhouse gas reductions for the city, and the larger the shift, the quicker the payback, which should be considered for time-specific environmental goals.

  9. Reducing fatigue damage for ships in transit through structured decision making

    USGS Publications Warehouse

    Nichols, J.M.; Fackler, P.L.; Pacifici, K.; Murphy, K.D.; Nichols, J.D.

    2014-01-01

    Research in structural monitoring has focused primarily on drawing inference about the health of a structure from the structure’s response to ambient or applied excitation. Knowledge of the current state can then be used to predict structural integrity at a future time and, in principle, allows one to take action to improve safety, minimize ownership costs, and/or increase the operating envelope. While much time and effort has been devoted toward data collection and system identification, research to-date has largely avoided the question of how to choose an optimal maintenance plan. This work describes a structured decision making (SDM) process for taking available information (loading data, model output, etc.) and producing a plan of action for maintaining the structure. SDM allows the practitioner to specify his/her objectives and then solves for the decision that is optimal in the sense that it maximizes those objectives. To demonstrate, we consider the problem of a Naval vessel transiting a fixed distance in varying sea-state conditions. The physics of this problem are such that minimizing transit time increases the probability of fatigue failure in the structural supports. It is shown how SDM produces the optimal trip plan in the sense that it minimizes both transit time and probability of failure in the manner of our choosing (i.e., through a user-defined cost function). The example illustrates the benefit of SDM over heuristic approaches to maintaining the vessel.

  10. Energies and E1, M1, E2, and M2 transition rates for states of the 2s22p3, 2s2p4, and 2p5 configurations in nitrogen-like ions between F III and Kr XXX

    NASA Astrophysics Data System (ADS)

    Rynkun, P.; Jönsson, P.; Gaigalas, G.; Froese Fischer, C.

    2014-03-01

    Based on relativistic wavefunctions from multiconfiguration Dirac-Hartree-Fock and configuration interaction calculations, E1, M1, E2, and M2 transition rates, weighted oscillator strengths, and lifetimes are evaluated for the states of the (1s2)2s22p3,2s2p4, and 2p5 configurations in all nitrogen-like ions between F III and Kr XXX. The wavefunction expansions include valence, core-valence, and core-core correlation effects through single-double multireference expansions to increasing sets of active orbitals. The computed energies agree very well with experimental values, with differences of only 300-600 cm-1 for the majority of the levels and ions in the sequence. Computed transitions rates are in close agreement with available data from MCHF-BP calculations by Tachiev and Froese Fischer [G.I. Tachiev, C. Froese Fischer, A&A 385 (2002) 716].

  11. Physical Aging of Thin and Ultrathin Free-Standing Polymer Films: Effect of Stress and Reduced Glass Transitions

    NASA Astrophysics Data System (ADS)

    Pye, Justin; Roth, Connie

    2014-03-01

    While great effort has been made in elucidating the effect of confinement on the glass transition (Tg) in polymers, considerably less work has been done on physical aging. Starting with supported films, we have previously shown that the reduced physical aging rates in ultrathin polystyrene (PS) films can be linked to the reduced Tg near the free surface [Macromolecules 2010, 43, 8296]. We then showed that high molecular weight (MW) free-standing PS films have two reduced Tgs suggesting that two separate mechanisms are acting simultaneously to propagate enhanced mobility at the free surface deeper into the film [PRL 2011, 107, 235701]. To help determine the mechanisms of these two reduced Tgs, we performed physical aging measurements on these high MW free-standing PS films. For thick films (220-1800 nm) in which there are no Tg reductions, we find that the physical aging rate depends strongly on stress caused by thermal expansion mismatch between film and support. This stress, applied to the films as they are quenched into the glassy state, can nearly double the physical aging rate when changing the frame material from polycarbonate to silicon [Macromolecules 2013, DOI:10.1021/ma401872u]. Finally, ultrathin high MW PS films held at a temperature between the two Tgs do exhibit physical aging, indicating that at least some of the film is glassy between these two transitions.

  12. Interactions of melatonin with mammalian mitochondria. Reducer of energy capacity and amplifier of permeability transition.

    PubMed

    Martinis, P; Zago, L; Maritati, M; Battaglia, V; Grancara, S; Rizzoli, V; Agostinelli, E; Bragadin, M; Toninello, A

    2012-05-01

    Melatonin, a metabolic product of the amino acid tryptophan, induces a dose-dependent energy drop correlated with a decrease in the oxidative phosphorylation process in isolated rat liver mitochondria. This effect involves a gradual decrease in the respiratory control index and significant alterations in the state 4/state 3 transition of membrane potential (ΔΨ). Melatonin, alone, does not affect the insulating properties of the inner membrane but, in the presence of supraphysiological Ca2+, induces a ΔΨ drop and colloid-osmotic mitochondrial swelling. These events are sensitive to cyclosporin A and the inhibitors of Ca2+ transport, indicative of the induction or amplification of the mitochondrial permeability transition. This phenomenon is triggered by oxidative stress induced by melatonin and Ca2+, with the generation of hydrogen peroxide and the consequent oxidation of sulfydryl groups, glutathione and pyridine nucleotides. In addition, melatonin, again in the presence of Ca2+, can also induce substantial release of cytochrome C and AIF (apoptosis-inducing factor), thus revealing its potential as a pro-apoptotic agent.

  13. High-precision B(E2) measurements of semi-magic 58,60,62,64Ni by Coulomb excitation

    SciTech Connect

    Allmond, James M; Brown, Alex; Stuchbery, Andrew E; Galindo-Uribarri, Alfredo {nmn}; Padilla-Rodal, Elizabeth; Radford, David C; Batchelder, J. C.; Howard, Meredith E; Liang, J Felix; Manning, Brett M; Varner Jr, Robert L; Yu, Chang-Hong

    2014-01-01

    High-precision reduced electric-quadrupole transition probabilities B(E2) have been measured from single-step Coulomb excitation of semi-magic 58,60,62,64 Ni (Z = 28) beams at 1.8 MeV per nucleon on a natural carbon target. The energy loss of the nickel beams through the carbon target were directly measured with a zero-degree Bragg detector and the absolute B(E2) values were normalized by Rutherford scattering. The B(E2) values disagree with recent lifetime studies that employed the Doppler-shift attenuation method. The present high-precision B(E2) values reveal an asymmetry about 62 Ni, midshell between N = 28 and 40, with larger values towards 56 Ni (Z = N = 28). The experimental B(E2) values are compared with shell-model calculations in the full pf model space and the results indicate a soft 56 Ni core.

  14. E2F and its developmental regulation in Xenopus laevis.

    PubMed Central

    Philpott, A; Friend, S H

    1994-01-01

    The transcription factor E2F has been implicated in cell cycle control by virtue of its association with cyclins, cyclin-dependent kinases, and pRb-related tumor suppressor gene products. Eggs and embryos from the frog Xenopus laevis have been used to investigate the characteristics of E2F-like molecules in the Xenopus cell cycle and throughout early development. We find multiple E2F species in Xenopus eggs, at least one of which is modified by phosphorylation. The vast majority of E2F remains in the free form throughout the very early embryonic cell cycle, and it also remains predominantly free until some time after the mid-blastula transition, the onset of zygotic transcription. At this time, E2F complexes significantly to pRb but not to cdk2, although cdk2 binding is found in tissue culture cells from a very advanced stage in embryogenesis. This suggests that the complexing of E2F to cyclins, cyclin-dependent kinases, and tumor suppressor gene products may be controlled separately in early Xenopus development. Thus, the association of E2F with other molecules may not result solely from processes affecting cell cycle progression but may also reflect developmental and differentiation cues. Images PMID:8007993

  15. Mutation in the SH1 helix reduces the activation energy of the ATP-induced conformational transition of myosin.

    PubMed

    Iwai, Sosuke; Chaen, Shigeru

    2007-05-25

    The SH1 helix is a joint that links the converter subdomain to the rest of the myosin motor domain. Recently, we showed that a mutation within the SH1 helix in Dictyostelium myosin II (R689H) reduced the elasticity and thermal stability of the protein. To reveal the involvement of the SH1 helix in ATP-dependent conformational changes of the motor domain, we have investigated the effects of the R689H mutation on the conformational changes of the converter, using a GFP-based fluorescence resonance energy transfer method. Although the mutation does not seem to strongly affect conformations, we found that it significantly reduced the activation energy required for the ATP-induced conformational transition corresponding to the recovery stroke. Given the effects of the mutation on the mechanical properties of myosin, we propose that the SH1 helix plays an important role in the mechanochemical energy conversion underlying the conformational change of the myosin motor domain.

  16. Modulated patterns in a reduced model of a transitional shear flow

    NASA Astrophysics Data System (ADS)

    Beaume, C.; Knobloch, E.; Chini, G. P.; Julien, K.

    2016-02-01

    We consider a close relative of plane Couette flow called Waleffe flow in which the fluid is confined between two free-slip walls and the flow driven by a sinusoidal force. We use a reduced model of such flows constructed elsewhere to compute stationary exact coherent structures in this flow in periodic domains with a large spanwise period. The computations reveal the emergence of stationary states exhibiting strong amplitude and wavelength modulation in the spanwise direction. These modulated states lie on branches exhibiting complex dependence on the Reynolds number but no homoclinic snaking.

  17. High-fat diet transition reduces brain DHA levels associated with altered brain plasticity and behaviour.

    PubMed

    Sharma, Sandeep; Zhuang, Yumei; Gomez-Pinilla, Fernando

    2012-01-01

    To assess how the shift from a healthy diet rich in omega-3 fatty acids to a diet rich in saturated fatty acid affects the substrates for brain plasticity and function, we used pregnant rats fed with omega-3 supplemented diet from their 2nd day of gestation period as well as their male pups for 12 weeks. Afterwards, the animals were randomly assigned to either a group fed on the same diet or a group fed on a high-fat diet (HFD) rich in saturated fats for 3 weeks. We found that the HFD increased vulnerability for anxiety-like behavior, and that these modifications harmonized with changes in the anxiety-related NPY1 receptor and the reduced levels of BDNF, and its signalling receptor pTrkB, as well as the CREB protein. Brain DHA contents were significantly associated with the levels of anxiety-like behavior in these rats.

  18. F-box protein Skp2: a novel transcriptional target of E2F

    PubMed Central

    Zhang, L; Wang, C

    2006-01-01

    The F-box-containing protein Skp2 plays a critical role in coordinating the G1/S transition and progression through the S phase of the mammalian cell cycle. Skp2 is overexpressed in a broad spectrum of human cancers and the expression level correlates with tumor malignancy. However, the Skp2 gene is neither amplified nor rearranged in most human cancers and the underlying mechanism of Skp2 overexpression remains poorly understood. We show here that the Skp2 gene contains a functional E2F response element (hSRE2). Ectopic expression of E2F1 induces expression of the endogenous Skp2 gene in human fibroblast cells, whereas antisense-mediated knockdown of E2F1 in human tumor cell lines reduces expression of endogenous Skp2 gene. The hSRE2 element not only participates in activation of Skp2 promoter function during normal cell cycle progression into S phase, it is also required for the high-level Skp2 gene expression in many human tumor cell lines. These results reveal Skp2 as a novel target for E2F regulation that is disrupted in several human tumor cell lines. PMID:16331253

  19. Targeting inflammation: multiple innovative ways to reduce prostaglandin E2

    PubMed Central

    Norberg, Jessica K; Sells, Earlphia; Chang, Hui-Hua; Alla, Srinivas R; Zhang, Shuxing; Meuillet, Emmanuelle J

    2014-01-01

    The PGE2 pathway is important in inflammation-driven diseases and specific targeting of the inducible mPGES-1 is warranted due to the cardiovascular problems associated with the long-term use of COX-2 inhibitors. This review focuses on patents issued on methods of measuring mPGES-1 activity, on drugs targeting mPGES-1 and on other modulators of free extracellular PGE2 concentration. Perspectives and conclusions regarding the status of these drugs are also presented. Importantly, no selective inhibitors targeting mPGES-1 have been identified and, despite the high number of published patents, none of these drugs have yet made it to clinical trials. PMID:24237030

  20. Convex-set description of quantum phase transitions in the transverse Ising model using reduced-density-matrix theory.

    PubMed

    Schwerdtfeger, Christine A; Mazziotti, David A

    2009-06-14

    Quantum phase transitions in N-particle systems can be identified and characterized by the movement of the two-particle reduced density matrix (2-RDM) along the boundary of its N-representable convex set as a function of the Hamiltonian parameter controlling the phase transition [G. Gidofalvi and D. A. Mazziotti, Phys. Rev. A 74, 012501 (2006)]. For the one-dimensional transverse Ising model quantum phase transitions as well as their finite-lattice analogs are computed and characterized by the 2-RDM movement with respect to the transverse magnetic field strength g. The definition of a 2-RDM "speed" quantifies the movement of the 2-RDM per unit of g, which reaches its maximum at the critical point of the phase transition. For the infinite lattice the convex set of 2-RDMs and the 2-RDM speed are computed from the exact solution of the 2-RDM in the thermodynamic limit of infinite N [P. Pfeuty, Ann. Phys. 57, 79 (1970)]. For the finite lattices we compute the 2-RDM convex set and its speed by the variational 2-RDM method [D. A. Mazziotti, Phys. Rev. Lett. 93, 213001 (2004)] in which approximate ground-state 2-RDMs are calculated without N-particle wave functions by using constraints, known as N-representability conditions, to restrict the 2-RDMs to represent quantum system of N fermions. Advantages of the method include: (i) rigorous lower bounds on the ground-state energies, (ii) polynomial scaling of the calculation with N, and (iii) independence of the N-representability conditions from a reference wave function, which enables the modeling of multiple quantum phases. Comparing the 2-RDM convex sets for the finite- and infinite-site lattices reveals that the variational 2-RDM method accurately captures the shape of the convex set and the signature of the phase transition in the 2-RDM movement. From the 2-RDM all one- and two-particle expectation values (or order parameters) of the quantum Ising model can also be computed including the pair correlation function, which

  1. Syntheses, crystal structures, anticancer activities of three reduce Schiff base ligand based transition metal complexes

    NASA Astrophysics Data System (ADS)

    Chang, Hui-Qin; Jia, Lei; Xu, Jun; Zhu, Tao-Feng; Xu, Zhou-Qing; Chen, Ru-Hua; Ma, Tie-Liang; Wang, Yuan; Wu, Wei-Na

    2016-02-01

    Three nickel(II) complexes, [Ni2(L1)2(tren)2(H2O)](ClO4)3 (1), [NiL2(tren)2](ClO4)·2.5H2O (2), [NiL2(tren)2]I·1.5H2O·CH3OH (3) based on amino acid reduced Schiff ligands are synthesized and characterized by physico-chemical and spectroscopic methods. The results show that in all complexes, the amino acid ligand is deprotonated and acts as an anionic ligand. In the dinuclear complex 1, each Ni(II) atom has a distorted octahedron geometry while with different coordination environment. However, the complexes 2 and 3 are mononuclear, almost with the same coordination environment. Furthermore, in vitro experiments are carried out, including MTT assay, Annexin V/PI flow cytometry and western blotting, to assess whether the complexes have antitumor effect. And the results show that all the three complexes have moderate anticancer activity towards human hepatic cancer (HepG2), human cervical cancer (HeLa) and human prostate (PC3) cell lines, in a concentration dependent way. The complex 1 exhibit higher cytotoxicity than the other two complexes and can induce human hepatic cancer cell (HepG2) to cell apoptosis by activating caspase 3.

  2. Transition from Pool to Flow Boiling: The Effect of Reduced Gravity

    NASA Technical Reports Server (NTRS)

    Dhir, Vijay K.

    2004-01-01

    Applications of boiling heat transfer in space can be found in the areas of thermal management, fluid handling and control, power systems, on-orbit storage and supply systems for cryogenic propellants and life support fluids, and for cooling of electronic packages for power systems associated with various instrumentation and control systems. Recent interest in exploration of Mars and other planets, and the concepts of in-situ resource utiliLation on Mars highlights the need to understand the effect of gravity on boiling heat transfer at gravity levels varying from 1>= g/g(sub e) >=10(exp -6). The objective of the proposed work was to develop a mechanistic understanding of nucleate boiling and critical heat flux under low and micro-gravity conditions when the velocity of the imposed flow is small. For pool boiling, the effect of reduced gravity is to stretch both the length scale as well as the time scale for the boiling process. At high flow velocities, the inertia of the liquid determines the time and the length scales and as such the gravitational acceleration plays little role. However, at low velocities and at low gravity levels both liquid inertia and buoyancy are of equal importance. At present, we have little understanding of the interacting roles of gravity and liquid inertia on the nucleate boiling process. Little data that has been reported in the literature does not have much practical value in that it can not serve as a basis for design of heat exchange components to be used in space. Both experimental and complete numerical simulations of the low velocity, low-gravity nucleate boiling process were carried out. A building block type of approach was used in that first the growth and detachment process of a single bubble and flow and heat transfer associated with the sliding motion of the bubble over the heater surface after detachment was studied. Liquid subcooling and flow velocity were varied parametrically. The experiments were conducted at 1 g(sub e

  3. Transcriptional silencing of ETS-1 abrogates epithelial-mesenchymal transition resulting in reduced motility of pancreatic cancer cells.

    PubMed

    Li, Chunyan; Wang, Zhonghan; Chen, Yan; Zhou, Min; Zhang, Haijun; Chen, Rong; Shi, Fangfang; Wang, Cailian; Rui, Zongdao

    2015-02-01

    v-ets erythroblastosis virus E26 oncogene homolog 1 (ETS-1) plays crucial roles in a spectrum of malignancies. ETS-1 has gained attention in cancer research for its importance in cell migration, invasion and proliferation. In the present study, we focused on the effect of ETS-1 on epithelial-mesenchymal transition (EMT), which is characterized by reduced E-cadherin expression and increased N-cadherin expression. We found that ETS-1 mRNA expression was positively correlated with N-cadherin and negatively correlated with E-cadherin mRNA expression in five pancreatic cancer cell lines. To elucidate the functionality of ETS-1 on EMT in pancreatic cancer cells, we constructed a green fluorescent protein (GFP)-expressing plasmid carrying ETS-1 short hairpin RNA (shRNA), and transfected Panc-1 cells with the plasmid. We detected reduced N-cadherin and vascular endothelial growth factor yet higher E-cadherin expression in the ETS-1-silenced cells compared with the control group. In addition, we observed reduced cell migration and increased adhesion in these cells. Our data showed that ETS-1 actively functioned as a regulator of EMT in Panc-1 cells, and provide additional evidence supporting a fundamental role for ETS-1 in metastatic pancreatic cancer cells. These results suggest that analysis of ETS-1 expression levels may provide an avenue for evaluating prognosis in pancreatic cancer.

  4. Chronic prednisolone treatment reduces hepatic insulin sensitivity while perturbing the fed-to-fasting transition in mice.

    PubMed

    Laskewitz, Anke J; van Dijk, Theo H; Bloks, Vincent W; Reijngoud, Dirk-Jan; van Lierop, Marie-José; Dokter, Wim H; Kuipers, Folkert; Groen, Albert K; Grefhorst, Aldo

    2010-05-01

    Chronic glucocorticoid use for treatment of inflammatory diseases is accompanied by severe side effects in humans (e.g. hyperglycemia and insulin resistance). The present studies were conducted to characterize consequences of chronic treatment with the synthetic glucocorticoid prednisolone on insulin sensitivity and blood glucose kinetics in mice. Prednisolone treatment increased fasting blood glucose and plasma insulin concentrations, but this apparently reduced insulin sensitivity could not be confirmed in hyperinsulinemic euglycemic clamp studies. Therefore, a novel method to study whole body glucose kinetics was used. This method revealed that prednisolone-treated mice show an increased hepatic glucose production (HGP). The increased HGP was accompanied by elevated plasma insulin concentrations, indicating reduced insulin sensitivity of hepatic glucose metabolism in prednisolone-treated mice. Compared with vehicle, prednisolone-treated mice had lower blood glucose concentrations, higher plasma free fatty acids, and higher plasma fibroblast growth factor-21 concentrations in the fed condition, i.e. mimicking a fasting situation. Next, the effects of 24-h fasting on energy metabolism were studied. Compared with controls, fasted prednisolone-treated mice had higher blood glucose concentrations and lower plasma beta-hydroxybutyrate concentrations. In conclusion, these results indicate that chronic prednisolone treatment reduces insulin sensitivity of HGP, induces a fasting-like phenotype in fed mice, and perturbs the fed-to-fasting transition.

  5. Energies and E1, M1, E2, and M2 transition rates for states of the 2s{sup 2}2p{sup 3}, 2s2p{sup 4}, and 2p{sup 5} configurations in nitrogen-like ions between F III and Kr XXX

    SciTech Connect

    Rynkun, P.; Jönsson, P.; Gaigalas, G.; Froese Fischer, C.

    2014-03-15

    Based on relativistic wavefunctions from multiconfiguration Dirac–Hartree–Fock and configuration interaction calculations, E1, M1, E2, and M2 transition rates, weighted oscillator strengths, and lifetimes are evaluated for the states of the (1s{sup 2})2s{sup 2}2p{sup 3},2s2p{sup 4}, and 2p{sup 5} configurations in all nitrogen-like ions between F III and Kr XXX. The wavefunction expansions include valence, core–valence, and core–core correlation effects through single–double multireference expansions to increasing sets of active orbitals. The computed energies agree very well with experimental values, with differences of only 300–600 cm{sup −1} for the majority of the levels and ions in the sequence. Computed transitions rates are in close agreement with available data from MCHF-BP calculations by Tachiev and Froese Fischer [G.I. Tachiev, C. Froese Fischer, A and A 385 (2002) 716].

  6. The {sup 12}C({alpha}, {gamma}){sup 16}O E2 cross section at stellar energies

    SciTech Connect

    Descouvemont, P.; Dufour, M.

    2010-08-12

    The E2 component of the {sup 12}C({alpha}, {gamma}){sup 16}O cross section is investigated by a microscopic cluster model, and by R-matrix fits. The first approach provides S{sub E2}(300 keV){approx_equal}50 keV-b for ground-state transitions. In the R-matrix theory, we show that the background term plays a crucial role, and cannot be determined without ambiguity. Only an upper limit on the extrapolated S factor can be obtained [S{sub E2}(300 keV)<190 keV-b]. To constrain the R-matrix analysis, we use the GCM Asymptotic Normalization Constant (ANC) of the 2{sub 1}{sup +} level. This procedure strongly reduces the uncertainties on the R-matrix fit, and we end up with a recommended value of S{sub E2}(300 keV) =42{+-}2 keV-b. As ANC values derived from indirect methods are not consistent with the {sup 12}C({alpha}, {gamma}){sup 16}O cascade transitions to the 2{sub 1}{sup +} state, we suggest a remeasurement of this cross section.

  7. Suppression of newborn natural killer cell activity by prostaglandin E2

    SciTech Connect

    Milch, P.O.; Salvatore, W.; Luft, B.; Baker, D.A.

    1988-10-01

    The effect of prostaglandin E2 on natural killer cell activity of cord blood was examined. Natural killer cell activity, determined by chromium 51 release, was significantly reduced after prostaglandin E2 (1 microgram/ml) treatment. Prostaglandin E2 has been found to enhance the cellular spread of herpesvirus. Thus prostaglandins may enhance viral infections indirectly by suppressing natural killer cell activity.

  8. Influence of transition metals on Streptomyces coelicolor and S. sioyaensis and generation of chromate-reducing mutants.

    PubMed

    Gren, Tetiana; Ostash, Bohdan; Hrubskyy, Yaroslav; Tistechok, Stepan; Fedorenko, Victor

    2014-03-01

    Bacteria-assisted bioremediation is widely recognized as a low-cost method to minimize the consequences of soil pollution with toxic metals originating from industrial sites. Strains used in bioremediation have to deal with high metal load via biosorption, reduction, bioprecipitation, metal sequestration, and/or chelation. Actinobacteria, and streptomycetes in particular, are considered a perspective group for bioremediation as natural soil inhabitants with extensive secondary metabolism. Nevertheless, there is no reference information on survival of the model streptomycetes in the presence of the most abundant metal pollutants. Also, there are no reports describing the selection approaches towards improvement of bioremediation properties. In this work, the resistance of Streptomyces coelicolor M145 and Streptomyces sioyaensis Lv81 to certain transition metals and their growth under different pH values are described for the first time. Spontaneous chromate-resistant S. sioyaensis Lv81-138 strain was selected in the course of this work. Strain Lv81-138 is the most efficient actinobacterial Cr(VI) reducer reported so far, capable of converting 12 mmol/L of Cr(VI) into Cr(III) in a medium supplemented with 50 mmol/L K2CrO4.

  9. The Mitotic Checkpoint Gene, SIL is Regulated by E2F1

    PubMed Central

    Erez, Ayelet; Chaussepied, Marie; Tina, Colaizzo-Anas; Aplan, Peter; Ginsberg, Doron; Izraeli, Shai

    2009-01-01

    The SIL gene expression is increased in multiple cancers and correlates with the expression of mitotic spindle checkpoint genes and with increased metastatic potential. SIL regulates mitotic entry, organization of the mitotic spindle and cell survival. The E2F transcription factors regulate cell cycle progression by controlling the expression of genes mediating the G1/S transition. More recently E2F has been shown to regulate mitotic spindle checkpoint genes as well. As SIL expression correlates with mitotic checkpoint genes we hypothesized that SIL is regulated by E2F. We mined raw data of published experiments and performed new experiments by modification of E2F expression in cell lines, reporter assays and chromatin immunoprecipitation. Ectopic expression or endogenous activation of E2F induced the expression of SIL, while knockdown of E2F by shRNA, downregulated SIL expression. E2F activated SIL promoter by reporter assay and bound to SIL promoter in-vivo. Taken together these data demonstrate that SIL is regulated by E2F. As SIL is essential for mitotic entry, E2F may regulate G2/M transition through the induction of SIL. Furthermore, as silencing of SIL cause apoptosis in cancer cells, these finding may have therapeutic relevance in tumors with constitutive activation of E2F. PMID:18649360

  10. E2F4 Function in G2

    PubMed Central

    Plesca, Dragos; Crosby, Meredith E.; Gupta, Damodar; Almasan, Alexandru

    2008-01-01

    Mammalian cells undergo cell cycle arrest in response to DNA damage through multiple checkpoint mechanisms. One such checkpoint pathway maintains genomic integrity by delaying mitotic progression in response to genotoxic stress. Transition though the G2 phase and entry into mitosis is considered to be regulated primarily by cyclin B1 and its associated catalytically active partner Cdk1. While not necessary for its initiation, the p130 and Rb-dependent target genes have emerged as being important for stable maintenance of a G2 arrest. It was recently demonstrated that by interacting with p130, E2F4 is present in the nuclei and plays a key role in the maintenance of this stable G2 arrest. Increased E2F4 levels and its translocation to the nucleus following genotoxic stress result in downregulation of many mitotic genes and as a result promote a G0-like state. Irradiation of E2F4-depleted cells leads to enhanced cellular DNA double-strand breaks that may be measured by comet assays. It also results in cell death that is characterized by caspase activation, sub-G1 and sub-G2 DNA content, and decreased clonogenic cell survival. Here we review these recent findings and discuss the mechanisms of G2 phase checkpoint activation and maintenance with a particular focus on E2F4. PMID:17507799

  11. What is the local air quality impact related to major transit sources and can barriers reduce exposure?

    EPA Science Inventory

    The presentation will describe measurement and modeling activities to study the dispersion of air pollution from transit emissions (highway, rail, port) and evaluation of barriers as a mitigation method.

  12. Tensile-strain effect of inducing the indirect-to-direct band-gap transition and reducing the band-gap energy of Ge

    SciTech Connect

    Inaoka, Takeshi Furukawa, Takuro; Toma, Ryo; Yanagisawa, Susumu

    2015-09-14

    By means of a hybrid density-functional method, we investigate the tensile-strain effect of inducing the indirect-to-direct band-gap transition and reducing the band-gap energy of Ge. We consider [001], [111], and [110] uniaxial tensility and (001), (111), and (110) biaxial tensility. Under the condition of no normal stress, we determine both normal compression and internal strain, namely, relative displacement of two atoms in the primitive unit cell, by minimizing the total energy. We identify those strain types which can induce the band-gap transition, and evaluate the critical strain coefficient where the gap transition occurs. Either normal compression or internal strain operates unfavorably to induce the gap transition, which raises the critical strain coefficient or even blocks the transition. We also examine how each type of tensile strain decreases the band-gap energy, depending on its orientation. Our analysis clearly shows that synergistic operation of strain orientation and band anisotropy has a great influence on the gap transition and the gap energy.

  13. Does "transition shoe" promote an intermediate biomechanical condition compared to running in conventional shoe and in reduced protection condition?

    PubMed

    da Silva Azevedo, Ana Paula; Mezêncio, Bruno; Valvassori, Raísa; Mochizuki, Luis; Amadio, Alberto Carlos; Serrão, Júlio Cerca

    2016-05-01

    This study evaluated if running in a "transition shoe" commercially available results in intermediate mechanical load upon lower extremities compared to conventional shoe and minimalist shoe/barefoot. Kinematic and kinetic parameters while running in different shoe conditions were compared. Fourteen runners (12 men, 2 women; age=28.4±7.3 years), inexperienced in minimalist shoes and barefoot running, ran on an instrumented treadmill within four experimental conditions (conventional shoe - CS, transition shoe - TrS, minimalist shoe - MS, and barefoot - BF). Running was performed at 9km/h for 10min in each experimental condition. Vertical ground reaction force (VGRF) and two-dimensional kinematic variables of lower limbs (both legs) were recorded. Nine data acquisitions (10s) were conducted for each footwear condition. Transition shoe lead to significant changes in VGRF variables related to impact control, while kinematic parameters were little affected. The TrS had smaller first peak of VGRF (Fy1) than CS (p≤0.001) and higher than MS (p=0.050) and BF (p≤0.001). Time to first peak of VGRF (tFy1) of TrS was smaller than CS (p≤0.001) and higher than MS (p≤0.001) and BF (p≤0.001). The TrS and MS induced to lesser knee flexion (p<0.001) and greater dorsiflexion (p<0.001) than CS and BF. Thus, results suggest the transition shoe (TrS) tested seem to promote an intermediate mechanical load condition only for VGRF parameters, presenting values of impact forces between those found for conventional shoe and minimalist shoe/barefoot. Such knowledge could be useful for the transition process from conventional running shoe to minimalist shoe/barefoot.

  14. Origin of superconductivity in the Weyl semimetal WT e2 under pressure

    NASA Astrophysics Data System (ADS)

    Lu, Pengchao; Kim, Joon-Seok; Yang, Jing; Gao, Hao; Wu, Juefei; Shao, Dexi; Li, Bin; Zhou, Dawei; Sun, Jian; Akinwande, Deji; Xing, Dingyu; Lin, Jung-Fu

    2016-12-01

    The structure and superconductivity of WT e2 under pressure are investigated using ab initio calculations combined with high-pressure synchrotron x-ray diffraction and Raman spectroscopy. We find that the emergence of superconductivity in WT e2 under pressure can be attributed to the phase transition from ambient Td phase to the monoclinic 1 T ' structure phase at around 4-5 GPa, which is associated with a sliding of the WT e2 layers, resulting in a critical point in the changes of Te-Te interlayer distance. This phase transition introduces an inversion center and eliminates the topological Weyl fermions in the Td structure. Electron-phonon coupling calculations predict a similar Tc as the reported value, implying that WT e2 might belong to conventional normal Bardeen-Cooper-Schrieffer superconductors.

  15. ${\\rm B(E2)}\\uparrow (0_{1}^{+} \\rightarrow 2_{1}^{+})$ predictions for even-even nuclei in the differential equation model

    NASA Astrophysics Data System (ADS)

    Nayak, R. C.; Pattnaik, S.

    2015-02-01

    We use the recently developed differential equation model (DEM) for the reduced electric quadrupole transition probability B(E2)↑ for the transition from the ground to the first 2+ state for predicting its values for a wide range of even-even nuclides almost throughout the nuclear landscape from Neon to Californium. This is made possible as the principal equation in the model, namely, the differential equation connecting the B(E2)↑ value of a given even-even nucleus with its derivatives with respect to the neutron and proton numbers, provides two different recursion relations, each connecting three different neighboring even-even nuclei from lower- to higher-mass numbers and vice versa. These relations are primarily responsible in extrapolating from known to unknown terrain of the B(E2)↑-landscape and thereby facilitate the predictions throughout. As a result, we have succeeded in predicting its hitherto unknown value for the adjacent 251 isotopes lying on either side of the known B(E2)↑ database.

  16. The 3α Process Studied Through Pair Conversion Transitions from the Hoyle State in 12C

    NASA Astrophysics Data System (ADS)

    Eriksen, T. K.; Kibédi, T.; Reed, M. W.; Stuchbery, A. E.; Akber, A.; de Vries, M.; Dowie, J.; Evitts, L. J.; Garnsworthy, A. B.; Gerathy, M.; Hota, S. S.; Lane, G. J.; Mitchell, A. J.; Palazzo, T.; Smallcombe, J.; Tornyi, T. G.

    The E0 and E2 pair transitions from the Hoyle state have been measured, with the aim of deducing the radiative width and 3α reaction rate by a new approach. The 3α process is the only way carbon is synthesised in stars and is a bottleneck in stellar nucleosynthesis. The new method, which requires the ratio of the pair transitions, is expected to reduce the uncertainty from 10 to 5%. We recently observed the E2 pair transition for the first time, confirming the feasibility of the method. However, more statistics are needed to obtain a precise value for the radiative width.

  17. Effects of roaming trajectories on the transition state theory rates of a reduced-dimensional model of ketene isomerization.

    PubMed

    Ulusoy, Inga S; Stanton, John F; Hernandez, Rigoberto

    2013-08-15

    The rates of chemical reactions (or any activated process) are by definition determined by the flux of reactants (or initial states) that end up as products (or final states). The forward flux through any surface that divides reactants from products is a constant as long as only those trajectories that were reactants in the infinite past and products in the infinite future are included in the flux once and only once. Transition state theory (TST) ignores this last clause, thereby overestimating the rate if any of the trajectories recross the dividing surface. However, its advantage is that it replaces a dynamical calculation with a statistical integral over the TST geometry. The recent identification of roaming trajectories-those that persist for a long time as neither reactant nor product without ever visiting near the col on the energy landscape-apparently challenges the dogma that TST's only error lies in the omission of recrossing trajectories. This question is investigated using the isomerization reaction of ketene in which the experimental values are verified to be in reasonable agreement with both the exact and TST values. We have found two trajectories for the ketene isomerization that carry the signature of roaming, but their effect on the calculation of the reaction rate constant using classical transition state theory is small. Indeed, the existence of roaming trajectories is seen to impose a limitation on which dividing surfaces are appropriate for the calculation of either exact or approximate TST rates, but in this case, they do not unseat the existence of dividing surfaces that can be used safely to calculate TST rates.

  18. Ultrafast Electron Pulse (e,2e) Processes

    NASA Astrophysics Data System (ADS)

    Shao, Hua-Chieh; Starace, Anthony; Madsen, Lars

    2012-06-01

    Techniques for producing ultrafast electron pulses have been proposedootnotetextP. Baum and A.H. Zewail, Proc. Natl. Acad. Sci. U.S.A. 104, 18409 (2007); S.A. Hilbert, C. Ulterwaal, B. Barwick, H. Betalaan, and A.H. Zewail, ibid. 106, 10558 (2009). and prospects for using such pulses to image electron dynamics in the H atom and the hydrogen molecular ion have been theoretically demonstrated.ootnotetextH.-C. Shao and A.F. Starace, Phys. Rev. Lett. 105, 263201 (2010). The (e,2e) process provides a means to directly image the momentum distribution of the target.ootnotetextM.A. Coplan, J.H. Moore, and J.P. Doering, Rev. Mod. Phys. 66, 985 (1994). We explore here the possibility of observing the time dependence of a coherent superposition of target orbitals by means of the (e,2e) process with ultrafast incident electron pulses. Using scattering theory for a longitudinally coherent beam,ootnotetextF. Robicheaux, Phys. Rev. A 62, 062706 (2000). we find that the momentum distribution of a coherent state of the H atom can be retrieved.

  19. The B lineage transcription factor E2A regulates apoptosis in chronic lymphocytic leukemia (CLL) cells.

    PubMed

    Kardava, Lela; Yang, Qi; St Leger, Anthony; Foon, Kenneth A; Lentzsch, Suzanne; Vallejo, Abbe N; Milcarek, Christine; Borghesi, Lisa

    2011-06-01

    Chronic lymphocytic leukemia (CLL) is a common malignancy characterized by the accumulation of B lymphocytes with an antigen-experienced activated CD19(+)CD5(+) clonal phenotype. Clinically, ∼50% of cases will behave more aggressively. Here, we investigate the role of the major B-cell transcription factor E2A, a known regulator of B-cell survival and proliferation, to CLL persistence. We show that E2A is elevated at the mRNA and protein levels relative to normal B-cell subsets. E2A silencing in primary CLL cells leads to a significant increase in spontaneous apoptosis in both CD38(+) (aggressive) and CD38(-) (indolent) cases. Moreover, E2A knockdown synergizes with the immunomodulatory drug lenalidomide to reduce CLL viability. E2A is known to restrain the proliferation of primary B and T lymphocytes at multiple stages of maturation and we report that targeted E2A disruption increases the frequency of Ki-67(+) CLL cells in the absence of effects on de novo proliferation. At the molecular level, E2A siRNA-treated CLL cells display reduced expression of key genes associated with survival and cell cycling including p27, p21 and mcl-1, of which the former two are known E2A target genes. Thus, E2A, a key transcription factor associated with the B-cell activation profile, regulates apoptosis in CLL and may contribute to disease pathology.

  20. Transcriptional regulation of human RANK ligand gene expression by E2F1

    SciTech Connect

    Hu Yan; Sun Meng; Nadiminty, Nagalakshmi; Lou Wei; Pinder, Elaine; Gao, Allen C.

    2008-06-06

    Receptor activator of nuclear factor kappa B ligand (RANKL) is a critical osteoclastogenic factor involved in the regulation of bone resorption, immune function, the development of mammary gland and cardiovascular system. To understand the transcriptional regulation of RANKL, we amplified and characterized a 1890 bp 5'-flanking sequence of human RANKL gene (-1782 bp to +108 bp relative to the transcription start site). Using a series of deletion mutations of the 1890 bp RANKL promoter, we identified a 72 bp region (-172 to -100 bp) mediating RANKL basal transcriptional activity. Sequence analysis revealed a putative E2F binding site within this 72 bp region in the human RANKL promoter. Overexpression of E2F1 increased RANKL promoter activity, while down-regulation of E2F1 expression by small interfering RNA decreased RANKL promoter activity. RT-PCR and enzyme linked immunosorbent assays (ELISA) further demonstrated that E2F1 induced the expression of RANKL. Electrophoretic gel mobility shift assays (EMSA) and antibody competition assays confirmed that E2F1 proteins bind to the consensus E2F binding site in the RANKL promoter. Mutation of the E2F consensus binding site in the RANKL promoter profoundly reduced the basal promoter activity and abolished the transcriptional modulation of RANKL by E2F1. These results suggest that E2F1 plays an important role in regulating RANKL transcription through binding to the E2F consensus binding site.

  1. Observing interference effect in binary (e, 2e) of molecules

    NASA Astrophysics Data System (ADS)

    Chen, Xiangjun; Yang, Jing; Shan, Xu; Zhang, Zhe; Tian, Qiguo; Wang, Enliang

    2015-04-01

    We present investigations on the two-center and multi-center interference effects of molecules in binary (e, 2e) experiments. The high energy resolution electron momentum spectroscopy (EMS) measurements on H2 are reported with final vibrational states resolved. The experimental momentum profiles for ionization transitions to the individual final vibrational states of the ion are obtained. The measured and calculated vibrational ratios of the cross sections deviate from Franck-Condon principle, which can be ascribed to the Young-type two-center interference. Furthermore, with the help of our latest version of EMS spectrometer which has considerably higher sensitivity and much wider momentum range from 0 to 8 a.u., we are able to extend our observations to multi-center interference effect in high symmetry molecules like NF3 and CF4 with several oscillation periods included.

  2. Energy budget increases reduce mean streamflow more than snow-rain transitions: using integrated modeling to isolate climate change impacts on Rocky Mountain hydrology

    NASA Astrophysics Data System (ADS)

    Foster, Lauren M.; Bearup, Lindsay A.; Molotch, Noah P.; Brooks, Paul D.; Maxwell, Reed M.

    2016-04-01

    In snow-dominated mountain regions, a warming climate is expected to alter two drivers of hydrology: (1) decrease the fraction of precipitation falling as snow; and (2) increase surface energy available to drive evapotranspiration. This study uses a novel integrated modeling approach to explicitly separate energy budget increases via warming from precipitation phase transitions from snow to rain in two mountain headwaters transects of the central Rocky Mountains. Both phase transitions and energy increases had significant, though unique, impacts on semi-arid mountain hydrology in our simulations. A complete shift in precipitation from snow to rain reduced streamflow between 11% and 18%, while 4 °C of uniform warming reduced streamflow between 19% and 23%, suggesting that changes in energy-driven evaporative loss, between 27% and 29% for these uniform warming scenarios, may be the dominant driver of annual mean streamflow in a warming climate. Phase changes induced a flashier system, making water availability more susceptible to precipitation variability and eliminating the runoff signature characteristic of snowmelt-dominated systems. The impact of a phase change on mean streamflow was reduced as aridity increased from west to east of the continental divide.

  3. THE E2/FRB PATHWAY REGULATION OF DNA REPLICATION AND PROTEIN BIOSYNTHESIS

    EPA Science Inventory

    The E2F/Rb pathway plays a pivotal role in the control of cell cycle progression and regulates the expression of genes required for Gl/S transition. Our study examines the genomic response in Drosophila embryos after overexpression and mutation of E2F/Rb pathway molecules. Hierar...

  4. Contribution of Redox Status to Hepatitis C Virus E2 Envelope Protein Function and Antigenicity*

    PubMed Central

    Fenouillet, Emmanuel; Lavillette, Dimitri; Loureiro, Silvia; Krashias, George; Maurin, Guillemette; Cosset, François-Loïc; Jones, Ian M.; Barbouche, Rym

    2008-01-01

    Disulfide bonding contributes to the function and antigenicity of many viral envelope glycoproteins. We assessed here its significance for the hepatitis C virus E2 envelope protein and a counterpart deleted for hypervariable region-1 (HVR1). All 18 cysteine residues of the antigens were involved in disulfides. Chemical reduction of up to half of these disulfides was compatible with anti-E2 monoclonal antibody reaction, CD81 receptor binding, and viral entry, whereas complete reduction abrogated these properties. The addition of 5,5′-dithiobis-2-nitrobenzoic acid had no effect on viral entry. Thus, E2 function is only weakly dependent on its redox status, and cell entry does not require redox catalysts, in contrast to a number of enveloped viruses. Because E2 is a major neutralizing antibody target, we examined the effect of disulfide bonding on E2 antigenicity. We show that reduction of three disulfides, as well as deletion of HVR1, improved antibody binding for half of the patient sera tested, whereas it had no effect on the remainder. Small scale immunization of mice with reduced E2 antigens greatly improved serum reactivity with reduced forms of E2 when compared with immunization using native E2, whereas deletion of HVR1 only marginally affected the ability of the serum to bind the redox intermediates. Immunization with reduced E2 also showed an improved neutralizing antibody response, suggesting that potential epitopes are masked on the disulfide-bonded antigen and that mild reduction may increase the breadth of the antibody response. Although E2 function is surprisingly independent of its redox status, its disulfide bonds mask antigenic domains. E2 redox manipulation may contribute to improved vaccine design. PMID:18667425

  5. Downregulation of ceramide synthase-6 during epithelial-to-mesenchymal transition reduces plasma membrane fluidity and cancer cell motility.

    PubMed

    Edmond, V; Dufour, F; Poiroux, G; Shoji, K; Malleter, M; Fouqué, A; Tauzin, S; Rimokh, R; Sergent, O; Penna, A; Dupuy, A; Levade, T; Theret, N; Micheau, O; Ségui, B; Legembre, P

    2015-02-19

    Epithelial-to-mesenchymal transition (EMT) promotes cell motility, which is important for the metastasis of malignant cells, and blocks CD95-mediated apoptotic signaling triggered by immune cells and chemotherapeutic regimens. CD95L, the cognate ligand of CD95, can be cleaved by metalloproteases and released as a soluble molecule (cl-CD95L). Unlike transmembrane CD95L, cl-CD95L does not induce apoptosis but triggers cell motility. Electron paramagnetic resonance was used to show that EMT and cl-CD95L treatment both led to augmentation of plasma membrane fluidity that was instrumental in inducing cell migration. Compaction of the plasma membrane is modulated, among other factors, by the ratio of certain lipids such as sphingolipids in the membrane. An integrative analysis of gene expression in NCI tumor cell lines revealed that expression of ceramide synthase-6 (CerS6) decreased during EMT. Furthermore, pharmacological and genetic approaches established that modulation of CerS6 expression/activity in cancer cells altered the level of C16-ceramide, which in turn influenced plasma membrane fluidity and cell motility. Therefore, this study identifies CerS6 as a novel EMT-regulated gene that has a pivotal role in the regulation of cell migration.

  6. An E2 Accessory Domain Increases Affinity for the Anaphase-promoting Complex and Ensures E2 Competition*

    PubMed Central

    Girard, Juliet R.; Tenthorey, Jeanette L.; Morgan, David O.

    2015-01-01

    The anaphase-promoting complex/cyclosome (APC/C) is a member of the RING family of E3 ubiquitin ligases, which promote ubiquitin transfer from an E2 ubiquitin-conjugating enzyme to a substrate. In budding yeast, the APC/C collaborates with two E2s, Ubc4 and Ubc1, to promote the initiation and elongation, respectively, of polyubiquitin chains on the substrate. Ubc4 and Ubc1 are thought to compete for the same site on the APC/C, but it is not clear how their affinities are balanced. Here, we demonstrate that a C-terminal ubiquitin-associated (UBA) domain enhances the affinity of Ubc1 for the APC/C. Deletion of the UBA domain reduced apparent APC/C affinity for Ubc1 and decreased polyubiquitin chain length. Surprisingly, the positive effect of the UBA domain was not due to an interaction with the acceptor ubiquitin attached to the APC/C substrate or the donor ubiquitin attached to Ubc1 itself. Instead, our evidence suggests that the UBA domain binds to a site on the APC/C core, thereby increasing Ubc1 affinity and enhancing its ability to compete with Ubc4. The UBA domain is required for normal Ubc1 function and E2 competition in vivo. Thus, the UBA domain of Ubc1 ensures efficient polyubiquitination of substrate by balancing Ubc1 affinity with that of Ubc4. PMID:26306044

  7. Reducing NPR 7120.5D to Practice: Transitioning from Design Reviews to the SIR Hardware Review

    NASA Technical Reports Server (NTRS)

    Taylor, Randall

    2011-01-01

    The Gravity Recovery And Interior Laboratory (GRAIL) mission was the first Jet Propulsion Laboratory (JPL) project initiated under NASA's revised rules for space flight project management, NPR 7120.5D, "NASA Space Flight Program and Project Management Requirements." NASA selected GRAIL through a competitive Announcement of Opportunity process and funded its Phase B Preliminary Design effort. The team's first major milestone was a JPL institutional milestone, the Project Mission System Review (PMSR), which proved an excellent tune-up for the end-of-Phase-B NASA life-cycle review, the Preliminary Design Review (PDR). Building on JPL experience on the Prometheus and Juno projects, the team successfully organized for and conducted these reviews on an aggressive schedule. For the Project Critical Design Review (CDR), lessons learned from the PDR and updated Standing Review Board (SRB) practices from the Agency were factored into the review preparation effort. Additionally, the review was held at the Principal Investigator's institution, the Massachusetts Institute of Technology, rather than at the project management center (JPL), which necessitated additional cross-country coordination steps. The PMSR, PDR, and CDR were design reviews and largely paper-oriented. For the System Integration Review (SIR), the project needed to transition to a hardware review and deal with paper in a very different manner. While many of the practices employed for the design reviews were modified and retained (e.g., review preparation team, gate products management, pre-reviews, SRB coordination), the review agenda, presentation style, and slide templates were significantly changed. A key success factor concerned the handling of project open paper, which was succinctly and effectively communicated to the SRB in presentations.This paper provides a brief overview of the GRAIL mission and its project management challenges, provides a detailed description of project SIR preparation and execution

  8. E2EDSM: An Edge-to-Edge Data Service Model for Mass Streaming Media Transmission

    NASA Astrophysics Data System (ADS)

    He, Junfeng; Wang, Hui; He, Ningwu; Sun, Zhigang; Gong, Zhenghu

    Existing distributed content delivery systems like P2P applications may provide significant benefits for content providers and end users. However, they just shifted the considerable cost and burden to Internet Service Providers (ISPs) and well-behaved end users. In P2P applications, the amount of data served by each ISP and payment of many costly transit links are increasing, but the corresponding service revenue from the peer-hosted data services provided doesn’t return. In this paper, we present a novel Edge-to-Edge Data Service Model (E2EDSM) which aims to avoid transferring redundant data over the costly core transit links as well as improving the transmission efficiency of mass streaming media. E2EDSM describes a new way for ISP to take part in the processing of content distribution and makes an effort to achieve a winwin goal. Experimental results based on simulation show that E2EDSM achieves better network performance.

  9. Warming reduces tall fescue abundance but stimulates toxic alkaloid concentrations in transition zone pastures of the U.S.

    PubMed Central

    McCulley, Rebecca L.; Bush, Lowell P.; Carlisle, Anna E.; Ji, Huihua; Nelson, Jim A.

    2014-01-01

    Tall fescue pastures cover extensive acreage in the eastern half of the United States and contribute to important ecosystem services, including the provisioning of forage for grazing livestock. Yet little is known concerning how these pastures will respond to climate change. Tall fescue's ability to persist and provide forage under a warmer and wetter environment, as is predicted for much of this region as a result of climate change, will likely depend on a symbiotic relationship the plant can form with the fungal endophyte, Epichloë coenophiala. While this symbiosis can confer environmental stress tolerance to the plant, the endophyte also produces alkaloids toxic to insects (e.g., lolines) and mammals (ergots; which can cause “fescue toxicosis” in grazing animals). The negative animal health and economic consequences of fescue toxicosis make understanding the response of the tall fescue symbiosis to climate change critical for the region. We experimentally increased temperature (+3°C) and growing season precipitation (+30% of the long-term mean) from 2009–2013 in a mixed species pasture, that included a tall fescue population that was 40% endophyte-infected. Warming reduced the relative abundance of tall fescue within the plant community, and additional precipitation did not ameliorate this effect. Warming did not alter the incidence of endophyte infection within the tall fescue population; however, warming significantly increased concentrations of ergot alkaloids (by 30–40%) in fall-harvested endophyte-infected individuals. Warming alone did not affect loline alkaloid concentrations, but when combined with additional precipitation, levels increased in fall-harvested material. Although future warming may reduce the dominance of tall fescue in eastern U.S. pastures and have limited effect on the incidence of endophyte infection, persisting endophyte-infected tall fescue will have higher concentrations of toxic alkaloids which may exacerbate fescue

  10. Warming reduces tall fescue abundance but stimulates toxic alkaloid concentrations in transition zone pastures of the U.S.

    NASA Astrophysics Data System (ADS)

    Mcculley, Rebecca; Bush, Lowell; Carlisle, Anna; Ji, Huihua; Nelson, Jim

    2014-10-01

    Tall fescue pastures cover extensive acreage in the eastern half of the United States and contribute to important ecosystem services, including the provisioning of forage for grazing livestock. Yet little is known concerning how these pastures will respond to climate change. Tall fescue’s ability to persist and provide forage under a warmer and wetter environment, as is predicted for much of this region as a result of climate change, will likely depend on a symbiotic relationship the plant can form with the fungal endophyte, Epichloë coenophiala. While this symbiosis can confer environmental stress tolerance to the plant, the endophyte also produces alkaloids toxic to insects (e.g., lolines) and mammals (ergots; which can cause ‘fescue toxicosis’ in grazing animals). The negative animal health and economic consequences of fescue toxicosis make understanding the response of the tall fescue symbiosis to climate change critical for the region. We experimentally increased temperature (+3oC) and growing season precipitation (+30% of the long-term mean) from 2009 - 2013 in a mixed species pasture, that included a tall fescue population that was 40% endophyte-infected. Warming reduced the relative abundance of tall fescue within the plant community, and additional precipitation did not ameliorate this effect. Warming did not alter the incidence of endophyte infection within the tall fescue population; however, warming significantly increased concentrations of ergot alkaloids (by 30-40%) in fall-harvested endophyte-infected individuals. Warming alone did not affect loline alkaloid concentrations, but when combined with additional precipitation, levels increased in fall-harvested material. Although future warming may reduce the dominance of tall fescue in eastern U.S. pastures and have limited effect on the incidence of endophyte infection, persisting endophyte-infected tall fescue will have higher concentrations of toxic alkaloids which may exacerbate fescue

  11. Competing E2 and SN2 Mechanisms for the F(-) + CH3CH2I Reaction.

    PubMed

    Yang, Li; Zhang, Jiaxu; Xie, Jing; Ma, Xinyou; Zhang, Linyao; Zhao, Chenyang; Hase, William L

    2017-02-09

    Anti-E2, syn-E2, inv-, and ret-SN2 reaction channels for the gas-phase reaction of F(-) + CH3CH2I were characterized with a variety of electronic structure calculations. Geometrical analysis confirmed synchronous E2-type transition states for the elimination of the current reaction, instead of nonconcerted processes through E1cb-like and E1-like mechanisms. Importantly, the controversy concerning the reactant complex for anti-E2 and inv-SN2 paths has been clarified in the present work. A positive barrier of +19.2 kcal/mol for ret-SN2 shows the least feasibility to occur at room temperature. Negative activation energies (-16.9, -16.0, and -4.9 kcal/mol, respectively) for inv-SN2, anti-E2, and syn-E2 indicate that inv-SN2 and anti-E2 mechanisms significantly prevail over the eclipsed elimination. Varying the leaving group for a series of reactions F(-) + CH3CH2Y (Y = F, Cl, Br, and I) leads to monotonically decreasing barriers, which relates to the gradually looser TS structures following the order F > Cl > Br > I. The reactivity of each channel nearly holds unchanged except for the perturbation between anti-E2 and inv-SN2. RRKM calculation reveals that the reaction of the fluorine ion with ethyl iodide occurs predominately via anti-E2 elimination, and the inv-SN2 pathway is suppressed, although it is energetically favored. This phenomenon indicates that, in evaluating the competition between E2 and SN2 processes, the kinetic or dynamical factors may play a significant role. By comparison with benchmark CCSD(T) energies, MP2, CAM-B3LYP, and M06 methods are recommended to perform dynamics simulations of the title reaction.

  12. Global analyses of brachiopod faunas through the Ordovician and Silurian transition: Reducing the role of the Lazarus effect

    USGS Publications Warehouse

    Rong, J.-Y.; Boucot, A.J.; Harper, D.A.T.; Zhan, R.-B.; Neuman, R.B.

    2006-01-01

    Global analyses of 88 families and 284 genera of brachiopods from middle Ashgill, Late Ordovician, to early-middle Rhuddanian, Early Silurian, indicate that 18.6% and 12.5% of families and 51.0% and 41.3% of genera were eliminated in the first and second phases of the end-Ordovician mass extinction, respectively, with the total loss of 28.4% of families and 69.0% of genera in the crisis. New investigation demonstrates that brachiopods, at both generic and familial levels, suffered greater during the first phase than during the second phase. Four groups (victims, relicts, survivors, and new arrivals) are distinguished by their stratigraphical ranges. Generic survivors, occurring in the Kosov Province during the Hirnantian, can be split into three types with respect to their changing abundance: increasing, declining, and Lazarus taxa. Among the 88 genera that survived, numerous declining genera occurred in the Hirnantian: 16 Lazarus families and 18 Lazarus genera are provisionally known and may be regarded as end members of the declining type. Comparison of the abundance, population size, and distribution patterns of declining and Lazarus taxa shows important similarities between these two types which contribute to a better understanding of the nature of Lazarus taxa. In addition to these biological attributes, taphonomic failure and generally poor preservation, together with collecting bias and inadequate systematic data, are clearly involved. More collections will undoubtedly globally reduce the number of Lazarus taxa. A single, common refugium for end-Ordovician brachiopods probably did not exist; rather, these taxa used paleogeographically scattered locations in a range of environments for survival. ?? 2006 NRC Canada.

  13. {sup 12}C({alpha},{gamma}){sup 16}O E2 cross section: R-matrix fits combined with a microscopic cluster model

    SciTech Connect

    Dufour, M.

    2008-07-15

    The E2 component of the {sup 12}C({alpha},{gamma}){sup 16}O cross section is investigated in two ways: by a microscopic cluster model, and by R-matrix fits. The {alpha}+{sup 12}C microscopic calculation is performed in the framework of the generator coordinate method (GCM) by including all {sup 12}C states (T=0) within the p shell. Using different nucleon-nucleon interactions we find S{sub E2}(300 keV){approx_equal}50 keV {center_dot} b for ground-state transitions. We also study cascade transitions to the 0{sub 2}{sup +} and 2{sub 1}{sup +} excited states of {sup 16}O. Then the S-factor is analyzed in the phenomenological R-matrix theory. We show that the background term plays a crucial role, and cannot be determined without ambiguity. Using the experimental phase shifts and capture cross sections, only an upper limit on the extrapolated S factor can be obtained [S{sub E2}(300 keV)<190 keV {center_dot} b]. To constrain the R-matrix analysis, we use the GCM asymptotic normalization constant (ANC) of the 2{sub 1}{sup +} level, well known to be a cluster state. This procedure strongly reduces the uncertainties on the R-matrix fit, and we end up with a recommended value of S{sub E2}(300 keV)=42{+-}2 keV {center_dot} b. We show that ANC values derived from indirect methods are not consistent with the {sup 12}C({alpha},{gamma}){sup 16}O cascade transitions to the 2{sub 1}{sup +} state, and suggest that a remeasurement of this cross section is desirable.

  14. Isolation, Characterization, and Degradation Performance of the 17β-Estradiol-Degrading Bacterium Novosphingobium sp. E2S

    PubMed Central

    Li, Shunyao; Liu, Juan; Sun, Minxia; Ling, Wanting; Zhu, Xuezhu

    2017-01-01

    A 17β-estradiol (E2)-degrading bacterium E2S was isolated from the activated sludge in a sewage treatment plant (STP). The morphology, biological characteristics, and 16S ribosomal RNA (rRNA) gene sequence of strain E2S indicated that it belonged to the genus Novosphingobium. The optimal degrading conditions were 30 °C and pH 7.0. The ideal inoculum volume was 5% (v/v), and a 20-mL degradation system was sufficient to support the removal ability of strain E2S. The addition of extra NaCl to the system did not benefit the E2 degradation in batch culture by this strain. Strain E2S exhibited high degradation efficiency with initial substrate concentrations of 10–50 mg·L−1. For example, in mineral salt medium containing 50 mg·L−1 of E2, the degradation efficiency was 63.29% after seven days. In cow manure samples supplemented with 50 mg·L−1 of E2, strain E2S exhibited 66.40% degradation efficiency after seven days. The finding of the E2-degrading strain E2S provided a promising method for removing E2 from livestock manure in order to reduce the potential environmental risks of E2. PMID:28125060

  15. Energies, E1, M1, and E2 transition rates, hyperfine structures, and Lande g{sub J} factors for states of the 2s{sup 2}2p{sup 2}, 2s2p{sup 3}, and 2p{sup 4} configurations in carbon-like ions between F IV and Ni XXIII

    SciTech Connect

    Joensson, P.; Rynkun, P.; Gaigalas, G.

    2011-11-15

    Energies, electric dipole, magnetic dipole, and electric quadrupole transition rates, hyperfine structures, and Lande g{sub J} factors from relativistic configuration interaction calculations are reported for the states of the (1s{sup 2})2s{sup 2}2p{sup 2}, 2s2p{sup 3}, and 2p{sup 4} configurations in all carbon-like ions between F IV and Ni XXIII. Valence, core-valence, and core-core correlation effects were accounted for through single/double-excitation-multireference expansions to increasing sets of active orbitals. The calculated energy levels generally agree within a few hundred cm{sup -1} with the experimentally compiled results, and the Babushkin (length), and Coulomb (velocity) forms of transition rates agree within less than 1% for a majority of the allowed transitions.

  16. Parent Training to Reduce Problem Behaviors over the Transition to High School: Tests of Indirect Effects through Improved Emotion Regulation Skills

    PubMed Central

    Mason, W. Alex; January, Stacy-Ann A.; Fleming, Charles B.; Thompson, Ronald W.; Parra, Gilbert R.; Haggerty, Kevin P.; Snyder, James J.

    2016-01-01

    Adolescent problem behaviors are costly for individuals and society. Promoting the self-regulatory functioning of youth may help prevent the development of such behaviors. Parent-training and family intervention programs have been shown to improve child and adolescent self-regulation. This study helps fill gaps in knowledge by testing for indirect effects of the Common Sense Parenting® (CSP) program on reduced substance use, conduct problems, and school suspensions through previously identified short-term improvements in parents’ reports of their children’s emotion regulation skills. Over two cohorts, 321 low income families of 8th graders were enrolled and randomly assigned to either the standard CSP program, an adapted CSP Plus program, or a minimal-contact control condition. Pretest, posttest, 1-year follow-up, and 2-year follow-up survey assessments were completed by parents and students with 94% retention. Intent-to-treat multivariate path analyses were conducted. Neither intervention had statistically significant total effects on the three targeted adolescent outcomes. CSP, but not CSP Plus, had statistically significant indirect effects on reduced substance use and school suspensions at the 1-year follow-up as well as conduct problems and school suspensions at the 2-year follow-up through increased child emotion regulation skills at posttest. Findings provide some support for emotion regulation as one pathway through which the intervention was associated, indirectly, with reduced substance use, conduct problems, and school suspensions among at-risk students over the high school transition. PMID:26778871

  17. Parent Training to Reduce Problem Behaviors over the Transition to High School: Tests of Indirect Effects through Improved Emotion Regulation Skills.

    PubMed

    Mason, W Alex; January, Stacy-Ann A; Fleming, Charles B; Thompson, Ronald W; Parra, Gilbert R; Haggerty, Kevin P; Snyder, James J

    2016-02-01

    Adolescent problem behaviors are costly for individuals and society. Promoting the self-regulatory functioning of youth may help prevent the development of such behaviors. Parent-training and family intervention programs have been shown to improve child and adolescent self-regulation. This study helps fill gaps in knowledge by testing for indirect effects of the Common Sense Parenting(®) (CSP) program on reduced substance use, conduct problems, and school suspensions through previously identified short-term improvements in parents' reports of their children's emotion regulation skills. Over two cohorts, 321 low income families of 8(th) graders were enrolled and randomly assigned to either the standard CSP program, an adapted CSP Plus program, or a minimal-contact control condition. Pretest, posttest, 1-year follow-up, and 2-year follow-up survey assessments were completed by parents and students with 94% retention. Intent-to-treat multivariate path analyses were conducted. Neither intervention had statistically significant total effects on the three targeted adolescent outcomes. CSP, but not CSP Plus, had statistically significant indirect effects on reduced substance use and school suspensions at the 1-year follow-up as well as conduct problems and school suspensions at the 2-year follow-up through increased child emotion regulation skills at posttest. Findings provide some support for emotion regulation as one pathway through which the intervention was associated, indirectly, with reduced substance use, conduct problems, and school suspensions among at-risk students over the high school transition.

  18. Correlating double-difference of charge radii with quadrupole deformation and B (E 2 ) in atomic nuclei

    NASA Astrophysics Data System (ADS)

    Sun, B. H.; Liu, C. Y.; Wang, H. X.

    2017-01-01

    A good linear correlation is found between the double-difference of charge radius δ R2 p -2 n(Z ,N ) with that of quadrupole deformation data in even-even nuclei. This results in a further improved charge radius relation that holds in a precision of about 5 ×10-3 fm. The new relation can be generalized to the reduced electric quadrupole transition probability B (E 2 ) between the first 2+ state and the 0+ ground state, and the mean lifetime τ of the first 2+ state. Same correlations are also seen in global nuclear models such as Hartree-Fock-Bogoliubov (HFB-24) and relativistic mean field (RMF); however, they are not consistent with the experimental data.

  19. Inactivation of E2F3 results in centrosome amplification.

    PubMed

    Saavedra, Harold I; Maiti, Baidehi; Timmers, Cynthia; Altura, Rachel; Tokuyama, Yukari; Fukasawa, Kenji; Leone, Gustavo

    2003-04-01

    The E2F family of transcription factors is critical for the control of cell cycle progression. We now show that the specific inactivation of E2F3 in mouse embryo fibroblasts (MEFs) results in a disruption of the centrosome duplication cycle. Loss of E2F3, but not E2F1, E2F2, E2F4, or E2F5 results in unregulated cyclin E-dependent kinase activity, defects in nucleophosmin B association with centrosomes, and premature centriole separation and duplication. Consequently, this defect leads to centrosome amplification, mitotic spindle defects, and aneuploidy. Our findings implicate the E2F3 transcription factor as an important link that orchestrates DNA and centrosome duplication cycles, ensuring the faithful transmission of genetic material to daughter cells.

  20. The Rb-E2F transcriptional regulatory pathway in tumor angiogenesis and metastasis.

    PubMed

    Schaal, Courtney; Pillai, Smitha; Chellappan, Srikumar P

    2014-01-01

    The retinoblastoma tumor suppressor protein Rb plays a major role in regulating G1/S transition and is a critical regulator of cell proliferation. Rb protein exerts its growth regulatory properties mainly by physically interacting with the transcriptionally active members of the E2F transcription factor family, especially E2Fs 1, 2, and 3. Given its critical role in regulating cell proliferation, it is not surprising that Rb is inactivated in almost all tumors, either through the mutation of Rb gene itself or through the mutations of its upstream regulators including K-Ras and INK4. Recent studies have revealed a significant role for Rb and its downstream effectors, especially E2Fs, in regulating various aspects of tumor progression, angiogenesis, and metastasis. Thus, components of the Rb-E2F pathway have been shown to regulate the expression of genes involved in angiogenesis, including VEGF and VEGFR, genes involved in epithelial-mesenchymal transition including E-cadherin and ZEB proteins, and genes involved in invasion and migration like matrix metalloproteinases. Rb has also been shown to play a major role in the functioning of normal and cancer stem cells; further, Rb and E2F appear to play a regulatory role in the energy metabolism of cancer cells. These findings raise the possibility that mutational events that initiate tumorigenesis by inducing uncontrolled cell proliferation might also contribute to the progression and metastasis of cancers through the mediation of the Rb-E2F transcriptional regulatory pathway. This review highlights these recent studies on tumor promoting functions of the Rb-E2F pathway.

  1. Characterization of hepatitis C virus recombinants with chimeric E1/E2 envelope proteins and identification of single amino acids in the E2 stem region important for entry.

    PubMed

    Carlsen, Thomas H R; Scheel, Troels K H; Ramirez, Santseharay; Foung, Steven K H; Bukh, Jens

    2013-02-01

    The hepatitis C virus (HCV) envelope proteins E1 and E2 play a key role in host cell entry and represent important targets for vaccine and drug development. Here, we characterized HCV recombinants with chimeric E1/E2 complexes in vitro. Using genotype 1a/2a JFH1-based recombinants expressing 1a core-NS2, we exchanged E2 with functional isolate sequences of genotypes 1a (alternative isolate), 1b, and 2a. While the 1a-E2 exchange did not impact virus viability, the 2a-E2 recombinant was nonviable. After E2 exchange from three 1b isolates, long delays were observed before spread of infection. For recovered 1b-E2 recombinants, single E2 stem region amino acid changes were identified at residues 706, 707, and 710. In reverse genetic studies, these mutations increased infectivity titers by ~100-fold, apparently without influencing particle stability or cell binding although introducing slight decrease in particle density. In addition, the 1b-E2 exchange led to a decrease in secreted core protein of 25 to 50%, which was further reduced by the E2 stem region mutations. These findings indicated that compensatory mutations permitted robust infectious virus production, without increasing assembly/release. Studies of E1/E2 heterodimerization showed no differences in intracellular E1/E2 interaction for chimeric constructs with or without E2 stem region mutations. Interestingly, the E2 stem region mutations allowed efficient entry, which was verified in 1a-E1/1b-E2 HCV pseudoparticle assays. A CD81 inhibition assay indicated that the mutations influenced a late step of the HCV entry pathway. Overall, this study identified specific amino acids in the E2 stem region of importance for HCV entry and for production of infectious virus particles.

  2. Chronic estradiol replacement to aged female rats reduces anxiety-like and depression-like behavior and enhances cognitive performance.

    PubMed

    Walf, Alicia A; Paris, Jason J; Frye, Cheryl A

    2009-07-01

    Decline in the ovarian steroid, estradiol (E(2)), with the menopause transition may influence cognitive and affective processing of older women and there is evidence that hormone replacement therapies (HRTs) with E(2)-mimetics may provide benefit in some, but not all, women. The parameters that play a role in determining whether the response to HRTs is positive are of interest. It may be that the likelihood for positive responses is related to the timing of E(2)-replacement following E(2) decline. As such, in the present study an animal model was utilized to investigate this. We investigated the effects of long- versus short-term E(2)-replacement by examining cognitive (object placement task), anxiety (open field, mirror maze, light-dark transition task), and depression (forced swim task) behavior of female rats that were ovariectomized (OVX) at middle-age (14 months) or older (19 months) and implanted with E(2)-filled implants at the time of surgery or after a delay of 5 months, or OVX at 14 months of age and never replaced with E(2). Rats were tested at 20 months of age. The hypothesis that was tested was that rats would have reduced anxiety and depression behavior and improved cognitive performance with E(2)-replacement at ovarian cessation, compared to a delay in E(2)-replacement. Performance in the object placement task was improved in rats that were OVX and then received continuous E(2)-replacement, compared to those that were OVX and continuously administered placebo vehicle. In the open field and forced swim task, there was an increase in anti-anxiety and anti-depression behavior, respectively, among rats that were OVX and then received continuous E(2)-replacement, compared to OVX rats administered vehicle or those that experienced a delay in E(2)-replacement. In the mirror maze and light-dark transition task, E(2)-replacement at OVX, or after a delay, reduced anxiety-like behavior. Thus, E(2)-replacement reduced anxiety and depression behavior and improved

  3. Quadrupole transition strength in the (74)Ni nucleus and core polarization effects in the neutron-rich Ni isotopes.

    PubMed

    Marchi, T; de Angelis, G; Valiente-Dobón, J J; Bader, V M; Baugher, T; Bazin, D; Berryman, J; Bonaccorso, A; Clark, R; Coraggio, L; Crawford, H L; Doncel, M; Farnea, E; Gade, A; Gadea, A; Gargano, A; Glasmacher, T; Gottardo, A; Gramegna, F; Itaco, N; John, P R; Kumar, R; Lenzi, S M; Lunardi, S; McDaniel, S; Michelagnoli, C; Mengoni, D; Modamio, V; Napoli, D R; Quintana, B; Ratkiewicz, A; Recchia, F; Sahin, E; Stroberg, R; Weisshaar, D; Wimmer, K; Winkler, R

    2014-10-31

    The reduced transition probability B(E2;0(+)→2(+)) has been measured for the neutron-rich nucleus (74)Ni in an intermediate energy Coulomb excitation experiment performed at the National Superconducting Cyclotron Laboratory at Michigan State University. The obtained B(E2;0(+)→2(+))=642(-226)(+216)  e(2) fm(4) value defines a trend which is unexpectedly small if referred to (70)Ni and to a previous indirect determination of the transition strength in (74)Ni. This indicates a reduced polarization of the Z=28 core by the valence neutrons. Calculations in the pfgd model space reproduce well the experimental result indicating that the B(E2) strength predominantly corresponds to neutron excitations. The ratio of the neutron and proton multipole matrix elements supports such an interpretation.

  4. E2F-1 gene therapy induces apoptosis and increases chemosensitivity in human pancreatic carcinoma cells.

    PubMed

    Elliott, Mary Jane; Farmer, Michael R; Atienza, Cesar; Stilwell, Ariel; Dong, Yan Bin; Yang, Hai Liang; Wong, Sandra L; McMasters, Kelly M

    2002-01-01

    Pancreatic cancer is often resistant to conventional chemotherapy. In this study, we examined the role of adenovirus-mediated overexpression of E2F-1 in inducing apoptosis and increasing the sensitivity of pancreatic cancer cells to chemotherapeutic agents. MIA PaCa-2 pancreatic head exocrine adenocarcinoma cells (mutant p53) were treated by mock infection or adenoviruses expressing beta-galactosidase or E2F-1 (Ad-E2F-1) alone or in combination with sublethal concentrations of each chemotherapeutic drug. Cell growth and viability were assessed at selected time points. Apoptosis was evaluated by flow cytometry, characteristic changes in cell morphology and poly (ADP-ribose) polymerase (PARP) cleavage. Western blot analysis was used to examine the expression of E2F-1 and Bcl-2 family member proteins and PARP cleavage. Western blot analysis revealed marked overexpression of E2F-1 at a multiplicity of infection (MOI) of 20 and 70. By 3 days after infection, Ad-E2F-1 treatment at an MOI of 70 resulted in approximately a 20-fold reduction in cell growth and 60% reduction in cell viability as compared to mock-infected cells. Cell cycle analysis, PARP cleavage and changes in cell morphology supported apoptosis as the mechanism of cell death in response to E2F-1. In order to test the efficacy of treatment with a combination of gene therapy and chemotherapy, we utilized concentrations of Ad-E2F-1 which reduced viability to 50% in combination with each chemotherapeutic agent. Cotreatment of the cells with E2F-1 virus and roscovitine (ROS) or etoposide resulted in an additive effect on cell growth inhibition and induction of apoptosis. Interestingly, 5-fluorouracil did not cooperate with Ad-E2F-1 in the mediation of tumor death or inhibition of cell growth. Immunoblotting for Bcl-2 family members revealed no significant changes in the expression levels of Bcl-2, Bcl X(L), Bax or Bak following gene or 'chemogene' therapy with E2F-1. However, a Bax cleavage product was noted

  5. MEF/ELF4 transactivation by E2F1 is inhibited by p53.

    PubMed

    Taura, Manabu; Suico, Mary Ann; Fukuda, Ryosuke; Koga, Tomoaki; Shuto, Tsuyoshi; Sato, Takashi; Morino-Koga, Saori; Okada, Seiji; Kai, Hirofumi

    2011-01-01

    Myeloid elf-1-like factor (MEF) or Elf4 is an E-twenty-six (ETS)-related transcription factor with strong transcriptional activity that influences cellular senescence by affecting tumor suppressor p53. MEF downregulates p53 expression and inhibits p53-mediated cellular senescence by transcriptionally activating MDM2. However, whether p53 reciprocally opposes MEF remains unexplored. Here, we show that MEF is modulated by p53 in human cells and mice tissues. MEF expression and promoter activity were suppressed by p53. While we found that MEF promoter does not contain p53 response elements, intriguingly, it contains E2F consensus sites. Subsequently, we determined that E2F1 specifically binds to MEF promoter and transactivates MEF. Nevertheless, E2F1 DNA binding and transactivation of MEF promoter was inhibited by p53 through the association between p53 and E2F1. Furthermore, we showed that activation of p53 in doxorubicin-induced senescent cells increased E2F1 and p53 interaction, diminished E2F1 recruitment to MEF promoter and reduced MEF expression. These observations suggest that p53 downregulates MEF by associating with and inhibiting the binding activity of E2F1, a novel transcriptional activator of MEF. Together with previous findings, our present results indicate that a negative regulatory mechanism exists between p53 and MEF.

  6. Oct3/4 directly regulates expression of E2F3a in mouse embryonic stem cells

    SciTech Connect

    Kanai, Dai; Ueda, Atsushi; Akagi, Tadayuki; Yokota, Takashi; Koide, Hiroshi

    2015-04-10

    Embryonic stem (ES) cells, derived from the inner cell mass of blastocysts, have a characteristic cell cycle with truncated G1 and G2 phases. Recent findings that suppression of Oct3/4 expression results in a reduced proliferation rate of ES cells suggest the involvement of Oct3/4 in the regulation of ES cell growth, although the underlying molecular mechanism remains unclear. In the present study, we identified E2F3a as a direct target gene of Oct3/4 in ES cells. Oct3/4 directly bound to the promoter region of the E2F3a gene and positively regulated expression of E2F3a in mouse ES cells. Suppression of E2F3a activity by E2F6 overexpression led to the reduced proliferation in ES cells, which was relieved by co-expression of E2F3a. Furthermore, cell growth retardation caused by loss of Oct3/4 was rescued by E2F3a expression. These results suggest that Oct3/4 upregulates E2F3a expression to promote ES cell growth. - Highlights: • Oct3/4 positively regulates E2F3a expression in ES cells. • Oct3/4 binds to the promoter region of the E2F3a gene. • Overexpression of E2F6, an inhibitor of E2F3a, reduces ES cell growth. • E2F3a recovers growth retardation of ES cells caused by Oct3/4 reduction.

  7. Identification of highly deformed even-even nuclei in the neutron- and proton-rich regions of the nuclear chart from the B(E2)↑ and E2 predictions in the generalized differential equation model

    NASA Astrophysics Data System (ADS)

    Nayak, R. C.; Pattnaik, S.

    2015-11-01

    We identify here the possible occurrence of large deformations in the neutron- and proton-rich (n-rich and p-rich) regions of the nuclear chart from extensive predictions of the values of the reduced quadrupole transition probability B(E2)↑ for the transition from the ground state to the first 2+ state and the corresponding excitation energy E2 of even-even nuclei in the recently developed generalized differential equation (GDE) model exclusively meant for these physical quantities. This is made possible from our analysis of the predicted values of these two physical quantities and the corresponding deformation parameters derived from them such as the quadrupole deformation β2, the ratio of β2 to the Weisskopf single-particle β2(sp) and the intrinsic electric quadrupole moment Q0, calculated for a large number of both known as well as hitherto unknown even-even isotopes of oxygen to fermium (0 to FM; Z = 8-100). Our critical analysis of the resulting data convincingly support possible existence of large collectivity for the nuclides 30,32Ne,34Mg, 60Ti, 42,62,64Cr,50,68Fe, 52,72Ni, 72,70,96Kr,74,76Sr,78,80,106,108Zr, 82,84,110,112Mo, 140Te,144Xe, 148Ba,122Ce, 128,156Nd,130,132,158,160Sm and 138,162,164,166Gd, whose values of β2 are found to exceed 0.3 and even 0.4 in some cases. Our findings of large deformations in the exotic n-rich regions support the existence of another “island of inversion” in the heavy-mass region possibly caused by breaking of the N = 70 subshell closure.

  8. Triaxial rotor model description of E2 properties in {sup 186,188,190,192}Os

    SciTech Connect

    Allmond, J. M.; Zaballa, R.; Oros-Peusquens, A. M.; Kulp, W. D.; Wood, J. L.

    2008-07-15

    The triaxial rotor model with independent inertia and electric quadrupole tensors is applied to the description of the extensive set of E2 matrix elements available for {sup 186,188,190,192}Os. Most large and medium transition E2 matrix elements can be reproduced to within {approx}10%, and most diagonal elements to within {approx}30%. Most small transition matrix elements can be reproduced to within {approx}30%, and they support the interference effect exhibited by the model between the inertia and E2 tensors: this is a new feature of quantum rotor models. The diagonal E2 matrix elements at higher spins in the K=2 band are extremely sensitive to admixtures of higher K values: the low experimental values in {sup 190,192}Os indicate significant admixtures of K=4 components. Attention is given to the K{sup {pi}}=4{sup +} bands in these nuclei and the controversial issue of whether they are of quadrupole or hexadecapole nature.

  9. Dietary supplementation with phytosterol and ascorbic acid reduces body mass accumulation and alters food transit time in a diet-induced obesity mouse model

    PubMed Central

    2011-01-01

    Previous research indicates that animals fed a high fat (HF) diet supplemented with disodium ascorbyl phytostanyl phosphate (DAPP) exhibit reduced mass accumulation when compared to HF control. This compound is a water-soluble phytostanol ester and consists of a hydrophobic plant stanol covalently bonded to ascorbic acid (Vitamin C). To provide insight into the mechanism of this response, we examined the in vivo effects of a high fat diet supplemented with ascorbic acid (AA) in the presence and absence of unesterified phytosterols (PS), and set out to establish whether the supplements have a synergistic effect in a diet-induced obesity mouse model. Our data indicate that HF diet supplementation with a combination of 1% w/w phytosterol and 1% w/w ascorbic acid results in reduced mass accumulation, with mean differences in absolute mass between PSAA and HF control of 10.05%; and differences in mass accumulation of 21.6% (i.e. the PSAA group gained on average 21% less mass each week from weeks 7-12 than the HF control group). In our previous study, the absolute mass difference between the 2% DAPP and HF control was 41%, while the mean difference in mass accumulation between the two groups for weeks 7-12 was 67.9%. Mass loss was not observed in animals supplemented with PS or AA alone. These data suggest that the supplements are synergistic with respect to mass accumulation, and the esterification of the compounds further potentiates the response. Our data also indicate that chronic administration of PS, both in the presence and absence of AA, results in changes to fecal output and food transit time, providing insight into the possibility of long-term changes in intestinal function related to PS supplementation. PMID:21711516

  10. Effects of helium on ductile-brittle transition behavior of reduced-activation ferritic steels after high-concentration helium implantation at high temperature

    NASA Astrophysics Data System (ADS)

    Hasegawa, A.; Ejiri, M.; Nogami, S.; Ishiga, M.; Kasada, R.; Kimura, A.; Abe, K.; Jitsukawa, S.

    2009-04-01

    The effects of He on the fracture behavior of reduced-activation ferritic/martensitic steels, including oxide dispersion-strengthened (ODS) steels and F82H, was determined by characterizing the microstructural evolution in and fracture behavior of these steels after He implantation up to 1000 appm at around 550 °C. He implantation was carried out by a cyclotron with a beam of 50 MeV α-particles. In the case of F82H, the ductile-to-brittle transition temperature (DBTT) increase induced by He implantation was about 70 °C and the grain boundary fracture surface was only observed in the He-implanted area of all the ruptured specimens in brittle manner. By contrast, no DBTT shift or fracture mode change was observed in He-implanted 9Cr-ODS and 14Cr-ODS steels. Microstructural characterization suggested that the difference in the bubble formation behavior of F82H and ODS steels might be attributed to the grain boundary rupture of He-implanted F82H.

  11. Focusing electrode and coaxial reflector used for reducing the guiding magnetic field of the Ku-band foilless transit-time oscillator

    SciTech Connect

    Ling, Junpu; Zhang, Jiande; He, Juntao Wang, Lei; Deng, Bingfang

    2014-08-15

    Based on the theoretical analysis of the intense relativistic electron beam propagation in the coaxial drift-tube, a focusing electrode and a coaxial reflector is proposed to lessen the demand of the coaxial Ku-band foilless transit-time oscillator (TTO) for the guiding magnetic field. Moreover, a Ku-band TTO with the focusing electrode and the coaxial reflector is designed and studied by particle in cell simulation. When the diode voltage is 390 kV, the beam current 7.8 kA, and the guiding magnetic field is only 0.3 T, the device can output 820 MW microwave pulse at 14.25 GHz by means of the simulation. However, for the device without them, the output power is only 320 MW. The primary experiments are also carried out. When the guiding magnetic field is 0.3 T, the output power of the device with the focusing electrode and the coaxial reflector is double that of the one without them. The simulation and experimental results prove that the focusing electrode and the coaxial reflector are effective on reducing the guiding magnetic field of the device.

  12. Focusing electrode and coaxial reflector used for reducing the guiding magnetic field of the Ku-band foilless transit-time oscillator

    NASA Astrophysics Data System (ADS)

    Ling, Junpu; Zhang, Jiande; He, Juntao; Wang, Lei; Deng, Bingfang

    2014-08-01

    Based on the theoretical analysis of the intense relativistic electron beam propagation in the coaxial drift-tube, a focusing electrode and a coaxial reflector is proposed to lessen the demand of the coaxial Ku-band foilless transit-time oscillator (TTO) for the guiding magnetic field. Moreover, a Ku-band TTO with the focusing electrode and the coaxial reflector is designed and studied by particle in cell simulation. When the diode voltage is 390 kV, the beam current 7.8 kA, and the guiding magnetic field is only 0.3 T, the device can output 820 MW microwave pulse at 14.25 GHz by means of the simulation. However, for the device without them, the output power is only 320 MW. The primary experiments are also carried out. When the guiding magnetic field is 0.3 T, the output power of the device with the focusing electrode and the coaxial reflector is double that of the one without them. The simulation and experimental results prove that the focusing electrode and the coaxial reflector are effective on reducing the guiding magnetic field of the device.

  13. Focusing electrode and coaxial reflector used for reducing the guiding magnetic field of the Ku-band foilless transit-time oscillator.

    PubMed

    Ling, Junpu; Zhang, Jiande; He, Juntao; Wang, Lei; Deng, Bingfang

    2014-08-01

    Based on the theoretical analysis of the intense relativistic electron beam propagation in the coaxial drift-tube, a focusing electrode and a coaxial reflector is proposed to lessen the demand of the coaxial Ku-band foilless transit-time oscillator (TTO) for the guiding magnetic field. Moreover, a Ku-band TTO with the focusing electrode and the coaxial reflector is designed and studied by particle in cell simulation. When the diode voltage is 390 kV, the beam current 7.8 kA, and the guiding magnetic field is only 0.3 T, the device can output 820 MW microwave pulse at 14.25 GHz by means of the simulation. However, for the device without them, the output power is only 320 MW. The primary experiments are also carried out. When the guiding magnetic field is 0.3 T, the output power of the device with the focusing electrode and the coaxial reflector is double that of the one without them. The simulation and experimental results prove that the focusing electrode and the coaxial reflector are effective on reducing the guiding magnetic field of the device.

  14. Determination of glass transition temperature of reduced graphene oxide-poly(vinyl alcohol) composites using temperature dependent Fourier transform infrared spectroscopy

    NASA Astrophysics Data System (ADS)

    Mahendia, Suman; Heena; Kandhol, Geeta; Deshpande, Uday P.; Kumar, Shyam

    2016-05-01

    In the present work, structural properties of reduced graphene oxide (RGO) synthesized using modified Hummer's method and its composites with Poly(vinyl alcohol) (PVA) fabricated using solution-cast method have been studied. The structural properties of prepared samples have been systematically studied through UV-Visible absorption, Raman, Fourier Transform Infrared (FTIR) and Differential Scanning Calorimeter (DSC) spectroscopy. Infrared spectroscopy indicates the grafting of PVA chains with graphene layer through the formation of H-bonding linkage in the composites. Temperature-dependent FTIR spectra of PVA-RGO composite films were recorded to obtain the glass transition temperature (Tg) and to study its molecular origin. From these spectra the values of Tg were obtained using two-dimensional (2D) mapping of the first derivative of the absorbance intensity with respect to temperature (dA/dT), over the space of wavenumber and temperature. The value of Tg obtained for pure PVA increases from 78 °C to 92 °C after loading 0.5 wt.% of RGO in PVA and can be attributed to the strong H-bonding interaction between polymer chains and grafted solid surface of RGO. These results are in good agreement with those obtained from DSC analysis. This clearly indicates that the thermal behavior of PVA gets modified with loading of RGO.

  15. E2F1 — EDRN Public Portal

    Cancer.gov

    The E2F1 protein belongs to the E2F/DP family of transcription factors. E2F1 binds DNA cooperatively with dp (differentiation regulated transcription factor proteins)proteins through the E2 recognition site, 5'-TTTC[CG]CGC-3' found in the promoter region of a number of genes whose products are involved in cell cycle regulation or in DNA replication. The E2F family plays a crucial role in the control of cell cycle and action of tumor suppressor proteins and is also a target of the transforming proteins of small DNA tumor viruses. E2F1 can mediate both cell proliferation and p53-dependent/independent apoptosis.

  16. Involvement of E2F transcription factor family in cancer.

    PubMed

    Tsantoulis, P K; Gorgoulis, V G

    2005-11-01

    The E2F family of transcription factors is a central modulator of important cellular events, including cell cycle progression, apoptosis and DNA damage response. The role of E2F family members in various human malignancies is yet unclear and may provide vital clues to the diagnosis, prognosis and therapy of cancer patients. In this review we provide a brief but concise overview of E2F function and its putative role in the most common human tumour types.

  17. Role of an adenovirus E2 promoter binding factor in E1A-mediated coordinate gene control.

    PubMed Central

    Kovesdi, I; Reichel, R; Nevins, J R

    1987-01-01

    A product of the adenovirus gene E1A is responsible for the stimulation of transcription from six viral promoters as well as at least two cellular promoters. We have detected a HeLa cell factor, termed E2 promoter binding factor (E2F), that appears to mediate the transcriptional stimulation of the viral E2 promoter. Competition experiments revealed that E2F did not recognize and bind to the E1B, E3, E4, or major late promoter sequences. Furthermore, three additional promoters stimulated by E1A, heat shock protein 70, beta-globin, and early simian virus 40, do not bind E2F. In contrast, the factor does recognize sequences in the E1A enhancer, and within the E1A enhancer are duplicated binding sites for E2F. Finally, a single E2F binding site from the E1A enhancer can confer increased transcription to a mouse beta-globin promoter, dependent on the action of the E1A gene product. This stimulation requires binding of E2F since methylation of the binding site, which blocks binding in vitro, reduces transcription stimulation in vivo. We, therefore, conclude that E2F is likely to be responsible for the E1A-mediated stimulation of the E1A gene as well as the E2 gene but is not involved in the activation of the other E1A-inducible promoters. Images PMID:2951737

  18. High CerS5 expression levels associate with reduced patient survival and transition from apoptotic to autophagy signalling pathways in colorectal cancer

    PubMed Central

    Fitzgerald, Seán; Sheehan, Katherine M; Espina, Virginia; O'Grady, Anthony; Cummins, Robert; Kenny, Dermot; Liotta, Lance; O'Kennedy, Richard; Kay, Elaine W

    2014-01-01

    Abstract Ceramide synthase 5 is involved in the de novo synthesis of ceramide, a sphingolipid involved in cell death and proliferation. In this study, we investigated the role of ceramide synthase 5 in colorectal cancer by examining ceramide synthase 5 expression, clinico‐pathological parameters and association with survival/death signalling pathways in cancer. Immunohistochemical analysis of CerS5 was performed on 102 colorectal cancer samples using tissue microarrays constructed from formalin‐fixed and paraffin‐embedded tissues. We found strong membranous ceramide synthase 5 staining in 57 of 102 (56%) colorectal cancers. A multivariate Cox regression analysis of ceramide synthase 5 expression adjusted for disease stage, differentiation and lymphovascular invasion revealed reduced 5‐year overall survival (p = 0.001) and 5‐year recurrence‐free survival (p = 0.002), with hazard ratios of 4.712 and 4.322, respectively. The effect of ceramide synthase 5 expression on tumourigenic processes was further characterised by reverse phase protein array analysis. Reverse phase protein arrays were generated from laser capture microdissection‐enriched carcinoma cells from 19 fresh‐frozen colorectal cancer tissues. Measurements of phosphorylation and total levels of signalling proteins involved in apoptosis, autophagy and other cancer‐related pathways revealed two distinct signalling networks; weak membranous ceramide synthase 5 intensity was associated with a proteomic network dominated by signalling proteins linked to apoptosis, whereas strong ceramide synthase 5 intensity was associated with a proteomic sub‐network mostly composed of proteins linked to autophagy. In conclusion, high ceramide synthase 5 expression was found in colorectal cancer tissue and was associated with poorer patient outcomes. Our findings suggest that this may be mediated by a transition from apoptotic to autophagy signalling pathways in ceramide synthase 5 High expressing

  19. Prevotella intermedia induces prostaglandin E2 via multiple signaling pathways.

    PubMed

    Guan, S-M; Fu, S-M; He, J-J; Zhang, M

    2011-01-01

    Prostaglandin E(2) (PGE(2)) plays important roles in the bone resorption of inflammatory diseases such as rheumatoid arthritis and periodontitis via specific prostaglandin receptors (i.e., EP1-EP4). In this study, the authors examined whether Prevotella intermedia regulates PGE(2) production and EP expression in human periodontal ligament fibroblasts (hPDLs); they also explored the potential signaling pathways involved in PGE(2) production. P. intermedia induced PGE(2) production and cyclooxygenase-2 (COX-2) expression in a dose- and time-dependent manner. Indomethacin and NS-398 completely abrogated the P. intermedia-induced PGE(2) production without modulating COX-2 expression. Specific inhibitors of extracellular signal-regulated kinase, c-Jun N-terminal kinase, p38, phosphatidylinositol 3-kinase, and protein kinase C--but not c-AMP and protein kinase A--significantly attenuated the P. intermedia-induced COX-2 and PGE(2) expression. P. intermedia reduced EP1 expression in a concentration- and time-dependent manner. The results indicate that the COX-2-dependent induction of PGE(2) by P. intermedia in hPDLs is mediated by multiple signaling pathways.

  20. Regression of Human Papillomavirus Intraepithelial Lesions Is Induced by MVA E2 Therapeutic Vaccine

    PubMed Central

    López-Contreras, Mario; Rosales, Carlos; Magallanes-Molina, Jose-Roberto; Gonzalez-Vergara, Roberto; Arroyo-Cazarez, Jose Martin; Ricardez-Arenas, Antonio; del Follo-Valencia, Armando; Padilla-Arriaga, Santiago; Guerrero, Miriam Veronica; Pirez, Miguel Angel; Arellano-Fiore, Claudia; Villarreal, Freddy

    2014-01-01

    Abstract Human papilloma viruses can induce warts, condylomas, and other intraepithelial cervical lesions that can progress to cancer. Cervical cancer is a serious problem in developing countries because early detection is difficult, and thus proper early treatment is many times missing. In this phase III clinical trial, we evaluated the potential use of MVA E2 recombinant vaccinia virus to treat intraepithelial lesions associated with papillomavirus infection. A total of 1176 female and 180 male patients with intraepithelial lesions were studied. They were injected with 107 MVA E2 virus particles directly into their uterus, urethra, vulva, or anus. Patients were monitored by colposcopy and cytology. Immune response was determined by measuring the antibody titer against MVA E2 virus and by analyzing the cytotoxic activity against cancer cells bearing papillomavirus DNA. Papillomavirus was determined by the Hybrid Capture method or by polymerase chain reaction analysis. By histology, 1051 (89.3%) female patients showed complete elimination of lesions after treatment with MVA E2. In 28 (2.4%) female patients, the lesion was reduced to CIN 1. Another 97 (8.3%) female patients presented isolated koilocytes after treatment. In men, all lesions were completely eliminated. All MVA E2–treated patients developed antibodies against the MVA E2 vaccine and generated a specific cytotoxic response against papilloma-transformed cells. Papillomavirus DNA was not detected after treatment in 83% of total patients treated. MVA E2 did not generate any apparent side effects. These data suggest that therapeutic vaccination with MVA E2 vaccine is an excellent candidate to stimulate the immune system and generate regression in intraepithelial lesions when applied locally. PMID:25275724

  1. Excitonic properties of semiconducting monolayer and bilayer MoT e2

    NASA Astrophysics Data System (ADS)

    Robert, C.; Picard, R.; Lagarde, D.; Wang, G.; Echeverry, J. P.; Cadiz, F.; Renucci, P.; Högele, A.; Amand, T.; Marie, X.; Gerber, I. C.; Urbaszek, B.

    2016-10-01

    MoT e2 belongs to the semiconducting transition-metal dichalcogenide family with certain properties differing from the other well-studied members (Mo ,W ) (S,Se ) 2 . The optical band gap is in the near-infrared region, and both monolayers and bilayers may have a direct optical band gap. We first simulate the single-particle band structure of both monolayer and bilayer MoT e2 with density-functional-theory-G W calculations. We find a direct (indirect) electronic band gap for the monolayer (bilayer). By solving in addition the Bethe-Salpeter equation, we find similar energies for the direct exciton transitions in monolayers and bilayers. We then study the optical properties by means of photoluminescence (PL) excitation, reflectivity, time-resolved PL, and power-dependent PL spectroscopy. With differential reflectivity, we find a similar oscillator strength for the optical transition observed in PL in both monolayers and bilayers suggesting a direct transition in both cases. We identify the same energy for the B -exciton state in the monolayer and the bilayer. Following circularly polarized excitation, we do not find any exciton polarization for a large range of excitation energies. At low temperatures (T =10 K ) , we measure similar PL decay times on the order of 4 ps for both monolayer and bilayer excitons with a slightly longer one for the bilayer. Finally, we observe a reduction of the exciton-exciton annihilation contribution to the nonradiative recombination in bilayers.

  2. Synergistic cooperation of MDM2 and E2F1 contributes to TAp73 transcriptional activity

    SciTech Connect

    Kasim, Vivi; Huang, Can; Zhang, Jing; Jia, Huizhen; Wang, Yunxia; Yang, Li; Miyagishi, Makoto; Wu, Shourong

    2014-07-04

    Highlights: • MDM2 is a novel positive regulator of TAp73 transcriptional activity. • MDM2 colocalizes together and physically interacts with E2F1. • Synergistic cooperation of MDM2 and E2F1 is crucial for TAp73 transcription. • MDM2 regulates TAp73 transcriptional activity in a p53-independent manner. - Abstract: TAp73, a structural homologue of p53, plays an important role in tumorigenesis. E2F1 had been reported as a transcriptional regulator of TAp73, however, the detailed mechanism remains to be elucidated. Here we reported that MDM2-silencing reduced the activities of the TAp73 promoters and the endogenous TAp73 expression level significantly; while MDM2 overexpression upregulated them. We further revealed that the regulation of TAp73 transcriptional activity occurs as a synergistic effect of MDM2 and E2F1, most probably through their physical interaction in the nuclei. Furthermore, we also suggested that MDM2 might be involved in DNA damage-induced TAp73 transcriptional activity. Finally, we elucidated that MDM2-silencing reduced the proliferation rate of colon carcinoma cells regardless of the p53 status. Our data show a synergistic effect of MDM2 and E2F1 on TAp73 transcriptional activity, suggesting a novel regulation pathway of TAp73.

  3. Lifetimes and electromagnetic transition strengths in 155Dy

    NASA Astrophysics Data System (ADS)

    Petkov, P.; Yavahchova, M. S.; Möller, O.; Dewald, A.; Tonev, D.; Saha, B.; Fitzler, A.; Jessen, K.; Klug, T.; Heinze, S.; Jolie, J.; von Brentano, P.; Goutev, N.; Bazzacco, D.; Ur, C. A.; Farnea, E.; Axiotis, M.; Lunardi, S.; de Angelis, G.; Napoli, D. R.; Marginean, N.; Martinez, T.; Caprio, M. A.

    2013-09-01

    Recoil distance Doppler-shift and Doppler-shift attenuation lifetime measurements were carried out for levels in 155Dy through the coincident detection of γ rays. Twenty-six lifetimes, most of them for the first time, were determined using the differential decay curve method for the analysis of the data. At low and medium spins, particle-plus-triaxial-rotor calculations reveal different quadrupole deformations for the one-quasineutron bands in this transitional nucleus. At high spin, the reduced B(E2) transition probabilities confirm with a better precision the results of a previous study implying decreased collectivity with increasing spin.

  4. Recruitment of Pontin/Reptin by E2f1 amplifies E2f transcriptional response during cancer progression

    PubMed Central

    Tarangelo, Amy; Lo, Nathanael; Teng, Rebecca; Kim, Eunsun; Le, Linh; Watson, Deborah; Furth, Emma E.; Raman, Pichai; Ehmer, Ursula; Viatour, Patrick

    2015-01-01

    Changes in gene expression during tumorigenesis are often considered the consequence of de novo mutations occurring in the tumour. An alternative possibility is that the transcriptional response of oncogenic transcription factors evolves during tumorigenesis. Here we show that aberrant E2f activity, following inactivation of the Rb gene family in a mouse model of liver cancer, initially activates a robust gene expression programme associated with the cell cycle. Slowly accumulating E2f1 progressively recruits a Pontin/Reptin complex to open the chromatin conformation at E2f target genes and amplifies the E2f transcriptional response. This mechanism enhances the E2f-mediated transactivation of cell cycle genes and initiates the activation of low binding affinity E2f target genes that regulate non-cell-cycle functions, such as the Warburg effect. These data indicate that both the physiological and the oncogenic activities of E2f result in distinct transcriptional responses, which could be exploited to target E2f oncogenic activity for therapy. PMID:26639898

  5. E2F1 promote the aggressiveness of human colorectal cancer by activating the ribonucleotide reductase small subunit M2

    SciTech Connect

    Fang, Zejun; Gong, Chaoju; Liu, Hong; Zhang, Xiaomin; Mei, Lingming; Song, Mintao; Qiu, Lanlan; Luo, Shuchai; Zhu, Zhihua; Zhang, Ronghui; Gu, Hongqian; Chen, Xiang

    2015-08-21

    As the ribonucleotide reductase small subunit, the high expression of ribonucleotide reductase small subunit M2 (RRM2) induces cancer and contributes to tumor growth and invasion. In several colorectal cancer (CRC) cell lines, we found that the expression levels of RRM2 were closely related to the transcription factor E2F1. Mechanistic studies were conducted to determine the molecular basis. Ectopic overexpression of E2F1 promoted RRM2 transactivation while knockdown of E2F1 reduced the levels of RRM2 mRNA and protein. To further investigate the roles of RRM2 which was activated by E2F1 in CRC, CCK-8 assay and EdU incorporation assay were performed. Overexpression of E2F1 promoted cell proliferation in CRC cells, which was blocked by RRM2 knockdown attenuation. In the migration and invasion tests, overexpression of E2F1 enhanced the migration and invasion of CRC cells which was abrogated by silencing RRM2. Besides, overexpression of RRM2 reversed the effects of E2F1 knockdown partially in CRC cells. Examination of clinical CRC specimens demonstrated that both RRM2 and E2F1 were elevated in most cancer tissues compared to the paired normal tissues. Further analysis showed that the protein expression levels of E2F1 and RRM2 were parallel with each other and positively correlated with lymph node metastasis (LNM), TNM stage and distant metastasis. Consistently, the patients with low E2F1 and RRM2 levels have a better prognosis than those with high levels. Therefore, we suggest that E2F1 can promote CRC proliferation, migration, invasion and metastasis by regulating RRM2 transactivation. Understanding the role of E2F1 in activating RRM2 transcription will help to explain the relationship between E2F1 and RRM2 in CRC and provide a novel predictive marker for diagnosis and prognosis of the disease. - Highlights: • E2F1 promotes RRM2 transactivation in CRC cells. • E2F1 promotes the proliferation of CRC cells by activating RRM2. • E2F1 promotes the migration and

  6. The Effects of Reducing the Structural Mass of the Transit Habitat on the Cryogenic Propellant Required for a Human Phobos Mission

    NASA Technical Reports Server (NTRS)

    Zipay, John Joseph

    2016-01-01

    A technique for rapidly determining the relationship between the pressurized volume, structural mass and the cryogenic propellant required to be delivered to Earth orbit for a Mars Transit Habitat is provided. This technique is based on assumptions for the required delta-V's, the Exploration Upper Stage performance and the historical structural masses for human spacecraft from Mercury Program through the International Space Station. If the Mars Transit Habitat is constructed from aluminum, structural mass estimates based on the habitat pressurized volume are accurate to within 15%. Other structural material options for the Mars Transit Habitat are also evaluated. The results show that small, achievable reductions in the structural mass of the Transit Habitat can save tens of thousands of pounds of cryogenic propellant that need to be delivered to Earth orbit for a human Phobos Mission.

  7. The Effects of Reducing the Structural Mass of the Transit Habitat on the Cryogenic Propellant Required for a Human Phobos Mission

    NASA Technical Reports Server (NTRS)

    Zipay, John J.

    2016-01-01

    A technique for rapidly determining the relationship between the pressurized volume, structural mass and the cryogenic propellant required to be delivered to Earth orbit for a Mars Transit Habitat is provided. This technique is based on assumptions for the required delta-V's, the Exploration Upper Stage performance and the historical structural masses for human spacecraft from Mercury Program through the International Space Station. If the Mars Transit Habitat is constructed from aluminum, structural mass estimates based on the habitat pressurized volume are accurate to within 15 percent. Other structural material options for the Mars Transit Habitat are also evaluated. The results show that small, achievable reductions in the structural mass of the Transit Habitat can save tens of thousands of pounds of cryogenic propellant that need to be delivered to Earth orbit for a human Phobos Mission.

  8. Assessment of the role of in situ generated (E)-2,4-diene-valproic acid in the toxicity of valproic acid and (E)-2-ene-valproic acid in sandwich-cultured rat hepatocytes

    SciTech Connect

    Surendradoss, Jayakumar; Chang, Thomas K.H.; Abbott, Frank S.

    2012-11-01

    Valproic acid (VPA) undergoes cytochrome P450-mediated desaturation to form 4-ene-VPA, which subsequently yields (E)-2,4-diene-VPA by β-oxidation. Another biotransformation pathway involves β-oxidation of VPA to form (E)-2-ene-VPA, which also generates (E)-2,4-diene-VPA by cytochrome P450-mediated desaturation. Although the synthetic form of (E)-2,4-diene-VPA is more hepatotoxic than VPA as shown in various experimental models, there is no conclusive evidence to implicate the in situ generated (E)-2,4-diene-VPA in VPA hepatotoxicity. The present study investigated the effects of modulating the in situ formation of (E)-2,4-diene-VPA on markers of oxidative stress (formation of 2′,7′-dichlorofluorescein; DCF), steatosis (accumulation of BODIPY 558/568 C{sub 12}), necrosis (release of lactate dehydrogenase; LDH), and on cellular total glutathione (GSH) levels in sandwich-cultured rat hepatocytes treated with VPA or (E)-2-ene-VPA. Treatment with either of these chemicals alone increased each of the toxicity endpoints. In VPA-treated hepatocytes, (E)-2,4-diene-VPA was detected only at trace levels, even after phenobarbital (PB) pretreatment and there was no effect on the toxicity of VPA. Furthermore, pretreatment with a cytochrome P450 enzyme inhibitor, 1-aminobenzotriazole (1-ABT), did not influence the extent of VPA toxicity in both PB-pretreated and vehicle-pretreated hepatocytes. However, in (E)-2-ene-VPA-treated hepatocytes, PB pretreatment greatly enhanced the levels of (E)-2,4-diene-VPA and this was accompanied by a further enhancement of the effects of (E)-2-ene-VPA on DCF formation, BODIPY accumulation, LDH release, and GSH depletion. Pretreatment with 1-ABT reduced the concentrations of (E)-2,4-diene-VPA and the extent of (E)-2-ene-VPA toxicity; however, this occurred in PB-pretreated hepatocytes, but not in control hepatocytes. In conclusion, in situ generated (E)-2,4-diene-VPA is not responsible for the hepatocyte toxicity of VPA, whereas it

  9. Random phage mimotopes recognized by monoclonal antibodies against the pyruvate dehydrogenase complex-E2 (PDC-E2).

    PubMed

    Cha, S; Leung, P S; Van de Water, J; Tsuneyama, K; Joplin, R E; Ansari, A A; Nakanuma, Y; Schatz, P J; Cwirla, S; Fabris, L E; Neuberger, J M; Gershwin, M E; Coppel, R L

    1996-10-01

    Dihydrolipoamide acetyltransferase, the E2 component of the pyruvate dehydrogenase complex (PDC-E2), is the autoantigen most commonly recognized by autoantibodies in primary biliary cirrhosis (PBC). We identified a peptide mimotope(s) of PDC-E2 by screening a phage-epitope library expressing random dodecapeptides in the pIII coat protein of fd phage using C355.1, a murine monoclonal antibody (mAb) that recognizes a conformation-dependent epitope in the inner lipoyl domain of PDC-E2 and uniquely stains the apical region of bile duct epithelium (BDE) only in patients with PBC. Eight different sequences were identified in 36 phage clones. WMSYPDRTLRTS was present in 29 clones; WESYPFRVGTSL, APKTYVSVSGMV, LTYVSLQGRQGH, LDYVPLKHRHRH, AALWGVKVRHVS, KVLNRIMAGVRH and GNVALVSSRVNA were singly represented. Three common amino acid motifs (W-SYP, TYVS, and VRH) were shared among all peptide sequences. Competitive inhibition of the immunohistochemical staining of PBC BDE was performed by incubating the peptides WMSYPDRTLRTS, WESYPDRTLRTS, APKTYVSVSGMV, and AALWGVKVRHVS with either C355.1 or a second PDC-E2-specific mAb, C150.1. Both mAbs were originally generated to PDC-E2 but map to distinct regions of PDC-E2. Two of the peptides, although selected by reaction with C355.1, strongly inhibited the staining of BDE by C150.1, whereas the peptide APKTYVSVSGMV consistently inhibited the staining of C355.1 on biliary duct epithelium more strongly than the typical mitochondrial staining of hepatocytes. Rabbit sera raised against the peptide WMSYPDRTLRTS stained BDE of livers and isolated bile duct epithelial cells of PBC patients more intensively than controls. The rabbit sera stained all size ducts in normals, but only small/medium-sized ductules in PBC livers. These studies provide evidence that the antigen present in BDE is a molecular mimic of PDC-E2, and not PDC-E2 itself.

  10. Detergent-Resistant Membrane Association of NS2 and E2 during Hepatitis C Virus Replication

    PubMed Central

    Shanmugam, Saravanabalaji; Saravanabalaji, Dhanaranjani

    2015-01-01

    ABSTRACT Previously, we demonstrated that the efficiency of hepatitis C virus (HCV) E2-p7 processing regulates p7-dependent NS2 localization to putative virus assembly sites near lipid droplets (LD). In this study, we have employed subcellular fractionations and membrane flotation assays to demonstrate that NS2 associates with detergent-resistant membranes (DRM) in a p7-dependent manner. However, p7 likely plays an indirect role in this process, since only the background level of p7 was detectable in the DRM fractions. Our data also suggest that the p7-NS2 precursor is not involved in NS2 recruitment to the DRM, despite its apparent targeting to this location. Deletion of NS2 specifically inhibited E2 localization to the DRM, indicating that NS2 regulates this process. Treatment of cells with methyl-β-cyclodextrin (MβCD) significantly reduced the DRM association of Core, NS2, and E2 and reduced infectious HCV production. Since disruption of the DRM localization of NS2 and E2, either due to p7 and NS2 defects, respectively, or by MβCD treatment, inhibited infectious HCV production, these proteins' associations with the DRM likely play an important role during HCV assembly. Interestingly, we detected the HCV replication-dependent accumulation of ApoE in the DRM fractions. Taking into consideration the facts that ApoE was shown to be a major determinant for infectious HCV particle production at the postenvelopment step and that the HCV Core protein strongly associates with the DRM, recruitment of E2 and ApoE to the DRM may allow the efficient coordination of Core particle envelopment and postenvelopment events at the DRM to generate infectious HCV production. IMPORTANCE The biochemical nature of HCV assembly sites is currently unknown. In this study, we investigated the correlation between NS2 and E2 localization to the detergent-resistant membranes (DRM) and HCV particle assembly. We determined that although NS2's DRM localization is dependent on p7, p7 was not

  11. A MUB E2 structure reveals E1 selectivity between cognate ubiquitin E2s in eukaryotes

    PubMed Central

    Lu, Xiaolong; Malley, Konstantin R.; Brenner, Caitlin C.; Koroleva, Olga; Korolev, Sergey; Downes, Brian P.

    2016-01-01

    Ubiquitin (Ub) is a protein modifier that controls processes ranging from protein degradation to endocytosis, but early-acting regulators of the three-enzyme ubiquitylation cascade are unknown. Here we report that the prenylated membrane-anchored ubiquitin-fold protein (MUB) is an early-acting regulator of subfamily-specific E2 activation. An AtMUB3:AtUBC8 co-crystal structure defines how MUBs inhibit E2∼Ub formation using a combination of E2 backside binding and a MUB-unique lap-bar loop to block E1 access. Since MUBs tether Arabidopsis group VI E2 enzymes (related to HsUbe2D and ScUbc4/5) to the plasma membrane, and inhibit E2 activation at physiological concentrations, they should function as potent plasma membrane localized regulators of Ub chain synthesis in eukaryotes. Our findings define a biochemical function for MUB, a family of highly conserved Ub-fold proteins, and provide an example of selective activation between cognate Ub E2s, previously thought to be constitutively activated by E1s. PMID:27550514

  12. A MUB E2 structure reveals E1 selectivity between cognate ubiquitin E2s in eukaryotes

    NASA Astrophysics Data System (ADS)

    Lu, Xiaolong; Malley, Konstantin R.; Brenner, Caitlin C.; Koroleva, Olga; Korolev, Sergey; Downes, Brian P.

    2016-08-01

    Ubiquitin (Ub) is a protein modifier that controls processes ranging from protein degradation to endocytosis, but early-acting regulators of the three-enzyme ubiquitylation cascade are unknown. Here we report that the prenylated membrane-anchored ubiquitin-fold protein (MUB) is an early-acting regulator of subfamily-specific E2 activation. An AtMUB3:AtUBC8 co-crystal structure defines how MUBs inhibit E2~Ub formation using a combination of E2 backside binding and a MUB-unique lap-bar loop to block E1 access. Since MUBs tether Arabidopsis group VI E2 enzymes (related to HsUbe2D and ScUbc4/5) to the plasma membrane, and inhibit E2 activation at physiological concentrations, they should function as potent plasma membrane localized regulators of Ub chain synthesis in eukaryotes. Our findings define a biochemical function for MUB, a family of highly conserved Ub-fold proteins, and provide an example of selective activation between cognate Ub E2s, previously thought to be constitutively activated by E1s.

  13. The E2P-like state induced by magnesium fluoride complexes in the Na,K-ATPase. Kinetics of formation and interaction with Rb(+).

    PubMed

    Montes, Mónica R; Ferreira-Gomes, Mariela S; Centeno, Mercedes; Rossi, Rolando C

    2015-07-01

    The first X-ray crystal structures of the Na,K-ATPase were obtained in the presence of magnesium and fluoride as E2(K2)Mg-MgF4, an E2∙Pi-like state capable to occlude K(+) (or Rb(+)). This work presents a functional characterization of the crystallized form of the enzyme and proposes a model to explain the interaction between magnesium, fluoride and Rb(+) with the Na,K-ATPase. We studied the effect of magnesium and magnesium fluoride complexes on the E1-E2 conformational transition and the kinetics of Rb(+) exchange between the medium and the E2(Rb2)Mg-MgF4 state. Our results show that both in the absence and in the presence of Rb(+), simultaneous addition of magnesium and fluoride stabilizes the Na,K-ATPase in an E2 conformation, presumably the E2Mg-MgF4 complex, that is unable to shift to E1 upon addition of Na(+). The time course of conformational change suggests the action of fluoride and magnesium at different steps of the E2Mg-MgF4 formation. Increasing concentrations of fluoride revert along a sigmoid curve the drop in the level of occluded Rb(+) caused by Mg(2+). Na(+)-induced release of Rb(+) from E2(Rb2)Mg-MgF4 occurs at the same rate as from E2(Rb2) but is insensitive to ADP. The rate of Rb(+) occlusion into the E2Mg-MgF4 state is 5-8 times lower than that described for the E2Mg-vanadate complex. Since the E2Mg-MgF4 and E2Mg-vanadate complexes represent different intermediates in the E2-P→E2 dephosphorylation sequence, the variation in occlusion rate could provide a tool to discriminate between these intermediates.

  14. Expression of ADAM12 is regulated by E2F1 in small cell lung cancer.

    PubMed

    Li, Zunling; Wang, Yaopeng; Kong, Lijun; Yue, Zhen; Ma, Ying; Chen, Xufang

    2015-12-01

    Our previous study reported that ADAM12 was highly expressed in small cell lung cancer (SCLC) and could be an effective marker for diagnosis and prognosis. Yet, the reason for the high expression of ADAM12 in SCLC requires further elucidation. Transcription factor E2F1 has been receiving increasing attention due to the complexity and diversity of its function in cancer. In the present study, the expression of ADAM12 was significantly decreased following silencing of E2F1 expression by siRNA, thus indicating that E2F1 may regulate the expression of ADAM12 at the level of transcription. Chromatin immunoprecipitation-to-sequence analysis identified three binding sites for E2F1 in the locus for ADAM12. They were Chr10: 128010444-128011026, located in the intron of ADAM12, named seq0; Chr10: 128076927‑128078127, located in the promoter of ADAM12, named seq1; and Chr10: 128086195‑128086876, located in the upstream 20 kb from the transcription start site of ADAM12, named: seq2. Dual‑luciferase reporter experiments revealed that seq1 not seq0 and seq2 was able to promote the expression of luciferase. Notably, co-transfection of E2F1 significantly increased the activity of seq1 not seq0 and seq2, but quantitative polymerase chain reaction results showed that seq0, seq1 and seq2 could recruit E2F1, indicating that the influence of E2F1 in regulating the expression of ADAM12 was complex. Sequence analysis clarified that seq1 was a part of the ADAM12 promoter, yet the functions of seq0 and seq2 were unknown. Fusion fragments containing seq0-seq1 or seq2-seq1 were analyzed in luciferase constructs. Compared with seq1 alone, the activities of these fusion fragments were non-significantly reduced. The activities of fusion fragments were significantly decreased following co-transfection with E2F1. Thus, the present findings support the conclusion that the E2F1 transcription factor regulates the expression of ADAM12 by binding differential cis-acting elements.

  15. Hepatitis C Virus E2 Envelope Glycoprotein Core Structure

    SciTech Connect

    Kong, Leopold; Giang, Erick; Nieusma, Travis; Kadam, Rameshwar U.; Cogburn, Kristin E.; Hua, Yuanzi; Dai, Xiaoping; Stanfield, Robyn L.; Burton, Dennis R.; Ward, Andrew B.; Wilson, Ian A.; Law, Mansun

    2014-08-26

    Hepatitis C virus (HCV), a Hepacivirus, is a major cause of viral hepatitis, liver cirrhosis, and hepatocellular carcinoma. HCV envelope glycoproteins E1 and E2 mediate fusion and entry into host cells and are the primary targets of the humoral immune response. The crystal structure of the E2 core bound to broadly neutralizing antibody AR3C at 2.65 angstroms reveals a compact architecture composed of a central immunoglobulin-fold β sandwich flanked by two additional protein layers. The CD81 receptor binding site was identified by electron microscopy and site-directed mutagenesis and overlaps with the AR3C epitope. The x-ray and electron microscopy E2 structures differ markedly from predictions of an extended, three-domain, class II fusion protein fold and therefore provide valuable information for HCV drug and vaccine design.

  16. E2F1 and TFDP1 Regulate PITX1 Expression in Normal and Osteoarthritic Articular Chondrocytes

    PubMed Central

    Wang, DaShen; Lavigne, Patrick; Moreau, Alain

    2016-01-01

    We previously reported a loss-of-PITX1 expression in patients suffering of knee/hip osteoarthritis (OA). Search for the mechanism underlying this event led us to discover that PITX1 repression was triggered by the aberrant nuclear accumulation of Prohibitin (PHB1), an E2F1 co-repressor, in OA articular chondrocytes. In the current study, we assessed in details the involvement of E2F transcription factors in regulating PITX1 expression. We also analyzed other genes that are similarly regulated by E2F in regard to osteoarthritis. The transcriptional regulation of the PITX1 promoter by E2F1 was analyzed with the luciferase reporter assay, and chromatin immunoprecipitation assays, which confirmed direct E2F1-PITX1 interactions. The probable binding sites for E2F1 in the PITX1 promoter were identified by DNA pulldown experiments. In silico and in vitro analyses show that the PITX1 proximal promoter region contains 2 specific sequences that are bound by E2F1. Overexpression of E2F1 enhances PITX1 promoter activity and mRNA transcription. In primary control and osteoarthritis chondrocytes, real time RT-PCR was used to measure the mRNA expression levels of candidate genes under E2F1 transcriptional control. Transcription Factor Dp-1 (TFDP1) knockdown experiments confirmed that the E2F1-TFDP1 complex regulates PITX1. Knockdown of TFDP1, an E2F1 dimerization partner, inhibits the activating effect of E2F1 and reduces both PITX1 promoter activity and mRNA transcription. Real time RT-PCR results reveal reduced expression of TFDP1 and a similar downregulation of their targets PITX1, BRCA1, CDKN1A, and RAD51 in mid-stage OA chondrocytes. Collectively, our data define a previously uncharacterized role for E2F1 and TFDP1 in the transcriptional regulation of PITX1 in articular chondrocytes. Additional E2F1 targets may be affected in OA pathogenesis. PMID:27802335

  17. Extra-amniotic prostaglandin E2 and the unfavourable cervix.

    PubMed

    Shepherd, J; Sims, C; Craft, I

    1976-10-02

    A small dose of prostaglandin E2 suspended in a viscous medium was instilled as a single application into the extra-amniotic space of patients with unfavourable induction features the day before planned induction in an attempt to improve the condition of the cervix. Two groups of 15 patients were studied, one receiving prostaglandin E2 250 mug suspended in methyl ethyl cellulose ('Tylose') 6% solution, and the other tylose alone. Cervical status did not change in those receiving tylose alone, whereas a significant improvement occurred in 14 out of 15 patients receiving the prostaglandin. Labour began before formal induction in 1 patient receiving tylose and in 8 receiving prostaglandin.

  18. Random phage mimotopes recognized by monoclonal antibodies against the pyruvate dehydrogenase complex-E2 (PDC-E2).

    PubMed Central

    Cha, S; Leung, P S; Van de Water, J; Tsuneyama, K; Joplin, R E; Ansari, A A; Nakanuma, Y; Schatz, P J; Cwirla, S; Fabris, L E; Neuberger, J M; Gershwin, M E; Coppel, R L

    1996-01-01

    Dihydrolipoamide acetyltransferase, the E2 component of the pyruvate dehydrogenase complex (PDC-E2), is the autoantigen most commonly recognized by autoantibodies in primary biliary cirrhosis (PBC). We identified a peptide mimotope(s) of PDC-E2 by screening a phage-epitope library expressing random dodecapeptides in the pIII coat protein of fd phage using C355.1, a murine monoclonal antibody (mAb) that recognizes a conformation-dependent epitope in the inner lipoyl domain of PDC-E2 and uniquely stains the apical region of bile duct epithelium (BDE) only in patients with PBC. Eight different sequences were identified in 36 phage clones. WMSYPDRTLRTS was present in 29 clones; WESYPFRVGTSL, APKTYVSVSGMV, LTYVSLQGRQGH, LDYVPLKHRHRH, AALWGVKVRHVS, KVLNRIMAGVRH and GNVALVSSRVNA were singly represented. Three common amino acid motifs (W-SYP, TYVS, and VRH) were shared among all peptide sequences. Competitive inhibition of the immunohistochemical staining of PBC BDE was performed by incubating the peptides WMSYPDRTLRTS, WESYPDRTLRTS, APKTYVSVSGMV, and AALWGVKVRHVS with either C355.1 or a second PDC-E2-specific mAb, C150.1. Both mAbs were originally generated to PDC-E2 but map to distinct regions of PDC-E2. Two of the peptides, although selected by reaction with C355.1, strongly inhibited the staining of BDE by C150.1, whereas the peptide APKTYVSVSGMV consistently inhibited the staining of C355.1 on biliary duct epithelium more strongly than the typical mitochondrial staining of hepatocytes. Rabbit sera raised against the peptide WMSYPDRTLRTS stained BDE of livers and isolated bile duct epithelial cells of PBC patients more intensively than controls. The rabbit sera stained all size ducts in normals, but only small/medium-sized ductules in PBC livers. These studies provide evidence that the antigen present in BDE is a molecular mimic of PDC-E2, and not PDC-E2 itself. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 PMID:8855289

  19. 26 CFR 31.3231(e)-2 - Contribution base.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 15 2011-04-01 2011-04-01 false Contribution base. 31.3231(e)-2 Section 31.3231... Contribution base. The term compensation does not include any remuneration paid during any calendar year by an employer to an employee for services rendered in excess of the applicable contribution base. For...

  20. 26 CFR 31.3231(e)-2 - Contribution base.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 15 2013-04-01 2013-04-01 false Contribution base. 31.3231(e)-2 Section 31.3231... Contribution base. The term compensation does not include any remuneration paid during any calendar year by an employer to an employee for services rendered in excess of the applicable contribution base. For...

  1. 26 CFR 31.3231(e)-2 - Contribution base.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 15 2010-04-01 2010-04-01 false Contribution base. 31.3231(e)-2 Section 31.3231... Contribution base. The term compensation does not include any remuneration paid during any calendar year by an employer to an employee for services rendered in excess of the applicable contribution base. For...

  2. 26 CFR 31.3231(e)-2 - Contribution base.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 15 2014-04-01 2014-04-01 false Contribution base. 31.3231(e)-2 Section 31.3231... Contribution base. The term compensation does not include any remuneration paid during any calendar year by an employer to an employee for services rendered in excess of the applicable contribution base. For...

  3. 26 CFR 31.3231(e)-2 - Contribution base.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 15 2012-04-01 2012-04-01 false Contribution base. 31.3231(e)-2 Section 31.3231... Contribution base. The term compensation does not include any remuneration paid during any calendar year by an employer to an employee for services rendered in excess of the applicable contribution base. For...

  4. Regulation of the retinoblastoma-E2F pathway by the ubiquitin-proteasome system.

    PubMed

    Sengupta, Satyaki; Henry, R William

    2015-10-01

    The retinoblastoma tumor suppressor (RB) and its related family members p107 and p130 regulate cell proliferation through the transcriptional repression of genes involved in cellular G1 to S phase transition. However, RB proteins are functionally versatile, and numerous genetic and biochemical studies point to expansive roles in cellular growth control, pluripotency, and apoptotic response. For the vast majority of genes, RB family members target the E2F family of transcriptional activators as an integral component of its gene regulatory mechanism. These interactions are regulated via reversible phosphorylation by Cyclin/Cyclin-dependent kinase (Cdk) complexes, a major molecular mechanism that regulates transcriptional output of RB/E2F target genes. Recent studies indicate an additional level of regulation involving the ubiquitin-proteasome system that renders pervasive control over each component of the RB pathway. Disruption of the genetic circuitry for proteasome-mediated targeting of the RB pathway has serious consequences on development and cellular transformation, and is associated with several forms of human cancer. In this review, we discuss the role of the ubiquitin-proteasome system in proteolytic control of RB-E2F pathway components, and recent data that points to surprising non-proteolytic roles for the ubiquitin-proteasome system in novel transcriptional regulatory mechanisms.

  5. Detection of vibrationally excited methyl formate in W51 e2

    NASA Astrophysics Data System (ADS)

    Demyk, K.; Wlodarczak, G.; Carvajal, M.

    2008-10-01

    Context: Hot cores in molecular clouds, such as Orion KL, Sgr B2, W51 e1/e2, are characterized by the presence of molecules at sufficiently high temperatures to populate their low-frequency vibrationally excited states significantly. Complex organic molecules, such as methyl formate, ethyl cyanide or dimethyl ether, are characterized by a dense spectrum both in the ground state and in the excited states and lines from vibrationally excited states certainly participate to the spectral confusion. Aims: Following a laboratory study of the first torsional excited mode of methyl formate, we search for methyl formate, HCOOCH3, in its first torsionally excited state (\\upsilon_t=1) in the molecular cloud W51 e2. Methods: We performed observations of the molecular cloud W51 e2 in different spectral regions at 1.3, 2, and 3 mm with the IRAM 30 m single dish antenna. Results: Methyl formate in its first torsionally excited state (\\upsilon_t=1 at 131 cm-1) is detected for the first time toward W51 e2. We detect 82 transitions among which 46 are unblended with other species. For a total of 16 A-E pairs in the observed spectrum, 9 are unblended; these 9 pairs are all detected. All transitions from excited methyl formate within the observed spectral range are detected and no strong lines are missing. The column density of the excited state is comparable to that of the ground state. For a source size of 7´´, we find that {T_rot} = 104 ± 14 K and N = 9.4+4.0-2.8 × 1016 cm-2 for the excited state and {T_rot} = 176 ± 24 K and N = 1.7+.2-.2 × 1017 cm-2 for the ground state. Lines from ethyl cyanide in its two first excited states (\\upsilon_t=1, torsion mode at 212 cm-1) and (\\upsilon_b=1, CCN in-plane bending mode at 206 cm-1) are also present in the observed spectrum. Blending problems prevent a precise estimate of its abundance, although as for methyl formate, it should be comparable to the value derived for the ground state for which we find {T_rot} = 103 ± 9 K and N = 3

  6. CMIP5 Historical Simulations (1850-2012) with GISS ModelE2

    NASA Technical Reports Server (NTRS)

    Miller, Ronald Lindsay; Schmidt, Gavin A.; Nazarenko, Larissa S.; Tausnev, Nick; Bauer, Susanne E.; DelGenio, Anthony D.; Kelley, Max; Lo, Ken K.; Ruedy, Reto; Shindell, Drew T.; Aleinov, Igor; Bauer, Mike; Bleck, Rainer; Canuto, Vittorio; Chen, Yonghua; Cheng, Ye; Clune, Thomas L.; Faluvegi, Greg; Healy, Richard J.; Kiang, Nancy Y.; Lacis, Andy A.; LeGrande, Allegra N.; Lerner, Jean; Rind, David; Russell, Gary L.

    2014-01-01

    Observations of climate change during the CMIP5 extended historical period (1850-2012) are compared to trends simulated by six versions of the NASA Goddard Institute for Space Studies ModelE2 Earth System Model. The six models are constructed from three versions of the ModelE2 atmospheric general circulation model, distinguished by their treatment of atmospheric composition and the aerosol indirect effect, combined with two ocean general circulation models, HYCOM and Russell. Forcings that perturb the model climate during the historical period are described. Five-member ensemble averages from each of the six versions of ModelE2 simulate trends of surface air temperature, atmospheric temperature, sea ice and ocean heat content that are in general agreement with observed trends, although simulated warming is slightly excessive within the past decade. Only simulations that include increasing concentrations of long-lived greenhouse gases match the warming observed during the twentieth century. Differences in twentieth-century warming among the six model versions can be attributed to differences in climate sensitivity, aerosol and ozone forcing, and heat uptake by the deep ocean. Coupled models with HYCOM export less heat to the deep ocean, associated with reduced surface warming in regions of deepwater formation, but greater warming elsewhere at high latitudes along with reduced sea ice. All ensembles show twentieth-century annular trends toward reduced surface pressure at southern high latitudes and a poleward shift of the midlatitude westerlies, consistent with observations.

  7. Response of Polish rivers (Vistula, Oder) to reduced pressure from point sources and agriculture during the transition period (1988-2008)

    NASA Astrophysics Data System (ADS)

    Pastuszak, Marianna; Stålnacke, Per; Pawlikowski, Krzysztof; Witek, Zbigniew

    2012-06-01

    The Vistula and Oder Rivers, two out of the seven largest rivers in the Baltic drainage basin, were responsible for 25% of total riverine nitrogen (TN) and 37% of total riverine phosphorus (TP) input to the Baltic Sea in 2000. The aim of this paper is to evaluate the response of these two rivers to changes that took place in Polish economy during the transition period (1988-2008). The economic changes encompassed: construction of nearly 900 waste water treatment plants in 1999-2008, modernization or closure of obsolete factories, economizing in water consumption, closure or change of ownership of State-owned farms, a drop in fertilizer application, and a decline in livestock stocking. More intensive agriculture and higher point source emissions in the Oder than in the Vistula basin resulted in higher concentrations of TN, nitrate (NO3-N), and TP in the Oder waters in the entire period of our studies. In both rivers, nutrient concentrations and loads showed significant declining trends in the period 1988-2008. TN loads decreased by ca. 20% and 25% in the Vistula and Oder; TP loads dropped by ca. 15% and 65% in the Vistula and Oder. The reduction in phosphorus loads was particularly pronounced in the Oder basin, which was characterized by efficient management systems aiming at mitigation of nutrient emission from the point sources and greater extent of structural changes in agricultural sector during the transition period. The trends in riverine loads are discussed in the paper in relation to socio-economical changes during the transition period, and with respect to physiographic features.

  8. Domain structure and reorientation in CoF e2O4

    NASA Astrophysics Data System (ADS)

    Abes, M.; Koops, C. T.; Hrkac, S. B.; McCord, J.; Urs, N. O.; Wolff, N.; Kienle, L.; Ren, W. J.; Bouchenoire, L.; Murphy, B. M.; Magnussen, O. M.

    2016-05-01

    The microscopic processes underlying magnetostriction in ferrites were studied for the case of CoF e2O4 single crystals by high-resolution in situ x-ray diffraction and complementary magnetic microscopy techniques. The data support the reports of Yang and Ren [Phys. Rev. B 77, 014407 (2008), 10.1103/PhysRevB.77.014407] that magnetostriction in these materials originates from the switching of crystallographic domains, similar to ferroelastic or ferroelectric domain switching, and reveals the presence of two coexisting tetragonal spinel structures, corresponding to domains of high and of low strain. The latter alternate in the crystal, separated by 90° domain boundaries, and can be explained by the effect of internal stress emerging during the transition into the ferrimagnetic phase. During magnetization of the sample two structural transitions are observed: a conversion of the transversal into axial domains at 1.95 kOe and a growth of the high-strain domains at the cost of the low-strain axial domains at 2.8 kOe. These microscopic changes are in good agreement with the macroscopic magnetization and magnetostriction behavior of CoF e2O4 .

  9. A naturally occurring substitution in the E2 protein of Salmonid alphavirus subtype 3 changes viral fitness.

    PubMed

    Karlsen, Marius; Andersen, Linda; Blindheim, Steffen H; Rimstad, Espen; Nylund, Are

    2015-01-22

    Phylogenetic analyses of the Salmonid alphavirus subtype 3 (SAV3) epizootic have suggested that a substitution from proline to serine in the receptor binding protein E2 position 206 has occurred after the introduction of virus from a wild reservoir to farmed salmonid fish in Norway. We modelled the 3D structure of P62, the uncleaved E3-E2 precursor, of SAVH20/03 based on its sequence homology to the Chikungunya virus (CHIKV), and studied in vitro and in vivo effects of the mutation using reverse genetics. E2(206) is located on the surface of the B-domain of E2, which is associated with receptor attachment in alphaviruses. Recombinant virus expressing the E2(206S) codon replicated slower and produced significantly less genomic copies than virus expressing the ancestral E2(206P) codon in vitro in Bluegill Fry (BF2) cells. The E2(206S) mutant was out-competed by the E2(206P) mutant after 5 passages in an in vitro competition assay, confirming that the substitution negatively affects the efficacy of virus multiplication in cell culture. Both mutants were highly infectious to Atlantic salmon (Salmo salar), produced similar viral RNA loads in gills, heart, kidney and brain, and induced similar histopathologic changes in these organs. The E2(206S) mutant produced a less persistent infection in salmon and was shed more rapidly to water than the E2(206P) mutant. Reduced generation time through more rapid shedding could therefore explain why a serine in this position became dominant in the viral population after SAV3 was introduced to farmed salmon from the wild reservoir.

  10. Aberrant E2F activation by polyglutamine expansion of androgen receptor in SBMA neurotoxicity

    PubMed Central

    Suzuki, Eriko; Zhao, Yue; Ito, Saya; Sawatsubashi, Shun; Murata, Takuya; Furutani, Takashi; Shirode, Yuko; Yamagata, Kaoru; Tanabe, Masahiko; Kimura, Shuhei; Ueda, Takashi; Fujiyama, Sally; Lim, Jinseon; Matsukawa, Hiroyuki; Kouzmenko, Alexander P.; Aigaki, Toshiro; Tabata, Tetsuya; Takeyama, Ken-ichi; Kato, Shigeaki

    2009-01-01

    Spinal and bulbar muscular atrophy (SBMA) is a neurodegenerative disorder caused by a polyglutamine repeat (polyQ) expansion within the human androgen receptor (AR). Unlike other neurodegenerative diseases caused by abnormal polyQ expansion, the onset of SBMA depends on androgen binding to mutant human polyQ-AR proteins. This is also observed in Drosophila eyes ectopically expressing the polyQ-AR mutants. We have genetically screened mediators of androgen-induced neurodegeneration caused by polyQ-AR mutants in Drosophila eyes. We identified Rbf (Retinoblastoma-family protein), the Drosophila homologue of human Rb (Retinoblastoma protein), as a neuroprotective factor. Androgen-dependent association of Rbf or Rb with AR was remarkably potentiated by aberrant polyQ expansion. Such potentiated Rb association appeared to attenuate recruitment of histone deacetyltransferase 1 (HDAC1), a corepressor of E2F function. Either overexpression of Rbf or E2F deficiency in fly eyes reduced the neurotoxicity of the polyQ-AR mutants. Induction of E2F function by polyQ-AR-bound androgen was suppressed by Rb in human neuroblastoma cells. We conclude that abnormal expansion of polyQ may potentiate innate androgen-dependent association of AR with Rb. This appears to lead to androgen-dependent onset of SBMA through aberrant E2F transactivation caused by suppressed histone deacetylation. PMID:19237573

  11. Aberrant E2F activation by polyglutamine expansion of androgen receptor in SBMA neurotoxicity.

    PubMed

    Suzuki, Eriko; Zhao, Yue; Ito, Saya; Sawatsubashi, Shun; Murata, Takuya; Furutani, Takashi; Shirode, Yuko; Yamagata, Kaoru; Tanabe, Masahiko; Kimura, Shuhei; Ueda, Takashi; Fujiyama, Sally; Lim, Jinseon; Matsukawa, Hiroyuki; Kouzmenko, Alexander P; Aigaki, Toshiro; Tabata, Tetsuya; Takeyama, Ken-ichi; Kato, Shigeaki

    2009-03-10

    Spinal and bulbar muscular atrophy (SBMA) is a neurodegenerative disorder caused by a polyglutamine repeat (polyQ) expansion within the human androgen receptor (AR). Unlike other neurodegenerative diseases caused by abnormal polyQ expansion, the onset of SBMA depends on androgen binding to mutant human polyQ-AR proteins. This is also observed in Drosophila eyes ectopically expressing the polyQ-AR mutants. We have genetically screened mediators of androgen-induced neurodegeneration caused by polyQ-AR mutants in Drosophila eyes. We identified Rbf (Retinoblastoma-family protein), the Drosophila homologue of human Rb (Retinoblastoma protein), as a neuroprotective factor. Androgen-dependent association of Rbf or Rb with AR was remarkably potentiated by aberrant polyQ expansion. Such potentiated Rb association appeared to attenuate recruitment of histone deacetyltransferase 1 (HDAC1), a corepressor of E2F function. Either overexpression of Rbf or E2F deficiency in fly eyes reduced the neurotoxicity of the polyQ-AR mutants. Induction of E2F function by polyQ-AR-bound androgen was suppressed by Rb in human neuroblastoma cells. We conclude that abnormal expansion of polyQ may potentiate innate androgen-dependent association of AR with Rb. This appears to lead to androgen-dependent onset of SBMA through aberrant E2F transactivation caused by suppressed histone deacetylation.

  12. Antibegomoviral activity of the agrobacterial virulence protein VirE2.

    PubMed

    Sunitha, Sukumaran; Marian, Dolly; Hohn, Barbara; Veluthambi, Karuppannan

    2011-12-01

    Mungbean yellow mosaic geminivirus (MYMV) causes severe yellow mosaic disease in blackgram, mungbean, Frenchbean, pigeonpea, soybean and mothbean. We attempted to induce resistance against this virus using the transcriptional activator protein gene deleted in the C-terminal activation domain (TrAP-∆AD) and Agrobacterium tumefaciens virE2. MYMV is known to replicate in agroinoculated tobacco leaf discs. Three transgenic tobacco plants which harboured a truncated MYMV transcriptional activator protein gene and two tobacco plants transformed with the octopine type A. tumefaciens virE2 gene were agroinoculated with an A. tumefaciens strain which harboured the partial dimers of both DNA A and DNA B of MYMV. The level of viral DNA accumulation in leaf discs of transgenic plants correlated inversely to the level of the MYMV TrAP-∆AD transcript. Two VirE2-transgenic plants, which complemented tumorigenesis of a virE2 mutant A. tumefaciens strain, effectively reduced MYMV DNA accumulation in the leaf disc agroinoculation assay.

  13. Synergistic functions of E2F7 and E2F8 are critical to suppress stress-induced skin cancer

    PubMed Central

    Thurlings, I; Martínez-López, L M; Westendorp, B; Zijp, M; Kuiper, R; Tooten, P; Kent, L N; Leone, G; Vos, H J; Burgering, B; de Bruin, A

    2017-01-01

    E2F transcription factors are important regulators of the cell cycle, and unrestrained activation of E2F-dependent transcription is considered to be an important driver of tumor formation and progression. Although highly expressed in normal skin and skin cancer, the role of the atypical E2Fs, E2F7 and E2F8, in keratinocyte homeostasis, regeneration and tumorigenesis is unknown. Surprisingly, keratinocyte-specific deletion of E2F7 and E2F8 in mice did not interfere with skin development and wound healing. However, the rate for successful isolation and establishment of E2f7/8-deficient primary keratinocyte cultures was much higher than for wild-type keratinocytes. Moreover, E2f7/8-deficient primary keratinocytes proliferate more efficiently under stress conditions, such as low/high confluence or DNA damage. Application of in vivo stress using the DMBA/TPA skin carcinogenesis protocol revealed that combined inactivation of E2f7/8 enhanced tumorigenesis and accelerated malignant progression. Loss of atypical E2Fs resulted in increased expression of E2F target genes, including E2f1. Additional loss of E2f1 did not rescue, but worsened skin tumorigenesis. We show that loss of E2F7/8 triggers apoptosis via induction of E2F1 in response to stress, indicating that the tumor-promoting effect of E2F7/8 inactivation can be partially compensated via E2F1-dependent apoptosis. Importantly, E2F7/8 repressed a large set of E2F target genes that are highly expressed in human patients with skin cancer. Together, our studies demonstrate that atypical E2Fs act as tumor suppressors, most likely via transcriptional repression of cell cycle genes in response to stress. PMID:27452520

  14. RORα Binds to E2F1 To Inhibit Cell Proliferation and Regulate Mammary Gland Branching Morphogenesis

    PubMed Central

    Xiong, Gaofeng

    2014-01-01

    Retinoic acid receptor-related orphan nuclear receptor alpha (RORα) is a potent tumor suppressor that reduces cell proliferation and inhibits tumor growth. However, the molecular mechanism by which it inhibits cell proliferation remains unknown. We demonstrate a noncanonical nuclear receptor pathway in which RORα binds to E2F1 to inhibit cell cycle progression. We showed that RORα bound to the heptad repeat and marked box region of E2F1 and suppressed E2F1-regulated transcription in epithelial cells. Binding of RORα inhibited E2F1 acetylation and its DNA-binding activity by recruiting histone deacetylase 1 (HDAC1) to the protein complexes. Knockdown of HDAC1 or inhibition of HDAC activity at least partially rescued transcription factor activity of E2F1 that was repressed by RORα. Importantly, RORα levels were increased in mammary ducts compared to terminal end buds and inversely correlated with expression of E2F1 target genes and cell proliferation. Silencing RORα in mammary epithelial cells significantly enhanced cell proliferation in the ductal epithelial cells and promoted side branching of the mammary ducts. These results reveal a novel link between RORα and E2F1 in regulating cell cycle progression and mammary tissue morphogenesis. PMID:24891616

  15. [ital E]2 properties of nuclei far from stability and the proton-halo problem of [sup 8]B

    SciTech Connect

    Nakada, H.; Otsuka, T. Department of Physics, Faculty of Science, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113 Institute for Nuclear Theory, University of Washington, NH-12, Seattle, Washington 98195 )

    1994-02-01

    [ital E]2 properties of [ital A]=6--10 nuclei, including those of nuclei far from stability, are studied by a (0+2)[h bar][omega] shell-model calculation which includes [ital E]2 core-polarization effects explicitly. The quadrupole moments and the [ital E]2 transition strengths in [ital A]=6--10 nuclei are described quite well by the present cal- culation. This result indicates that the relatively large value of the quadrupole moment of [sup 8]B can be understood without introducing the proton halo in [sup 8]B. An interesting effect of the 2[h bar][omega] core-polarization is found for effective charges used in the 0[h bar][omega] shell model; although isoscalar effective charges are almost constant as a function of nucelus, appreciable variations are needed for isovector effective charges which play important roles in nuclei with high isospin values.

  16. Chang'e-2 spacecraft observations of asteroid 4179 Toutatis

    NASA Astrophysics Data System (ADS)

    Ji, Jianghui; Jiang, Yun; Zhao, Yuhui; Wang, Su; Yu, Liangliang

    2016-01-01

    On 13 December 2012, Chang'e-2 completed a successful flyby of the near-Earth asteroid 4179 Toutatis at a closest distance of 770 meters from the asteroid's surface. The observations show that Toutatis has an irregular surface and its shape resembles a ginger-root of a smaller lobe (head) and a larger lobe (body). Such bilobate shape is indicative of a contact binary origin for Toutatis. In addition, the high-resolution images better than 3 meters provide a number of new discoveries about this asteroid, such as an 800-meter depression at the end of the large lobe, a sharply perpendicular silhouette near the neck region, boulders, indicating that Toutatis is probably a rubble-pile asteroid. Chang'e-2 observations have significantly revealed new insights into the geological features and the formation and evolution of this asteroid. In final, we brief the future Chinese asteroid mission concept.

  17. Advanced Stirling Convertor (ASC-E2) Characterization Testing

    NASA Technical Reports Server (NTRS)

    Williams, Zachary D.; Oriti, Salvatore M.

    2012-01-01

    Testing has been conducted on Advanced Stirling Convertors (ASCs)-E2 at NASA Glenn Research Center in support of the Advanced Stirling Radioisotope Generator (ASRG) project. This testing has been conducted to understand sensitivities of convertor parameters due to environmental and operational changes during operation of the ASRG in missions to space. This paper summarizes test results and explains the operation of the ASRG during space missions

  18. Prostaglandin E2 Regulation of Chondrocyte Proliferation and Differentiation

    DTIC Science & Technology

    1994-05-01

    increases bone prostaglandin E. Effect of acetylsalicylic acid on disuse osteoporosis studied in dogs. Acta Orthopaedica Scandinavica, 62:238-243. 121...bovine serum, 1% antibiotics, and 50 pg/ml ascorbic acid in 100% humidity at 37oC. Prostaglandin E2 was added to confluent, fourth passage cultures... acid from membrane phospholipids. This, in turn, may lead to the formation of prostaglandins, thromboxanes and prostacyclins through the metabolism of

  19. Advanced Stirling Convertor (ASC-E2) Characterization Testing

    NASA Technical Reports Server (NTRS)

    Williams, Zachary D.; Oriti, Salvatore M.

    2012-01-01

    Testing has been conducted on Advanced Stirling Convertor (ASC-E2) convertors at NASA Glenn Research Center in support of the Advanced Stirling Radioisotope Generator (ASRG) Project. This testing has been conducted to understand sensitivities of convertor parameters due to environmental and operational changes during operation of the ASRG in missions to space. This paper summarizes test results and explains in terms of operation of the ASRG during space missions.

  20. Neutralizing activities of caprine antibodies towards conserved regions of the HCV envelope glycoprotein E2

    PubMed Central

    2011-01-01

    Anti HCV vaccine is not currently available and the present antiviral therapies fail to cure approximately half of the treated HCV patients. This study was designed to assess the immunogenic properties of genetically conserved peptides derived from the C-terminal region of HVR-1 and test their neutralizing activities in a step towards developing therapeutic and/or prophylactic immunogens against HCV infection. Antibodies were generated by vaccination of goats with synthetic peptides derived from HCV E2. Viral neutralizing capacity of the generated anti E2 antibodies was tested using in vitro assays. Goats immunized with E2 synthetic peptides termed p412 [a.a 412-419], p430 [a.a 430-447] and p517 [a.a 517-531] generated high titers of antibody responses 2 to 4.5 fold higher than comparable titers of antibodies to the same epitopes in chronic HCV patients. In post infection experiments of native HCV into cultured Huh7.5 cells anti p412 and anti p 517 were proven to be neutralizing to HCV genotype 4a from patients' sera (87.5% and 75% respectively). On the contrary anti p430 exhibited weak viral neutralization capacity on the same samples (31.25%). Furthermore Ab mixes containing anti p430 exhibited reduced viral neutralization properties. From these experiments one could predict that neutralization by Abs towards different E2-epitopes varies considerably and success in the enrichment of neutralization epitope-specific antibodies may be accompanied by favorable results in combating HCV infection. Also, E2 conserved peptides p517 and p412 represent potential components of a candidate peptide vaccine against HCV infection. PMID:21819575

  1. Association of Human Papillomavirus 16 E2 with Rad50-Interacting Protein 1 Enhances Viral DNA Replication

    PubMed Central

    Campos-León, Karen; Wijendra, Kalpanee; Siddiqa, Abida; Pentland, Ieisha; Feeney, Katherine M.; Knapman, Alison; Davies, Rachel

    2016-01-01

    ABSTRACT Rad50-interacting protein 1 (Rint1) associates with the DNA damage response protein Rad50 during the transition from the S phase to the G2/M phase and functions in radiation-induced G2 checkpoint control. It has also been demonstrated that Rint1 is essential in vesicle trafficking from the Golgi apparatus to the endoplasmic reticulum (ER) through an interaction with Zeste-White 10 (ZW10). We have isolated a novel interaction between Rint1 and the human papillomavirus 16 (HPV16) transcription and replication factor E2. E2 binds to Rint1 within its ZW10 interaction domain, and we show that in the absence of E2, Rint1 is localized to the ER and associates with ZW10. E2 expression results in a disruption of the Rint1-ZW10 interaction and an accumulation of nuclear Rint1, coincident with a significant reduction in vesicle movement from the ER to the Golgi apparatus. Interestingly, nuclear Rint1 and members of the Mre11/Rad50/Nbs1 (MRN) complex were found in distinct E2 nuclear foci, which peaked during mid-S phase, indicating that the recruitment of Rint1 to E2 foci within the nucleus may also result in the recruitment of this DNA damage-sensing protein complex. We show that exogenous Rint1 expression enhances E2-dependent virus replication. Conversely, the overexpression of a truncated Rint1 protein that retains the E2 binding domain but not the Rad50 binding domain acts as a dominant negative inhibitor of E2-dependent HPV replication. Put together, these experiments demonstrate that the interaction between Rint1 and E2 has an important function in HPV replication. IMPORTANCE HPV infections are an important driver of many epithelial cancers, including those within the anogenital and oropharyngeal tracts. The HPV life cycle is tightly regulated and intimately linked to the differentiation of the epithelial cells that it infects. HPV replication factories formed in the nucleus are locations where viral DNA is copied to support virus persistence and amplification

  2. Association of Human Papillomavirus 16 E2 with Rad50-Interacting Protein 1 Enhances Viral DNA Replication.

    PubMed

    Campos-León, Karen; Wijendra, Kalpanee; Siddiqa, Abida; Pentland, Ieisha; Feeney, Katherine M; Knapman, Alison; Davies, Rachel; Androphy, Elliot J; Parish, Joanna L

    2017-03-01

    Rad50-interacting protein 1 (Rint1) associates with the DNA damage response protein Rad50 during the transition from the S phase to the G2/M phase and functions in radiation-induced G2 checkpoint control. It has also been demonstrated that Rint1 is essential in vesicle trafficking from the Golgi apparatus to the endoplasmic reticulum (ER) through an interaction with Zeste-White 10 (ZW10). We have isolated a novel interaction between Rint1 and the human papillomavirus 16 (HPV16) transcription and replication factor E2. E2 binds to Rint1 within its ZW10 interaction domain, and we show that in the absence of E2, Rint1 is localized to the ER and associates with ZW10. E2 expression results in a disruption of the Rint1-ZW10 interaction and an accumulation of nuclear Rint1, coincident with a significant reduction in vesicle movement from the ER to the Golgi apparatus. Interestingly, nuclear Rint1 and members of the Mre11/Rad50/Nbs1 (MRN) complex were found in distinct E2 nuclear foci, which peaked during mid-S phase, indicating that the recruitment of Rint1 to E2 foci within the nucleus may also result in the recruitment of this DNA damage-sensing protein complex. We show that exogenous Rint1 expression enhances E2-dependent virus replication. Conversely, the overexpression of a truncated Rint1 protein that retains the E2 binding domain but not the Rad50 binding domain acts as a dominant negative inhibitor of E2-dependent HPV replication. Put together, these experiments demonstrate that the interaction between Rint1 and E2 has an important function in HPV replication.IMPORTANCE HPV infections are an important driver of many epithelial cancers, including those within the anogenital and oropharyngeal tracts. The HPV life cycle is tightly regulated and intimately linked to the differentiation of the epithelial cells that it infects. HPV replication factories formed in the nucleus are locations where viral DNA is copied to support virus persistence and amplification of

  3. Levels of the E2 interacting protein TopBP1 modulate papillomavirus maintenance stage replication

    SciTech Connect

    Kanginakudru, Sriramana; DeSmet, Marsha; Thomas, Yanique; Morgan, Iain M.; Androphy, Elliot J.

    2015-04-15

    The evolutionarily conserved DNA topoisomerase II beta-binding protein 1 (TopBP1) functions in DNA replication, DNA damage response, and cell survival. We analyzed the role of TopBP1 in human and bovine papillomavirus genome replication. Consistent with prior reports, TopBP1 co-localized in discrete nuclear foci and was in complex with papillomavirus E2 protein. Similar to E2, TopBP1 is recruited to the region of the viral origin of replication during G1/S and early S phase. TopBP1 knockdown increased, while over-expression decreased transient virus replication, without affecting cell cycle. Similarly, using cell lines harboring HPV-16 or HPV-31 genome, TopBP1 knockdown increased while over-expression reduced viral copy number relative to genomic DNA. We propose a model in which TopBP1 serves dual roles in viral replication: it is essential for initiation of replication yet it restricts viral copy number. - Highlights: • Protein interaction study confirmed In-situ interaction between TopBP1 and E2. • TopBP1 present at papillomavirus ori in G1/S and early S phase of cell cycle. • TopBP1 knockdown increased, over-expression reduced virus replication. • TopBP1 protein level change did not influence cell survival or cell cycle. • TopBP1 displaced from papillomavirus ori after initiation of replication.

  4. Caenorhabditis elegans lin-35/Rb, efl-1/E2F and other synthetic multivulva genes negatively regulate the anaphase-promoting complex gene mat-3/APC8.

    PubMed

    Garbe, David; Doto, Jeffrey B; Sundaram, Meera V

    2004-06-01

    Retinoblastoma (Rb)/E2F complexes repress expression of many genes important for G(1)-to-S transition, but also appear to regulate gene expression at other stages of the cell cycle. In C. elegans, lin-35/Rb and other synthetic Multivulva (SynMuv) group B genes function redundantly with other sets of genes to regulate G(1)/S progression, vulval and pharyngeal differentiation, and other unknown processes required for viability. Here we show that lin-35/Rb, efl-1/E2F, and other SynMuv B genes negatively regulate a component of the anaphase-promoting complex or cyclosome (APC/C). The APC/C is a multisubunit complex that promotes metaphase-to-anaphase progression and G(1) arrest by targeting different substrates for ubiquitination and proteasome-mediated destruction. The C. elegans APC/C gene mat-3/APC8 has been defined by temperature-sensitive embryonic lethal alleles that strongly affect germline meiosis and mitosis but only weakly affect somatic development. We describe severe nonconditional mat-3 alleles and a hypomorphic viable allele (ku233), all of which affect postembryonic cell divisions including those of the vulval lineage. The ku233 lesion is located outside of the mat-3 coding region and reduces mat-3 mRNA expression. Loss-of-function alleles of lin-35/Rb and other SynMuv B genes suppress mat-3(ku233) defects by restoring mat-3 mRNA to wild-type levels. Therefore, Rb/E2F complexes appear to repress mat-3 expression.

  5. Theophylline prevents the inhibitory effect of prostaglandin E2 on glucose-induced insulin secretion in man.

    PubMed

    Giugliano, D; Cozzolino, D; Salvatore, T; Giunta, R; Torella, R

    1988-06-01

    This study was undertaken to assess the mechanism by which prostaglandins of the E series inhibit glucose-induced insulin secretion in man. Acute insulin response (mean change 3-10 min) to iv glucose (0.33 g/kg) was decreased by 40% during the infusion of prostaglandin E2 (10 micrograms/min) and glucose disappearance rates were reduced (P less than 0.05). Insulin response to arginine (5 g iv) and tolbutamide (1 g iv) were not affected by the same rate of prostaglandin E2 infusion. The inhibitory effect of prostaglandin E2 on glucose-induced insulin secretion was prevented by theophylline (100 mg as a loading dose followed by a 5 mg/min infusion), a drug that increases the intracellular cAMP concentrations by inhibiting phosphodiesterase activity. Our data suggest the involvement of the adenylate cyclase system in the inhibitory action of prostaglandin E2 on glucose-induced insulin secretion in man.

  6. Poster 14: Explorer of Enceladus and Titan (E2T)

    NASA Astrophysics Data System (ADS)

    Mitri, Giuseppe; Tobie, Gabriel; Postberg, Frank; Soderblom, Jason M.; Wurz, Peter; Barnes, Jason W.; Berga, Marco; Coustenis, Athena; D'Ottavio, Andrea Hayes, Alexander G.; Hayne, Paul O.; Lebreton, Jean-Pierre; Lorenz, Ralph D.; Martelli, Andrea; Petropoulos, Anastassios E.; Yen, Chen-wan L.; Reh, Kim R.; Sotin, Christophe; Srama, Ralf; Tortora, Paolo

    2016-06-01

    The NASA-ESA Cassini-Huygens mission has revealed Titan and Enceladus to be two of the most enigmatic worlds in the Solar System. Titan, with its organically rich and dynamic atmosphere and geology, and Enceladus, with its active plume, both harboring subsurface oceans, are prime environments in which to investigate the conditions for the emergence of life and the habitability of Ocean Worlds. Explorer of Enceladus and Titan (E2T) is dedicated to investigating the evolution and habitability of these Saturnian satellites and will be proposed as a medium-class mission led by ESA in collaboration with NASA in response to ESA's M5 Call. E2T has a focused payload that will provide in-situ sampling and high-resolution imaging during multiple flybys of Enceladus and Titan using a solar-electric powered spacecraft in orbit around Saturn. The E2T mission will provide high-resolution mass spectroscopy of the plume emanating from Enceladus' south polar terrain (SPT) and of Titan's upper atmosphere as well as high-resolution IR imaging of the plume and the source fractures on Enceladus' SPT, and it will detail Titan's geomorphology at 50-100 m resolution. The E2T mission has three scientific goals: 1) Investigate the origin and evolution of volatile-rich icy worlds by examining both Enceladus and Titan, 2) Investigate the habitability and potential for life in ocean worlds on both Enceladus and Titan and 3) Investigate Titan as an Earth-like world with an evolving climate and landscape. These investigations will be accomplished by measuring the nature, abundance and isotopic properties of solid- and vapor-phase species in Enceladus' plume and Titan's upper atmosphere. E2T's high-resolution time-of-flight mass spectrometers will enable us to untangle the ambiguities left by Cassini regarding the identification of low-mass organic species, identify high-mass organic species for the first time, further constrain trace species such as the noble gases, and clarify the evolution of

  7. Conserved Motifs within Hepatitis C Virus Envelope (E2) RNA and Protein Independently Inhibit T Cell Activation

    PubMed Central

    Bhattarai, Nirjal; McLinden, James H.; Xiang, Jinhua; Kaufman, Thomas M.; Stapleton, Jack T.

    2015-01-01

    T cell receptor (TCR) signaling is required for T-cell activation, proliferation, differentiation, and effector function. Hepatitis C virus (HCV) infection is associated with impaired T-cell function leading to persistent viremia, delayed and inconsistent antibody responses, and mild immune dysfunction. Although multiple factors appear to contribute to T-cell dysfunction, a role for HCV particles in this process has not been identified. Here, we show that incubation of primary human CD4+ and CD8+ T-cells with HCV RNA-containing serum, HCV-RNA containing extracellular vesicles (EVs), cell culture derived HCV particles (HCVcc) and HCV envelope pseudotyped retrovirus particles (HCVpp) inhibited TCR-mediated signaling. Since HCVpp’s contain only E1 and E2, we examined the effect of HCV E2 on TCR signaling pathways. HCV E2 expression recapitulated HCV particle-induced TCR inhibition. A highly conserved, 51 nucleotide (nt) RNA sequence was sufficient to inhibit TCR signaling. Cells expressing the HCV E2 coding RNA contained a short, virus-derived RNA predicted to be a Dicer substrate, which targeted a phosphatase involved in Src-kinase signaling (PTPRE). T-cells and hepatocytes containing HCV E2 RNA had reduced PTPRE protein levels. Mutation of 6 nts abolished the predicted Dicer interactions and restored PTPRE expression and proximal TCR signaling. HCV RNA did not inhibit distal TCR signaling induced by PMA and Ionomycin; however, HCV E2 protein inhibited distal TCR signaling. This inhibition required lymphocyte-specific tyrosine kinase (Lck). Lck phosphorylated HCV E2 at a conserved tyrosine (Y613), and phospho-E2 inhibited nuclear translocation of NFAT. Mutation of Y613 restored distal TCR signaling, even in the context of HCVpps. Thus, HCV particles delivered viral RNA and E2 protein to T-cells, and these inhibited proximal and distal TCR signaling respectively. These effects of HCV particles likely aid in establishing infection and contribute to viral persistence

  8. The TRAF-interacting protein (TRAIP) is a novel E2F target with peak expression in mitosis.

    PubMed

    Chapard, Christophe; Hohl, Daniel; Huber, Marcel

    2015-08-28

    The TRAF-interacting protein (TRAIP) is an E3 ubiquitin ligase required for cell proliferation. TRAIP mRNA is downregulated in human keratinocytes after inhibition of the PI3K/AKT/mTOR signaling. Since E2F transcription factors are downstream of PI3K/AKT/mTOR we investigated whether they regulate TRAIP expression. E2F1 expression significantly increased the TRAIP mRNA level in HeLa cells. Reporter assays with the 1400 bp 5'-upstream promoter in HeLa cells and human keratinocytes showed that E2F1-, E2F2- and E2F4-induced upregulation of TRAIP expression is mediated by 168 bp upstream of the translation start site. Mutating the E2F binding site within this fragment reduced the E2F1- and E2F2-dependent promoter activities and protein-DNA complex formation in gel shift assays. Abundance of TRAIP mRNA and protein was regulated by the cell cycle with a peak in G2/M. Expression of GFP and TRAIP-GFP demonstrated that TRAIP-GFP protein has a lower steady-state concentration than GFP despite similar mRNA levels. Cycloheximide inhibition experiments indicated that the TRAIP protein has a half-life of around four hours. Therefore, the combination of cell cycle-dependent transcription of the TRAIP gene by E2F and rapid protein degradation leads to cell cycle-dependent expression with a maximum in G2/M. These findings suggest that TRAIP has important functions in mitosis and tumorigenesis.

  9. EGF-reduced Wnt5a transcription induces epithelial-mesenchymal transition via Arf6-ERK signaling in gastric cancer cells

    PubMed Central

    Zhang, Yujie; Du, Jun; Zheng, Jianchao; Liu, Jiaojing; Xu, Rui; Shen, Tian; Zhu, Yichao; Chang, Jun; Wang, Hong; Zhang, Zhihong; Meng, Fanqing; Wang, Yan; Chen, Yongchang; Xu, Yong; Gu, Luo

    2015-01-01

    Wnt5a, a ligand for activating the non-canonical Wnt signaling pathway, is commonly associated with Epithelial-to-mesenchymal transition (EMT) in cancer cell metastasis. Here, we show that downregulation of Wnt5a mRNA and protein by EGF is necessary for EGF-induced EMT in gastric cancer SGC-7901 cells. To further explore the mechanisms, we investigated the effect of EGF signaling on Wnt5a expression. EGF increased Arf6 and ERK activity, while blockade of Arf6 activation repressed ERK activity, up-regulated Wnt5a expression and repressed EMT in response to EGF. We also demonstrate that EGF inactivated Wnt5a transcription by direct recruitment of ERK to the Wnt5a promoter. On the other hand, inhibition of ERK phosphorylation resulted in decreased movement of ERK from the cytoplasm to the nucleus, following rescued Wnt5a mRNA and protein expression and favored an epithelial phenotype of SGC-7901 cells. In addition, we notice that kinase-dead, nuclear-localised ERK has inhibitory effect on Wnt5a transcription. Analysis of gastric cancer specimens revealed an inverse correlation between P-ERK and Wnt5a protein levels and an association between Wnt5a expression and better prognosis. These findings indicate that Wnt5a is a potential suppressor of EMT and identify a novel Arf6/ERK signaling pathway for EGF-regulated Wnt5a expression at transcriptional level of gastric cancer cells. PMID:25779663

  10. Deletion of Mylk1 in oocytes causes delayed morula-to-blastocyst transition and reduced fertility without affecting folliculogenesis and oocyte maturation in mice.

    PubMed

    Liang, Qiu-Xia; Zhang, Qing-Hua; Qi, Shu-Tao; Wang, Zhong-Wei; Hu, Meng-Wen; Ma, Xue-Shan; Zhu, Min-Sheng; Schatten, Heide; Wang, Zhen-Bo; Sun, Qing-Yuan

    2015-04-01

    The mammalian oocyte undergoes two rounds of asymmetric cell divisions during meiotic maturation and fertilization. Acentric spindle positioning and cortical polarity are two major factors involved in asymmetric cell division, both of which are thought to depend on the dynamic interaction between myosin II and actin filaments. Myosin light chain kinase (MLCK), encoded by the Mylk1 gene, could directly phosphorylate and activate myosin II. To determine whether MLCK was required for oocyte asymmetric division, we specifically disrupted the Mylk1 gene in oocytes by Cre-loxP conditional knockout system. We found that Mylk1 mutant female mice showed severe subfertility. Unexpectedly, contrary to previously reported in vitro findings, our data showed that oocyte meiotic maturation including spindle organization, polarity establishment, homologous chromosomes separation, and polar body extrusion were not affected in Mylk1(fl/fl);GCre(+) females. Follicular development, ovulation, and early embryonic development up to compact morula occurred normally in Mylk1(fl/fl);GCre(+) females, but deletion of MLCK caused delayed morula-to-blastocyst transition. More than a third of embryos were at morula stage at 3.5 Days Postcoitum in vivo. The delayed embryos could develop further to early blastocyst stage in vitro on Day 4 when most control embryos reached expanded blastocysts. Our findings provide evidence that MLCK is linked to timely blastocyst formation, though it is dispensable for oocyte meiotic maturation.

  11. PPAR{gamma} ligands suppress the feedback loop between E2F2 and cyclin-E1

    SciTech Connect

    Komatsu, Yoko; Ito, Ichiaki; Wayama, Mitsutoshi; Fujimura, Akiko; Akaogi, Kensuke; Machida, Hikaru; Nakajima, Yuka; Kuroda, Takao; Ohmori, Kazuji; Murayama, Akiko; Kimura, Keiji; Yanagisawa, Junn

    2008-05-23

    PPAR{gamma} is a nuclear hormone receptor that plays a key role in the induction of peroxisome proliferation. A number of studies showed that PPAR{gamma} ligands suppress cell cycle progression; however, the mechanism remains to be determined. Here, we showed that PPAR{gamma} ligand troglitazone inhibited G1/S transition in colon cancer cells, LS174T. Troglitazone did not affect on either expression of CDK inhibitor (p18) or Wnt signaling pathway, indicating that these pathways were not involved in the troglitazone-dependent cell cycle arrest. GeneChip and RT-PCR analyses revealed that troglitazone decreased mRNA levels of cell cycle regulatory factors E2F2 and cyclin-E1 whose expression is activated by E2F2. Down-regulation of E2F2 by troglitazone results in decrease of cyclin-E1 transcription, which could inhibit phosphorylation of Rb protein, and consequently evoke the suppression of E2F2 transcriptional activity. Thus, we propose that troglitazone suppresses the feedback loop containing E2F2, cyclin-E1, and Rb protein.

  12. The maximum overlap method: A general and efficient scheme for reducing basis sets. Application to the generation of approximate AO's for the 3 d transition metal atoms and ions

    NASA Astrophysics Data System (ADS)

    Francisco, E.; Seijo, L.; Pueyo, L.

    1986-07-01

    The method of maximum overlap, often applied to the problem of basis set reduction, is formulated in terms of weighted least squares with orthogonality restrictions. An analytical solution for the linear parameters of the reduced set is given. In this form, the method is a general and efficient scheme for reducing basis sets. As an application, orthogonal radial wavefunctions of the STO type have been obtained for the 3 d transition metal atoms and ions by simulation of the high-quality sets of Clementi and Roetti. The performance of the reduction has been evaluated by examining several one- and two-electron interactions. Results of these tests reveal that the new functions are highly accurate simulations of the reference AO's. They appear to be appropriate for molecular and solid state calculations.

  13. Astro-E2 Magnesium Diboride High Current Leads

    NASA Technical Reports Server (NTRS)

    Panek, J. S.; Tuttle, J. G.; Riall, S.; Mustafi, S.; Gray, A.; Edmonds, R.; Marrero, V.

    2003-01-01

    The recent discovery of superconducting properties in MgB_2 and rapid development of small diameter steel-clad wires has opened up the possibility of enhancing the design of the baseline Astro-E2 high current lead assembly. Replacing YBCO filaments with MgB_2 wires and modifying the heat sink location can give much higher margins against quench from temperature oscillations of the 4 K heat sink, although wih some overall thermal penalty. The design and performance of a new lead assembly during flight qualification is discussed, with emphasis on thermal, structural, and electrical test results.

  14. Effectiveness of a parental training programme in enhancing the parent–child relationship and reducing harsh parenting practices and parental stress in preparing children for their transition to primary school: a randomised controlled trial

    PubMed Central

    2013-01-01

    Background Entering primary school is an important childhood milestone, marking the beginning of a child’s formal education. Yet the change creates a time of vulnerability for the child, the parents and the parent–child relationship. Failure to adjust to the transition may place the family in a psychologically devastating position. The aims of this study were to test the effectiveness of a parental training programme in enhancing the parent–child relationship and decreasing parental stress by reducing harsh parenting in preparing children for the transition to primary school. Methods A randomised controlled trial incorporating a two-group pre-test and repeated post-test was conducted in one of the largest public housing estates in Hong Kong. A total of 142 parents were recruited, with 72 parents randomly assigned to the experimental group and 70 to the control group. Harsh parenting practices, parent–child relationships and parental stress were assessed. Results In comparison to parents in the control group, those in the experimental group engaged in less harsh parenting practices and reported better parent–child relationships. However, parental stress scores did not differ significantly between the two groups. Conclusion This study addressed a gap in the literature by examining the effectiveness of the training programme for enhancing parent–child relationship and decreasing parental stress at the time of a child’s transition to primary school. The findings from this study provide empirical evidence of the effectiveness of the parental training programme and highlight the significance of parenting in promoting a smooth transition for children from kindergarten to primary 1. Trial registration ClinicalTrials.gov: NCT01845948. PMID:24237718

  15. ROS production is essential for the apoptotic function of E2F1 in pheochromocytoma and neuroblastoma cell lines.

    PubMed

    Espada, Lilia; Meo-Evoli, Nathalie; Sancho, Patricia; Real, Sebastian; Fabregat, Isabel; Ambrosio, Santiago; Tauler, Albert

    2012-01-01

    In this study we demonstrate that accumulation of reactive oxygen species (ROS) is essential for E2F1 mediated apoptosis in ER-E2F1 PC12 pheochromocytoma, and SH-SY5Y and SK-N-JD neuroblastoma stable cell lines. In these cells, the ER-E2F1 fusion protein is expressed in the cytosol; the addition of 4-hydroxytamoxifen (OHT) induces its translocation to the nucleus and activation of E2F1target genes. Previously we demonstrated that, in ER-E2F1 PC12 cells, OHT treatment induced apoptosis through activation of caspase-3. Here we show that caspase-8 activity did not change upon treatment with OHT. Moreover, over-expression of Bcl-xL arrested OHT-induced apoptosis; by contrast, over-expression of c-FLIP, did not have any effect on OHT-induced apoptosis. OHT addition induces BimL expression, its translocation to mitochondria and activation of Bax, which is paralleled by diminished mitochondrial enrichment of Bcl-xL. Treatment with a Bax-inhibitory peptide reduced OHT-induced apoptosis. These results point out the essential role of mitochondria on the apoptotic process driven by E2F1. ROS accumulation followed E2F1 induction and treatment with the antioxidant N-acetylcysteine, inhibited E2F1-induced Bax translocation to mitochondria and subsequent apoptosis. The role of ROS in mediating OHT-induced apoptosis was also studied in two neuroblastoma cell lines, SH-SY5Y and SK-N-JD. In SH-SY5Y cells, activation of E2F1 by the addition of OHT induced ROS production and apoptosis, whereas over-expression of E2F1 in SK-N-JD cells failed to induce either response. Transcriptional profiling revealed that many of the genes responsible for scavenging ROS were down-regulated following E2F1-induction in SH-SY5Y, but not in SK-N-JD cells. Finally, inhibition of GSK3β blocked ROS production, Bax activation and the down regulation of ROS scavenging genes. These findings provide an explanation for the apparent contradictory role of E2F1 as an apoptotic agent versus a cell cycle activator.

  16. Anomalous transition in {sup 10}B

    SciTech Connect

    Kurath, D.

    1995-08-01

    The transitions between the J,T = 3,0 ground state of {sup 10}B and the 3,0 state at 4.77 MeV present some puzzling features. The gamma transition between the states is of unknown multipolarity and very weak, with a strength of only 0.1 WU even if it is a pure E2. The shell model with the Cohen-Kurath POT interaction predicts a nearly pure E2 transition but with a transition probability about 4 times too strong. Recent inelastic pion scattering experiments on {sup 10}B excited this state with a strength only one tenth the value predicted by the shell model. It was found that these weak transitions are very sensitive to the wave functions and that orthogonally mixing the states with an intensity of 2% can satisfy both the pion scattering and the {gamma} decay (60% E2, 40% M1).

  17. Transition Planning

    ERIC Educational Resources Information Center

    Statfeld, Jenna L.

    2011-01-01

    Post-school transition is the movement of a child with disabilities from school to activities that occur after the completion of school. This paper provides information about: (1) post-school transition; (2) transition plan; (3) transition services; (4) transition planning; (5) vocational rehabilitation services; (6) services that are available…

  18. Overexpression of SerpinE2/protease nexin-1 Contribute to Pathological Cardiac Fibrosis via increasing Collagen Deposition

    PubMed Central

    Li, Xuelian; Zhao, Dandan; Guo, Zhenfeng; Li, Tianshi; Qili, Muge; Xu, Bozhi; Qian, Ming; Liang, Haihai; E, Xiaoqiang; Chege Gitau, Samuel; Wang, Lu; Huangfu, Longtao; Wu, Qiuxia; Xu, Chaoqian; Shan, Hongli

    2016-01-01

    Although increases in cardiovascular load (pressure overload) are known to elicit ventricular remodeling including cardiomyocyte hypertrophy and interstitial fibrosis, the molecular mechanisms of pressure overload or AngII -induced cardiac interstitial fibrosis remain elusive. In this study, serpinE2/protease nexin-1 was over-expressed in a cardiac fibrosis model induced by pressure-overloaded via transverse aortic constriction (TAC) in mouse. Knockdown of serpinE2 attenuates cardiac fibrosis in a mouse model of TAC. At meantime, the results showed that serpinE2 significantly were increased with collagen accumulations induced by AngII or TGF-β stimulation in vitro. Intriguingly, extracellular collagen in myocardial fibroblast was reduced by knockdown of serpinE2 compared with the control in vitro. In stark contrast, the addition of exogenous PN-1 up-regulated the content of collagen in myocardial fibroblast. The MEK1/2- ERK1/2 signaling probably promoted the expression of serpinE2 via transcription factors Elk1 in myocardial fibroblast. In conclusion, stress-induced the ERK1/2 signaling pathway activation up-regulated serpinE2 expression, consequently led accumulation of collagen protein, and contributed to cardiac fibrosis. PMID:27876880

  19. Transition probabilities in neutron-rich Se,8684

    NASA Astrophysics Data System (ADS)

    Litzinger, J.; Blazhev, A.; Dewald, A.; Didierjean, F.; Duchêne, G.; Fransen, C.; Lozeva, R.; Sieja, K.; Verney, D.; de Angelis, G.; Bazzacco, D.; Birkenbach, B.; Bottoni, S.; Bracco, A.; Braunroth, T.; Cederwall, B.; Corradi, L.; Crespi, F. C. L.; Désesquelles, P.; Eberth, J.; Ellinger, E.; Farnea, E.; Fioretto, E.; Gernhäuser, R.; Goasduff, A.; Görgen, A.; Gottardo, A.; Grebosz, J.; Hackstein, M.; Hess, H.; Ibrahim, F.; Jolie, J.; Jungclaus, A.; Kolos, K.; Korten, W.; Leoni, S.; Lunardi, S.; Maj, A.; Menegazzo, R.; Mengoni, D.; Michelagnoli, C.; Mijatovic, T.; Million, B.; Möller, O.; Modamio, V.; Montagnoli, G.; Montanari, D.; Morales, A. I.; Napoli, D. R.; Niikura, M.; Pollarolo, G.; Pullia, A.; Quintana, B.; Recchia, F.; Reiter, P.; Rosso, D.; Sahin, E.; Salsac, M. D.; Scarlassara, F.; Söderström, P.-A.; Stefanini, A. M.; Stezowski, O.; Szilner, S.; Theisen, Ch.; Valiente Dobón, J. J.; Vandone, V.; Vogt, A.

    2015-12-01

    Reduced quadrupole transition probabilities for low-lying transitions in neutron-rich Se,8684 are investigated with a recoil distance Doppler shift (RDDS) experiment. The experiment was performed at the Istituto Nazionale di Fisica Nucleare (INFN) Laboratori Nazionali di Legnaro using the Cologne Plunger device for the RDDS technique and the AGATA Demonstrator array for the γ -ray detection coupled to the PRISMA magnetic spectrometer for an event-by-event particle identification. In 86Se the level lifetime of the yrast 21+ state and an upper limit for the lifetime of the 41+ state are determined for the first time. The results of 86Se are in agreement with previously reported predictions of large-scale shell-model calculations using Ni78-I and Ni78-II effective interactions. In addition, intrinsic shape parameters of lowest yrast states in 86Se are calculated. In semimagic 84Se level lifetimes of the yrast 41+ and 61+ states are determined for the first time. Large-scale shell-model calculations using effective interactions Ni78-II, JUN45, jj4b, and jj4pna are performed. The calculations describe B (E 2 ;21+→01+) and B (E 2 ;61+→41+) fairly well and point out problems in reproducing the experimental B (E 2 ;41+→21+) .

  20. miR-17 and miR-20a temper an E2F1-induced G1 checkpoint to regulate cell cycle progression.

    PubMed

    Pickering, M T; Stadler, B M; Kowalik, T F

    2009-01-08

    The stringent regulation of cell cycle progression helps to maintain genetic stability in cells. MicroRNAs (miRNAs) are critical regulators of gene expression in diverse cellular pathways, including developmental patterning, hematopoietic differentiation and antiviral defense. Here, we show that two c-Myc-regulated miRNAs, miR-17 and miR-20a, govern the transition through G1 in normal diploid human cells. Inhibition of these miRNAs leads to a G1 checkpoint due to an accumulation of DNA double-strand breaks, resulting from premature temporal accumulation of the E2F1 transcription factor. Surprisingly, gross changes in E2F1 levels were not required to initiate the DNA damage response and checkpoint, as these responses could occur with a less than twofold change in E2F1 protein levels. Instead, our findings indicate that the precise timing of E2F1 expression dictates S-phase entry and that accurate timing of E2F1 accumulation requires converging signals from the Rb/E2F pathway and the c-Myc-regulated miR-17 and miR-20a miRNAs to circumvent a G1 checkpoint arising from the untimely accumulation of E2F1. These data provide a mechanistic view of miRNA-based regulation of E2F1 in the context of the emerging model that miRNAs coordinate the timing of cell cycle progression.

  1. Using Group-Inquiry to Study Differing Reaction Conditions in the E2 Elimination of Cyclohexyl Halides

    ERIC Educational Resources Information Center

    Long, Robert D.

    2012-01-01

    In this experiment, students individually conduct one of several variations of an E2 dehydrohalogenation reaction on a cyclohexyl halide substrate for 30 min, which is sufficient only for a partial reaction to occur. The variations examine reaction conditions including different leaving groups, decreased reaction temperature, or reduced base…

  2. E-2D Advanced Hawkeye: primary flight display

    NASA Astrophysics Data System (ADS)

    Paolillo, Paul W.; Saxena, Ragini; Garruba, Jonathan; Tripathi, Sanjay; Blanchard, Randy

    2006-05-01

    This paper is a response to the challenge of providing a large area avionics display for the E-2D AHE aircraft. The resulting display design provides a pilot with high-resolution visual information content covering an image area of almost three square feet (Active Area of Samsung display = 33.792cm x 27.0336 cm = 13.304" x 10.643" = 141.596 square inches = 0.983 sq. ft x 3 = 2.95 sq. ft). The avionics display application, design and performance being described is the Primary Flight Display for the E-2D Advanced Hawkeye aircraft. This cockpit display has a screen diagonal size of 17 inches. Three displays, with minimum bezel width, just fit within the available instrument panel area. The significant design constraints of supporting an upgrade installation have been addressed. These constraints include a display image size that is larger than the mounting opening in the instrument panel. This, therefore, requires that the Electromagnetic Interference (EMI) window, LCD panel and backlight all fit within the limited available bezel depth. High brightness and a wide dimming range are supported with a dual mode Cold Cathode Fluorescent Tube (CCFT) and LED backlight. Packaging constraints dictated the use of multiple U shaped fluorescent lamps in a direct view backlight design for a maximum display brightness of 300 foot-Lamberts. The low intensity backlight levels are provided by remote LEDs coupled through a fiber optic mesh. This architecture generates luminous uniformity within a minimum backlight depth. Cross-cockpit viewing is supported with ultra-wide field-of-view performance including contrast and the color stability of an advanced LCD cell design supports. Display system design tradeoffs directed a priority to high optical efficiency for minimum power and weight.

  3. The prostaglandin E2 receptor EP4 is integral to a positive feedback loop for prostaglandin E2 production in human macrophages infected with Mycobacterium tuberculosis.

    PubMed

    Nishimura, Tomoyasu; Zhao, Xiaomin; Gan, Huixian; Koyasu, Shigeo; Remold, Heinz G

    2013-09-01

    Prostaglandin E2 (PGE2) is an important biological mediator involved in the defense against Mycobacterium tuberculosis (Mtb) infection. Previously, we reported that in macrophages (Mϕs), infection with avirulent Mtb H37Ra resulted in inhibition of necrosis by an inhibitory effect on mitochondrial permeability transition via the PGE2 receptor EP2. However, human Mϕs also express EP4, a PGE2 receptor functionally closely related to EP2 that also couples to stimulatory guanine nucleotide binding protein, but the functional differences between EP2 and EP4 in Mtb-infected Mϕs have been unclear. EP4 antagonist addition to H37Ra-infected Mϕs inhibited the expression of cyclooxygenase 2 (COX2) and microsomal prostaglandin E synthase-1 (mPGES-1), which are involved in PGE2 production. Moreover, H37Ra infection induced PGE2 production through the Toll-like receptor (TLR) 2/p38 mitogen-activated protein kinase (MAPK) signaling pathway. Induction of COX2 and mPGES-1 expression by TLR2 stimulation or Mtb infection was increased after additional stimulation with EP4 agonist. Hence, in Mtb-infected Mϕs, PGE2 production induced by pathogen recognition receptors/p38 MAPK signaling is up-regulated by EP4-triggered signaling to maintain an effective PGE2 concentration.

  4. Analysis of the cell cycle regulatory protein (E2F1) after infection of cultured cells with bovine herpesvirus 1 (BHV-1) or herpes simplex virus type 1 (HSV-1).

    PubMed

    Workman, Aspen; Jones, Clinton

    2011-09-01

    The E2F family of cellular transcription factors controls cell cycle progression and cell death. During cell cycle progression, activated cyclin-dependent kinases phosphorylate the retinoblastoma (Rb) protein, causing the release and activation of E2F family members. Previous studies demonstrated that bovine herpes virus 1 (BHV-1) productive infection increases E2F1 protein levels, the bICP0 early promoter is activated more than 100 fold by E2F1 or E2F2, and silencing E2F1 reduced the efficiency of productive infection. In this study, the effect of herpes simplex virus type 1 (HSV-1) productive infection on E2F protein levels and regulation of E2F dependent transcription was compared to BHV-1 infection in the same permissive cell line, rabbit skin (RS) cells. Silencing E2F1 with a specific siRNA reduced HSV-1 productive infection approximately 10 fold in RS cells, and total E2F1 protein levels increased during productive infection. In contrast to RS cells infected with BHV-1, a fraction of total E2F1 protein was localized to the cytoplasm in HSV-1 infected RS cells. Furthermore, E2F1 did not efficiently trans-activate the HSV-1 ICP0 or ICP4 promoter. When RS cells were transfected with an E2F reporter construct or the cyclin D1 promoter and then infected with BHV-1, promoter activity increased after infection. In contrast, HSV-1 infection of RS cells had little effect on E2F dependent transcription and cyclin D1 promoter activity was reduced. In summary, these studies indicated that silencing E2F1 reduced the efficiency of HSV-1 and BHV-1 productive infection. However, only BHV-1 productive infection induced E2F dependent transcription.

  5. Algorithmic-Reducibility = Renormalization-Group Fixed-Points; ``Noise''-Induced Phase-Transitions (NITs) to Accelerate Algorithmics (``NIT-Picking'') Replacing CRUTCHES!!!: Gauss Modular/Clock-Arithmetic Congruences = Signal X Noise PRODUCTS..

    NASA Astrophysics Data System (ADS)

    Siegel, J.; Siegel, Edward Carl-Ludwig

    2011-03-01

    Cook-Levin computational-"complexity"(C-C) algorithmic-equivalence reduction-theorem reducibility equivalence to renormalization-(semi)-group phase-transitions critical-phenomena statistical-physics universality-classes fixed-points, is exploited with Gauss modular/clock-arithmetic/model congruences = signal X noise PRODUCT reinterpretation. Siegel-Baez FUZZYICS=CATEGORYICS(SON of ``TRIZ''): Category-Semantics(C-S) tabular list-format truth-table matrix analytics predicts and implements "noise"-induced phase-transitions (NITs) to accelerate versus to decelerate Harel [Algorithmics(1987)]-Sipser[Intro. Theory Computation(1997) algorithmic C-C: "NIT-picking" to optimize optimization-problems optimally(OOPO). Versus iso-"noise" power-spectrum quantitative-only amplitude/magnitude-only variation stochastic-resonance, this "NIT-picking" is "noise" power-spectrum QUALitative-type variation via quantitative critical-exponents variation. Computer-"science" algorithmic C-C models: Turing-machine, finite-state-models/automata, are identified as early-days once-workable but NOW ONLY LIMITING CRUTCHES IMPEDING latter-days new-insights!!!

  6. Persistent magnetism in silver-doped BaF e2A s2 crystals

    NASA Astrophysics Data System (ADS)

    Li, Li; Cao, Huibo; Parker, David S.; Kuhn, Stephen J.; Sefat, Athena S.

    2016-10-01

    We investigate the thermodynamic and transport properties of silver-substituted BaF e2A s2 (122) crystals up to ˜4.5 % . Similar to other transition-metal substitutions in 122, Ag diminishes the antiferromagnetic (TN) and structural (TS) transition temperatures, but unlike other electron-doped 122s, TN and TS coincide without splitting. Although magnetism drops precipitously to TN= 84 K at doping x =0.029 , it only weakly changes above this x , settling at TN= 80 K at x =0.045 . Compared to this persistent magnetism in Ag-122, doping other group 11 elements of either Cu or Au in 122 diminished TN and induced superconductivity near Tc= 2 K at x =0.044 or 0.031, respectively. Ag-122 crystals show reflective surfaces with surprising thicker cross sections for x ≥0.019 , the appearance that is in contrast to the typical thin stacked layered feature seen in all other flux-grown x122 and lower Ag-122. This physical trait may be a manifest of intrinsic weak changes in c lattice and TN. Our theoretical calculations suggest that Ag doping produces strong electronic scattering and yet a relatively small disruption of the magnetic state, both of which preclude superconductivity in this system.

  7. The Hypervariable Region 1 of the E2 Glycoprotein of Hepatitis C Virus Binds to Glycosaminoglycans, but This Binding Does Not Lead to Infection in a Pseudotype System

    PubMed Central

    Basu, Arnab; Beyene, Aster; Meyer, Keith; Ray, Ranjit

    2004-01-01

    The hypervariable region 1 (HVR1) of hepatitis C virus (HCV) E2 envelope glycoprotein is a 27-amino-acid sequence located at its N terminus. In this study, we investigated the functional role of HVR1 for interaction with the mammalian cell surface. The C-terminal truncated E2 glycoprotein was appended to a transmembrane domain and cytoplasmic tail of vesicular stomatitis virus (VSV) G protein for generation of the chimeric E2-G gene construct. A deletion of the HVR1 sequence from E2 was created for the construction of E2ΔHVR1-G. Pseudotype virus, generated separately by infection of a stable cell line expressing E2-G or E2ΔHVR1-G with a temperature-sensitive mutant of VSV (VSVts045), displayed unique functional properties compared to VSVts045 as a negative control. Virus generated from E2ΔHVR1-G had a reduced plaquing efficiency (∼50%) in HepG2 cells compared to that for the E2-G virus. Cells prior treated with pronase (0.5 U/ml) displayed a complete inhibition of infectivity of the E2ΔHVR1-G or E2-G pseudotypes, whereas heparinase I treatment (8 U/ml) of cells reduced 40% E2-G pseudotype virus titer only. E2ΔHVR1-G pseudotypes were not sensitive to heparin (6 to 50 μg/ml) as an inhibitor of plaque formation compared to the E2-G pseudotype virus. Although the HVR1 sequence itself does not match with the known heparin-binding domain, a synthetic peptide representing 27 amino acids of the E2 HVR1 displayed a strong affinity for heparin in an enzyme-linked immunosorbent assay. This binding was competitively inhibited by a peptide from the V3 loop of a human immunodeficiency virus glycoprotein subunit (gp120) known to bind with cell surface heparin. Taken together, our results suggest that the HVR1 of E2 glycoprotein binds to the cell surface proteoglycans and may facilitate virus-host interaction for replication cycle of HCV. PMID:15078928

  8. Hierarchical Post-transcriptional Regulation of Colicin E2 Expression in Escherichia coli

    PubMed Central

    Opitz, Madeleine; Frey, Erwin

    2016-01-01

    Post-transcriptional regulation of gene expression plays a crucial role in many bacterial pathways. In particular, the translation of mRNA can be regulated by trans-acting, small, non-coding RNAs (sRNAs) or mRNA-binding proteins, each of which has been successfully treated theoretically using two-component models. An important system that includes a combination of these modes of post-transcriptional regulation is the Colicin E2 system. DNA damage, by triggering the SOS response, leads to the heterogeneous expression of the Colicin E2 operon including the cea gene encoding the toxin colicin E2, and the cel gene that codes for the induction of cell lysis and release of colicin. Although previous studies have uncovered the system’s basic regulatory interactions, its dynamical behavior is still unknown. Here, we develop a simple, yet comprehensive, mathematical model of the colicin E2 regulatory network, and study its dynamics. Its post-transcriptional regulation can be reduced to three hierarchically ordered components: the mRNA including the cel gene, the mRNA-binding protein CsrA, and an effective sRNA that regulates CsrA. We demonstrate that the stationary state of this system exhibits a pronounced threshold in the abundance of free mRNA. As post-transcriptional regulation is known to be noisy, we performed a detailed stochastic analysis, and found fluctuations to be largest at production rates close to the threshold. The magnitude of fluctuations can be tuned by the rate of production of the sRNA. To study the dynamics in response to an SOS signal, we incorporated the LexA-RecA SOS response network into our model. We found that CsrA regulation filtered out short-lived activation peaks and caused a delay in lysis gene expression for prolonged SOS signals, which is also seen in experiments. Moreover, we showed that a stochastic SOS signal creates a broad lysis time distribution. Our model thus theoretically describes Colicin E2 expression dynamics in detail and

  9. Interplay between the E2F pathway and β-adrenergic signaling in the pathological hypertrophic response of myocardium.

    PubMed

    Major, Jennifer L; Salih, Maysoon; Tuana, Balwant S

    2015-07-01

    The E2F/Pocket protein (Rb) pathway regulates cell growth, differentiation, and death by modulating gene expression. We previously examined this pathway in the myocardium via manipulation of the unique E2F repressor, E2F6, which is believed to repress gene activity independently of Rb. Mice with targeted expression of E2F6 in postnatal myocardium developed dilated cardiomyopathy (DCM) without hypertrophic growth. We assessed the mechanisms of the apparent failure of compensatory hypertrophic growth as well as their response to the β-adrenergic agonist isoproterenol. As early as 2 weeks, E2F6 transgenic (Tg) mice present with dilated thinner left ventricles and significantly reduced ejection fraction and fractional shortening which persists at 6 weeks of age, but with no apparent increase in left ventricle weight: body weight (LVW:BW). E2F6-Tg mice treated with isoproterenol (6.1 mg/kg/day) show double the increase in LVW:BW than their Wt counterparts (32% vs 16%, p-value: 0.007). Western blot analysis revealed the activation of the adrenergic pathway in Tg heart tissue under basal conditions with ~2-fold increase in the level of β2-adrenergic receptors (p-value: 8.9E-05), protein kinase A catalytic subunit (PKA-C) (p-value: 0.0176), activated c-Src tyrosine-protein kinase (p-value: 0.0002), extracellular receptor kinase 2 (ERK2) (p-value: 0.0005), and induction of the anti-apoptotic protein Bcl2 (p-value 0. 0.00001). In contrast, a ~60% decrease in the cardiac growth regulator: AKT1 (p-value 0.0001) and a ~four fold increase in cyclic AMP dependent phosphodiesterase 4D (PDE4D), the negative regulator of PKA activity, were evident in the myocardium of E2F6-Tg mice. The expression of E2F3 was down-regulated by E2F6, but was restored by isoproterenol. Further, Rb expression was down-regulated in Tg mice in response to isoproterenol implying a net activation of the E2F pathway. Thus the unique regulation of E2F activity by E2F6 renders the myocardium hypersensitive

  10. A remote monitoring and telephone nurse coaching intervention to reduce readmissions among patients with heart failure: study protocol for the Better Effectiveness After Transition - Heart Failure (BEAT-HF) randomized controlled trial

    PubMed Central

    2014-01-01

    Background Heart failure is a prevalent health problem associated with costly hospital readmissions. Transitional care programs have been shown to reduce readmissions but are costly to implement. Evidence regarding the effectiveness of telemonitoring in managing the care of this chronic condition is mixed. The objective of this randomized controlled comparative effectiveness study is to evaluate the effectiveness of a care transition intervention that includes pre-discharge education about heart failure and post-discharge telephone nurse coaching combined with home telemonitoring of weight, blood pressure, heart rate, and symptoms in reducing all-cause 180-day hospital readmissions for older adults hospitalized with heart failure. Methods/Design A multi-center, randomized controlled trial is being conducted at six academic health systems in California. A total of 1,500 patients aged 50 years and older will be enrolled during a hospitalization for treatment of heart failure. Patients in the intervention group will receive intensive patient education using the ‘teach-back’ method and receive instruction in using the telemonitoring equipment. Following hospital discharge, they will receive a series of nine scheduled health coaching telephone calls over 6 months from nurses located in a centralized call center. The nurses also will call patients and patients’ physicians in response to alerts generated by the telemonitoring system, based on predetermined parameters. The primary outcome is readmission for any cause within 180 days. Secondary outcomes include 30-day readmission, mortality, hospital days, emergency department (ED) visits, hospital cost, and health-related quality of life. Discussion BEAT-HF is one of the largest randomized controlled trials of telemonitoring in patients with heart failure, and the first explicitly to adapt the care transition approach and combine it with remote telemonitoring. The study population also includes patients with a

  11. Prostaglandin E2 As a Modulator of Viral Infections

    PubMed Central

    Sander, Willem J.; O'Neill, Hester G.; Pohl, Carolina H.

    2017-01-01

    Viral infections are a major cause of infectious diseases worldwide. Inflammation and the immune system are the major host defenses against these viral infection. Prostaglandin E2 (PGE2), an eicosanoid generated by cyclooxygenases, has been shown to modulate inflammation and the immune system by regulating the expression/concentration of cytokines. The effect of PGE2 on viral infection and replication is cell type- and virus-family-dependent. The host immune system can be modulated by PGE2, with regards to immunosuppression, inhibition of nitrogen oxide (NO) production, inhibition of interferon (IFN) and apoptotic pathways, and inhibition of viral receptor expression. Furthermore, PGE2 can play a role in viral infection directly by increasing the production and release of virions, inhibiting viral binding and replication, and/or stimulating viral gene expression. PGE2 may also have a regulatory role in the induction of autoimmunity and in signaling via Toll-like receptors. In this review the known effects of PGE2 on the pathogenesis of various infections caused by herpes simplex virus, rotavirus, influenza A virus and human immunodeficiency virus as well the therapeutic potential of PGE2 are discussed. PMID:28261111

  12. Plasmon resonant (e, 2e) spectroscopy on Be(0001)

    NASA Astrophysics Data System (ADS)

    Di Filippo, Gianluca; Sbaraglia, Damiano; Ruocco, Alessandro; Stefani, Giovanni

    2016-10-01

    We investigated the mechanisms of secondary electron (SE) emission from Be(0001) by impact of 100 and 150 eV electrons. We made use of (e, 2e) spectroscopy to disentangle the different SE production mechanisms. We observed a large increase in the SE yield when the energy loss of the primary electron equals the characteristic energy of volume and surface plasmons. The line shape of the SE spectrum associated with plasmon excitation reveals that one relevant emission mechanism corresponds to direct single-particle excitation in which the plasmon energy and momentum are transferred to a valence band electron of the solid. The contributions to the SE yield associated with surface and volume plasmon excitation are comparable in the case of specular geometry, where the projectile momentum is mainly transferred perpendicular to the surface. On the contrary, the emission of SEs associated with surface plasmon excitation is significantly enhanced when the exchanged momentum lies close to the surface plane and electrons are emitted from Be surface state. This reflects the increased sensitivity to surface modes of the latter geometry. Finally, the coupling between the direct ionization channel and the plasmon-assisted one results in a resonant increase of the secondary emission.

  13. STS-70 Launch - Nikon E-2 Digital Image

    NASA Technical Reports Server (NTRS)

    1995-01-01

    This test image was taken with a Nikon E-2 Digital Imaging System camera and are provided courtesy of Nikon (GIF 450x450 JPEG 1280x1000): The second Shuttle launch in 16 days hurtles off the pad into a sweltering summer sky. The unstable weather typical to Florida in the summertime didn't have a chance to coalesce and impact this morning's launch window, and the Space Shuttle Discovery began its planned seven-day, 22-hour flight on Mission STS-70 from Launch Pad 39B at 9:41:55.078 a.m. EDT, just seconds off schedule. On board for Discovery's 21st spaceflight are a crew of five: Commander Terence 'Tom' Henricks; Pilot Kevin R. Kregel; and Mission Specialists Nancy Jane Currie, Donald A. Thomas and Mary Ellen Weber. The crew's primary objective during the 70th Shuttle flight is to deploy the Tracking and Data Relay Satellite (TDRS-G), which will join a constellation of other TDRS spacecraft already on orbit. TDRS-G is destined to become an on- orbit, fully operational 'ready reserve' satellite, available along with one other ready reserve TDRS spacecraft to back up the two primary TDRS satellites positions, TDRS East over the Atlantic Ocean and TDRS West over the Pacific. Assured capability of the TDRS communications network is essential for linking Earth-orbiting spacecraft such as the Shuttle and the Hubble Space Telescope with the ground.

  14. STS-70 Launch - Nikon E-2 Digital Image

    NASA Technical Reports Server (NTRS)

    1995-01-01

    This test images was taken with a Nikon E-2 Digital Imaging System camera and are provided courtesy of Nikon (GIF 450x450 JPEG 1280x1000): The second Shuttle launch in 16 days hurtles off the pad into a sweltering summer sky. The unstable weather typical to Florida in the summertime didn't have a chance to coalesce and impact this morning's launch window, and the Space Shuttle Discovery began its planned seven-day, 22-hour flight on Mission STS-70 from Launch Pad 39B at 9:41:55.078 a.m. EDT, just seconds off schedule. On board for Discovery's 21st spaceflight are a crew of five: Commander Terence 'Tom' Henricks; Pilot Kevin R. Kregel; and Mission Specialists Nancy Jane Currie, Donald A. Thomas and Mary Ellen Weber. The crew's primary objective during the 70th Shuttle flight is to deploy the Tracking and Data Relay Satellite (TDRS-G), which will join a constellation of other TDRS spacecraft already on orbit. TDRS-G is destined to become an on- orbit, fully operational 'ready reserve' satellite, available along with one other ready reserve TDRS spacecraft to back up the two primary TDRS satellites positions, TDRS East over the Atlantic Ocean and TDRS West over the Pacific. Assured capability of the TDRS communications network is essential for linking Earth-orbiting spacecraft such as the Shuttle and the Hubble Space Telescope with the ground.

  15. Functional interactions between ubiquitin E2 enzymes and TRIM proteins.

    PubMed

    Napolitano, Luisa M; Jaffray, Ellis G; Hay, Ronald T; Meroni, Germana

    2011-03-01

    The TRIM (tripartite motif) family of proteins is characterized by the presence of the tripartite motif module, composed of a RING domain, one or two B-box domains and a coiled-coil region. TRIM proteins are involved in many cellular processes and represent the largest subfamily of RING-containing putative ubiquitin E3 ligases. Whereas their role as E3 ubiquitin ligases has been presumed, and in several cases established, little is known about their specific interactions with the ubiquitin-conjugating E2 enzymes or UBE2s. In the present paper, we report a thorough screening of interactions between the TRIM and UBE2 families. We found a general preference of the TRIM proteins for the D and E classes of UBE2 enzymes, but we also revealed very specific interactions between TRIM9 and UBE2G2, and TRIM32 and UBE2V1/2. Furthermore, we demonstrated that the TRIM E3 activity is only manifest with the UBE2 with which they interact. For most specific interactions, we could also observe subcellular co-localization of the TRIM involved and its cognate UBE2 enzyme, suggesting that the specific selection of TRIM-UBE2 pairs has physiological relevance. Our findings represent the basis for future studies on the specific reactions catalysed by the TRIM E3 ligases to determine the fate of their targets.

  16. Prostaglandin E2 regulates vertebrate haematopoietic stem cell homeostasis

    PubMed Central

    North, Trista E.; Goessling, Wolfram; Walkley, Carl R.; Lengerke, Claudia; Kopani, Kamden R.; Lord, Allegra M.; Weber, Gerhard J.; Bowman, Teresa V.; Jang, Il-Ho; Grosser, Tilo; FitzGerald, Garret A.; Daley, George Q.; Orkin, Stuart H.; Zon, Leonard I.

    2009-01-01

    Haematopoietic stem cell (HSC) homeostasis is tightly controlled by growth factors, signalling molecules and transcription factors. Definitive HSCs derived during embryogenesis in the aorta-gonad-mesonephros region subsequently colonize fetal and adult haematopoietic organs1,2. To identify new modulators of HSC formation and homeostasis, a panel of biologically active compounds was screened for effects on stem cell induction in the zebrafish aorta-gonad-mesonephros region. Here, we show that chemicals that enhance prostaglandin (PG) E2 synthesis increased HSC numbers, and those that block prostaglandin synthesis decreased stem cell numbers. The cyclooxygenases responsible for PGE2 synthesis were required for HSC formation. A stable derivative of PGE2 improved kidney marrow recovery following irradiation injury in the adult zebrafish. In murine embryonic stem cell differentiation assays, PGE2 caused amplification of multipotent progenitors. Furthermore, ex vivo exposure to stabilized PGE2 enhanced spleen colony forming units at day 12 post transplant and increased the frequency of long-term repopulating HSCs present in murine bone marrow after limiting dilution competitive transplantation. The conserved role for PGE2 in the regulation of vertebrate HSC homeostasis indicates that modulation of the prostaglandin pathway may facilitate expansion of HSC number for therapeutic purposes. PMID:17581586

  17. (e,2e) ionization studies of diatomic & triatomic molecules

    NASA Astrophysics Data System (ADS)

    Nixon, Kate; Murray, Andrew; Kaiser, Christian; Al-Hagan, Ola; Colgan, James; Madison, Don

    2009-10-01

    (e,2e) studies yield the most detailed experimental data on electron impact ionization of atomic & molecular targets for comparison to quantum collision theories. Coincidence techniques are here used to measure the probability of ionization as a function of the incident electron scattering angle and angle of the electron ejected from the target. In Manchester we study this process at low energies, where the ionization probability is greatest & the interaction most complex. We recently considered ionization of simple molecules (eg H2 & H2O) from a coplanar geometry to the perpendicular plane[1-4], and have discovered the interaction is far more complex than for ionization of atoms [5]. We here present comparisons between theory & experiment, and discuss new methods we intend to implement to study ionization from laser-aligned atoms & molecules. References. [1] J Colgan et al Phys Rev Lett 101 233201 (2008) [2] O Al-Hagan et al Nature Physics 5 59 (2009) [3] J Colgan et al Phys Rev A 79 052704 (2009) [4] C Kaiser et al J Phys B 40 2563 (2007) [5] A J Murray et al J Phys B 36 4875 (2003) & references therein

  18. Prostaglandin E2 Prevents Disuse-Induced Cortical Bone Loss

    NASA Technical Reports Server (NTRS)

    Jee, Webster S. S.; Akamine, T.; Ke, Hua Zhu; Li, Xiao Jian; Tang, L. Y.; Zeng, Q. Q.

    1992-01-01

    The object of this study was to determine whether prostaglandin E2 (PGE2) can prevent disuse (underloaded)-induced cortical bone loss as well as add extra bone to underloaded bones. Thirteen-month-old retired female Sprague-Dawley breeders served as controls or were subjected to simultaneous right hindlimb immobilization by bandaging and daily subcutaneous doses of 0, 1, 3, or 6 mg PGE2/kg/d for two and six weeks. Histomorphometric analyses were performed on double-fluorescent labeled undecalcified tibial shaft sections (proximal to the tibiofibular junction). Disuse-induced cortical bone loss occurred by enlarging the marrow cavity and increasing intracortical porosity. PGE2 treatment of disuse shafts further increased intracortical porosity above that in disuse alone controls. This bone loss was counteracted by enhancement of periosteal and corticoendosteal bone formation. Stimulation of periosteal and corticoendosteal bone formation slightly enlarged the total tissue (cross-sectional) area and inhibited marrow cavity enlargement. These PGE2-induced activities netted the same percentage of cortical bone with a different distribution than the beginning and age related controls. These findings indicate the PGE2-induced increase in bone formation compensated for the disuse and PGE2-induced bone loss, and thus prevented immobilization induced bone loss.

  19. Long-range magnetic order in the Heisenberg pyrochlore antiferromagnets G d2G e2O7 and G d2P t2O7 synthesized under high pressure

    NASA Astrophysics Data System (ADS)

    Li, X.; Cai, Y. Q.; Cui, Q.; Lin, C. J.; Dun, Z. L.; Matsubayashi, K.; Uwatoko, Y.; Sato, Y.; Kawae, T.; Lv, S. J.; Jin, C. Q.; Zhou, J.-S.; Goodenough, J. B.; Zhou, H. D.; Cheng, J.-G.

    2016-12-01

    G d2S n2O7 and G d2T i2O7 have been regarded as good experimental realizations of the classical Heisenberg pyrochlore antiferromagnet with dipolar interaction. The former was found to adopt the Palmer-Chalker state via a single, first-order transition at TN≈1 K , while the latter enters a distinct, partially ordered state through two successive transitions at TN 1≈1 K and TN 2= 0.75 K . To shed more light on their distinct magnetic ground states, we have synthesized two more gadolinium-based pyrochlore oxides, G d2G e2O7 and G d2P t2O7 , under high-pressure conditions and performed detailed characterizations via x-ray powder diffraction, dc and ac magnetic susceptibility, and specific heat measurements down to 100 mK. We found that both compounds enter a long-range antiferromagnetically ordered state through a single, first-order transition at TN= 1.4 K for G d2G e2O7 and TN= 1.56 K for G d2P t2O7 , with the specific heat anomaly similar to that of G d2S n2O7 rather than G d2T i2O7 . Interestingly, the low-temperature magnetic specific heat values of both G d2G e2O7 and G d2P t2O7 were found to follow nicely the T3 dependence as expected for a three-dimensional antiferromagnet with gapless spin-wave excitations. We have rationalized the enhancement of TN in terms of the reduced Gd-Gd distances for the chemically pressurized G d2G e2O7 and the addition of extra superexchange pathways through the empty Pt -eg orbitals for G d2P t2O7 . Our current study has expanded the family of gadolinium-based pyrochlores and permits us to achieve a better understanding of their distinct magnetic properties in a more comprehensive perspective.

  20. B (E2) strength ratio of one-phonon 2+ states of 94Zr from electron scattering at low momentum transfer

    NASA Astrophysics Data System (ADS)

    Scheikh Obeid, A.; Aslanidou, S.; Birkhan, J.; Krugmann, A.; von Neumann-Cosel, P.; Pietralla, N.; Poltoratska, I.; Ponomarev, V. Yu.

    2014-03-01

    Background: The B (E2) transition strength to the 22+ state in 94Zr was initially reported to be larger by a factor of 1.63 than the one to the 21+ state from lifetime measurements with the Doppler-shift attenuation method using the (n,n'γ) reaction [Elhami et al., Phys. Rev. C 75, 011301(R) (2007), 10.1103/PhysRevC.75.011301]. This surprising behavior was recently revised in a new measurement by the same group using the same experimental technique leading to a ratio below unity as expected in vibrational nuclei. Purpose: The goal is an independent determination of the ratio of B (E2) strengths for the transitions to the 21,2+ states of 94Zr with inelastic electron scattering. Method: The relative population of the 21,2+ states in the (e,e') reaction was measured at the S-DALINAC in a momentum transfer range q =0.17-0.51 fm-1 and analyzed in plane-wave Born approximation with the method described by Scheikh Obeid et al. [Phys. Rev. C 87, 014337 (2013), 10.1103/PhysRevC.87.014337]. Results: The extracted B (E2) strength ratio of 0.789(43) between the excitation of the 21+ and 22+ states of 94Zr is consistent with but more precise than the latest (n,n'γ) experiment. Using the B (E2) transition strength to the first excited state from the literature a value of 3.9(9) Weisskopf units is deduced for the B (E2;22+→01+) transition. Conclusions: The electron scattering result independently confirms the latest interpretation of the different (n,n'γ) results for the transition to the 22+ state in 94Zr.

  1. Prostaglandin E2 increases the skeletal response to mechanical loading

    NASA Technical Reports Server (NTRS)

    Tang, L. Y.; Cullen, D. M.; Yee, J. A.; Jee, W. S.; Kimmel, D. B.

    1997-01-01

    The study tested the influence of prostaglandin E2 (PGE2) on the skeletal response to increased in vivo mechanical loading through a four-point bending device. One hundred and twenty Sprague-Dawley female rats (6 months old, 354 +/- 34 g) were divided into 12 groups to accommodate all possible combinations of doses of loads (25, 30, or 35 N) and PGE2 (0, 0.1, 0.3, or 1 mg/kg). Rats received subcutaneous injections of PGE2 daily and in vivo loading of the right tibia every Monday, Wednesday, and Friday for four weeks. Histomorphometric analysis of the periosteal and endocortical surfaces following in vivo dual fluorochrome labeling was performed on both the loaded region of the right tibial diaphysis and a similar region of the left tibial diaphysis. Without PGE2, the threshold for loading to stimulate bone formation was 30 N (peak strain 1360 mu epsilon) at the periosteal surface and 25 N (peak strain 580 mu epsilon) at the endocortical surface. Without loading, the minimum dose of PGE2 to stimulate bone formation at all surfaces was 1 mg/kg/day. When 1 mg/kg/day PGE2 was combined with the minimum effective load, an additive effect of PGE2 and loading on bone formation was observed at the endocortical surface, but a synergistic effect was noted at the periosteal surface. No combined effect of ineffective doses of loading and PGE2 was found. A synergistic effect at peak strains of approximately 1625 mu epsilon on the periosteal surface could suggest either the involvement of locally produced growth factors or autoregulation of endogenous synthesis of PGE2 by exogenously administered PGE2.

  2. Tropical Cyclones in the GISS ModelE2

    NASA Technical Reports Server (NTRS)

    Camargo, Suzana J.; Sobel, Adam H.; Del Genio, Anthony; Jonas, Jeffrey A.; Kelley, Maxwell; Lu, Yun; Shaevitz, Daniel; Henderson, Naomi

    2016-01-01

    The authors describe the characteristics of tropical cyclone (TC) activity in the GISS general circulation ModelE2 with a horizontal resolution 1deg x 1deg. Four model simulations are analyzed. In the first, the model is forced with sea surface temperature (SST) from the recent historical climatology. The other three have different idealized climate change simulations, namely (1) a uniform increase of SST by 2 deg., (2) doubling of the CO2 concentration and (3) a combination of the two. These simulations were performed as part of the US Climate Variability and Predictability Program Hurricane Working Group. Diagnostics of standard measures of TC activity are computed from the recent historical climatological SST simulation and compared with the same measures computed from observations. The changes in TC activity in the three idealized climate change simulations, by comparison with that in the historical climatological SST simulation, are also described. Similar to previous results in the literature, the changes in TC frequency in the simulation with a doubling CO2 and an increase in SST are approximately the linear sum of the TC frequency in the other two simulations. However, in contrast with previous results, in these simulations the effects of CO2 and SST on TC frequency oppose each other. Large-scale environmental variables associated with TC activity are then analyzed for the present and future simulations. Model biases in the large-scale fields are identified through a comparison with ERA-Interim reanalysis. Changes in the environmental fields in the future climate simulations are shown and their association with changes in TC activity discussed.

  3. The atypical E2F family member E2F7 couples the p53 and RB pathways during cellular senescence.

    PubMed

    Aksoy, Ozlem; Chicas, Agustin; Zeng, Tianying; Zhao, Zhen; McCurrach, Mila; Wang, Xiaowo; Lowe, Scott W

    2012-07-15

    Oncogene-induced senescence is an anti-proliferative stress response program that acts as a fail-safe mechanism to limit oncogenic transformation and is regulated by the retinoblastoma protein (RB) and p53 tumor suppressor pathways. We identify the atypical E2F family member E2F7 as the only E2F transcription factor potently up-regulated during oncogene-induced senescence, a setting where it acts in response to p53 as a direct transcriptional target. Once induced, E2F7 binds and represses a series of E2F target genes and cooperates with RB to efficiently promote cell cycle arrest and limit oncogenic transformation. Disruption of RB triggers a further increase in E2F7, which induces a second cell cycle checkpoint that prevents unconstrained cell division despite aberrant DNA replication. Mechanistically, E2F7 compensates for the loss of RB in repressing mitotic E2F target genes. Together, our results identify a causal role for E2F7 in cellular senescence and uncover a novel link between the RB and p53 pathways.

  4. The atypical E2F family member E2F7 couples the p53 and RB pathways during cellular senescence

    PubMed Central

    Aksoy, Ozlem; Chicas, Agustin; Zeng, Tianying; Zhao, Zhen; McCurrach, Mila; Wang, Xiaowo; Lowe, Scott W.

    2012-01-01

    Oncogene-induced senescence is an anti-proliferative stress response program that acts as a fail-safe mechanism to limit oncogenic transformation and is regulated by the retinoblastoma protein (RB) and p53 tumor suppressor pathways. We identify the atypical E2F family member E2F7 as the only E2F transcription factor potently up-regulated during oncogene-induced senescence, a setting where it acts in response to p53 as a direct transcriptional target. Once induced, E2F7 binds and represses a series of E2F target genes and cooperates with RB to efficiently promote cell cycle arrest and limit oncogenic transformation. Disruption of RB triggers a further increase in E2F7, which induces a second cell cycle checkpoint that prevents unconstrained cell division despite aberrant DNA replication. Mechanistically, E2F7 compensates for the loss of RB in repressing mitotic E2F target genes. Together, our results identify a causal role for E2F7 in cellular senescence and uncover a novel link between the RB and p53 pathways. PMID:22802529

  5. Regulation of Matrix Metalloproteinase Genes by E2F transcription factors: Rb-Raf-1 interaction as a novel target for metastatic disease

    PubMed Central

    Johnson, Jackie L.; Pillai, Smitha; Pernazza, Danielle; Sebti, Said M.; Lawrence, Nicholas J.; Chellappan, Srikumar P.

    2011-01-01

    The Rb-E2F transcriptional regulatory pathway plays a major role in cell cycle regulation, but its role in invasion and metastasis is less understood. We find that many genes involved in the invasion of cancer cells, such as matrix metalloproteinases, have potential E2F binding sites in their promoters. E2F binding sites were predicted on all 23 human MMP gene promoters, many of which harbored multiple E2F binding sites. Studies presented here show that MMP genes such as MMP9, MMP14, and MMP15 which are overexpressed in non-small cell lung cancer (NSCLC) have multiple E2F binding sites and are regulated by the Rb-E2F pathway. Chromatin immunoprecipitation assays showed the association of E2F1 with the MMP9, MMP14, and MMP15 promoters and transient transfection experiments showed that these promoters are E2F responsive. Correspondingly, depletion of E2F family members by RNAi techniques reduced the expression of these genes with a corresponding reduction in collagen degradation activity. Further, activating Rb by inhibiting the interaction of Raf-1 with Rb using the Rb-Raf-1 disruptor RRD-251 was sufficient to inhibit MMP transcription. This led to reduced invasion and migration of cancer cells in vitro and metastatic foci development in a tail vein lung metastasis model in mice. These results suggest that E2F transcription factors may play a role in promoting metastasis through regulation of MMP genes, and that targeting the Rb-Raf-1 interaction is a promising approach for the treatment of metastatic disease. PMID:22086850

  6. Elevated intracellular dCTP levels reduce the induction of GC-->AT transitions in yeast by ethyl methanesulfonate or N-methyl-N'-nitro-N- nitrosoguanidine but increase alkylation-induced GC-->CG transversions.

    PubMed

    Kohalmi, S E; Roche, H M; Kunz, B A

    1993-09-01

    The effect of an increased intracellular dCTP:dTTP ratio on the specificities of ethyl methanesulfonate (EMS) and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) mutagenesis was examined in the yeast Saccharomyces cerevisiae. To do so, we used a dCMP deaminase-deficient (dcd1) strain having a dCTP:dTTP ratio > 77-fold larger than its isogenic wild-type parent under the treatment conditions employed. This DNA precursor imbalance lowered the frequencies of EMS- or MNNG-induced SUP4-o mutations by 75 or 45%, respectively, relative to the corresponding values for the wild-type strain. A total of 405 SUP4-o mutations produced by the alkylating agents in the dcd1 background were characterized by DNA sequencing and the mutational spectra were compared to those for 399 mutations induced in the wild-type parent and 207 mutations that arose spontaneously in the dcd1 strain. Unexpectedly, the frequencies of EMS- and MNNG-induced GC-->AT transitions in the dcd1 strain were found to be reduced by 93 and 68%, respectively, considerably more than the decreases for the overall SUP4-o mutation frequencies. The differences were due mainly to substantial increases in the frequencies of GC-->CG transversions. Although these events were the predominant type of spontaneous substitution in the dcd1 strain, they were more frequent after alkylation treatment and were distributed differently than the spontaneous GC-->CG transversions. Preferences for the EMS- or MNNG-induced GC-->AT transitions to occur at GC sites having the guanine located on the transcribed strand or preceded by a 5' purine, respectively, also were diminished in the dcd1 strain.(ABSTRACT TRUNCATED AT 250 WORDS)

  7. E2F1 enhances 8-chloro-adenosine-induced G2/M arrest and apoptosis in A549 and H1299 lung cancer cells.

    PubMed

    Duan, Hong-Ying; Cao, Ji-Xiang; Qi, Jun-Juan; Wu, Guo-Sheng; Li, Shu-Yan; An, Guo-Shun; Jia, Hong-Ti; Cai, Wang-Wei; Ni, Ju-Hua

    2012-03-01

    The E2F1 transcription factor is a well known regulator of cell proliferation and apoptosis, but its role in response to DNA damage is less clear. 8-Chloro-adenosine (8-Cl-Ado), a nucleoside analog, can inhibit proliferation in a variety of human tumor cells. However, it is still elusive how the agent acts on tumors. Here we show that A549 and H1299 cells formed DNA double-strand breaks after 8-Cl-Ado exposure, accompanied by E2F1 upregulation at protein level. Overexpressed wild-type (E2F1-wt) colocalized with double-strand break marker γ-H2AX and promoted G2/M arrest in 8-Cl-Ado-exposed A549 and H1299, while expressed S31A mutant of E2F1 (E2F1-mu) significantly reduced ability to accumulate at sites of DNA damage and G2/M arrest, suggesting that E2F1 is required for activating G2/M checkpoint pathway upon DNA damage. Transfection of either E2F1-wt or E2F1-mu plasmid promoted apoptosis in 8-Cl-Ado-exposed cells, indicating that 8-Cl-Ado may induce apoptosis in E2F1-dependent and E2F1-independent ways. These findings demonstrate that E2F1 plays a crucial role in 8-Cl-Ado-induced G2/M arrest but is dispensable for 8-Cl-Ado-induced apoptosis. These data also suggest that the mechanism of 8-Cl-Ado action is complicated.

  8. Work transitions.

    PubMed

    Fouad, Nadya A; Bynner, John

    2008-01-01

    Individuals make choices in, and adjust to, a world of work that is often a moving target. Because work is so central to human functioning, and transitions in and out of work can have major mental health repercussions, the authors argue that applied psychologists in health services need to understand those transitions. This article focuses on the different types of transition throughout a person's working life and the resources needed at different stages to ensure the success of these transitions. The authors start by examining the roles of capability and adaptability in supporting and facilitating adjustment to work transitions and their relation to identity development. They then examine the role of social and institutional contexts in shaping work transitions and their outcomes. The authors focus on voluntary versus involuntary transitions and then broaden the lens in discussing the policy implications of research on work transitions.

  9. Detection of ethylene glycol - toward W51/e2 and G34.3+0.02

    NASA Astrophysics Data System (ADS)

    Lykke, Julie M.; Favre, Cécile

    2014-07-01

    Ethylene glycol (HOCH2CH2OH), also commenly known as antifreeze, is the reduced alcohol version of glycolaldehyde (CH2OHCHO). Glycoladehyde - the simplest possible aldehyde sugar (Marstokk and Møllendal 1973) - is the first intermediate step in the path toward forming more complex and biologically relevant molecules through the the formose reaction, which begins with formaldehyde (H2CO) and ends with the formation of sugars and ultimately ribose, the backbone of RNA (e.g., Larralde et al. 1995). The presence of glycolaldehyde is therefore an important indication that processes leading to biologically relevant molecules are taking place. It is however, still unclear as to how glycolaldehyde and ethylene glycol are formed in the ISM. It has been proposed that they share a common formation pathway through UV-irradiation of methanol (CH3OH) ices mixed with CO (Öberg et al. 2009). So far, ethylene glycol, in its lower energy con-former (g’Ga(CH2OH)2), has been detected toward SgrB2 (N) by Hollis et al. (2002), tentatively toward IRAS 16293-2422 (Jørgensen et al. 2012) and marginally by Kalenskii and Johansson (2010) toward W51 e1/e2. Here we present a firm detection of ethylene glycol toward W51/e2 as well as a first detection toward G34.3+0.02 at 1mm and 3mm using the IRAM 30m telescope.

  10. E2 protein cage as a multifunctional nanoplatform

    NASA Astrophysics Data System (ADS)

    Dalmau Mallorqui, Merce

    Caged protein systems such as viral capsids, heat shock proteins, and ferritin are spherical structures that occur naturally in living organisms and are a growing class of biomimetic templates used to create new materials in nanotechnology. Such systems have been proposed as general drug carriers since they form highly symmetric nanoscale architectures that offer the potential to be tailored according to the desired application. Within this framework, this dissertation focuses on the design and development of a new drug delivery nanoplatform based on the E2 subunit of the pyruvate dehydrogenase protein from Bacillus stearothermophilus. This scaffold forms a 25-nm nanocapsule structure with a hollow cavity. We produced a variant of this protein consisting only of the structural core, and found the thermostability of this self-assembled scaffold to be unusually high, with an onset unfolding temperature of 81.1 +/- 0.9°C and an apparent midpoint unfolding temperature of 91.4 +/- 1.4°C. To evaluate the potential of this scaffold for encapsulation of guest molecules in the internal cavity, we made variants which altered the physicochemical properties of the hollow internal surface. These mutants, yielding up to 240 mutations within this cavity, assembled into correct architectures and exhibited high thermostability that was also comparable to the wild-type scaffold. To show the applicability of this scaffold we coupled two drug-like small molecules to the internal cavity. We also developed a new strategy for encapsulation of small hydrophobic drug molecules. This method is based on hydrophobic differences between the interior cavity and the external buffer to nucleate drug-like agents inside the protein cage. We demonstrate that internal mutations can introduce non-native functionality and enable molecular encapsulation within the cavity while still retaining the dodecahedral structure. Another surface amenable to modifications is the interface between subunits. Such

  11. Structural models of the membrane anchors of envelope glycoproteins E1 and E2 from pestiviruses

    SciTech Connect

    Wang, Jimin Li, Yue; Modis, Yorgo

    2014-04-15

    The membrane anchors of viral envelope proteins play essential roles in cell entry. Recent crystal structures of the ectodomain of envelope protein E2 from a pestivirus suggest that E2 belongs to a novel structural class of membrane fusion machinery. Based on geometric constraints from the E2 structures, we generated atomic models of the E1 and E2 membrane anchors using computational approaches. The E1 anchor contains two amphipathic perimembrane helices and one transmembrane helix; the E2 anchor contains a short helical hairpin stabilized in the membrane by an arginine residue, similar to flaviviruses. A pair of histidine residues in the E2 ectodomain may participate in pH sensing. The proposed atomic models point to Cys987 in E2 as the site of disulfide bond linkage with E1 to form E1–E2 heterodimers. The membrane anchor models provide structural constraints for the disulfide bonding pattern and overall backbone conformation of the E1 ectodomain. - Highlights: • Structures of pestivirus E2 proteins impose constraints on E1, E2 membrane anchors. • Atomic models of the E1 and E2 membrane anchors were generated in silico. • A “snorkeling” arginine completes the short helical hairpin in the E2 membrane anchor. • Roles in pH sensing and E1–E2 disulfide bond formation are proposed for E1 residues. • Implications for E1 ectodomain structure and disulfide bonding pattern are discussed.

  12. Inhibition of the entomopathogenic fungus Metarhizium anisopliae in vitro by the bed bug defensive secretions (E)-2-hexenal and (E)-2-octenal

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The two major aldehydes (E)-2-hexenal and (E)-2-octenal emitted as defensive secretions by bed bugs Cimex lectularius L. (Hemiptera: Cimicidae), inhibit the in vitro growth of Metarhizium anisopliae (Metsch.) Sokorin (Hypocreales: Clavicipitaceae). These chemicals inhibit fungal growth by direct con...

  13. Ability of the bed bug (Hemiptera: Cimicidae) defensive secretions (E)-2-hexenal and (E)-2-octenal to attract adult bed bugs

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Accurate and timely surveillance of bed bug infestations is critical for development of effective control strategies. While the bed bug produced volatiles (E)-2-hexenal and (E)-2-octenal are considered defensive secretions, through use of EthoVision® video-tracking software we demonstrate that low ...

  14. The E2F transcription factor family regulates CENH3 expression in Arabidopsis thaliana.

    PubMed

    Heckmann, Stefan; Lermontova, Inna; Berckmans, Barbara; De Veylder, Lieven; Bäumlein, Helmut; Schubert, Ingo

    2011-11-01

    To elucidate the epigenetic maintenance mechanism for functional plant centromeres, we studied transcriptional regulation of the centromere-specific histone H3 variant CENH3 in Arabidopsis thaliana. We focused on the structure and activity of the CENH3 promoter (CENH3pro) and its regulation by E2F transcription factors. Use of CENH3pro::GUS reporter gene constructs showed that CENH3pro is active in dividing tissues, and that full expression in root meristems depends on intragenic regulatory elements within the second intron. Chromatin immunoprecipitation identified CENH3 as an E2F target gene. Transient co-expression of a CENH3pro::GUS reporter gene construct with various E2F transcription factors in A. thaliana protoplasts showed that E2Fa and E2Fb (preferentially with dimerization protein DPb) activate CENH3pro. Stable over-expression of E2Fa and E2Fb increased the CENH3 transcript level in planta, whereas over-expression of E2Fc decreased the CENH3 transcript level. Surprisingly, mutation of the two E2F binding sites of CENH3pro, in particular the more upstream one (E2F2), caused an increase in CENH3pro activity, indicating E2F-dependent transcriptional repression. CENH3pro repression may be triggered by the interplay of typical and atypical E2Fs in a cell cycle-dependent manner, and/or by interaction of typical E2Fs with retinoblastoma-related (RBR) protein. We speculate that E2Fs are involved in differential transcriptional regulation of CENH3 versus H3, as H3 promoters lack E2F binding motifs. E2F binding motifs are also present in human and Drosophila CENH3pro regions, thus cell cycle-dependent transcriptional regulation of CENH3 may be highly conserved.

  15. Elucidating the Specificity Determinants of the AtxE2 Lasso Peptide Isopeptidase.

    PubMed

    Maksimov, Mikhail O; Koos, Joseph D; Zong, Chuhan; Lisko, Bozhena; Link, A James

    2015-12-25

    Lasso peptide isopeptidase is an enzyme that specifically hydrolyzes the isopeptide bond of lasso peptides, rendering these peptides linear. To carry out a detailed structure-activity analysis of the lasso peptide isopeptidase AtxE2 from Asticcacaulis excentricus, we solved NMR structures of its substrates astexin-2 and astexin-3. Using in vitro enzyme assays, we show that the C-terminal tail portion of these peptides is dispensable with regards to isopeptidase activity. A collection of astexin-2 and astexin-3 variants with alanine substitutions at each position within the ring and the loop was constructed, and we showed that all of these peptides except for one were cleaved by the isopeptidase. Thus, much like the lasso peptide biosynthetic enzymes, lasso peptide isopeptidase has broad substrate specificity. Quantitative analysis of the cleavage reactions indicated that alanine substitutions in loop positions of these peptides led to reduced cleavage, suggesting that the loop is serving as a recognition element for the isopeptidase.

  16. 26 CFR 1.669(e)-2A - Illustration of the provisions of section 669.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 8 2010-04-01 2010-04-01 false Illustration of the provisions of section 669. 1.669(e)-2A Section 1.669(e)-2A Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY... Taxable Years Beginning Before January 1, 1969 § 1.669(e)-2A Illustration of the provisions of section...

  17. 26 CFR 1.669(e)-2A - Illustration of the provisions of section 669.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 8 2014-04-01 2014-04-01 false Illustration of the provisions of section 669. 1.669(e)-2A Section 1.669(e)-2A Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY... Applicable to Taxable Years Beginning Before January 1, 1969 § 1.669(e)-2A Illustration of the provisions...

  18. 26 CFR 1.669(e)-2A - Illustration of the provisions of section 669.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 8 2012-04-01 2012-04-01 false Illustration of the provisions of section 669. 1.669(e)-2A Section 1.669(e)-2A Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY... Applicable to Taxable Years Beginning Before January 1, 1969 § 1.669(e)-2A Illustration of the provisions...

  19. 26 CFR 1.669(e)-2A - Illustration of the provisions of section 669.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 8 2013-04-01 2013-04-01 false Illustration of the provisions of section 669. 1.669(e)-2A Section 1.669(e)-2A Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY... Applicable to Taxable Years Beginning Before January 1, 1969 § 1.669(e)-2A Illustration of the provisions...

  20. 26 CFR 1.669(e)-2A - Illustration of the provisions of section 669.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 8 2011-04-01 2011-04-01 false Illustration of the provisions of section 669. 1.669(e)-2A Section 1.669(e)-2A Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY... Applicable to Taxable Years Beginning Before January 1, 1969 § 1.669(e)-2A Illustration of the provisions...

  1. E2fl1 is a meiosis-specific transcription factor in the protist Tetrahymena thermophila.

    PubMed

    Zhang, Jing; Tian, Miao; Yan, Guan-Xiong; Shodhan, Anura; Miao, Wei

    2017-01-02

    Members of the E2F family of transcription factors have been reported to regulate the expression of genes involved in cell cycle control, DNA replication, and DNA repair in multicellular eukaryotes. Here, E2FL1, a meiosis-specific E2F transcription factor gene, was identified in the model ciliate Tetrahymena thermophila. Loss of this gene resulted in meiotic arrest prior to anaphase I. The cytological experiments revealed that the meiotic homologous pairing was not affected in the absence of E2FL1, but the paired homologous chromosomes did not separate and assumed a peculiar tandem arrangement. This is the first time that an E2F family member has been shown to regulate meiotic events. Moreover, BrdU incorporation showed that DSB processing during meiosis was abnormal upon the deletion of E2FL1. Transcriptome sequencing analysis revealed that E2FL1 knockout decreased the expression of genes involved in DNA replication and DNA repair in T. thermophila, suggesting that the function of E2F is highly conserved in eukaryotes. In addition, E2FL1 deletion inhibited the expression of related homologous chromosome segregation genes in T. thermophila. The result may explain the meiotic arrest phenotype at anaphase I. Finally, by searching for E2F DNA-binding motifs in the entire T. thermophila genome, we identified 714 genes containing at least one E2F DNA-binding motif; of these, 235 downregulated represent putative E2FL1 target genes.

  2. Enhanced transcriptional activation by E2 proteins from the oncogenic human papillomaviruses.

    PubMed Central

    Kovelman, R; Bilter, G K; Glezer, E; Tsou, A Y; Barbosa, M S

    1996-01-01

    A systematic comparison of transcriptional activation by papillomavirus E2 proteins revealed that the E2 proteins from high-risk human papillomaviruses (human papillomavirus type 16 [HPV-16] and HPV-18) are much more active than are the E2 proteins from low-risk HPVs (HPV-6b and HPV-11). Despite the tropism of HPVs for particular epithelial cell types, this difference in transcriptional activation was observed in a number of different epithelial and nonepithelial cells. The enhanced activities of the E2 proteins from high-risk HPVs did not result from higher steady-state levels of protein in vivo, and in vitro DNA-binding assays revealed similar binding properties for these two classes of E2 proteins. These results demonstrate that the E2 proteins from high-risk HPVs have an intrinsically enhanced potential to activate transcription from promoters with E2-responsive elements. We found that there are also substantial differences between the activation properties of the bovine papillomavirus type 1 E2 protein and those of either of the two classes of HPV E2 proteins, especially with regard to requirements for particular configurations of E2 binding sites in the target promoter. Our results indicate that there are at least three distinct functional classes of E2 proteins and that these classes of E2 proteins may perform different roles during the respective viral life cycles. PMID:8892874

  3. The repression of E2F-1 is critical for the activity of Minerval against cancer.

    PubMed

    Martínez, Jordi; Gutiérrez, Antonio; Casas, Jesús; Lladó, Victoria; López-Bellan, Alicia; Besalduch, Joan; Dopazo, Ana; Escribá, Pablo V

    2005-10-01

    The recently discovered anticancer drug Minerval (2-hydroxy-9-cis-octadecenoic acid) is a synthetic fatty acid that modifies the structure of the membrane. This restructuring facilitates the recruitment of protein kinase C (PKC) alpha to membranes and is associated with the antineoplastic activity of Minerval in cellular and animal models of cancer. Minerval is a derivative of oleic acid (OA) with an enhanced antiproliferative activity in human cancer cells and animal models of cancer, which is associated with PKCalpha activation and p21(CIP) overexpression. However, the signaling cascades involved in its pharmacological activity remain largely unknown. Here, we showed that this drug induced cell cycle arrest before entry into S phase, human lung adenocarcinoma (A549) cells accumulating in the G0/G1 phase. This cell cycle arrest was associated with a marked decrease in the expression of E2F-1. This transcription factor activates several cell cycle-related genes, and, accordingly, the expression of certain cyclins and cyclin-dependent kinases (cdks) was markedly lower upon exposure to Minerval. The reduced availability of these kinase heterodimers was associated with reduced phosphorylation of the retinoblastoma protein (pRb) observed after drug treatment. Significantly, hypophosphorylated pRb remains bound to E2F-1 and maintains this transcription factor inactive. The modulation of these antiproliferative mechanisms by Minerval explains its anticancer potency, through a new therapeutic strategy that can be used to develop new antitumor drugs. On the other hand, apoptosis did not seem to be involved in its pharmacological mechanism. Interestingly, whereas the changes induced by OA were only modest, they may reflect the beneficial effects of high olive oil intake against cancer.

  4. Deregulation of Rb-E2F1 Axis Causes Chromosomal Instability by Engaging the Transactivation Function of Cdc20–Anaphase-Promoting Complex/Cyclosome

    PubMed Central

    Nath, Somsubhra; Chowdhury, Abhishek; Dey, Sanjib; Roychoudhury, Anirban; Ganguly, Abira; Bhattacharyya, Dibyendu

    2014-01-01

    The E2F family of transcription factors regulates genes involved in various aspects of the cell cycle. Beyond the well-documented role in G1/S transition, mitotic regulation by E2F has also been reported. Proper mitotic progression is monitored by the spindle assembly checkpoint (SAC). The SAC ensures bipolar separation of chromosomes and thus prevents aneuploidy. There are limited reports on the regulation of the SAC by E2F. Our previous work identified the SAC protein Cdc20 as a novel transcriptional regulator of the mitotic ubiquitin carrier protein UbcH10. However, none of the Cdc20 transcription complex proteins have any known DNA binding domain. Here we show that an E2F1-DP1 heterodimer is involved in recruitment of the Cdc20 transcription complex to the UBCH10 promoter and in transactivation of the gene. We further show that inactivation of Rb can facilitate this transactivation process. Moreover, this E2F1-mediated regulation of UbcH10 influences mitotic progression. Deregulation of this pathway results in premature anaphase, chromosomal abnormalities, and aneuploidy. We conclude that excess E2F1 due to Rb inactivation recruits the complex of Cdc20 and the anaphase-promoting complex/cyclosome (Cdc20-APC/C) to deregulate the expression of UBCH10, leading to chromosomal instability in cancer cells. PMID:25368385

  5. Phase transitions of BaTi{sub 0.9}Rh{sub 0.1}O{sub 3±δ} perovskite-type oxides under reducing environments

    SciTech Connect

    Rodríguez, G.C.Mondragón; Gönüllü, Y.; Ferri, Davide; Eyssler, Arnim; Otal, Eugenio; Saruhan, B.

    2015-01-15

    Highlights: • Solid solution formation BaTi{sub 0.9}Rh{sub 0.1}O{sub 3±δ} with a new wet chemical synthesis method. • Rhodium in the BaTiO{sub 3} perovskite stabilizes the hexagonal structure. • New Rh segregation mechanism for hexagonal BaTi{sub 0.9}Rh{sub 0.1}O{sub 3±δ} upon reduction. - Abstract: Perovskite-type oxides of composition BaTi{sub 0.9}Rh{sub 0.1}O{sub 3±δ} were prepared following a new chemical route that avoids the formation of hydroxyl species and precipitation, and allows the homogeneous distribution of Rh in the final mixed metal oxide. The high dispersion of Rh and the formation of the solid solution between Rh and the BaTiO{sub 3} perovskite is confirmed by means of X-ray diffraction (XRD) and extended X-ray absorption fine structure spectroscopy (EXAFS). The presence of Rh stabilized the hexagonal BaTi{sub 0.9}Rh{sub 0.1}O{sub 3±δ} phase, which decomposes into barium orthotitanate (BaTi{sub 2}O{sub 4}) and metallic Rh° in reducing environment. This phase transition starts already at 700 °C and is only partially completed at 900 °C suggesting that part of the Rh present in the perovskite lattice might not be easily reduced by hydrogen. These aspects and further open questions are discussed.

  6. Involvement of retinoblastoma (Rb) and E2F transcription factors during photodynamic therapy of human epidermoid carcinoma cells A431.

    PubMed

    Ahmad, N; Gupta, S; Mukhtar, H

    1999-03-11

    Photodynamic therapy (PDT), a promising new therapeutic modality for the management of a variety of solid malignancies and many non-malignant diseases, is a bimodal therapy using a porphyrin based photosensitizing chemical and visible light. The proper understanding of the mechanism of PDT-mediated cancer cell-kill may result in improving the efficacy of this treatment modality. Earlier we have shown (Proc. Natl. Acad. Sci. USA; 95: 6977-6982, 1998) that silicon phthalocyanine (Pc4)-PDT results in an induction of the cyclin kinase inhibitor WAF1/CIP1/p21 which, by inhibiting cyclins (E and D1) and cyclin dependent kinases (cdk2 and cdk6), results in a G0/G1-phase arrest followed by apoptosis in human epidermoid carcinoma cells A431. We have also demonstrated the generation of nitric oxide during PDT-mediated apoptosis (Cancer Res.; 58: 1785-1788, 1998). Retinoblastoma (pRb) and E2F family transcription factors are important proteins, which regulate the G1-->S transition in the cell cycle. Here, we provide evidence for the involvement of pRb-E2F/DP machinery as an important contributor of PDT-mediated cell cycle arrest and apoptosis. Western blot analysis demonstrated a decrease in the hyper-phosphorylated form of pRb at 3, 6 and 12 h post-PDT with a relative increase in hypo-phosphorylated pRb. Western blot analysis also revealed that PDT-caused decrease in phosphorylation of pRb occurs at serine-780. The ELISA data demonstrated a time dependent accumulation of hypo-phosphorylated pRb by PDT. This response was accompanied with down-regulation in the protein expression of all five E2F (1-5) family transcription factors, and their heterodimeric partners DP1 and DP2. These results suggest that Pc4-PDT of A431 cells results in a down regulation of hyper-phosphorylated pRb protein with a relative increase in hypo-phosphorylated pRb that, in turn, compromises with the availability of free E2F. We suggest that these events result in a stoppage of the cell cycle

  7. Thorium distribution on the lunar surface observed by Chang'E-2 gamma-ray spectrometer

    NASA Astrophysics Data System (ADS)

    Wang, Xianmin; Zhang, Xubing; Wu, Ke

    2016-07-01

    The thorium distribution on the lunar surface is critical for understanding the lunar evolution. This work reports a global map of the thorium distribution on the lunar surface observed by Chang'E-2 gamma-ray spectrometer (GRS). Our work exhibits an interesting symmetrical structure of thorium distribution along the two sides of the belt of Th hot spots. Some potential positions of KREEP volcanism are suggested, which are the Fra Mauro region, Montes Carpatus, Aristarchus Plateau and the adjacent regions of Copernicus Crater. Based on the lunar map of thorium distribution, we draw some conclusions on two critical links of lunar evolution: (1) the thorium abundance within the lunar crust and mantle, in the last stage of Lunar Magma Ocean (LMO) crystallization, may have a positive correlation with the depth in the crust, reaches a peak when coming through the transitional zone between the crust and mantle, and decreases sharply toward the inside of the mantle; thus, the Th-enhanced materials originated from the lower crust and the layer between the crust and mantle, (2) in PKT, KREEP volcanism might be the primary mechanism of Th-elevated components to the lunar surface, whereas the Imbrium impact acted as a relatively minor role.

  8. Prostaglandin E2 promotes tumor progression by inducing myeloid-derived suppressor cells.

    PubMed

    Sinha, Pratima; Clements, Virginia K; Fulton, Amy M; Ostrand-Rosenberg, Suzanne

    2007-05-01

    A causative relationship between chronic inflammation and cancer has been postulated for many years, and clinical observations and laboratory experiments support the hypothesis that inflammation contributes to tumor onset and progression. However, the precise mechanisms underlying the relationship are not known. We recently reported that the proinflammatory cytokine, interleukin-1beta, induces the accumulation and retention of myeloid-derived suppressor cells (MDSC), which are commonly found in many patients and experimental animals with cancer and are potent suppressors of adaptive and innate immunity. This finding led us to hypothesize that inflammation leads to cancer through the induction of MDSC, which inhibit immunosurveillance and thereby allow the unchecked persistence and proliferation of premalignant and malignant cells. We now report that host MDSC have receptors for prostaglandin E2 (PGE2) and that E-prostanoid receptor agonists, including PGE2, induce the differentiation of Gr1(+)CD11b(+) MDSC from bone marrow stem cells, whereas receptor antagonists block differentiation. BALB/c EP2 knockout mice inoculated with the spontaneously metastatic BALB/c-derived 4T1 mammary carcinoma have delayed tumor growth and reduced numbers of MDSC relative to wild-type mice, suggesting that PGE2 partially mediates MDSC induction through the EP2 receptor. Treatment of 4T1-tumor-bearing wild-type mice with the cyclooxygenase 2 inhibitor, SC58236, delays primary tumor growth and reduces MDSC accumulation, further showing that PGE2 induces MDSC and providing a therapeutic approach for reducing this tumor-promoting cell population.

  9. Multipole character of the proposed 220 eV transition in [sup 229]Pa

    SciTech Connect

    Dragoun, O.; Rysavy, M. ); Guenther, C. )

    1993-02-01

    Internal conversion coefficients (ICC's) have been calculated for protactinium and transition energies between 170 eV and 10 keV. The ICC's for [ital E]1 multipolarity show an unusual behavior, which cannot be approximated by an exponential dependence on the transition energy, whereas the ICC's for [ital M]1 and [ital E]2 multipolarities closely follow such a dependence. Using the newly calculated ICC's the unusually strong enhancement'' of a possible 220 eV [ital E]1 transition in [sup 229]Pa proposed earlier is reduced by a factor of [similar to]5, yielding an induced electric dipole moment similar to that observed in the neighboring octupole-deformed isotopes.

  10. A novel exendin-4 human serum albumin fusion protein, E2HSA, with an extended half-life and good glucoregulatory effect in healthy rhesus monkeys

    SciTech Connect

    Zhang, Ling; Wang, Lin; Meng, Zhiyun; Gan, Hui; Gu, Ruolan; Wu, Zhuona; Gao, Lei; Zhu, Xiaoxia; Sun, Wenzhong; Li, Jian; Zheng, Ying; Dou, Guifang

    2014-03-07

    Highlights: • E2HSA has an extended half-life and good plasma stability. • E2HSA could improve glucose-dependent insulin secretion. • E2HSA has excellent glucoregulatory effects in vivo. • E2HSA could potentially be used as a new long-acting GLP-1 receptor agonist for type 2 diabetes management. - Abstract: Glucagon-like peptide-1 (GLP-1) has attracted considerable research interest in terms of the treatment of type 2 diabetes due to their multiple glucoregulatory functions. However, the short half-life, rapid inactivation by dipeptidyl peptidase-IV (DPP-IV) and excretion, limits the therapeutic potential of the native incretin hormone. Therefore, efforts are being made to develop the long-acting incretin mimetics via modifying its structure. Here we report a novel recombinant exendin-4 human serum albumin fusion protein E2HSA with HSA molecule extends their circulatory half-life in vivo while still retaining exendin-4 biological activity and therapeutic properties. In vitro comparisons of E2HSA and exendin-4 showed similar insulinotropic activity on rat pancreatic islets and GLP-1R-dependent biological activity on RIN-m5F cells, although E2HSA was less potent than exendin-4. E2HSA had a terminal elimation half-life of approximate 54 h in healthy rhesus monkeys. Furthermore, E2HSA could reduce postprandial glucose excursion and control fasting glucose level, dose-dependent suppress food intake. Improvement in glucose-dependent insulin secretion and control serum glucose excursions were observed during hyperglycemic clamp test (18 h) and oral glucose tolerance test (42 h) respectively. Thus the improved physiological characterization of E2HSA make it a new potent anti-diabetic drug for type 2 diabetes therapy.

  11. Molecular functions of the transcription factors E2A and E2-2 in controlling germinal center B cell and plasma cell development

    PubMed Central

    Wöhner, Miriam; Tagoh, Hiromi; Bilic, Ivan; Jaritz, Markus; Poliakova, Daniela Kostanova; Fischer, Maria

    2016-01-01

    E2A is an essential regulator of early B cell development. Here, we have demonstrated that E2A together with E2-2 controlled germinal center (GC) B cell and plasma cell development. As shown by the identification of regulated E2A,E2-2 target genes in activated B cells, these E-proteins directly activated genes with important functions in GC B cells and plasma cells by inducing and maintaining DNase I hypersensitive sites. Through binding to multiple enhancers in the Igh 3′ regulatory region and Aicda locus, E-proteins regulated class switch recombination by inducing both Igh germline transcription and AID expression. By regulating 3′ Igk and Igh enhancers and a distal element at the Prdm1 (Blimp1) locus, E-proteins contributed to Igk, Igh, and Prdm1 activation in plasmablasts. Together, these data identified E2A and E2-2 as central regulators of B cell immunity. PMID:27261530

  12. dE2F2-independent rescue of proliferation in cells lacking an activator dE2F1.

    PubMed

    Ambrus, Aaron M; Nicolay, Brandon N; Rasheva, Vanya I; Suckling, Richard J; Frolov, Maxim V

    2007-12-01

    In Drosophila melanogaster, the loss of activator de2f1 leads to a severe reduction in cell proliferation and repression of E2F targets. To date, the only known way to rescue the proliferation block in de2f1 mutants was through the inactivation of dE2F2. This suggests that dE2F2 provides a major contribution to the de2f1 mutant phenotype. Here, we report that in mosaic animals, in addition to de2f2, the loss of a DEAD box protein Belle (Bel) also rescues proliferation of de2f1 mutant cells. Surprisingly, the rescue occurs in a dE2F2-independent manner since the loss of Bel does not relieve dE2F2-mediated repression. In the eye disc, bel mutant cells fail to undergo a G1 arrest in the morphogenetic furrow, delay photoreceptor recruitment and differentiation, and show a reduction of the transcription factor Ci155. The down-regulation of Ci155 is important since it is sufficient to partially rescue proliferation of de2f1 mutant cells. Thus, mutation of bel relieves the dE2F2-mediated cell cycle arrest in de2f1 mutant cells through a novel Ci155-dependent mechanism without functional inactivation of the dE2F2 repressor.

  13. E2F7 overexpression leads to tamoxifen resistance in breast cancer cells by competing with E2F1 at miR-15a/16 promoter.

    PubMed

    Chu, Junjun; Zhu, Yinghua; Liu, Yujie; Sun, Lijuan; Lv, Xiaobin; Wu, Yanqin; Hu, Pengnan; Su, Fengxi; Gong, Chang; Song, Erwei; Liu, Bodu; Liu, Qiang

    2015-10-13

    About 50-70% of breast cancers are estrogen receptor α (ERα) positive and most of them are sensitive to endocrine therapy including tamoxifen. However, one third of these patients will eventually develop resistance and relapse. We found that the expression of miR-15a and miR-16 were significantly decreased in tamoxifen resistant ER positive breast cancer cell lines. Exogenous expression of miR-15a/16 mimics re-sensitized resistant cells to tamoxifen by inhibiting Cyclin E1 and B cell lymphoma-2 (Bcl-2) to induce cell growth arrest and apoptosis respectively. Further, we identified that a repressive member of E2F family, E2F7, was responsible for the suppression of miR-15a/16 cluster by competing with E2F1 for E2F binding site at the promoter of their host gene DLEU2. Moreover, high expression of E2F7 is correlated with high risk of relapse and poor prognosis in breast cancer patients receiving tamoxifen treatment. Together, our results suggest that overexpression of E2F7 represses miR-15a/16 and then increases Cyclin E1 and Bcl-2 that result in tamoxifen resistance. E2F7 may be a valuable prognostic marker and a therapeutic target of tamoxifen resistance in breast cancer.

  14. E2F7 overexpression leads to tamoxifen resistance in breast cancer cells by competing with E2F1 at miR-15a/16 promoter

    PubMed Central

    Chu, Junjun; Zhu, Yinghua; Liu, Yujie; Sun, Lijuan; Lv, Xiaobin; Wu, Yanqin; Hu, Pengnan; Su, Fengxi; Gong, Chang; Song, Erwei; Liu, Bodu; Liu, Qiang

    2015-01-01

    About 50–70% of breast cancers are estrogen receptor α (ERα) positive and most of them are sensitive to endocrine therapy including tamoxifen. However, one third of these patients will eventually develop resistance and relapse. We found that the expression of miR-15a and miR-16 were significantly decreased in tamoxifen resistant ER positive breast cancer cell lines. Exogenous expression of miR-15a/16 mimics re-sensitized resistant cells to tamoxifen by inhibiting Cyclin E1 and B cell lymphoma-2 (Bcl-2) to induce cell growth arrest and apoptosis respectively. Further, we identified that a repressive member of E2F family, E2F7, was responsible for the suppression of miR-15a/16 cluster by competing with E2F1 for E2F binding site at the promoter of their host gene DLEU2. Moreover, high expression of E2F7 is correlated with high risk of relapse and poor prognosis in breast cancer patients receiving tamoxifen treatment. Together, our results suggest that overexpression of E2F7 represses miR-15a/16 and then increases Cyclin E1 and Bcl-2 that result in tamoxifen resistance. E2F7 may be a valuable prognostic marker and a therapeutic target of tamoxifen resistance in breast cancer. PMID:26397135

  15. High-pressure synthesis of the layered iron oxyselenide BaF e2S e2O with strong magnetic anisotropy

    NASA Astrophysics Data System (ADS)

    Takeiri, Fumitaka; Matsumoto, Yuki; Yamamoto, Takafumi; Hayashi, Naoaki; Li, Zhi; Tohyama, Takami; Tassel, Cédric; Ritter, Clemens; Narumi, Yasuo; Hagiwara, Masayuki; Kageyama, Hiroshi

    2016-11-01

    Using a high-pressure reaction, we successfully synthesized BaF e2S e2O with a uniform stack of [F e2S e2O ] layers. Magnetic susceptibility, heat capacity, Mössbauer spectroscopy, and neutron-diffraction measurements revealed that BaF e2S e2O undergoes antiferromagnetic order at 106 K with a 2-k spin structure where each Fe moment points to a neighboring oxide anion. The same spin structure has been observed in the related iron oxyselenides but with a staggered stack of [F e2C h2O ] (where Ch represents chalcogen) layers (Ch =S ,Se ) . We propose that the strong uniaxial anisotropy inferred from the 2-k structure originates from spin-orbit coupling (SOC) induced by a trans -Fe O2S e4 octahedron, which provides a quasilinear coordination environment as often found in single molecule magnetic complexes. A first-principles calculation with inclusion of SOC supports the stabilization of the 2-k spin structure, giving an unquenched orbital momentum of 0.1 μB/Fe . The present paper provides an idea of how to design magnetic lattices of uniaxial anisotropy using oxychalcogenides and more generally mixed-anion compounds.

  16. Mechanisms of Estrogen Carcinogenesis: The Role of E2/E1- Quinone Metabolites Suggests New Approaches to Preventive Intervention – A Review

    PubMed Central

    Yager, James D.

    2014-01-01

    . Pretreatment with SFN decreased depurinating DNA adducts while increasing levels of 4-OCH3E1/2 and 4-OHE1/2-glutathione conjugates. Treatment of MCF-10F cells with E2 or 4-OH-E2 also caused increased depurinating DNA adducts and neoplastic transformation while pretreatment with resveratrol caused a reduction in adduct levels and neoplastic transformation. Increased levels of estrogen-quinone conjugates and DNA adducts have also been detected in urine of women at increased risk for and with breast cancer. These observations support the notion that targeting the estrogen/estrone metabolism pathway may be another way to reduce breast cancer risk. PMID:25159108

  17. Investigation of EO transition rates

    NASA Astrophysics Data System (ADS)

    Colvin, G. G.; Schreckenbach, K.

    1985-01-01

    Basic ideas on the nature of electric monopole transitions and their experimental realisation are presented. Some feeling for the sensitivity obtainable for X=B(EO)/B(E2) ratios are discussed. Examples of measurements performed using the electron spectrometer BILL are described to demonstrate their relevance in testing nuclei models. These include even-even and odd-even nuclei such as nuclei close to Z=50, rare-earth nuclei, Pt-Os isotopes and the actinides.

  18. Regulation of human genome expression and RNA splicing by human papillomavirus 16 E2 protein.

    PubMed

    Gauson, Elaine J; Windle, Brad; Donaldson, Mary M; Caffarel, Maria M; Dornan, Edward S; Coleman, Nicholas; Herzyk, Pawel; Henderson, Scott C; Wang, Xu; Morgan, Iain M

    2014-11-01

    Human papillomavirus 16 (HPV16) is causative in human cancer. The E2 protein regulates transcription from and replication of the viral genome; the role of E2 in regulating the host genome has been less well studied. We have expressed HPV16 E2 (E2) stably in U2OS cells; these cells tolerate E2 expression well and gene expression analysis identified 74 genes showing differential expression specific to E2. Analysis of published gene expression data sets during cervical cancer progression identified 20 of the genes as being altered in a similar direction as the E2 specific genes. In addition, E2 altered the splicing of many genes implicated in cancer and cell motility. The E2 expressing cells showed no alteration in cell growth but were altered in cell motility, consistent with the E2 induced altered splicing predicted to affect this cellular function. The results present a model system for investigating E2 regulation of the host genome.

  19. The banana E2 gene family: Genomic identification, characterization, expression profiling analysis.

    PubMed

    Dong, Chen; Hu, Huigang; Jue, Dengwei; Zhao, Qiufang; Chen, Hongliang; Xie, Jianghui; Jia, Liqiang

    2016-04-01

    The E2 is at the center of a cascade of Ub1 transfers, and it links activation of the Ub1 by E1 to its eventual E3-catalyzed attachment to substrate. Although the genome-wide analysis of this family has been performed in some species, little is known about analysis of E2 genes in banana. In this study, 74 E2 genes of banana were identified and phylogenetically clustered into thirteen subgroups. The predicted banana E2 genes were distributed across all 11 chromosomes at different densities. Additionally, the E2 domain, gene structure and motif compositions were analyzed. The expression of all of the banana E2 genes was analyzed in the root, stem, leaf, flower organs, five stages of fruit development and under abiotic stresses. All of the banana E2 genes, with the exception of few genes in each group, were expressed in at least one of the organs and fruit developments, which indicated that the E2 genes might involve in various aspects of the physiological and developmental processes of the banana. Quantitative RT-PCR (qRT-PCR) analysis identified that 45 E2s under drought and 33 E2s under salt were induced. To the best of our knowledge, this report describes the first genome-wide analysis of the banana E2 gene family, and the results should provide valuable information for understanding the classification, cloning and putative functions of this family.

  20. EWS-FLI1 employs an E2F switch to drive target gene expression

    PubMed Central

    Schwentner, Raphaela; Papamarkou, Theodore; Kauer, Maximilian O.; Stathopoulos, Vassilios; Yang, Fan; Bilke, Sven; Meltzer, Paul S.; Girolami, Mark; Kovar, Heinrich

    2015-01-01

    Cell cycle progression is orchestrated by E2F factors. We previously reported that in ETS-driven cancers of the bone and prostate, activating E2F3 cooperates with ETS on target promoters. The mechanism of target co-regulation remained unknown. Using RNAi and time-resolved chromatin-immunoprecipitation in Ewing sarcoma we report replacement of E2F3/pRB by constitutively expressed repressive E2F4/p130 complexes on target genes upon EWS-FLI1 modulation. Using mathematical modeling we interrogated four alternative explanatory models for the observed EWS-FLI1/E2F3 cooperation based on longitudinal E2F target and regulating transcription factor expression analysis. Bayesian model selection revealed the formation of a synergistic complex between EWS-FLI1 and E2F3 as the by far most likely mechanism explaining the observed kinetics of E2F target induction. Consequently we propose that aberrant cell cycle activation in Ewing sarcoma is due to the de-repression of E2F targets as a consequence of transcriptional induction and physical recruitment of E2F3 by EWS-FLI1 replacing E2F4 on their target promoters. PMID:25712098

  1. EWS-FLI1 employs an E2F switch to drive target gene expression.

    PubMed

    Schwentner, Raphaela; Papamarkou, Theodore; Kauer, Maximilian O; Stathopoulos, Vassilios; Yang, Fan; Bilke, Sven; Meltzer, Paul S; Girolami, Mark; Kovar, Heinrich

    2015-03-11

    Cell cycle progression is orchestrated by E2F factors. We previously reported that in ETS-driven cancers of the bone and prostate, activating E2F3 cooperates with ETS on target promoters. The mechanism of target co-regulation remained unknown. Using RNAi and time-resolved chromatin-immunoprecipitation in Ewing sarcoma we report replacement of E2F3/pRB by constitutively expressed repressive E2F4/p130 complexes on target genes upon EWS-FLI1 modulation. Using mathematical modeling we interrogated four alternative explanatory models for the observed EWS-FLI1/E2F3 cooperation based on longitudinal E2F target and regulating transcription factor expression analysis. Bayesian model selection revealed the formation of a synergistic complex between EWS-FLI1 and E2F3 as the by far most likely mechanism explaining the observed kinetics of E2F target induction. Consequently we propose that aberrant cell cycle activation in Ewing sarcoma is due to the de-repression of E2F targets as a consequence of transcriptional induction and physical recruitment of E2F3 by EWS-FLI1 replacing E2F4 on their target promoters.

  2. The swine CD81 enhances E2-based DNA vaccination against classical swine fever.

    PubMed

    Li, Wenliang; Mao, Li; Zhou, Bin; Liu, Xia; Yang, Leilei; Zhang, Wenwen; Jiang, Jieyuan

    2015-07-09

    Classical swine fever (CSF) is a highly contagious and economically important viral disease that affects the pig industry worldwide. The glycoprotein E2 of CSFV can induce neutralizing antibodies and protective immunity, and is widely used for novel vaccine development. The objective of this study was to explore whether a tetraspanin molecule CD81 could improve the immune responses of an E2-based DNA vaccine. Plasmids pVAX-CD81, pVAX-E2 and pVAX-CD81-E2 were constructed and the expression of target proteins was confirmed in BHK-21 cells by indirect immunofluorescence assay. BALB/c mice were divided into 5 groups and immunized with different plasmids (pVAX-E2, pVAX-CD81-E2, pVAX-E2+pVAX-CD81, pVAX-CD81 and PBS) three times with two weeks interval. The results showed that the introduction of CD81 promoted higher humoral and cellular immune responses than E2 expression alone (P<0.05). In addition, immunization with pVAX-CD81-E2 induced stronger immune responses than pVAX-E2+pVAX-CD81. Furthermore, four groups of pigs were immunized with pVAX-E2, pVAX-CD81-E2, pVAX-CD81 and PBS, respectively. Humoral and cellular immune responses detection showed similar results with those in mice. Compared to pVAX-E2, pVAX-CD81-E2 induced higher titers of neutralizing antibodies after viral challenge and conferred stronger protection. These results confirmed the capacity of swine CD81 enhancing the humoral and cellular responses with an adjuvant effect on CSFV DNA vaccine. This is the first report demonstrating the adjuvant effect of CD81 to enhance the DNA vaccination for swine pathogen.

  3. Interaction of L-SIGN with hepatitis C virus envelope protein E2 up-regulates Raf-MEK-ERK pathway.

    PubMed

    Zhao, Lan-Juan; Wang, Wen; Ren, Hao; Qi, Zhong-Tian

    2013-07-01

    Liver/lymph node-specific intercellular adhesion molecule-3-grabbing integrin (L-SIGN) facilitates hepatitis C virus (HCV) infection through interaction with HCV envelope protein E2. Signaling events triggered by the E2 via L-SIGN are poorly understood. Here, kinase cascades of Raf-MEK-ERK pathway were defined upon the E2 treatment in NIH3T3 cells with stable expression of L-SIGN. The E2 bound to the cells through interaction with L-SIGN and such binding subsequently resulted in phosphorylation and activation of Raf, MEK, and ERK. Blockage of L-SIGN with antibody against L-SIGN reduced the E2-induced phosphorylation of Raf, MEK, and ERK. In the cells infected with cell culture-derived HCV, phosphorylation of these kinases was enhanced by the E2. Up-regulation of Raf-MEK-ERK pathway by HCV E2 via L-SIGN provides new insights into signaling cascade of L-SIGN, and might be a potential target for control and prevention of HCV infection.

  4. A Single-Amino-Acid Polymorphism in Chikungunya Virus E2 Glycoprotein Influences Glycosaminoglycan Utilization

    PubMed Central

    Silva, Laurie A.; Khomandiak, Solomiia; Ashbrook, Alison W.; Weller, Romy; Heise, Mark T.; Morrison, Thomas E.

    2014-01-01

    ABSTRACT Chikungunya virus (CHIKV) is a reemerging arbovirus responsible for outbreaks of infection throughout Asia and Africa, causing an acute illness characterized by fever, rash, and polyarthralgia. Although CHIKV infects a broad range of host cells, little is known about how CHIKV binds and gains access to the target cell interior. In this study, we tested whether glycosaminoglycan (GAG) binding is required for efficient CHIKV replication using CHIKV vaccine strain 181/25 and clinical isolate SL15649. Preincubation of strain 181/25, but not SL15649, with soluble GAGs resulted in dose-dependent inhibition of infection. While parental Chinese hamster ovary (CHO) cells are permissive for both strains, neither strain efficiently bound to or infected mutant CHO cells devoid of GAG expression. Although GAGs appear to be required for efficient binding of both strains, they exhibit differential requirements for GAGs, as SL15649 readily infected cells that express excess chondroitin sulfate but that are devoid of heparan sulfate, whereas 181/25 did not. We generated a panel of 181/25 and SL15649 variants containing reciprocal amino acid substitutions at positions 82 and 318 in the E2 glycoprotein. Reciprocal exchange at residue 82 resulted in a phenotype switch; Gly82 results in efficient infection of mutant CHO cells but a decrease in heparin binding, whereas Arg82 results in reduced infectivity of mutant cells and an increase in heparin binding. These results suggest that E2 residue 82 is a primary determinant of GAG utilization, which likely mediates attenuation of vaccine strain 181/25. IMPORTANCE Chikungunya virus (CHIKV) infection causes a debilitating rheumatic disease that can persist for months to years, and yet there are no licensed vaccines or antiviral therapies. Like other alphaviruses, CHIKV displays broad tissue tropism, which is thought to be influenced by virus-receptor interactions. In this study, we determined that cell-surface glycosaminoglycans are

  5. The evolutionary history of the E2F and DEL genes in Viridiplantae.

    PubMed

    Rauber, Rafael; Cabreira, Caroline; de Freitas, Loreta Brandão; Turchetto-Zolet, Andreia Carina; Margis-Pinheiro, Marcia

    2016-06-01

    The E2 promoter binding factor (E2F) proteins are present in almost all eukaryotic organisms and are essential to control several processes, such as the cell cycle progression, cell division, DNA replication, and apoptosis. The E2F family comprises two different types of proteins: the typical E2Fs and atypical E2Fs, which differ structurally and have specific functions. The E2F gene family was described for the first time in plants in 1999, and since then several studies have focused on the functional aspects, but the evolutionary history of this gene family is still unknown. Here, we investigated the evolutionary history of the E2F gene family in plants. Our findings suggest that E2F proteins arose early after the emergence of the eukaryotic species, while DEL proteins appear to have arisen before the metazoan and plants origin probably through a partial duplication of an ancient E2F protein. Our data also suggest that E2Fs activators and repressors appeared twice during evolution, once in the metazoan lineage and again in the embryophyte lineage.

  6. E2f8 mediates tumor suppression in postnatal liver development

    PubMed Central

    Kent, Lindsey N.; Rakijas, Jessica B.; Pandit, Shusil K.; Westendorp, Bart; Chen, Hui-Zi; Huntington, Justin T.; Tang, Xing; Bae, Sooin; Srivastava, Arunima; Senapati, Shantibhusan; Martin, Chelsea K.; Cuitino, Maria C.; Perez, Miguel; Clouse, Julian M.; Chokshi, Veda; Shinde, Neelam; Kladney, Raleigh; Sun, Daokun; Perez-Castro, Antonio; Matondo, Ramadhan B.; Nantasanti, Sathidpak; Mokry, Michal; Machiraju, Raghu; Fernandez, Soledad; Rosol, Thomas J.; Pohar, Kamal S.; Pipas, James M.; Schmidt, Carl R.; de Bruin, Alain

    2016-01-01

    E2F-mediated transcriptional repression of cell cycle–dependent gene expression is critical for the control of cellular proliferation, survival, and development. E2F signaling also interacts with transcriptional programs that are downstream of genetic predictors for cancer development, including hepatocellular carcinoma (HCC). Here, we evaluated the function of the atypical repressor genes E2f7 and E2f8 in adult liver physiology. Using several loss-of-function alleles in mice, we determined that combined deletion of E2f7 and E2f8 in hepatocytes leads to HCC. Temporal-specific ablation strategies revealed that E2f8’s tumor suppressor role is critical during the first 2 weeks of life, which correspond to a highly proliferative stage of postnatal liver development. Disruption of E2F8’s DNA binding activity phenocopied the effects of an E2f8 null allele and led to HCC. Finally, a profile of chromatin occupancy and gene expression in young and tumor-bearing mice identified a set of shared targets for E2F7 and E2F8 whose increased expression during early postnatal liver development is associated with HCC progression in mice. Increased expression of E2F8-specific target genes was also observed in human liver biopsies from HCC patients compared to healthy patients. In summary, these studies suggest that E2F8-mediated transcriptional repression is a critical tumor suppressor mechanism during postnatal liver development. PMID:27454291

  7. E2F in vivo binding specificity: Comparison of consensus versus nonconsensus binding sites

    PubMed Central

    Rabinovich, Alina; Jin, Victor X.; Rabinovich, Roman; Xu, Xiaoqin; Farnham, Peggy J.

    2008-01-01

    We have previously shown that most sites bound by E2F family members in vivo do not contain E2F consensus motifs. However, differences between in vivo target sites that contain or lack a consensus E2F motif have not been explored. To understand how E2F binding specificity is achieved in vivo, we have addressed how E2F family members are recruited to core promoter regions that lack a consensus motif and are excluded from other regions that contain a consensus motif. Using chromatin immunoprecipitation coupled with DNA microarray analysis (ChIP-chip) assays, we have shown that the predominant factors specifying whether E2F is recruited to an in vivo binding site are (1) the site must be in a core promoter and (2) the region must be utilized as a promoter in that cell type. We have tested three models for recruitment of E2F to core promoters lacking a consensus site, including (1) indirect recruitment, (2) looping to the core promoter mediated by an E2F bound to a distal motif, and (3) assisted binding of E2F to a site that weakly resembles an E2F motif. To test these models, we developed a new in vivo assay, termed eChIP, which allows analysis of transcription factor binding to isolated fragments. Our findings suggest that in vivo (1) a consensus motif is not sufficient to recruit E2Fs, (2) E2Fs can bind to isolated regions that lack a consensus motif, and (3) binding can require regions other than the best match to the E2F motif. PMID:18836037

  8. Early neutralizing IgG response to Chikungunya virus in infected patients targets a dominant linear epitope on the E2 glycoprotein

    PubMed Central

    Kam, Yiu-Wing; Lum, Fok-Moon; Teo, Teck-Hui; Lee, Wendy W L; Simarmata, Diane; Harjanto, Sumitro; Chua, Chong-Long; Chan, Yoke-Fun; Wee, Jin-Kiat; Chow, Angela; Lin, Raymond T P; Leo, Yee-Sin; Le Grand, Roger; Sam, I-Ching; Tong, Joo-Chuan; Roques, Pierre; Wiesmüller, Karl-Heinz; Rénia, Laurent; Rötzschke, Olaf; Ng, Lisa F P

    2012-01-01

    Chikungunya virus (CHIKV) and related arboviruses have been responsible for large epidemic outbreaks with serious economic and social impact. The immune mechanisms, which control viral multiplication and dissemination, are not yet known. Here, we studied the antibody response against the CHIKV surface antigens in infected patients. With plasma samples obtained during the early convalescent phase, we showed that the naturally-acquired IgG response is dominated by IgG3 antibodies specific mostly for a single linear epitope ‘E2EP3’. E2EP3 is located at the N-terminus of the E2 glycoprotein and prominently exposed on the viral envelope. E2EP3-specific antibodies are neutralizing and their removal from the plasma reduced the CHIKV-specific antibody titer by up to 80%. Screening of E2EP3 across different patient cohorts and in non-human primates demonstrated the value of this epitope as a good serology detection marker for CHIKV infection already at an early stage. Mice vaccinated by E2EP3 peptides were protected against CHIKV with reduced viremia and joint inflammation, providing a pre-clinical basis for the design of effective vaccine against arthralgia-inducing CHIKV and other alphaviruses. PMID:22389221

  9. Hyperforin, an Anti-Inflammatory Constituent from St. John's Wort, Inhibits Microsomal Prostaglandin E(2) Synthase-1 and Suppresses Prostaglandin E(2) Formation in vivo.

    PubMed

    Koeberle, Andreas; Rossi, Antonietta; Bauer, Julia; Dehm, Friederike; Verotta, Luisella; Northoff, Hinnak; Sautebin, Lidia; Werz, Oliver

    2011-01-01

    The acylphloroglucinol hyperforin (Hyp) from St. John's wort possesses anti-inflammatory and anti-carcinogenic properties which were ascribed among others to the inhibition of 5-lipoxygenase. Here, we investigated whether Hyp also interferes with prostanoid generation in biological systems, particularly with key enzymes participating in prostaglandin (PG)E(2) biosynthesis, i.e., cyclooxygenases (COX)-1/2 and microsomal PGE(2) synthase (mPGES)-1 which play key roles in inflammation and tumorigenesis. Similar to the mPGES-1 inhibitors MK-886 and MD-52, Hyp significantly suppressed PGE(2) formation in whole blood assays starting at 0.03-1 μM, whereas the concomitant generation of COX-derived 12(S)-hydroxy-5-cis-8,10-trans-heptadecatrienoic acid, thromboxane B(2), and 6-keto PGF(1α) was not significantly suppressed up to 30 μM. In cell-free assays, Hyp efficiently blocked the conversion of PGH(2) to PGE(2) mediated by mPGES-1 (IC(50) = 1 μM), and isolated COX enzymes were not (COX-2) or hardly (COX-1) suppressed. Intraperitoneal (i.p.) administration of Hyp (4 mg kg(-1)) to rats impaired exudate volume and leukocyte numbers in carrageenan-induced pleurisy associated with reduced PGE(2) levels, and Hyp (given i.p.) inhibited carrageenan-induced mouse paw edema formation (ED(50) = 1 mg kg(-1)) being superior over indomethacin (ED(50) = 5 mg kg(-1)). We conclude that the suppression of PGE(2) biosynthesis in vitro and in vivo by acting on mPGES-1 critically contributes to the anti-inflammatory efficiency of Hyp.

  10. Structural and Electronic Properties of Reduced Transition Metal Oxide Clusters, M 3 O 8 and M 3 O 8 - (M = Cr, W), from Photoelectron Spectroscopy and Quantum Chemical Calculations

    SciTech Connect

    Li, Shenggang; Zhai, Hua-Jin; Wang, Lai-Sheng; Dixon, David A.

    2009-09-28

    We report a comparative study of reduced transition metal oxide clusters, M₃O₈⁻ (M = Cr, W) anions and their neutrals, via anion photoelectron spectroscopy (PES) and density functional theory (DFT) and molecular orbital theory (CCSD(T)) calculations. Well-resolved PES spectra are obtained for M₃O₈⁻ (M = Cr, W) at 193 and 157 nm photon energies. Different PES spectra are observed for M = Cr versus M = W. ExtensiveDFT and CCSD(T) calculations are performed to locate the ground and low-lying excited states for the neutrals and anions. The ground states of Cr₃O₈ and Cr₃O₈⁻ are predicted to be the ³B₂ and ⁴B₂ states of a C₂v structure, respectively, revealing ferromagnetic spin coupling for Cr 3d electrons. In contrast, the ground states of W₃O₈ and W₃O₈⁻ are predicted to be the ¹A' state (Cs symmetry) and the ²A₁ state (C₂v symmetry), respectively, showing metal-metal d-d bonding in the anion. The current cluster geometries are in qualitative agreement with prior DFT studies at the PBE level for M = Cr and the B3LYP level for M = W. The BP86 and PW91 functionals significantly outperform the B3LYP functional for the Cr species, in terms of relative energies, electron detachment energies, and electronic excitation energies, whereas the B3LYP functional is better for the W species. Accurate heats of formation for the ground states of M₃O₈ are calculated from the clustering energies and the heats of formation of MO₂ and MO₃. The energetics have been used to predict redox reaction thermochemistry.

  11. In aging, the vulnerability of rat brain mitochondria is enhanced due to reduced level of 2',3'-cyclic nucleotide-3'-phosphodiesterase (CNP) and subsequently increased permeability transition in brain mitochondria in old animals.

    PubMed

    Krestinina, Olga; Azarashvili, Tamara; Baburina, Yulia; Galvita, Anastasia; Grachev, Dmitry; Stricker, Rolf; Reiser, Georg

    2015-01-01

    Aging is accompanied by progressive dysfunction of mitochondria associated with a continuous decrease of their capacity to produce ATP. Mitochondria isolated from brain of aged animals show an increased mitochondrial permeability transition pore (mPTP) opening. We recently detected new regulators of mPTP function in brain mitochondria, the enzyme 2', 3'-cyclic nucleotide 3'-phosphodiesterase (CNP) and its substrates 2', 3'-cAMP and 2', 3'-cNADP, and the neuronal protein p42(IP4). Here, we compared parameters of mPTP opening in non-synaptic brain mitochondria isolated from young and old rats. In mitochondria from old rats (>18 months), mPTP opening occurred at a lower threshold of Ca(2+) concentration than in mitochondria from young rats (<3 months). mPTP opening in mitochondria from old rats was accelerated by 2', 3'-cAMP, which further lowered the threshold Ca(2+) concentration. In non-synaptic mitochondria from old rats, the CNP level was decreased by 34%. Lowering of the CNP level in non-synaptic mitochondria with aging was accompanied by decreased levels of voltage-dependent anion channel (VDAC; by 69%) and of p42(IP4) (by 59%). Thus, reduced levels of CNP in mitochondria could lead to a rise in the concentration of the mPTP promoter 2', 3'-cAMP. The level of CNP and p42(IP4) and, probably VDAC, might be essential for myelination and electrical activity of axons. We propose that in aging the reduction in the level of these proteins leads to mitochondrial dysfunction, in particular, to a decreased threshold Ca(2+) concentration to induce mPTP opening. This might represent initial steps of age-related mitochondrial dysfunction, resulting in myelin and axonal pathology.

  12. Revised and extended calculations of level energies, M1 and E2 radiative rates for highly charged tungsten ions from W57+ to W60+

    NASA Astrophysics Data System (ADS)

    Singh, Gajendra; Puri, Nitin K.

    2016-10-01

    We have applied systematically enlarged multiconfiguration Dirac-Fock wavefunctions using Grasp2K to calculate the transition energies, oscillator strengths and transition probabilities for fine structure M1 and E2 transitions between the low-lying levels of the 3s23p5, 3s23p4, 3s23p3 and 3s23p2 configurations of highly charged tungsten ions from {{{W}}}57+ to {{{W}}}60+. Large wavefunction expansions are applied to calculate the transition probabilities, which are indispensable for calculating various plasma parameters accurately. In the present calculations, our theoretical data agrees well with that obtained in precise electron beam ion trap measurements, and is therefore important for the identification of weak forbidden lines for plasma diagnostic applications.

  13. Transitional Care

    ERIC Educational Resources Information Center

    Naylor, Mary; Keating, Stacen A.

    2008-01-01

    Transitional care encompasses a broad range of services and environments designed to promote the safe and timely passage of patients between levels of health care and across care settings. High-quality transitional care is especially important for older adults with multiple chronic conditions and complex therapeutic regimens, as well as for their…

  14. Prostaglandin E2 negatively regulates AMP-activated protein kinase via protein kinase A signaling pathway.

    PubMed

    Funahashi, Koji; Cao, Xia; Yamauchi, Masako; Kozaki, Yasuko; Ishiguro, Naoki; Kambe, Fukushi

    2009-01-01

    We investigated possible involvement of prostaglandin (PG) E2 in regulation of AMP-activated protein kinase (AMPK). When osteoblastic MG63 cells were cultured in serum-deprived media, Thr-172 phosphorylation of AMPK alpha-subunit was markedly increased. Treatment of the cells with PGE2 significantly reduced the phosphorylation. Ser-79 phosphorylation of acetyl-CoA carboxylase, a direct target for AMPK, was also reduced by PGE2. On the other hand, PGE2 reciprocally increased Ser-485 phosphorylation of the alpha-subunit that could be associated with inhibition of AMPK activity. These effects of PGE2 were mimicked by PGE2 receptor EP2 and EP4 agonists and forskolin, but not by EP1 and EP3 agonists, and the effects were suppressed by an adenylate cyclase inhibitor SQ22536 and a protein kinase A inhibitor H89. Additionally, the PGE2 effects were duplicated in primary calvarial osteoblasts. Together, the present study demonstrates that PGE2 negatively regulates AMPK activity via activation of protein kinase A signaling pathway.

  15. Sulforaphane Inhibits Prostaglandin E2 Synthesis by Suppressing Microsomal Prostaglandin E Synthase 1

    PubMed Central

    Zhou, Jiping; Joplin, Denise G.; Cross, Janet V.; Templeton, Dennis J.

    2012-01-01

    Sulforaphane (SFN) is a dietary cancer preventive with incompletely characterized mechanism(s) of cancer prevention. Since prostaglandin E2 (PGE2) promotes cancer progression, we hypothesized that SFN may block PGE2 synthesis in cancer cells. We found that SFN indeed blocked PGE2 production in human A549 cancer cells not by inhibiting COX-2, but rather by suppressing the expression of microsomal prostaglandin E synthase (mPGES-1), the enzyme that directly synthesizes PGE2. We identified the Hypoxia Inducible Factor 1 alpha (HIF-1α) as the target of SFN-mediated mPGES-1 suppression. SFN suppressed HIF-1α protein expression and the presence of HIF-1α at the mPGES-1 promoter, resulting in reduced transcription of mPGES-1. Finally, SFN also reduced expression of mPGES-1 and PGE2 production in A549 xenograft tumors in mice. Together, these results point to the HIF-1α, mPGES-1 and PGE2 axis as a potential mediator of the anti-cancer effects of SFN, and illustrate the potential of SFN for therapeutic control of cancer and inflammation. Harmful side effects in patients taking agents that target the more upstream COX-2 enzyme render the downstream target mPGES-1 a significant target for anti-inflammatory therapy. Thus, SFN could prove to be an important therapeutic approach to both cancer and inflammation. PMID:23166763

  16. Cellular Transformation of Mouse Embryo Fibroblasts in the Absence of Activator E2Fs

    PubMed Central

    Gupta, Tushar; Sáenz Robles, Maria Teresa

    2015-01-01

    ABSTRACT The E2F family of transcription factors, broadly divided into activator and repressor E2Fs, regulates cell cycle genes. Current models indicate that activator E2Fs are necessary for cell cycle progression and tumorigenesis and are also required to mediate transformation induced by DNA tumor viruses. E2Fs are negatively regulated by the retinoblastoma (RB) family of tumor suppressor proteins, and virus-encoded oncogenes disrupt the RB-E2F repressor complexes. This results in the release of activator E2Fs and induction of E2F-dependent genes. In agreement, expression of large tumor T antigens (TAg) encoded by polyomaviruses in mammalian cells results in increased transcriptional levels of E2F target genes. In addition, tumorigenesis induced by transgenic expression of simian virus 40 (SV40) TAg in choroid plexus or intestinal villi requires at least one activator E2F. In contrast, we show that SV40 TAg-induced transformation in mouse embryonic fibroblasts is independent of activator E2Fs. This work, coupled with recent studies showing that proliferation in stem and progenitor cells is independent of activator E2Fs, suggests the presence of parallel pathways governing cell proliferation and tumorigenesis. IMPORTANCE The RB-E2F pathway is altered in many cancers and is also targeted by DNA tumor viruses. Viral oncoprotein action on RBs results in the release of activator E2Fs and upregulation of E2F target genes; thus, activator E2Fs are considered essential for normal and tumorigenic cell proliferation. However, we have observed that SV40 large T antigen can induce cell proliferation and transformation in the absence of activator E2Fs. Our results also suggest that TAg action on pRBs regulates both E2F-dependent and -independent pathways that govern proliferation. Thus, specific cell proliferation pathways affected by RB alterations in cancer may be a factor in tumor behavior and response to therapy. PMID:25717106

  17. Residue 82 of the Chikungunya Virus E2 Attachment Protein Modulates Viral Dissemination and Arthritis in Mice

    PubMed Central

    Ashbrook, Alison W.; Burrack, Kristina S.; Silva, Laurie A.; Montgomery, Stephanie A.; Heise, Mark T.; Morrison, Thomas E.

    2014-01-01

    ABSTRACT Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that has reemerged to cause profound epidemics of fever, rash, and arthralgia throughout sub-Saharan Africa, Southeast Asia, and the Caribbean. Like other arthritogenic alphaviruses, mechanisms of CHIKV pathogenesis are not well defined. Using the attenuated CHIKV strain 181/25 and virulent strain AF15561, we identified a residue in the E2 viral attachment protein that is a critical determinant of viral replication in cultured cells and pathogenesis in vivo. Viruses containing an arginine at E2 residue 82 displayed enhanced infectivity in mammalian cells but reduced infectivity in mosquito cells and diminished virulence in a mouse model of CHIKV disease. Mice inoculated with virus containing an arginine at this position exhibited reduced swelling at the site of inoculation with a concomitant decrease in the severity of necrosis in joint-associated tissues. Viruses containing a glycine at E2 residue 82 produced higher titers in the spleen and serum at early times postinfection. Using wild-type and glycosaminoglycan (GAG)-deficient Chinese hamster ovary (CHO) cell lines and soluble GAGs, we found that an arginine at residue 82 conferred greater dependence on GAGs for infection of mammalian cells. These data suggest that CHIKV E2 interactions with GAGs diminish dissemination to lymphoid tissue, establishment of viremia, and activation of inflammatory responses early in infection. Collectively, these results suggest a function for GAG utilization in regulating CHIKV tropism and host responses that contribute to arthritis. IMPORTANCE CHIKV is a reemerging alphavirus of global significance with high potential to spread into new, immunologically naive populations. The severity of CHIKV disease, particularly its propensity for chronic musculoskeletal manifestations, emphasizes the need for identification of genetic determinants that dictate CHIKV virulence in the host. To better understand mechanisms of

  18. Plant γH2AX foci are required for proper DNA DSB repair responses and colocalize with E2F factors.

    PubMed

    Lang, Julien; Smetana, Ondrej; Sanchez-Calderon, Lenin; Lincker, Frédéric; Genestier, Julie; Schmit, Anne-Catherine; Houlné, Guy; Chabouté, Marie-Edith

    2012-04-01

    Cellular responses to DNA double-strand breaks (DSBs) are linked in mammals and yeasts to the phosphorylated histones H2AX (γH2AX) repair foci which are multiproteic nuclear complexes responsible for DSB sensing and signalling. However, neither the components of these foci nor their role are yet known in plants. In this paper, we describe the effects of γH2AX deficiency in Arabidopsis thaliana plants challenged with DSBs in terms of genotoxic sensitivity and E2F-mediated transcriptional responses. We further establish the existence, restrictive to the G1/S transition, of specific DSB-induced foci containing tobacco E2F transcription factors, in both A. thaliana roots and BY-2 tobacco cells. These E2F foci partially colocalize with γH2AX foci while their formation is ataxia telangiectasia mutated (ATM)-dependent, requires the E2F transactivation domain with its retinoblastoma-binding site and is optimal in the presence of functional H2AXs. Overall, our results unveil a new interplay between plant H2AX and E2F transcriptional activators during the DSB response.

  19. Polymorphic genetic characterization of E2 gene of bovine viral diarrhea virus in China.

    PubMed

    Lang, Yifei; Gao, Shandian; Du, Junzheng; Shao, Junjun; Cong, Guozheng; Lin, Tong; Zhao, Furong; Liu, Lihong; Chang, Huiyun

    2014-12-05

    Bovine viral diarrhea virus (BVDV) is one of the wide distributed pathogenic viruses of livestock and wild animals worldwide. E2 glycoprotein is a major structural component of the BVDV virion and plays a key role in viral attachment to host cells and inducing immune responses against viral infection. In order to gain detailed information of the E2 coding region of BVDV circulating in China, 46 positive samples were tested by RT-PCR for the E2 coding region. The 1122 nt nucleotide sequences of full-length E2 were harvested and analyzed. The results suggested that full-length E2 was an ideal target for BVDV genotyping and divided the domestic BVDV isolates into 9 subgenotypes, namely BVDV-1a, -1b1, -1c, -1d, -1o, -1m, -1p, -1q and BVDV-2a, showing great diversity. The difference of nonsynonymous and synonymous substitution rates (dN-dS) inferred both positive and purifying selection of the E2. However, combination of positive and purifying selection at different points indicated purifying selection within the complete E2. Protein properties analysis based on glycosylation sites and epitope prediction demonstrated that the biological character of E2 among individual BVDV subgenotype was similar, but may alter due to amino acid changes. For the first time, the comprehensive collection of E2 sequences of Chinese BVDV isolates was elucidated, which would provide information for future vaccine design and BVD control in China.

  20. E2A is a transcriptional regulator of CD38 expression in chronic lymphocytic leukemia.

    PubMed

    Saborit-Villarroya, I; Vaisitti, T; Rossi, D; D'Arena, G; Gaidano, G; Malavasi, F; Deaglio, S

    2011-03-01

    CD38, a nucleotide-metabolizing ectoenzyme and a receptor, is a negative prognostic marker for chronic lymphocytic leukemia (CLL) patients. CD38 has a genetic polymorphism, with a C → G variation in a putative E-box located in a regulatory region. E2A, the predominant E-box factor in B lymphocytes, was found to be highly expressed by CD38(+) CLL patients. The highest CD38 levels scored by E2A(+)/G carrier patients suggested that E2A is (i) directly associated with CD38 expression, and that (ii) the binding of the transcription factor is influenced by the CD38 genotype. Chromatin immunoprecipitation indicated that E2A directly interacts with the CD38 regulatory region. Furthermore, E2A binding was stronger in the presence of the G allele. Experiments of E2A silencing led to a significant reduction of surface levels of CD38, confirming the working hypothesis. A direct functional interplay between E2A and CD38 was shown by exposing CLL cells to interleukin-2 and TLR-9 ligands, both inducers of CD38 expression. Under these conditions, CD38 upregulation was primarily conditioned by the presence of E2A and then by the G allele. The results of this study link E2A and CD38 expression within a common pathway, in which E-protein activity is required for the efficient induction of CD38 transcription.

  1. Characterization of the nuclear localization signal of high risk HPV16 E2 protein

    SciTech Connect

    Klucevsek, Kristin; Wertz, Mary; Lucchi, John; Leszczynski, Anna; Moroianu, Junona . E-mail: moroianu@bc.edu

    2007-03-30

    The E2 protein of high risk human papillomavirus type 16 (HPV16) contains an amino-terminal (N) domain, a hinge (H) region and a carboxyl-terminal (C) DNA-binding domain. Using enhanced green fluorescent protein (EGFP) fusions with full length E2 and E2 domains in transfection assays in HeLa cells, we found that the C domain is responsible for the nuclear localization of E2 in vivo, whereas the N and H domains do not contain additional nuclear localization signals (NLSs). Deletion analysis of EGFP-E2 and EGFP-cE2 determined that the C domain contains an {alpha} helix cNLS that overlaps with the DNA-binding region. Mutational analysis revealed that the arginine and lysine residues in this cNLS are essential for nuclear localization of HPV16 E2. Interestingly, these basic amino acid residues are well conserved among the E2 proteins of BPV-1 and some high risk HPV types but not in the low risk HPV types, suggesting that there are differences between the NLSs and corresponding nuclear import pathways between these E2 proteins.

  2. Structure and partial genomic sequence of the human E2F1 gene.

    PubMed

    Neuman, E; Sellers, W R; McNeil, J A; Lawrence, J B; Kaelin, W G

    1996-09-16

    The E2F family of transcription factors appears to play a critical role in the transcription of certain genes required for cell cycle progression. E2F1, the first cloned member of this family, is regulated during the cell cycle at the mRNA level by changes in transcription of the E2F1 gene and at the protein level by complex formation with proteins such as the retinoblastoma gene product (pRB), cyclin A and DP1. E2F1 can override a pRB-induced G1/S block and can behave as an oncogene in certain cells. E2F1 was cloned and was found to contain seven exons. The dinucleotides at the 5' and 3' splice sites of intron 4 do not agree with consensus splice site sequences. Fluorescence in situ hybridization localized E2F1 to chromosome 20q11. Knowledge of the organization of E2F1 may facilitate identification of additional E2F family members, as well as detection of E2F1 abnormalities in human tumors.

  3. Arginine methylation-dependent reader-writer interplay governs growth control by E2F-1.

    PubMed

    Zheng, Shunsheng; Moehlenbrink, Jutta; Lu, Yi-Chien; Zalmas, Lykourgos-Panagiotis; Sagum, Cari A; Carr, Simon; McGouran, Joanna F; Alexander, Leila; Fedorov, Oleg; Munro, Shonagh; Kessler, Benedikt; Bedford, Mark T; Yu, Qiang; La Thangue, Nicholas B

    2013-10-10

    The mechanisms that underlie and dictate the different biological outcomes of E2F-1 activity have yet to be elucidated. We describe the residue-specific methylation of E2F-1 by the asymmetric dimethylating protein arginine methyltransferase 1 (PRMT1) and symmetric dimethylating PRMT5 and relate the marks to different functional consequences of E2F-1 activity. Methylation by PRMT1 hinders methylation by PRMT5, which augments E2F-1-dependent apoptosis, whereas PRMT5-dependent methylation favors proliferation by antagonizing methylation by PRMT1. The ability of E2F-1 to prompt apoptosis in DNA damaged cells coincides with enhanced PRMT1 methylation. In contrast, cyclin A binding to E2F-1 impedes PRMT1 methylation and augments PRMT5 methylation, thus ensuring that E2F-1 is locked into its cell-cycle progression mode. The Tudor domain protein p100-TSN reads the symmetric methylation mark, and binding of p100-TSN downregulates E2F-1 apoptotic activity. Our results define an exquisite level of precision in the reader-writer interplay that governs the biological outcome of E2F-1 activity.

  4. Arginine methylation-dependent reader-writer interplay governs growth control by E2F-1

    PubMed Central

    Zheng, Shunsheng; Moehlenbrink, Jutta; Lu, Yi-Chien; Zalmas, Lykourgos-Panagiotis; Sagum, Cari A.; Carr, Simon; McGouran, Joanna F.; Alexander, Leila; Fedorov, Oleg; Munro, Shonagh; Kessler, Benedikt; Bedford, Mark T.; Yu, Qiang; La Thangue, Nicholas B.

    2014-01-01

    Summary The mechanisms that underlie and dictate the different biological outcomes of E2F-1 activity have yet to be elucidated. We describe the residue-specific methylation of E2F-1 by the asymmetric dimethylating protein arginine methyltransferase (PRMT) 1 and symmetric dimethylating PRMT5, and relate the marks to different functional consequences of E2F-1 activity. Methylation by PRMT1 hinders methylation by PRMT5, which augments E2F-1-dependent apoptosis, whereas PRMT5-dependent methylation favours proliferation by antagonising methylation by PRMT1. The ability of E2F-1 to prompt apoptosis in DNA damaged cells coincides with enhanced PRMT1 methylation. In contrast, cyclin A binding to E2F-1 impedes PRMT1 methylation and augments PRMT5 methylation, thus ensuring that E2F-1 is locked into its cell cycle progression mode. The Tudor domain protein p100-TSN reads the symmetric methylation mark, and binding of p100-TSN down-regulates E2F-1 apoptotic activity. Our results define an exquisite level of precision in the reader-writer interplay that governs the biological outcome of E2F-1 activity. PMID:24076217

  5. E2F1 transcription factor and its impact on growth factor and cytokine signaling.

    PubMed

    Ertosun, Mustafa Gokhan; Hapil, Fatma Zehra; Osman Nidai, Ozes

    2016-10-01

    E2F1 is a transcription factor involved in cell cycle regulation and apoptosis. The transactivation capacity of E2F1 is regulated by pRb. In its hypophosphorylated form, pRb binds and inactivates DNA binding and transactivating functions of E2F1. The growth factor stimulation of cells leads to activation of CDKs (cyclin dependent kinases), which in turn phosphorylate Rb and hyperphosphorylated Rb is released from E2F1 or E2F1/DP complex, and free E2F1 can induce transcription of several genes involved in cell cycle entry, induction or inhibition of apoptosis. Thus, growth factors and cytokines generally utilize E2F1 to direct cells to either fate. Furthermore, E2F1 regulates expressions of various cytokines and growth factor receptors, establishing positive or negative feedback mechanisms. This review focuses on the relationship between E2F1 transcription factor and cytokines (IL-1, IL-2, IL-3, IL-6, TGF-beta, G-CSF, LIF), growth factors (EGF, KGF, VEGF, IGF, FGF, PDGF, HGF, NGF), and interferons (IFN-α, IFN-β and IFN-γ).

  6. E2-25K SUMOylation inhibits proteasome for cell death during cerebral ischemia/reperfusion

    PubMed Central

    Jeong, Eun Il; Chung, Hae Won; Lee, Won Jea; Kim, Seo-Hyun; Kim, Hyunjoo; Choi, Seon-Guk; Jung, Yong-Keun

    2016-01-01

    Cerebral ischemia/reperfusion (I/R) causes brain damage accompanied by ubiquitin accumulation and impairment of proteasome activity. In this study, we report that E2-25K, an E2-conjugating enzyme, is SUMOylated during oxidative stress and regulates cerebral I/R-induced damage. Knockdown of E2-25K expression protects against oxygen/glucose deprivation and reoxygenation (OGD/R)-induced neuronal cell death, whereas ectopic expression of E2-25K stimulates it. Compared with the control mice, cerebral infarction lesions and behavioral/neurological disorders are ameliorated in E2-25K knockout mice during middle cerebral artery occlusion and reperfusion. In particular, E2-25K is SUMOylated at Lys14 under oxidative stress, OGD/R and I/R to prompt cell death. Further, E2-25K downregulates the proteasome subunit S5a to impair proteasome complex and thus restrain proteasome activity under oxidative stress. This proteasome inhibitory activity of E2-25K is dependent on its SUMOylation. These results suggest that E2-25K has a crucial role in oxidative stress and cerebral I/R-induced damage through inhibiting proteasome via its SUMOylation. PMID:28032866

  7. An Interaction between Human Papillomavirus 16 E2 and TopBP1 Is Required for Optimum Viral DNA Replication and Episomal Genome Establishment

    PubMed Central

    Donaldson, Mary M.; Mackintosh, Lorna J.; Bodily, Jason M.; Dornan, Edward S.; Laimins, Laimonis A.

    2012-01-01

    In human papillomavirus DNA replication, the viral protein E2 forms homodimers and binds to 12-bp palindromic DNA sequences surrounding the origin of DNA replication. Via a protein-protein interaction, it then recruits the viral helicase E1 to an A/T-rich origin of replication, whereupon a dihexamer forms, resulting in DNA replication initiation. In order to carry out DNA replication, the viral proteins must interact with host factors that are currently not all known. An attractive cellular candidate for regulating viral replication is TopBP1, a known interactor of the E2 protein. In mammalian DNA replication, TopBP1 loads DNA polymerases onto the replicative helicase after the G1-to-S transition, and this process is tightly cell cycle controlled. The direct interaction between E2 and TopBP1 would allow E2 to bypass this cell cycle control, resulting in DNA replication more than once per cell cycle, which is a requirement for the viral life cycle. We report here the generation of an HPV16 E2 mutant compromised in TopBP1 interaction in vivo and demonstrate that this mutant retains transcriptional activation and repression functions but has suboptimal DNA replication potential. Introduction of this mutant into a viral life cycle model results in the failure to establish viral episomes. The results present a potential new antiviral target, the E2-TopBP1 interaction, and increase our understanding of the viral life cycle, suggesting that the E2-TopBP1 interaction is essential. PMID:22973044

  8. Transition metals

    PubMed Central

    Rodrigo-Moreno, Ana; Poschenrieder, Charlotte; Shabala, Sergey

    2013-01-01

    Transition metals such as Iron (Fe) and Copper (Cu) are essential for plant cell development. At the same time, due their capability to generate hydroxyl radicals they can be potentially toxic to plant metabolism. Recent works on hydroxyl-radical activation of ion transporters suggest that hydroxyl radicals generated by transition metals could play an important role in plant growth and adaptation to imbalanced environments. In this mini-review, the relation between transition metals uptake and utilization and oxidative stress-activated ion transport in plant cells is analyzed, and a new model depicting both apoplastic and cytosolic mode of ROS signaling to plasma membrane transporters is suggested. PMID:23333964

  9. Effect of inhibition of prostaglandin E2 production on pancreatic infection in experimental acute pancreatitis

    PubMed Central

    Coelho, Ana Maria M.; Sampietre, Sandra; Patzina, Rosely; Jukemura, Jose; Cunha, Jose Eduardo M.; Machado, Marcel C.C.

    2007-01-01

    Objective. Acute pancreatitis is one the important causes of systemic inflammatory response syndrome (SIRS). SIRS results in gut barrier dysfunction that allows bacterial translocation and pancreatic infection to occur. Indomethacin has been used to reduce inflammatory process and bacterial translocation in experimental models. The purpose of this study was to determine the effect of inhibition of prostaglandin E2 (PGE2) production on pancreatic infection. Materials and methods. An experimental model of severe acute pancreatitis (AP) was utilized. The animals were divided into three groups: sham (surgical procedure without AP induction); pancreatitis (AP induction); and indomethacin (AP induction plus administration of 3 mg/kg of indomethacin). Serum levels of interleukin (IL)-6 and IL-10, PGE2, and tumor necrosis factor (TNF)-α were measured 2 h after the induction of AP. We analyzed the occurrence of pancreatic infection with bacterial cultures performed 24 h after the induction of AP. The occurrence of pancreatic infection (considered positive when the CFU/g was >105), pancreatic histologic analysis, and mortality rate were studied. Results. In spite of the reduction of IL-6, IL-10, and PGE2 levels in the indomethacin group, TNF-α level, bacterial translocation, and pancreatic infection were not influenced by administration of indomethacin. The inhibition of PGE2 production did not reduce pancreatic infection, histologic score, or mortality rate. Conclusion. The inhibition of PGE2 production was not able to reduce the occurrence of pancreatic infection and does not have any beneficial effect in this experimental model. Further investigations will be necessary to discover a specific inhibitor that would make it possible to develop an anti-inflammatory therapy. PMID:18345325

  10. Epigenetic involvement of Alien/ESET complex in thyroid hormone-mediated repression of E2F1 gene expression and cell proliferation

    SciTech Connect

    Hong, Wei; Li, Jinru; Wang, Bo; Chen, Linfeng; Niu, Wenyan; Yao, Zhi; Baniahmad, Aria

    2011-12-02

    Highlights: Black-Right-Pointing-Pointer Corepressor Alien interacts with histone methyltransferase ESET in vivo. Black-Right-Pointing-Pointer Alien/ESET complex is recruited to nTRE of T3-responsive gene by liganded TR{beta}1. Black-Right-Pointing-Pointer ESET-mediated H3K9 methylation is required for liganded TR{beta}1-repressed transcription. Black-Right-Pointing-Pointer ESET is involved in T3-repressed G1/S phase transition and proliferation. -- Abstract: The ligand-bound thyroid hormone receptor (TR) is known to repress via a negative TRE (nTRE) the expression of E2F1, a key transcription factor that controls the G1/S phase transition. Alien has been identified as a novel interacting factor of E2F1 and acts as a corepressor of E2F1. The detailed molecular mechanism by which Alien inhibits E2F1 gene expression remains unclear. Here, we report that the histone H3 lysine 9 (H3K9) methyltransferase (HMT) ESET is an integral component of the corepressor Alien complex and the Alien/ESET complex is recruited to both sites, the E2F1 and the nTRE site of the E2F1 gene while the recruitment to the negative thyroid hormone response element (nTRE) is induced by the ligand-bound TR{beta}1 within the E2F1 gene promoter. We show that, overexpression of ESET promotes, whereas knockdown of ESET releases, the inhibition of TR{beta}1-regulated gene transcription upon T3 stimulation; and H3K9 methylation is required for TR{beta}1-repressed transcription. Furthermore, depletion of ESET impairs thyroid hormone-repressed proliferation as well as the G1/S transition of the cell cycle. Taken together, our data indicate that ESET is involved in TR{beta}1-mediated transcription repression and provide a molecular basis of thyroid hormone-induced repression of proliferation.

  11. The E2F2 Transcription Factor Sustains Hepatic Glycerophospholipid Homeostasis in Mice

    PubMed Central

    Maldonado, Eduardo N.; Delgado, Igotz; Furland, Natalia E.; Buqué, Xabier; Iglesias, Ainhoa; Aveldaño, Marta I.; Zubiaga, Ana; Fresnedo, Olatz; Ochoa, Begoña

    2014-01-01

    Increasing evidence links metabolic signals to cell proliferation, but the molecular wiring that connects the two core machineries remains largely unknown. E2Fs are master regulators of cellular proliferation. We have recently shown that E2F2 activity facilitates the completion of liver regeneration after partial hepatectomy (PH) by regulating the expression of genes required for S-phase entry. Our study also revealed that E2F2 determines the duration of hepatectomy-induced hepatic steatosis. A transcriptomic analysis of normal adult liver identified “lipid metabolism regulation” as a major E2F2 functional target, suggesting that E2F2 has a role in lipid homeostasis. Here we use wild-type (E2F2+/+) and E2F2 deficient (E2F2−/−) mice to investigate the in vivo role of E2F2 in the composition of liver lipids and fatty acids in two metabolically different contexts: quiescence and 48-h post-PH, when cellular proliferation and anabolic demands are maximal. We show that liver regeneration is accompanied by large triglyceride and protein increases without changes in total phospholipids both in E2F2+/+ and E2F2−/− mice. Remarkably, we found that the phenotype of quiescent liver tissue from E2F2−/− mice resembles the phenotype of proliferating E2F2+/+ liver tissue, characterized by a decreased phosphatidylcholine to phosphatidylethanolamine ratio and a reprogramming of genes involved in generation of choline and ethanolamine derivatives. The diversity of fatty acids in total lipid, triglycerides and phospholipids was essentially preserved on E2F2 loss both in proliferating and non-proliferating liver tissue, although notable exceptions in inflammation-related fatty acids of defined phospholipid classes were detected. Overall, our results indicate that E2F2 activity sustains the hepatic homeostasis of major membrane glycerolipid components while it is dispensable for storage glycerolipid balance. PMID:25396754

  12. E2 conjugating enzyme selectivity and requirements for function of the E3 ubiquitin ligase CHIP.

    PubMed

    Soss, Sarah E; Yue, Yuanyuan; Dhe-Paganon, Sirano; Chazin, Walter J

    2011-06-17

    The transfer of ubiquitin (Ub) to a substrate protein requires a cascade of E1 activating, E2 conjugating, and E3 ligating enzymes. E3 Ub ligases containing U-box and RING domains bind both E2∼Ub conjugates and substrates to facilitate transfer of the Ub molecule. Although the overall mode of action of E3 ligases is well established, many of the mechanistic details that determine the outcome of ubiquitination are poorly understood. CHIP (carboxyl terminus of Hsc70-interacting protein) is a U-box E3 ligase that serves as a co-chaperone to heat shock proteins and is critical for the regulation of unfolded proteins in the cytosol. We have performed a systematic analysis of the interactions of CHIP with E2 conjugating enzymes and found that only a subset bind and function. Moreover, some E2 enzymes function in pairs to create products that neither create individually. Characterization of the products of these reactions showed that different E2 enzymes produce different ubiquitination products, i.e. that E2 determines the outcome of Ub transfer. Site-directed mutagenesis on the E2 enzymes Ube2D1 and Ube2L3 (UbcH5a and UbcH7) established that an SPA motif in loop 7 of E2 is required for binding to CHIP but is not sufficient for activation of the E2∼Ub conjugate and consequent ubiquitination activity. These data support the proposal that the E2 SPA motif provides specificity for binding to CHIP, whereas activation of the E2∼Ub conjugate is derived from other molecular determinants.

  13. E2F1 enhances glycolysis through suppressing Sirt6 transcription in cancer cells.

    PubMed

    Wu, Minghui; Seto, Edward; Zhang, Jingsong

    2015-05-10

    The fast proliferation of cancer cells requires reprogramming of its energy metabolism with aerobic glycolysis as a major energy source. Sirt6, a class III histone deacetylase, has been shown to down regulate glycolysis by inhibiting the expression of several key glycolytic genes. Based on the published study on the metabolic phenotype of E2F1 -/- mice and SIRT6 -/- mice, we hypothesize that E2F1 enhances glycolysis and inhibits the expression of Sirt6. Indeed, over-expressing of E2F1, but not its DNA binding deficient mutant, significantly enhanced glucose uptake and lactate production in bladder and prostate cancer cell lines. E2F1 over-expression also suppressed Sirt6 expression and function. Moreover, E2F1 directly bound to Sirt6 promoter and suppressed Sirt6 promoter activity under both normoxic and hypoxic culture conditions. E2F1 siRNA blocked the up-regulation of E2F1 under hypoxia, increased Sirt6 expression and decreased glycolysis compared to those of scrambled siRNA transected cells. Furthermore, HDAC1 deacetylated E2F1 and diminished its transcription suppression of Sirt6 promoter. Treatment with the HDAC inhibitor, trichostatin A (TSA), suppressed Sirt6 promoter activity with increased binding of acetylated E2F1 to Sirt6 promoter. Mutating the E2F1 binding site on the proximal Sirt6 promoter abolished the suppression of Sirt6 transcription by TSA. These data indicate a novel oncogenic role of E2F1, i.e. enhancing glycolysis by suppressing Sirt6 transcription.

  14. US NDC Modernization Iteration E2 Prototyping Report: OSD & PC Software Infrastructure

    SciTech Connect

    Prescott, Ryan; Marger, Bernard L.; Chiu, Ailsa

    2014-12-01

    During the second iteration of the US NDC Modernization Elaboration phase (E2), the SNL US NDC Modernization project team completed follow-on COTS surveys & exploratory prototyping related to the Object Storage & Distribution (OSD) mechanism, and the processing control software infrastructure. This report summarizes the E2 prototyping work.

  15. Insights into the mechanism of human papillomavirus E2-induced procaspase-8 activation and cell death

    NASA Astrophysics Data System (ADS)

    Singh, Nitu; Senapati, Sanjib; Bose, Kakoli

    2016-02-01

    High-risk human papillomavirus (HR-HPV) E2 protein, the master regulator of viral life cycle, induces apoptosis of host cell that is independent of its virus-associated regulatory functions. E2 protein of HR-HPV18 has been found to be involved in novel FADD-independent activation of caspase-8, however, the molecular basis of this unique non-death-fold E2-mediated apoptosis is poorly understood. Here, with an interdisciplinary approach that involves in silico, mutational, biochemical and biophysical probes, we dissected and characterized the E2-procasapse-8 binding interface. Our data demonstrate direct non-homotypic interaction of HPV18 E2 transactivation domain (TAD) with α2/α5 helices of procaspase-8 death effector domain-B (DED-B). The observed interaction mimics the homotypic DED-DED complexes, wherein the conserved hydrophobic motif of procaspase-8 DED-B (F122/L123) occupies a groove between α2/α3 helices of E2 TAD. This interaction possibly drives DED oligomerization leading to caspase-8 activation and subsequent cell death. Furthermore, our data establish a model for E2-induced apoptosis in HR-HPV types and provide important clues for designing E2 analogs that might modulate procaspase-8 activation and hence apoptosis.

  16. E2F and GATA switches turn off WD repeat domain 77 expression in differentiating cells

    PubMed Central

    Yu, Min; Wang, Ulrica; Wang, Zhengxin

    2017-01-01

    WD repeat domain 77 (WDR77) is expressed during earlier lung development when cells are rapidly proliferating and absent in adult lung. It is re-activated during lung tumorigenesis and is essential for lung cancer cell proliferation. Signaling pathways/molecules that control WDR77 gene expression are unknown. Promoter mapping, gel shift assay, and chromatin immunoprecipitation revealed that the WDR77 promoter contains bona fide response elements for E2F and GATA transcriptional factors as demonstrated in prostate cancer, lung cancer and erythroid cells as well as in mouse lung tissues. The WDR77 promoter is transactivated by E2F1, E2F3, GATA2, and GATA6 but suppressed by E2F6, GATA1 and GATA3 in prostate cancer PC3 cells. WDR77 expression is associated with the E2F1, E2F3, GATA2, and GATA6 occupancy on the WDR77 gene and while in contrast the E2F6, GATA2, and GATA3 occupancy is associated with the loss of WDR77 expression during the erythroid maturation and lung development. More importantly, the loss of WDR77 expression that resulted from E2F and GATA switches is required for cellular differentiation of erythroid and lung epithelial cells. In contrast, lung cancer cells avoid post-mitotic differentiation by sustaining WDR77 expression. Altogether, this work provides a novel molecular mechanism by which WDR77 is regulated during erythroid and lung development and lung tumorigenesis. PMID:27274086

  17. Rb inactivation leads to E2F1-mediated DNA double-strand break accumulation.

    PubMed

    Pickering, M T; Kowalik, T F

    2006-02-02

    Although it is unclear which cellular factor(s) is responsible for the genetic instability associated with initiating and sustaining cell transformation, it is known that many cancers have mutations that inactivate the Rb-mediated proliferation pathway. We show here that pRb inactivation and the resultant deregulation of one E2F family member, E2F1, leads to DNA double-strand break (DSB) accumulation in normal diploid human cells. These DSBs occur independent of Atm, p53, caspases, reactive oxygen species, and apoptosis. Moreover, E2F1 does not contribute to c-Myc-associated DSBs, indicating that the DSBs associated with these oncoproteins arise through distinct pathways. We also find E2F1-associated DSBs in an Rb mutated cancer cell line in the absence of an exogenous DSB stimulus. These basal, E2F1-associated DSBs are not observed in a p16(ink4a) inactivated cancer cell line that retains functional pRb, unless pRb is depleted. Thus, Rb status is key to regulating both the proliferation promoting functions associated with E2F and for preventing DNA damage accumulation if E2F1 becomes deregulated. Taken together, these data suggest that loss of Rb creates strong selective pressure, via DSB accumulation, for inactivating p53 mutations and that E2F1 contributes to the genetic instability associated with transformation and tumorigenesis.

  18. Structural analysis and evolution of specificity of the SUMO UFD E1-E2 interactions

    PubMed Central

    Liu, Bing; Lois, L. Maria; Reverter, David

    2017-01-01

    SUMO belongs to the ubiquitin-like family (UbL) of protein modifiers. SUMO is conserved among eukaryotes and is essential for the regulation of processes such as DNA damage repair, transcription, DNA replication and mitosis. UbL modification of proteins occurs via a specific enzymatic cascade formed by the crosstalk between the E1-activating enzyme, the E2-conjugating enzyme and the E3-ligase. An essential discrimination step in all UbL modifiers corresponds to the interaction between E1 and E2 enzymes, which is mediated by the recruitment of the E2 to the UFD domain (Ubiquitin-Fold Domain) of the E1 enzyme. To gain insights in the properties of this interface, we have compared the structures of the complexes between E1 UFD domain and E2 in human and yeast, revealing two alternative UFD platforms that interact with a conserved E2. Comparative sequence analysis of the E1 UFD domain indicates that the E2 binding region has been conserved across phylogenetic closely related species, in which higher sequence conservation can be found in the E2 binding region than in the entire UFD domain. These distinctive strategies for E1-E2 interactions through the UFD domain might be the consequence of a high selective pressure to ensure specificity of each modifier conjugation system. PMID:28165030

  19. Retinoblastoma protein (RB) interacts with E2F3 to control terminal differentiation of Sertoli cells.

    PubMed

    Rotgers, E; Rivero-Müller, A; Nurmio, M; Parvinen, M; Guillou, F; Huhtaniemi, I; Kotaja, N; Bourguiba-Hachemi, S; Toppari, J

    2014-06-05

    The retinoblastoma protein (RB) is essential for normal cell cycle control. RB function depends, at least in part, on interactions with the E2F family of DNA-binding transcription factors (E2Fs). To study the role of RB in the adult testis, a Sertoli cell (SC)-specific Rb knockout mouse line (SC-RbKO) was generated using the Cre/loxP recombination system. SC-RbKO mice exhibited an age-dependent testicular atrophy, impaired fertility, severe SC dysfunction, and spermatogenic defects. Removal of Rb in SC induced aberrant SC cycling, dedifferentiation, and apoptosis. Here we show that E2F3 is the only E2F expressed in mouse SCs and that RB interacts with E2F3 during mouse testicular development. In the absence of RB, the other retinoblastoma family members p107 and p130 began interacting with E2F3 in the adult testes. In vivo silencing of E2F3 partially restored the SC maturation and survival as well as spermatogenesis in the SC-RbKO mice. These results point to RB as a key regulator of SC function in adult mice and that the RB/E2F3 pathway directs SC maturation, cell cycle quiescence, and RB protects SC from apoptosis.

  20. 17 CFR 270.6e-2 - Exemptions for certain variable life insurance separate accounts.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... variable life insurance separate accounts. 270.6e-2 Section 270.6e-2 Commodity and Securities Exchanges...-2 Exemptions for certain variable life insurance separate accounts. (a) A separate account, and the... are derived solely from the sale of variable life insurance contracts as defined in paragraph...

  1. Insights into the mechanism of human papillomavirus E2-induced procaspase-8 activation and cell death

    PubMed Central

    Singh, Nitu; Senapati, Sanjib; Bose, Kakoli

    2016-01-01

    High-risk human papillomavirus (HR-HPV) E2 protein, the master regulator of viral life cycle, induces apoptosis of host cell that is independent of its virus-associated regulatory functions. E2 protein of HR-HPV18 has been found to be involved in novel FADD-independent activation of caspase-8, however, the molecular basis of this unique non-death-fold E2-mediated apoptosis is poorly understood. Here, with an interdisciplinary approach that involves in silico, mutational, biochemical and biophysical probes, we dissected and characterized the E2-procasapse-8 binding interface. Our data demonstrate direct non-homotypic interaction of HPV18 E2 transactivation domain (TAD) with α2/α5 helices of procaspase-8 death effector domain-B (DED-B). The observed interaction mimics the homotypic DED-DED complexes, wherein the conserved hydrophobic motif of procaspase-8 DED-B (F122/L123) occupies a groove between α2/α3 helices of E2 TAD. This interaction possibly drives DED oligomerization leading to caspase-8 activation and subsequent cell death. Furthermore, our data establish a model for E2-induced apoptosis in HR-HPV types and provide important clues for designing E2 analogs that might modulate procaspase-8 activation and hence apoptosis. PMID:26906543

  2. NRIP enhances HPV gene expression via interaction with either GR or E2

    SciTech Connect

    Chang, Szu-Wei; Lu, Pei-Yu; Guo, Jih-Huong; Tsai, Tzung-Chieh; Tsao, Yeou-Ping; Chen, Show-Li

    2012-02-05

    We previously identified a gene, nuclear receptor-interaction protein (NRIP), which functions as a transcription cofactor in glucocorticoid receptor (GR) and human papillomavirus E2 (HPV E2)-driven gene expression. Here, we comprehensively evaluated the role of NRIP in HPV-16 gene expression. NRIP acts as a transcription cofactor to enhance GR-regulated HPV-16 gene expression in the presence of hormone. NRIP also can form complex with E2 that caused NRIP-induced HPV gene expression via E2-binding sites in a hormone-independent manner. Furthermore, NRIP can associate with GR and E2 to form tri-protein complex to activate HPV gene expression via GRE, not the E2-binding site, in a hormone-dependent manner. These results indicate that NRIP and GR are viral E2-binding proteins and that NRIP regulates HPV gene expression via GRE and/or E2 binding site in the HPV promoter in a hormone-dependent or independent manner, respectively.

  3. Structural analysis and evolution of specificity of the SUMO UFD E1-E2 interactions.

    PubMed

    Liu, Bing; Lois, L Maria; Reverter, David

    2017-02-06

    SUMO belongs to the ubiquitin-like family (UbL) of protein modifiers. SUMO is conserved among eukaryotes and is essential for the regulation of processes such as DNA damage repair, transcription, DNA replication and mitosis. UbL modification of proteins occurs via a specific enzymatic cascade formed by the crosstalk between the E1-activating enzyme, the E2-conjugating enzyme and the E3-ligase. An essential discrimination step in all UbL modifiers corresponds to the interaction between E1 and E2 enzymes, which is mediated by the recruitment of the E2 to the UFD domain (Ubiquitin-Fold Domain) of the E1 enzyme. To gain insights in the properties of this interface, we have compared the structures of the complexes between E1 UFD domain and E2 in human and yeast, revealing two alternative UFD platforms that interact with a conserved E2. Comparative sequence analysis of the E1 UFD domain indicates that the E2 binding region has been conserved across phylogenetic closely related species, in which higher sequence conservation can be found in the E2 binding region than in the entire UFD domain. These distinctive strategies for E1-E2 interactions through the UFD domain might be the consequence of a high selective pressure to ensure specificity of each modifier conjugation system.

  4. NRIP enhances HPV gene expression via interaction with either GR or E2.

    PubMed

    Chang, Szu-Wei; Lu, Pei-Yu; Guo, Jih-Huong; Tsai, Tzung-Chieh; Tsao, Yeou-Ping; Chen, Show-Li

    2012-02-05

    We previously identified a gene, nuclear receptor-interaction protein (NRIP), which functions as a transcription cofactor in glucocorticoid receptor (GR) and human papillomavirus E2 (HPV E2)-driven gene expression. Here, we comprehensively evaluated the role of NRIP in HPV-16 gene expression. NRIP acts as a transcription cofactor to enhance GR-regulated HPV-16 gene expression in the presence of hormone. NRIP also can form complex with E2 that caused NRIP-induced HPV gene expression via E2-binding sites in a hormone-independent manner. Furthermore, NRIP can associate with GR and E2 to form tri-protein complex to activate HPV gene expression via GRE, not the E2-binding site, in a hormone-dependent manner. These results indicate that NRIP and GR are viral E2-binding proteins and that NRIP regulates HPV gene expression via GRE and/or E2 binding site in the HPV promoter in a hormone-dependent or independent manner, respectively.

  5. Functional characterization of the Sindbis virus E2 glycoprotein by transposon linker-insertion mutagenesis

    SciTech Connect

    Navaratnarajah, Chanakha K.; Kuhn, Richard J. . E-mail: kuhnr@purdue.edu

    2007-06-20

    The glycoprotein envelope of alphaviruses consists of two proteins, E1 and E2. E1 is responsible for fusion and E2 is responsible for receptor binding. An atomic structure is available for E1, but one for E2 has not been reported. In this study, transposon linker-insertion mutagenesis was used to probe the function of different domains of E2. A library of mutants, containing 19 amino acid insertions in the E2 glycoprotein sequence of the prototype alphavirus, Sindbis virus (SINV), was generated. Fifty-seven independent E2 insertions were characterized, of which more than half (67%) gave rise to viable virus. The wild-type-like mutants identify regions that accommodate insertions without perturbing virus production and can be used to insert targeting moieties to direct SINV to specific receptors. The defective and lethal mutants give insight into regions of E2 important for protein stability, transport to the cell membrane, E1-E2 contacts, and receptor binding.

  6. The transcription factors E2A and HEB act in concert to induce the expression of FOXO1 in the common lymphoid progenitor

    PubMed Central

    Welinder, Eva; Mansson, Robert; Mercer, Elinore M.; Bryder, David; Sigvardsson, Mikael; Murre, Cornelis

    2011-01-01

    Recent studies have identified a number of transcriptional regulators, including E proteins, EBF1, FOXO1, and PAX5, that act together to orchestrate the B-cell fate. However, it still remains unclear as to how they are linked at the earliest stages of B-cell development. Here, we show that lymphocyte development in HEB-ablated mice exhibits a partial developmental arrest, whereas B-cell development in E2A+/−HEB−/− mice is completely blocked at the LY6D− common lymphoid progenitor stage. We show that the transcription signatures of E2A- and HEB-ablated common lymphoid progenitors significantly overlap. Notably, we found that Foxo1 expression was substantially reduced in the LY6D− HEB- and E2A-deficient cells. Finally, we show that E2A binds to enhancer elements across the FOXO1 locus to activate Foxo1 expression, linking E2A and FOXO1 directly in a common pathway. In summary, the data indicate that the earliest event in B-cell specification involves the induction of FOXO1 expression and requires the combined activities of E2A and HEB. PMID:21972416

  7. LIMD1 antagonizes E2F1 activity and cell cycle progression by enhancing Rb function in cancer cells.

    PubMed

    Mayank, Adarsh K; Sharma, Shipra; Deshwal, Ravi K; Lal, Sunil K

    2014-07-01

    Tumour suppressor genes restrain inappropriate cell growth and division, as well as stimulate cell death to maintain tissue homeostasis. Loss of function leads to abnormal cellular behaviour, including hyperproliferation of cell and perturbation of cell cycle regulation. LIMD1 is a tumour suppressor gene located at chromosome 3p21.3, a region commonly deleted in many solid malignancies. LIMD1 interacts with retinoblastoma (Rb) and is involved in Rb-mediated downregulation of E2F1-target genes. However, the role of LIMD1 in cell cycle regulation remains unclear. We propose that LIMD1 induces cell cycle arrest, utilising Rb-E2F1 axis, and show that ectopic expression of LIMD1 in A549 cells results in hypo-phosphorylation that potentiates Rb function, which correlates with downregulation of E2F1. In agreement with these observations, LIMD1 overexpression retards cell cycle progression and blocks S-phase entry, as cells accumulate in G0/G1 phase and have reduced incorporation of BrdU. Most significantly, LIMD1-dependent effects on Rb function and cell cycle are reversed on depletion of endogenous LIMD1, underscoring its centrality in Rb-mediated cell cycle regulation. Hence, our findings provide new insight into cell cycle control by Rb-LIMD1 nexus.

  8. Draft genome sequence of Lactobacillus plantarum strains E2C2 and E2C5 isolated from human stool culture.

    PubMed

    Suryavanshi, Mangesh V; Paul, Dhiraj; Doijad, Swapnil P; Bhute, Shrikant S; Hingamire, Tejashri B; Gune, Rahul P; Shouche, Yogesh S

    2017-01-01

    Probiotic Lactobacillus species offer various health benefits, thus have been employed in treatment and prevention of various diseases. Due to the differences in the isolation source and the site of action, most of the lactobacilli tested in-vitro for probiotics properties fail to extend similar effects in-vivo. Consequently, the search of autochthonous, efficacious and probably population specific probiotics is a high priority in the probiotics research. In this regards, whole genome sequencing of as many Lactobacillus as possible will help to deepen our understanding of biology and their health effects. Here, we provide the genomic insights of two coherent oxalic acid tolerant Lactobacillus species (E2C2 and E2C5) isolated from two different healthy human gut flora. These two isolates were found to have higher tolerance towards oxalic acid (300 mM sodium oxalate). The draft genome of strain E2C2 consists of 3,603,563 bp with 3289 protein-coding genes, 94 RNA genes, and 43.99% GC content, while E2C5 contained 3,615,168 bp, 3293 coding genes (93.4% of the total genes), 95 RNA genes and 43.97% GC content. Based on 16S rRNA gene sequence analysis followed by in silico DNA-DNA hybridization studies, both the strains were identified as Lactobacillus plantarum belonging to family Lactobacillaceae within the phylum Firmicutes. Both the strains were genomically identical, sharing 99.99% CDS that showed 112 SNPs. Both the strains also exhibited deconjugation activity for the bile salts while genome analysis revealed that the L. plantarum strains E2C2 and E2C5 also have the ability to produce vitamins, biotin, alpha- and beta- glucosidase suggesting potential probiotic activities of the isolates. The description presented here is based on the draft genomes of strains E2C2 and E2C5 which are submitted to GenBank under the accession numbers LSST00000000.1 and LTCD00000000.1, respectively.

  9. Equilibrium dissociation and unfolding of the dimeric human papillomavirus strain-16 E2 DNA-binding domain.

    PubMed Central

    Mok, Y. K.; de Prat Gay, G.; Butler, P. J.; Bycroft, M.

    1996-01-01

    The equilibrium unfolding reaction of the C-terminal 80-amino-acid dimeric DNA-binding domain of human papillomavirus (HPV) strain 16 E2 protein has been investigated using fluorescence, far-UV CD, and equilibrium sedimentation. The stability of the HPV-16 E2 DNA-binding domain is concentration-dependent, and the unfolding reaction is well described as a two-state transition from folded dimer to unfolded monomer. The conformational stability of the protein, delta GH2O, was found to be 9.8 kcal/mol at pH 5.6, with the corresponding equilibrium unfolding/dissociation constant, Ku, being 6.5 x 10(-8) M. Equilibrium sedimentation experiments give a Kd of 3.0 x 10(-8) M, showing an excellent agreement between the two different techniques. Denaturation by temperature followed by the change in ellipticity also shows a concomitant disappearance of secondary and tertiary structures. The Ku changes dramatically at physiologically relevant pH's: with a change in pH from 6.1 to 7.0, it goes from 5.5 x 10(-8) M to 4.4 x 10(10) M. Our results suggest that, at the very low concentration of protein where DNA binding is normally measured (e.g., 10(-11) M), the protein is predominantly monomeric and unfolded. They also stress the importance of the coupling between folding and DNA binding. PMID:8745409

  10. Expression of E2F transcription factor family genes during chick wing development.

    PubMed

    Towers, Matthew; Fisunov, Gleb; Tickle, Cheryll

    2009-10-01

    The E2F family of transcriptional regulators activate or repress gene expression during specific phases of the cell cycle and control various processes including proliferation, apoptosis and differentiation. However, little is known about the developmental roles of E2F transcription factors in higher vertebrates. The chick wing is an excellent system for studying these processes because, in addition to having a rich classical embryology, it is increasingly amenable to molecular and genomic approaches. We show that the human and mouse complement of eight E2F transcription factors is conserved in the chicken and that chicken E2F genes are expressed in different spatial and temporal patterns during wing development. We discuss how the expression patterns of the eight chicken E2F transcription factors might be related to important morphogenetic events.

  11. Prostaglandin E2 regulates macrophage colony stimulating factor secretion by human bone marrow stromal cells.

    PubMed

    Besse, A; Trimoreau, F; Faucher, J L; Praloran, V; Denizot, Y

    1999-07-08

    Bone marrow stromal cells regulate marrow haematopoiesis by secreting growth factors such as macrophage colony stimulating factor (M-CSF) that regulates the proliferation, differentiation and several functions of cells of the mononuclear-phagocytic lineage. By using a specific ELISA we found that their constitutive secretion of M-CSF is enhanced by tumour necrosis factor-alpha (TNF-alpha). The lipid mediator prostaglandin E2 (PGE2) markedly reduces in a time- and dose-dependent manner the constitutive and TNF-alpha-induced M-CSF synthesis by bone marrow stromal cells. In contrast, other lipid mediators such as 12-HETE, 15-HETE, leukotriene B4, leukotriene C4 and lipoxin A4 have no effect. EP2/EP4 selective agonists (11-deoxy PGE1 and 1-OH PGE1) and EP2 agonist (19-OH PGE2) inhibit M-CSF synthesis by bone marrow stromal cells while an EP1/EP3 agonist (sulprostone) has no effect. Stimulation with PGE2 induces an increase of intracellular cAMP levels in bone marrow stromal cells. cAMP elevating agents (forskolin and cholera toxin) mimic the PGE2-induced inhibition of M-CSF production. In conclusion, PGE2 is a potent regulator of M-CSF production by human bone marrow stromal cells, its effects being mediated via cAMP and PGE receptor EP2/EP4 subtypes.

  12. Prostaglandin E2 restrains macrophage maturation via E prostanoid receptor 2/protein kinase A signaling

    PubMed Central

    Zasłona, Zbigniew; Serezani, Carlos H.; Okunishi, Katsuhide; Aronoff, David M.

    2012-01-01

    Prostaglandin E2 (PGE2) is a lipid mediator that acts by ligating 4 distinct G protein–coupled receptors, E prostanoid (EP) 1 to 4. Previous studies identified the importance of PGE2 in regulating macrophage functions, but little is known about its effect on macrophage maturation. Macrophage maturation was studied in vitro in bone marrow cell cultures, and in vivo in a model of peritonitis. EP2 was the most abundant PGE2 receptor expressed by bone marrow cells, and its expression further increased during macrophage maturation. EP2-deficient (EP2−/−) macrophages exhibited enhanced in vitro maturation compared with wild-type cells, as evidenced by higher F4/80 expression. An EP2 antagonist also increased maturation. In the peritonitis model, EP2−/− mice exhibited a higher percentage of F4/80high/CD11bhigh cells and greater expression of macrophage colony-stimulating factor receptor (M-CSFR) in both the blood and the peritoneal cavity. Subcutaneous injection of the PGE2 analog misoprostol decreased M-CSFR expression in bone marrow cells and reduced the number of peritoneal macrophages in wild-type mice but not EP2−/− mice. The suppressive effect of EP2 ligation on in vitro macrophage maturation was mimicked by a selective protein kinase A agonist. Our findings reveal a novel role for PGE2/EP2/protein kinase A signaling in the suppression of macrophage maturation. PMID:22234697

  13. Dose-dependent effects of prostaglandin E2 in macrophage adhesion and migration.

    PubMed

    Osma-Garcia, Inés C; Punzón, Carmen; Fresno, Manuel; Díaz-Muñoz, Manuel D

    2016-03-01

    Macrophage migration to the focus of infection is a hallmark of the innate immune response. Macrophage spreading, adhesion, and migration through the extracellular matrix require dynamic remodeling of the actin cytoskeleton associated to integrin clustering in podosomes and focal adhesions. Here, we show that prostaglandin E2 (PGE2 ), the main prostaglandin produced by macrophages during inflammation, promote the distinctive dose-dependent formation of podosomes or focal adhesions in macrophages. Low concentrations of PGE2 increased p110γ PI3K expression, phosphorylation of actin-related protein 2, and formation of podosomes, which enhanced macrophage migration in response to chemokines. However, high doses of PGE2 increased phosphorylation of paxillin and focal adhesion kinase, the expression of serine/threonine protein kinase 1, and promoted focal adhesion formation and macrophage adhesion, reducing macrophage chemotaxis. In summary, we describe the dual role of PGE2 as a promoter of macrophage chemotaxis and adhesion, proposing a new model of macrophage migration to the inflammatory focus in the presence of a gradient of PGE2 .

  14. Elucidating the Specificity Determinants of the AtxE2 Lasso Peptide Isopeptidase*

    PubMed Central

    Maksimov, Mikhail O.; Koos, Joseph D.; Zong, Chuhan; Lisko, Bozhena; Link, A. James

    2015-01-01

    Lasso peptide isopeptidase is an enzyme that specifically hydrolyzes the isopeptide bond of lasso peptides, rendering these peptides linear. To carry out a detailed structure-activity analysis of the lasso peptide isopeptidase AtxE2 from Asticcacaulis excentricus, we solved NMR structures of its substrates astexin-2 and astexin-3. Using in vitro enzyme assays, we show that the C-terminal tail portion of these peptides is dispensable with regards to isopeptidase activity. A collection of astexin-2 and astexin-3 variants with alanine substitutions at each position within the ring and the loop was constructed, and we showed that all of these peptides except for one were cleaved by the isopeptidase. Thus, much like the lasso peptide biosynthetic enzymes, lasso peptide isopeptidase has broad substrate specificity. Quantitative analysis of the cleavage reactions indicated that alanine substitutions in loop positions of these peptides led to reduced cleavage, suggesting that the loop is serving as a recognition element for the isopeptidase. PMID:26534965

  15. A Novel Selective Prostaglandin E2 Synthesis Inhibitor Relieves Pyrexia and Chronic Inflammation in Rats.

    PubMed

    Sugita, Ryusuke; Kuwabara, Harumi; Sugimoto, Kotaro; Kubota, Kazufumi; Imamura, Yuichiro; Kiho, Toshihiro; Tengeiji, Atsushi; Kawakami, Katsuhiro; Shimada, Kohei

    2016-04-01

    Prostaglandin E2 (PGE2) is a terminal prostaglandin in the cyclooxygenase (COX) pathway. Inhibition of PGE2 production may relieve inflammatory symptoms such as fever, arthritis, and inflammatory pain. We report here the profile of a novel selective PGE2 synthesis inhibitor, compound A [N-[(1S,3S)-3-carbamoylcyclohexyl]-1-(6-methyl-3-phenylquinolin-2-yl)piperidine-4-carboxamide], in animal models of pyrexia and inflammation. The compound selectively suppressed the synthesis of PGE2 in human alveolar adenocarcinoma cell line A549 cells and rat macrophages. In the lipopolysaccharide-induced pyrexia model, this compound selectively reduced PGE2 production in cerebrospinal fluid and showed an anti-pyretic effect. In the adjuvant-induced arthritis model, compound A therapeutically decreased foot swelling in the established arthritis. Our data demonstrates that selective suppression of PGE2 synthesis shows anti-pyretic and anti-inflammatory effects, suggesting that selective PGE2 synthesis inhibitors can be applied as an alternative treatment to nonsteroidal, anti-inflammatory drugs (NSAIDs) or COX-2-selective inhibitors.

  16. In vivo delivery of bovine viral diahorrea virus, E2 protein using hollow mesoporous silica nanoparticles

    NASA Astrophysics Data System (ADS)

    Mahony, D.; Cavallaro, A. S.; Mody, K. T.; Xiong, L.; Mahony, T. J.; Qiao, S. Z.; Mitter, N.

    2014-05-01

    Our work focuses on the application of mesoporous silica nanoparticles as a combined delivery vehicle and adjuvant for vaccine applications. Here we present results using the viral protein, E2, from bovine viral diarrhoea virus (BVDV). BVDV infection occurs in the target species of cattle and sheep herds worldwide and is therefore of economic importance. E2 is a major immunogenic determinant of BVDV and is an ideal candidate for the development of a subunit based nanovaccine using mesoporous silica nanoparticles. Hollow type mesoporous silica nanoparticles with surface amino functionalisation (termed HMSA) were characterised and assessed for adsorption and desorption of E2. A codon-optimised version of the E2 protein (termed Opti-E2) was produced in Escherichia coli. HMSA (120 nm) had an adsorption capacity of 80 μg Opti-E2 per mg HMSA and once bound E2 did not dissociate from the HMSA. Immunisation studies in mice with a 20 μg dose of E2 adsorbed to 250 μg HMSA was compared to immunisation with Opti-E2 (50 μg) together with the traditional adjuvant Quillaja saponaria Molina tree saponins (QuilA, 10 μg). The humoral responses with the Opti-E2/HMSA nanovaccine although slightly lower than those obtained for the Opti-E2 + QuilA group demonstrated that HMSA particles are an effective adjuvant that stimulated E2-specific antibody responses. Importantly the cell-mediated immune responses were consistently high in all mice immunised with Opti-E2/HMSA nanovaccine formulation. Therefore we have shown the Opti-E2/HMSA nanoformulation acts as an excellent adjuvant that gives both T-helper 1 and T-helper 2 mediated responses in a small animal model. This study has provided proof-of-concept towards the development of an E2 subunit nanoparticle based vaccine.Our work focuses on the application of mesoporous silica nanoparticles as a combined delivery vehicle and adjuvant for vaccine applications. Here we present results using the viral protein, E2, from bovine viral

  17. The induction of second trimester abortions using an intra-amniotic injection of urea and prostaglandin E2.

    PubMed

    Bowen-Simpkins, P

    1973-09-01

    Induction of 2nd-trimester abortion in 31 patients in England is described. An intraamniotic injection of 80g urea was administered after ensuring a free flow of amniotic fluid. The injection was followed by 5mg PGE2 (prostaglandin E2) injected into the amniotic cavity. The procedure was successful in 30 of the 31 patients, requiring a mean injection-to-abortion time of 10 hours and 30 minutes (ranging from 4 hours 10 minutes to 26 hours). 6 of the successful cases required general anesthesia for subsequent evacuation of retained conception products. Neither gestational age nor parity was associated with the injection-to-abortion interval. The described procedure is judged to be safe, rapid, and relatively inexpensive. It reduces the risk of maternal mortality connected with saline injection. It reduces the time required for urea injection alone. It reduces the cost of intraamniotic PG alone.

  18. E2F Transcription Factors Control the Roller Coaster Ride of Cell Cycle Gene Expression.

    PubMed

    Thurlings, Ingrid; de Bruin, Alain

    2016-01-01

    Initially, the E2F transcription factor was discovered as a factor able to bind the adenovirus E2 promoter and activate viral genes. Afterwards it was shown that E2F also binds to promoters of nonviral genes such as C-MYC and DHFR, which were already known at that time to be important for cell growth and DNA metabolism, respectively. These findings provided the first clues that the E2F transcription factor might be an important regulator of the cell cycle. Since this initial discovery in 1987, several additional E2F family members have been identified, and more than 100 targets genes have been shown to be directly regulated by E2Fs, the majority of these are important for controlling the cell cycle. The progression of a cell through the cell cycle is accompanied with the increased expression of a specific set of genes during one phase of the cell cycle and the decrease of the same set of genes during a later phase of the cell cycle. This roller coaster ride, or oscillation, of gene expression is essential for the proper progression through the cell cycle to allow accurate DNA replication and cell division. The E2F transcription factors have been shown to be critical for the temporal expression of the oscillating cell cycle genes. This review will focus on how the oscillation of E2Fs and their targets is regulated by transcriptional, post-transcriptional and post-translational mechanism in mammals, yeast, flies, and worms. Furthermore, we will discuss the functional impact of E2Fs on the cell cycle progression and outline the consequences when E2F expression is disturbed.

  19. Agrobacterium delivers VirE2 protein into host cells via clathrin-mediated endocytosis

    PubMed Central

    Li, Xiaoyang; Pan, Shen Q.

    2017-01-01

    Agrobacterium tumefaciens can cause crown gall tumors on a wide range of host plants. As a natural genetic engineer, the bacterium can transfer both single-stranded DNA (ssDNA) [transferred DNA (T-DNA)] molecules and bacterial virulence proteins into various recipient cells. Among Agrobacterium-delivered proteins, VirE2 is an ssDNA binding protein that is involved in various steps of the transformation process. However, it is not clear how plant cells receive the T-DNA or protein molecules. Using a split–green fluorescent protein approach, we monitored the VirE2 delivery process inside plant cells in real time. We observed that A. tumefaciens delivered VirE2 from the bacterial lateral sides that were in close contact with plant membranes. VirE2 initially accumulated on plant cytoplasmic membranes at the entry points. VirE2-containing membranes were internalized through clathrin-mediated endocytosis to form endomembrane compartments. VirE2 colocalized with the early endosome marker SYP61 but not with the late endosome marker ARA6, suggesting that VirE2 escaped from early endosomes for subsequent trafficking inside the cells. Dual endocytic motifs at the carboxyl-terminal tail of VirE2 were involved in VirE2 internalization and could interact with the μ subunit of the plant clathrin-associated adaptor AP2 complex (AP2M). Both the VirE2 cargo motifs and AP2M were important for the transformation process. Because AP2-mediated endocytosis is well conserved, our data suggest that the A. tumefaciens pathogen hijacks conserved endocytic pathways to facilitate the delivery of virulence factors. This might be important for Agrobacterium to achieve both a wide host range and a high transformation efficiency. PMID:28345032

  20. Interrupted E2F1-miR-34c-SCF negative feedback loop by hyper-methylation promotes colorectal cancer cell proliferation

    PubMed Central

    Yang, Shu; Wu, Bo; Sun, Haimei; Ji, Fengqing; Sun, Tingyi; Zhao, Yan; Zhou, Deshan

    2015-01-01

    Tumour suppressor miR-34c deficiency resulted from hyper-methylation in its promoter is believed to be one of the main causes of colorectal cancer (CRC). Till date, miR-34c has been validated as a direct target of p53; but previous evidence suggested other transcription factor(s) must be involved in miR-34c transcription. In the present study, we in the first place identified a core promoter region (−1118 to −883 bp) of pre-miR-34c which was embedded within a hyper-methylated CpG island. Secondly, E2F1 promoted miR-34c transcription by physical interaction with the miR-34c promoter at site −897 to −889 bp. The transcriptional activating effect of E2F1 on miR-34c was in a p53 independent manner but profoundly promoted in the presence of p53 with exposure to 5-aza-2′-deoxycytidine (DAC). Thirdly, stem cell factor (SCF), a miR-34c target, was specifically reduced upon an introduction of E2F1 which lead to suppression of CRC cell proliferation. The E2F1-suppressed cell proliferation was partially abrogated by additional miR-34c inhibitor, indicating that the anti-proliferation effect of E2F1 was probably through activating miR-34c-SCF axis. Finally, SCF/KIT signalling increased E2F1 production by reducing its proteosomal degradation dependent on PI3K/Akt-GSK3β pathway. In conclusion, our results suggested the existence of E2F1-miR-34c-SCF negative feedback loop which was interrupted by the hyper-methylation of miR-34c promoter in CRC cells and increased cell proliferation. PMID:26704889

  1. Chimpanzee GB virus C and GB virus A E2 envelope glycoproteins contain a peptide motif that inhibits human immunodeficiency virus type 1 replication in human CD4⁺ T-cells.

    PubMed

    McLinden, James H; Stapleton, Jack T; Klinzman, Donna; Murthy, Krishna K; Chang, Qing; Kaufman, Thomas M; Bhattarai, Nirjal; Xiang, Jinhua

    2013-04-01

    GB virus type C (GBV-C) is a lymphotropic virus that can cause persistent infection in humans. GBV-C is not associated with any disease, but is associated with reduced mortality in human immunodeficiency virus type 1 (HIV-1)-infected individuals. Related viruses have been isolated from chimpanzees (GBV-Ccpz) and from New World primates (GB virus type A, GBV-A). These viruses are also capable of establishing persistent infection. We determined the nucleotide sequence encoding the envelope glycoprotein (E2) of two GBV-Ccpz isolates obtained from the sera of captive chimpanzees. The deduced GBV-Ccpz E2 protein differed from human GBV-C by 31 % at the amino acid level. Similar to human GBV-C E2, expression of GBV-Ccpz E2 in a tet-off human CD4(+) Jurkat T-cell line significantly inhibited the replication of diverse HIV-1 isolates. This anti-HIV-replication effect of GBV-Ccpz E2 protein was reversed by maintaining cells in doxycycline to reduce E2 expression. Previously, we found a 17 aa region within human GBV-C E2 that was sufficient to inhibit HIV-1. Although GBV-Ccpz E2 differed by 3 aa differences in this region, the chimpanzee GBV-C 17mer E2 peptide inhibited HIV-1 replication. Similarly, the GBV-A peptide that aligns with this GBV-C E2 region inhibited HIV-1 replication despite sharing only 5 aa with the human GBV-C E2 sequence. Thus, despite amino acid differences, the peptide region on both the GBV-Ccpz and the GBV-A E2 protein inhibit HIV-1 replication similar to human GBV-C. Consequently, GBV-Ccpz or GBV-A infection of non-human primates may provide an animal model to study GB virus-HIV interactions.

  2. The prostaglandin E2 receptor EP2 is required for cyclooxygenase 2-mediated mammary hyperplasia.

    PubMed

    Chang, Sung-Hee; Ai, Youxi; Breyer, Richard M; Lane, Timothy F; Hla, Timothy

    2005-06-01

    Expression of cyclooxygenase 2 (COX-2) in breast cancer correlates with poor prognosis, and COX-2 enzyme inhibitors reduce breast cancer incidence in humans. We recently showed that COX-2 overexpression in the mammary gland of transgenic mice induced mammary cancer. Because prostaglandin E2 (PGE2) is the major eicosanoid and because the EP2 subtype of the PGE2 receptor is highly expressed in the mammary tumors, we tested if this G protein-coupled receptor is required for tumorigenesis. We crossed the MMTV-COX-2 transgenic mice with Ep2-/- mice and studied tumor development in bigenic mice. Lack of EP2 receptor strongly suppressed COX-2-induced effects such as precocious development of the mammary gland in virgins and the development of mammary hyperplasia in multiparous female mice. Interestingly, the expression of amphiregulin, a potent mammary epithelial cell growth factor was down regulated in mammary glands of Ep2-/- mice. Total cyclic AMP (cAMP) levels were reduced in Ep2-/- mammary glands suggesting that PGE2 signaling via the EP2 receptor activates the Gs/cAMP/protein kinase A pathway. In mammary tumor cell lines, expression of the EP2 receptor followed by treatment with CAY10399, an EP2-specific agonist, strongly induced amphiregulin mRNA levels in a protein kinase A-dependent manner. These data suggest that PGE2 signaling via the EP2 receptor in mammary epithelial cells regulate mammary gland hyperplasia by the cAMP-dependent induction of amphiregulin. Inhibition of the EP2 pathway in the mammary gland may be a novel approach in the prevention and/or treatment of mammary cancer.

  3. Interplay between the prostaglandin transporter OATP2A1 and prostaglandin E2-mediated cellular effects.

    PubMed

    Bujok, Krystyna; Glaeser, Hartmut; Schuh, Wolfgang; Rau, Tilman T; Schmidt, Ingrid; Fromm, Martin F; Mandery, Kathrin

    2015-03-01

    Prostaglandins such as prostaglandin E2 (PGE2) play a pivotal role in physiological and pathophysiological pathways in gastric mucosa. Little is known about the interrelation of the prostaglandin E (EP) receptors with the prostaglandin transporter OATP2A1 in the gastric mucosa and gastric carcinoma. Therefore, we first investigated the expression of OATP2A1 and EP4 in normal and carcinoma gastric mucosa. Different PGE2-mediated cellular pathways and mechanisms were investigated using human embryonic kidney cells (HEK293) and the human gastric carcinoma cell line AGS stably transfected with OATP2A1. Colocalization and expression of OATP2A1 and EP4 were detected in mucosa of normal gastric tissue and of gastric carcinomas. OATP2A1 reduced the PGE2-mediated cAMP production in HEK293 and AGS cells overexpressing EP4 and OATP2A1. The expression of OATP2A1 in AGS cells resulted in a reduction of [(3)H]-thymidine incorporation which was in line with a higher accumulation of AGS-OATP2A1 cells in S-phase of the cell cycle compared to control cells. In contrast, the expression of OATP2A1 in HEK293 cells had no influence on the distribution in the S-phase compared to control cells. OATP2A1 also diminished the PGE2-mediated expression of interleukin-8 mRNA (IL-8) and hypoxia-inducible-factor 1α (HIF1α) protein in AGS-OATP2A1 cells. The expression of OATP2A1 increased the sensitivity of AGS cells against irinotecan which led to reduced cell viability. Taken together, these data show that OATP2A1 influences PGE2-mediated cellular pathways. Therefore, OATP2A1 needs to be considered as a key determinant for the understanding of the physiology and pathophysiology of prostaglandins in healthy and tumorous gastric mucosa.

  4. Inflammatory prostaglandin E2 signaling in a mouse model of Alzheimer’s disease

    PubMed Central

    Shi, Ju; Wang, Qian; Johansson, Jenny U.; Liang, Xibin; Woodling, Nathaniel S.; Priyam, Prachi; Loui, Taylor M.; Merchant, Milton; Breyer, Richard M.; Montine, Thomas J.; Andreasson, Katrin

    2012-01-01

    Objective There is significant evidence for a central role of inflammation in the development of Alzheimer’s disease (AD). Epidemiological studies indicate that chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) reduces the risk of developing AD in healthy aging populations. As NSAIDs inhibit the enzymatic activity of the inflammatory cyclooxygenases COX-1 and COX-2, these findings suggest that downstream prostaglandin signaling pathways function in the pre-clinical development of AD. Here, we investigate the function of prostaglandin E2 (PGE2) signaling through its EP3 receptor in the neuroinflammatory response to Aβ peptide. Methods The function of PGE2 signaling through its EP3 receptor was examined in vivo a model of subacute neuroinflammation induced by administration of Aβ42 peptides. Our findings were then confirmed in young adult APPSwe-PS1 ΔE9 transgenic mice. Results Deletion of the PGE2 EP3 receptor in a model of Aβ42 peptide-induced neuroinflammation reduced pro-inflammatory gene expression, cytokine production, and oxidative stress. In the APPSwe-PS1 ΔE9 model of Familial AD, deletion of the EP3 receptor blocked induction of pro-inflammatory gene and protein expression and lipid peroxidation. In addition, levels of Aβ peptides were significantly decreased, as were BACE-1 and β-CTF levels, suggesting that generation of Aβ peptides may be increased as a result of pro-inflammatory EP3 signaling. Finally, deletion of EP3 receptor significantly reversed the decline in pre-synaptic proteins seen in APPSwe-PS1 ΔE9 mice. Interpretation Our findings identify the PGE2 EP3 receptor as a novel pro-inflammatory, pro-amyloidogenic, and synaptotoxic signaling pathway, and suggest a role for COX-PGE2-EP3 signaling in the development of AD. PMID:22915243

  5. Estrogen receptors regulate the estrous behavior induced by progestins, peptides, and prostaglandin E2.

    PubMed

    Lima-Hernández, F J; Gómora-Arrati, P; García-Juárez, M; Blaustein, J D; Etgen, A M; Beyer, C; González-Flores, O

    2014-07-01

    The role of classical estrogen receptors (ERs) in priming female reproductive behavior has been studied previously; however, the participation of this receptor during activation of estrous behavior has not been extensively studied. The purpose of this work was to test the possibility that the facilitation of lordosis behavior in estrogen-primed rats by progesterone (P) and its 5α- and 5β-reduced metabolites, gonadotropin-releasing hormone (GnRH), leptin, prostaglandin E2 (PGE2) and vagino-cervical stimulation (VCS) involves interactions with classical ERs by using the selective ER modulator, tamoxifen. To further assess the role of ERs, we also explored the effects of the pure ER antagonist, ICI182780 (ICI), on estrous behavior induced by P and GnRH. Ovariectomized, estrogen-primed rats (5μg estradiol benzoate 40h earlier) were injected intraventricularly with the above-mentioned compounds, or they received VCS. All compounds and VCS effectively facilitated estrous behavior when tested at 60, 120 or 240min after infusion or application of VCS. Intraventricular infusion of tamoxifen (5μg), 30min before, significantly attenuated estrous behaviors induced in estradiol-primed rats by P, most of its 5α- and 5β-reduced metabolites, GnRH, and PGE2, but not by VCS. Although there was a trend for reduction, tamoxifen did not significantly decrease lordosis in females treated with 5β-pregnan-3,20-dione. ICI also inhibited lordosis behavior induced by P and GnRH at some testing intervals. These results suggest that activation of classical ERs participates in the triggering effects on estrous behavior induced by agents with different chemical structures that do not bind directly to ERs.

  6. How alkyl halide structure affects E2 and SN2 reaction barriers: E2 reactions are as sensitive as SN2 reactions.

    PubMed

    Rablen, Paul R; McLarney, Brett D; Karlow, Brandon J; Schneider, Jean E

    2014-02-07

    High-level electronic structure calculations, including a continuum treatment of solvent, are employed to elucidate and quantify the effects of alkyl halide structure on the barriers of SN2 and E2 reactions. In cases where such comparisons are available, the results of these calculations show close agreement with solution experimental data. Structural factors investigated include α- and β-methylation, adjacency to unsaturated functionality (allyl, benzyl, propargyl, α to carbonyl), ring size, and α-halogenation and cyanation. While the influence of these factors on SN2 reactivity is mostly well-known, the present study attempts to provide a broad comparison of both SN2 and E2 reactivity across many cases using a single methodology, so as to quantify relative reactivity trends. Despite the fact that most organic chemistry textbooks say far more about how structure affects SN2 reactions than about how it affects E2 reactions, the latter are just as sensitive to structural variation as are the former. This sensitivity of E2 reactions to structure is often underappreciated.

  7. Materials characterization activities for %E2%80%9CTake Our Sons&Daughters to Work Day%E2%80%9D 2013.

    SciTech Connect

    Mowry, Curtis Dale; Pimentel, Adam S.; Sparks, Elizabeth Schares; Hanlon, Brittany Paula

    2013-09-01

    We created interactive demonstration activities for Take Our Daughters&Sons to Work Day (TODSTWD) 2013 in order to promote general interest in chemistry and also generate awareness of the type of work our laboratories can perform. %E2%80%9CCurious about Mars Rover Curiosity?%E2%80%9D performed an elemental analysis on rocks brought to our lab using the same technique utilized on the planet Mars by the NASA robotic explorer Curiosity. %E2%80%9CFood is Chemistry?%E2%80%9D utilized a mass spectrometer to measure, in seconds, each participant's breath in order to identify the food item consumed for the activity. A total of over 130 children participated in these activities over a 3 hour block, and feedback was positive. This document reports the materials (including handouts), experimental procedures, and lessons learned so that future demonstrations can benefit from the baseline work performed. We also present example results used to prepare the Food activity and example results collected during the Curiosity demo.

  8. Combined effects of E2F1 and E2F2 polymorphisms on risk and early onset of squamous cell carcinoma of the head and neck

    PubMed Central

    Lu, Meixia; Liu, Zhensheng; Yu, Hongping; Wang, Li-E; Li, Guojun; Sturgis, Erich M.; Johnson, David G.; Wei, Qingyi

    2012-01-01

    Deregulated expression of most members of the E2F family has been detected in many human cancers. We examined the association of common single nucleotide polymorphisms (SNPs) of E2F1 and E2F2 with risk of squamous cell carcinoma of the head and neck (SCCHN) in 1,096 SCCHN patients and 1,090 cancer-free controls. We genotyped ten selected SNPs in E2F1 and E2F2, including those at the near 5′ UTR, miRNA binding sites at the near 3′ UTR and tagSNPs according to bioinfotmatics analysis. Although none of the selected SNPs alone was significantly associated with risk of SCCHN, there was a statistically significantly increased risk of SCCHN associated with the combined risk genotypes (i.e. rs3213182 AA, rs3213183 GG, rs3213180 GG, rs321318121 GG, rs2742976 GT+TT, rs6667575 GA+AA, rs3218203 CC, rs3218148 AA, rs3218211 CC, rs3218123 GT+TT). Compared with those with 0–4 risk genotypes, an increased risk was observed for those who carried 5–8 risk genotypes (adjusted OR = 1.04; 95% CI = 0.86–1.26) and 9–10 risk genotypes (adjusted OR = 1.62; 95% CI = 1.14–2.30) in a dose-response manner (P = 0.045). Furthermore, the joint effect was more pronounced among patients with oropharyngeal cancer, younger adults (≤57 years old), men, non-smokers, non-drinkers, and individuals with family history of cancer first-degree relatives. Additionally, we also observed that those with 5–10 risk genotypes had an earlier SCCHN onset than those with 0–4 risk genotypes, particularly for non-smokers and/or non-drinkers. We concluded that E2F1 and E2F2 genetic variants may jointly play important roles in head and neck carcinogenesis. PMID:22344756

  9. The Retinoblastoma Tumor Suppressor Protein (pRb)/E2 Promoter Binding Factor 1 (E2F1) Pathway as a Novel Mediator of TGFβ-induced Autophagy.

    PubMed

    Korah, Juliana; Canaff, Lucie; Lebrun, Jean-Jacques

    2016-01-29

    TGFβ is a multifunctional cytokine that regulates cell proliferation, cell immortalization, and cell death, acting as a key homeostatic mediator in various cell types and tissues. Autophagy is a programmed mechanism that plays a pivotal role in controlling cell fate and, consequently, many physiological and pathological processes, including carcinogenesis. Although autophagy is often considered a pro-survival mechanism that renders cells viable in stressful conditions and thus might promote tumor growth, emerging evidence suggests that autophagy is also a tumor suppressor pathway. The relationship between TGFβ signaling and autophagy is context-dependent and remains unclear. TGFβ-mediated activation of autophagy has recently been suggested to contribute to the growth inhibitory effect of TGFβ in hepatocarcinoma cells. In the present study, we define a novel process of TGFβ-mediated autophagy in cancer cell lines of various origins. We found that autophagosome initiation and maturation by TGFβ is dependent on the retinoblastoma tumor suppressor protein/E2 promoter binding factor (pRb/E2F1) pathway, which we have previously established as a critical signaling axis leading to various TGFβ tumor suppressive effects. We further determined that TGFβ induces pRb/E2F1-dependent transcriptional activation of several autophagy-related genes. Together, our findings reveal that TGFβ induces autophagy through the pRb/E2F1 pathway and transcriptional activation of autophagy-related genes and further highlight the central relevance of the pRb/E2F1 pathway downstream of TGFβ signaling in tumor suppression.

  10. E2F-7 couples DNA damage-dependent transcription with the DNA repair process.

    PubMed

    Zalmas, Lykourgos-Panagiotis; Coutts, Amanda S; Helleday, Thomas; La Thangue, Nicholas B

    2013-09-15

    The cellular response to DNA damage, mediated by the DNA repair process, is essential in maintaining the integrity and stability of the genome. E2F-7 is an atypical member of the E2F family with a role in negatively regulating transcription and cell cycle progression under DNA damage. Surprisingly, we found that E2F-7 makes a transcription-independent contribution to the DNA repair process, which involves E2F-7 locating to and binding damaged DNA. Further, E2F-7 recruits CtBP and HDAC to the damaged DNA, altering the local chromatin environment of the DNA lesion. Importantly, the E2F-7 gene is a target for somatic mutation in human cancer and tumor-derived mutant alleles encode proteins with compromised transcription and DNA repair properties. Our results establish that E2F-7 participates in 2 closely linked processes, allowing it to directly couple the expression of genes involved in the DNA damage response with the DNA repair machinery, which has relevance in human malignancy.

  11. Phosphorylation regulates binding of the human papillomavirus type 8 E2 protein to host chromosomes.

    PubMed

    Sekhar, Vandana; McBride, Alison A

    2012-09-01

    The papillomavirus E2 proteins are indispensable for the viral life cycle, and their functions are subject to tight regulation. The E2 proteins undergo posttranslational modifications that regulate their properties and roles in viral transcription, replication, and genome maintenance. During persistent infection, the E2 proteins from many papillomaviruses act as molecular bridges that tether the viral genomes to host chromosomes to retain them within the host nucleus and to partition them to daughter cells. The betapapillomavirus E2 proteins bind to pericentromeric regions of host mitotic chromosomes, including the ribosomal DNA loci. We recently reported that two residues (arginine 250 and serine 253) within the chromosome binding region of the human papillomavirus type 8 (HPV8) E2 protein are required for this binding. In this study, we show that serine 253 is phosphorylated, most likely by protein kinase A, and this modulates the interaction of the E2 protein with cellular chromatin. Furthermore, we show that this phosphorylation occurs in S phase, increases the half-life of the E2 protein, and promotes chromatin binding from S phase through mitosis.

  12. E2 ubiquitin conjugating enzymes regulate the deubiquitinating activity of OTUB1

    PubMed Central

    Wiener, Reuven; DiBello, Anthony T.; Lombardi, Patrick; Guzzo, Catherine M.; Zhang, Xiangbin; Matunis, Michael J.; Wolberger, Cynthia

    2014-01-01

    OTUB1 is a Lys48-specific deubiquitinating enzyme that forms a complex in vivo with E2 ubiquitin conjugating enzymes including UBC13 and UBCH5. OTUB1 binds to E2~Ub thioester intermediates and prevent ubiquitin transfer, thereby non-catalytically inhibiting accumulation of polyubiquitin. We report here that a second role of OTUB1-E2 interactions is to stimulate OTUB1 cleavage of Lys48 polyubiquitin, and that this stimulation is regulated by the ratio of charged to uncharged E2 and by the concentration of Lys48-linked polyubiquitin and free ubiquitin. Structural and biochemical studies of human and worm OTUB1 and UBCH5B show that the E2 stimulates binding of the Lys48 polyubiquitin substrate by stabilizing folding of the OTUB1 N-terminal ubiquitin-binding helix. Our results suggest that OTUB1-E2 complexes in the cell are poised to regulate polyubiquitin chain elongation or degradation in response to changing levels of E2 charging and available free ubiquitin. PMID:23955022

  13. OTUB1 co-opts Lys48-linked ubiquitin recognition to suppress E2 enzyme function

    PubMed Central

    Juang, Yu-Chi; Landry, Marie-Claude; Sanches, Mario; Vittal, Vinayak; Leung, Charles; Ceccarelli, Derek F.; Mateo, Abigail-Rachele F.; Pruneda, Jonathan N.; Mao, Dan; Szilard, Rachel K.; Orlicky, Stephen; Munro, Meagan; Brzovic, Peter S.; Klevit, Rachel E.; Sicheri, Frank; Durocher, Daniel

    2012-01-01

    SUMMARY Ubiquitylation entails the concerted action of E1, E2 and E3 enzymes. We recently reported that OTUB1, a deubiquitylase, inhibits the DNA damage response independently of its isopeptidase activity. OTUB1 does so by blocking ubiquitin transfer by UBC13, the cognate E2 enzyme for RNF168. OTUB1 also inhibits E2s of the UBE2D and UBE2E families. Here we elucidate the structural mechanism by which OTUB1 binds E2s to inhibit ubiquitin transfer. OTUB1 recognizes ubiquitin-charged E2s through contacts with both donor ubiquitin and the E2 enzyme. Surprisingly, free ubiquitin associates with the canonical distal ubiquitin-binding site on OTUB1 to promote formation of the inhibited E2 complex. Lys48 of donor ubiquitin lies near the OTUB1 catalytic site and the C-terminus of free ubiquitin, a configuration that mimics the products of Lys48-linked ubiquitin chain cleavage. OTUB1 therefore co-opts Lys48-linked ubiquitin chain recognition to suppress ubiquitin conjugation and the DNA damage response. PMID:22325355

  14. Capturing a substrate in an activated RING E3/E2-SUMO complex

    PubMed Central

    Streich, Frederick C.; Lima, Christopher D.

    2016-01-01

    Summary Post-translational protein modification by ubiquitin (Ub) and ubiquitin-like (Ubl) proteins such as small ubiquitin like modifier (SUMO) regulates processes including protein homeostasis, the DNA damage response, and the cell cycle. Proliferating cell nuclear antigen (PCNA) is modified by Ub or poly-Ub at Lys164 after DNA damage to recruit repair factors. Yeast PCNA is modified by SUMO on Lys164 and Lys127 during S-phase to recruit the anti-recombinogenic helicase Srs2. Lys164 modification requires specialized E2/E3 enzyme pairs for SUMO or Ub conjugation. For SUMO, Lys164 modification is strictly dependent on the E3 ligase Siz1, suggesting the E3 alters E2 specificity to promote Lys164 modification. The structural basis for substrate interactions in activated E3/E2-Ub/Ubl complexes remains unclear. Here, we report an engineered E2 protein and cross-linking strategies that trap an E3/E2-Ubl/substrate complex for structure determination, illustrating how an E3 can bypass E2 specificity to force-feed a substrate lysine into the E2 active site. PMID:27509863

  15. Highly sensitive detection of E2 activity in ubiquitination using an artificial RING finger.

    PubMed

    Miyamoto, Kazuhide; Sumida, Miho; Yuasa-Sunagawa, Mayumi; Saito, Kazuki

    2017-03-01

    The ubiquitin-conjugating (E2) enzymes of protein ubiquitination are associated with various diseases such as leukemia, lung cancer, and breast cancer. Rapid and accurate detection of E2 enzymatic activities remains poor. Here, we described the detection of E2 activity on a signal accumulation ISFET biosensor (AMIS sensor) using an artificial RING finger (ARF). The use of ARF enables the simplified detection of E2 activity without a substrate. The high-sensitivity quantitative detection of E2 activities was demonstrated via real-time monitoring over a response range of femtomolar to micromolar concentrations. Furthermore, the monitoring of E2 activities was successfully achieved using human acute promyelocytic leukemia cells following treatment with the anticancer drug bortezomib, which allowed the assessment of the pathological conditions. This strategy is extremely simple and convenient, and the present detection could be widely applied to specific E2s for various types of cancers. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.

  16. OTUB1 Co-opts Lys48-Linked Ubiquitin Recognition to Suppress E2 Enzyme Function

    SciTech Connect

    Juang, Yu-Chi; Landry, Marie-Claude; Sanches, Mario; Vittal, Vinayak; Leung, Charles C.Y.; Ceccarelli, Derek F.; Mateo, Abigail-Rachele F.; Pruneda, Jonathan N.; Mao, Daniel Y.L.; Szilard, Rachel K.; Orlicky, Stephen; Munro, Meagan; Brzovic, Peter S.; Klevit, Rachel E.; Sicheri, Frank; Durocher, Daniel

    2012-03-26

    Ubiquitylation entails the concerted action of E1, E2, and E3 enzymes. We recently reported that OTUB1, a deubiquitylase, inhibits the DNA damage response independently of its isopeptidase activity. OTUB1 does so by blocking ubiquitin transfer by UBC13, the cognate E2 enzyme for RNF168. OTUB1 also inhibits E2s of the UBE2D and UBE2E families. Here we elucidate the structural mechanism by which OTUB1 binds E2s to inhibit ubiquitin transfer. OTUB1 recognizes ubiquitin-charged E2s through contacts with both donor ubiquitin and the E2 enzyme. Surprisingly, free ubiquitin associates with the canonical distal ubiquitin-binding site on OTUB1 to promote formation of the inhibited E2 complex. Lys48 of donor ubiquitin lies near the OTUB1 catalytic site and the C terminus of free ubiquitin, a configuration that mimics the products of Lys48-linked ubiquitin chain cleavage. OTUB1 therefore co-opts Lys48-linked ubiquitin chain recognition to suppress ubiquitin conjugation and the DNA damage response.

  17. Several different upstream promoter elements can potentiate transactivation by the BPV-1 E2 protein.

    PubMed Central

    Ham, J; Dostatni, N; Arnos, F; Yaniv, M

    1991-01-01

    The enhancer and upstream promoter regions of RNA polymerase II transcribed genes modulate the rate of transcription initiation and establish specific patterns of gene expression. Both types of region consist of clusters of DNA binding sites for nuclear proteins. To determine how efficiently the same factor can activate transcription when acting as an enhancer or promoter factor, we have studied transactivation by the BPV-1 E2 protein, a papillomavirus transcriptional regulator. By cotransfecting a BPV-1 E2 expression vector and a series of reporter plasmids containing well-defined chimeric promoters we have found that whilst E2 can strongly stimulate complex promoters such as that of the HSV tk gene, it does not efficiently activate constructions containing only a TATA box and initiation site. We show that insertion of upstream promoter elements, but not of spacer DNA, between E2 binding sites and the TATA box greatly increases E2 activation. This effect was observed with more than one type of upstream promoter element, is not related to the strength of the promoter and is unlikely to result from co-operative DNA binding by E2 and the transcription factors tested. These results would suggest that E2 has the properties of an enhancer rather than promoter factor and that in certain cases promoter and enhancer factors may affect different steps in the process of transcriptional activation. Images PMID:1655407

  18. Isolation of a differentially regulated splicing isoform of human NF-E2.

    PubMed Central

    Pischedda, C; Cocco, S; Melis, A; Marini, M G; Kan, Y W; Cao, A; Moi, P

    1995-01-01

    The transcription factor NF-E2 (nuclear factor erythroid 2), interacting via DNA motifs within regulatory regions of several hematopoietic genes, is thought to mediate the enhancer activity of the globin locus control regions. By screening a human fetal liver cDNA library with probes derived from mouse NF-E2, we have isolated a splicing variant of the NF-E2 gene (fNF-E2) that differs in the 5' untranslated region from the previously reported cDNA (aNF-E2). The fNF-E2 isoform is transcribed from an alternative promoter located in the 3' end of the first intron and joined by alternative splicing to the second and third exons, which are shared by both RNA isoforms. Although the two forms produce the same protein, they are expressed in different ratios during development. fNF-E2 is more abundant in the fetal liver and less abundant in the adult bone marrow compared to the previously described form. Their distribution apparently follows the differential expression of fetal and adult hemoglobins. Images Fig. 5 Fig. 6 Fig. 7 PMID:7724591

  19. Insights into Nuclear Triaxiality from Interference Effects in E2 Matrix Elements

    NASA Astrophysics Data System (ADS)

    Allmond, J. M.; Wood, J. L.; Kulp, W. D.

    2007-10-01

    Recently, we have introduced [1] a triaxial rotor model with independent inertia and E2 tensors. The E2 matrix elements [2] of the osmium isotopes (186, 188, 190, and 192) are studied in the framework of this model (59 of 84 E2 matrix elements deviate by 30% or less). It is shown that interference effects in the inertia tensor (K-mixing) and the E2 tensor can lead to significant reductions in the diagonal E2 matrix elements. In some instances, the diagonal E2 matrix elements may decrease with increasing spin. Additionally, a sum rule for diagonal E2 matrix elements is shown and used to explore missing strength from K-admixtures. [1] J.L. Wood, A-M. Oros-Peusquens, R. Zaballa, J.M. Allmond, and W.D. Kulp, Phys. Rev. C 70, 024308 (2004). [2] C.Y. Wu, D. Cline, T. Czosnyka, A. Backlin, C. Baktash, R.M. Diamond, G.D. Dracoulis, L. Hasselgren, H. Kluge, et al., Nucl. Phys. A607, 178 (1996).

  20. Genomic and Genetic Variation in E2F1 in Men with Non-Obstructive Azoospermia

    PubMed Central

    Jorgez, Carolina J.; Wilken, Nathan; Addai, Josephine B.; Newberg, Justin; Vangapandu, Hima V.; Pastuszak, Alexander W.; Mukherjee, Sarmistha; Rosenfeld, Jill A.; Lipshultz, Larry I.; Lamb, Dolores J.

    2014-01-01

    Objective To identify gene dosage changes associated with non-obstructive azoospermia (NOA) using array comparative genomic hybridization (aCGH). Design Prospective study. Patients 110 men with NOA and 78 fertile controls. Settings Medical School Interventions None Main Outcome Measure The study has four distinct analytic components: aCGH, a molecular karyotype that detects copy-number-variations (CNV), Taqman-CNV assays to validate CNVs, mutation identification by Sanger sequencing and histologic analyses of testicular tissues. Results A microduplication at 20q11.22 encompassing E2F1 was identified in one of eight men with NOA analyzed using aCGH. CNVs were confirmed and an additional 102 men with NOA screened using Taqman CNV assays for a total of 110 NOA men analyzed for CNVs in E2F1. Eight of 110 (7.3%) NOA men had microduplications or microdeletions of E2F1 that were absent in fertile controls. Conclusions E2F1 microduplications or microdeletions are present in NOA men (7.3%). Duplications or deletions of E2F1 occur very rarely in the general population (0.011%), but E2F1 gene dosage changes, previously reported only in cancers, are present in a subset of NOA men. These results recapitulate the infertility phenotype seen in mice lacking or over-expressing E2f1. PMID:25439843

  1. HPV-16 E2 physical status and molecular evolution in vivo in cervical carcinomas.

    PubMed

    Kahla, Saloua; Kochbati, Lotfi; Chanoufi, Mohamed Badis; Maalej, Mongi; Oueslati, Ridha

    2014-03-24

    A key event in the development of cervical carcinoma is the deregulated expression of high-risk human papillomavirus (HR-HPV) oncogenes, most commonly due to HPV integration into host DNA. Here we explored whether HPV-16 E2 gene integrity is a biomarker of progressive disease with oncogenes expression. HPV-16 genome disruption was assessed by amplification of the entire E2 gene, while mRNA expression patterns of the E1, E2, E6, and E7 genes were evaluated by reverse transcription PCR (RT-PCR). As expected, E2 disruption was significantly higher among patients with cervical cancers than subjects with benign lesions (p=0.02). The status of the E2 gene correlated with tumorogenesis, and seemed also to correlate with the stage of the carcinomas, since integrated HPV-16 DNA was frequently detected in patients with advanced cancer stages (75% of stage III vs 60% stages I and II). In bivariate analysis, the lesions’ grade was most significantly associated with HPV-16 DNA disruption (p<0.05). In cervical carcinoma the deletion pattern involved more frequently the E2 gene rather than the E1 gene (62.5% vs 45.8%). The prevalence of the E6/E7 HPV-16 transcripts in cervical carcinoma specimens and in benign cervical lesions were detected with frequencies of, respectively, 91.6% and 45.4%. The mRNA levels of the HPV-16 E6/E7 genes were expressed at approximately the same levels in each physical state. We consistently observed that E6/E7 were absent or weakly detectable in the presence of E2. However, in the absence of E2 the levels of E6/E7 markedly increased (p<0.05). This study underscores the significance of investigating alternative mechanisms of E2 expression and oncogenes E6/E7 transcripts in vivo as biomarkers for disease severity in cervical carcinomas.

  2. Rendezvous with Toutatis from the Moon: The Chang'e-2 mission

    NASA Astrophysics Data System (ADS)

    Huang, J.; Tang, X.; Meng, L.

    2014-07-01

    Chang'e-2 probe was the second lunar probe of China, with the main objectives to demonstrate some key features of the new lunar soft landing technology, and its applications to future exploration missions. After completing the planned mission successfully, Chang'e-2 flew away from the Moon and entered into the interplanetary space. Later, at a distance of 7 million km from the Earth, Chang'e-2 encountered asteroid (4179) Toutatis with a very close fly-by distance and obtained colorful images with a 3-m resolution. Given some surplus velocity increment as well as the promotion of autonomous flight ability and improvement of control, propulsion, and thermal systems in the initial design, Chang'e-2 had the capabilities necessary for escaping from the Moon. By taking advantage of the unique features of the Lagrangian point, the first close fly-by of asteroid Toutatis was realized despite the tight constraints of propellant allocation, spacecraft-Earth communication, and coordination of execution sequences. Chang'e-2 realized the Toutatis flyby with a km-level distance at closest approach. In the absence of direct measurement method, based on the principle of relative navigation and through the use of the sequence of target images, we calculated the rendezvous parameters such as relative distance and image resolution. With the help of these parameters, some fine and new scientific discoveries about the asteroid were obtained by techniques of optical measurements and image processing. Starting with an innovative design, followed by high-fidelity testing and demonstration, elaborative implementation, and optimal usage of residual propellant, Chang'e-2 has for the first time successfully explored the Moon, L2 point and an asteroid, while achieving the purpose of 'faster, better, cheaper'. What Chang'e-2 has accomplished was far beyond our expectations. *J. Huang is the chief designer (PI) of Chang'e-2 probe, planned Chang'e-2's multi-objective and multitasking exploration

  3. Growth suppression by an E2F-binding-defective retinoblastoma protein (RB): contribution from the RB C pocket.

    PubMed

    Whitaker, L L; Su, H; Baskaran, R; Knudsen, E S; Wang, J Y

    1998-07-01

    Growth suppression by the retinoblastoma protein (RB) is dependent on its ability to form complexes with transcription regulators. At least three distinct protein-binding activities have been identified in RB: the large A/B pocket binds E2F, the A/B pocket binds the LXCXE peptide motif, and the C pocket binds the nuclear c-Abl tyrosine kinase. Substitution of Trp for Arg 661 in the B region of RB (mutant 661) inactivates both E2F and LXCXE binding. The tumor suppression function of mutant 661 is not abolished, because this allele predisposes its carriers to retinoblastoma development with a low penetrance. In cell-based assays, 661 is shown to inhibit G1/S progression. This low-penetrance mutant also induces terminal growth arrest with reduced but detectable activity. We have constructed mutations that disrupt C pocket activity. When overproduced, the RB C-terminal fragment did not induce terminal growth arrest but could inhibit G1/S progression, and this activity was abolished by the C-pocket mutations. In full-length RB, the C-pocket mutations reduced but did not abolish RB function. Interestingly, combination of the C-pocket and 661 mutations completely abolished RB's ability to cause an increase in the percentage of cells in G1 and to induce terminal growth arrest. These results suggest that the A/B or C region can induce a prolongation of G1 through mechanisms that are independent of each other. In contrast, long-term growth arrest requires combined activities from both regions of RB. In addition, E2F and LXCXE binding are not the only mechanisms through which RB inhibits cell growth. The C pocket also contributes to RB-mediated growth suppression.

  4. Cellular Ubc2/Rad6 E2 ubiquitin-conjugating enzyme facilitates tombusvirus replication in yeast and plants

    SciTech Connect

    Imura, Yoshiyuki Molho, Melissa; Chuang, Chingkai; Nagy, Peter D.

    2015-10-15

    Mono- and multi-ubiquitination alters the functions and subcellular localization of many cellular and viral proteins. Viruses can co-opt or actively manipulate the ubiquitin network to support viral processes or suppress innate immunity. Using yeast (Saccharomyces cerevisiae) model host, we show that the yeast Rad6p (radiation sensitive 6) E2 ubiquitin-conjugating enzyme and its plant ortholog, AtUbc2, interact with two tombusviral replication proteins and these E2 ubiquitin-conjugating enzymes could be co-purified with the tombusvirus replicase. We demonstrate that TBSV RNA replication and the mono- and bi-ubiquitination level of p33 is decreased in rad6Δ yeast. However, plasmid-based expression of AtUbc2p could complement both defects in rad6Δ yeast. Knockdown of UBC2 expression in plants also decreases tombusvirus accumulation and reduces symptom severity, suggesting that Ubc2p is critical for virus replication in plants. We provide evidence that Rad6p is involved in promoting the subversion of Vps23p and Vps4p ESCRT proteins for viral replicase complex assembly. - Highlights: • Tombusvirus p33 replication protein interacts with cellular RAD6/Ubc2 E2 enzymes. • Deletion of RAD6 reduces tombusvirus replication in yeast. • Silencing of UBC2 in plants inhibits tombusvirus replication. • Mono- and bi-ubiquitination of p33 replication protein in yeast and in vitro. • Rad6p promotes the recruitment of cellular ESCRT proteins into the tombusvirus replicase.

  5. Presidential Transitions

    DTIC Science & Technology

    2006-06-09

    Podesta for the Heads of Executive Departments and Agencies, “Presidential Transition Guidance,” Nov. 13, 2000. 89 U.S. General Services Administration...2000, presidential election, White House Chief of Staff John Podesta issued a November 13, 2000, memorandum to executive branch agencies stating that

  6. Tessellations & Transitions.

    ERIC Educational Resources Information Center

    Cassidy, Joan

    1998-01-01

    Describes two sixth-grade lessons on the work of M. C. Escher: (1) the first lesson instructs students on tessellations, or tiles that interlock in a repeated pattern; (2) the second lesson explores Escher's drawings of transitions from two- to three-dimensional space. (DSK)

  7. Novel functions for the transcription factor E2F4 in development and disease

    PubMed Central

    Sage, Julien

    2016-01-01

    ABSTRACT The E2F family of transcription factors is a key determinant of cell proliferation in response to extra- and intra-cellular signals. Within this family, E2F4 is a transcriptional repressor whose activity is critical to engage and maintain cell cycle arrest in G0/G1 in conjunction with members of the retinoblastoma (RB) family. However, recent observations challenge this paradigm and indicate that E2F4 has a multitude of functions in cells besides this cell cycle regulatory role, including in embryonic and adult stem cells, during regenerative processes, and in cancer. Some of these new functions are independent of the RB family and involve direct activation of target genes. Here we review the canonical functions of E2F4 and discuss recent evidence expanding the role of this transcription factor, with a focus on cell fate decisions in tissue homeostasis and regeneration. PMID:27753528

  8. Anomalous behaviors of E1/E2 deep level defects in 6H silicon carbide

    NASA Astrophysics Data System (ADS)

    Chen, X. D.; Ling, C. C.; Gong, M.; Fung, S.; Beling, C. D.; Brauer, G.; Anwand, W.; Skorupa, W.

    2005-01-01

    Deep level defects E1/E2 were observed in He-implanted, 0.3 and 1.7MeV electron-irradiated n-type 6H-SiC. Similar to others' results, the behaviors of E1 and E2 (like the peak intensity ratio, the annealing behaviors or the introduction rates) often varied from sample to sample. This anomalous result is not expected of E1/E2 being usually considered arising from the same defect located at the cubic and hexagonal sites respectively. The present study shows that this anomaly is due to another DLTS peak overlapping with the E1/E2. The activation energy and the capture cross section of this defect are EC-0.31eV and σ ˜8×10-14cm2, respectively.

  9. The RB/E2F pathway and regulation of RNA processing

    SciTech Connect

    Ahlander, Joseph; Bosco, Giovanni

    2009-07-03

    The retinoblastoma tumor suppressor protein (RB) is inactivated in a majority of cancers. RB restricts cell proliferation by inhibiting the E2F family of transcription factors. The current model for RB/E2F function describes its role in regulating transcription at gene promoters. Whether the RB or E2F proteins might play a role in gene expression beyond transcription initiation is not well known. This review describes evidence that points to a novel role for the RB/E2F network in the regulation of RNA processing, and we propose a model as a framework for future research. The elucidation of a novel role of RB in RNA processing will have a profound impact on our understanding of the role of this tumor suppressor family in cell and developmental biology.

  10. Interaction of E2 Glycoprotein with Heparan Sulfate Is Crucial for Cellular Infection of Sindbis Virus

    PubMed Central

    Yang, Yiliang; Jia, Juan; Fu, Shihong; Feng, Yun; He, Ying; Li, Jin-Ping; Liang, Guodong

    2010-01-01

    Cell culture-adapted strains of Sindbis virus (SINV) initially attach to cells by the ability to interact with heparan sulfate (HS) through selective mutation for positively charged amino acid (aa) scattered in E2 glycoprotein (W. B. Klimstra, K. D. Ryman, and R. E. Johnston, J. Virol. 72: 7357–7366, 1998). Here we have further confirmed that interaction of E2 protein with HS is crucial for cellular infection of SINV based on the reverse genetic system of XJ-160 virus, a Sindbis-like virus (SINLV). Both SINV YN87448 and SINLV XJ-160 displayed similar infectivity on BHK-21, Vero, or C6/36 cells, but XJ-160 failed to infect mouse embryonic fibroblast (MEF) cells. The molecular mechanisms underlying the selective infectivity of XJ-160 were approached by substituting the E1, E2, or both genes of XJ-160 with that of YN87448, and the chimeric virus was denominated as XJ-160/E1, XJ-160/E2, or XJ-160/E1E2, respectively. In contrast to the parental XJ-160, all chimeric viruses became infectious to wild-type MEF cells (MEF-wt). While MEF-Ext−/− cells, producing shortened HS chains, were resistant not only to XJ-160, but also to YN87448 as well as the chimeric viruses, indicating that the inability of XJ-160 to infect MEF-wt cells likely due to its incompetent discrimination of cellular HS. Treatment with heparin or HS-degrading enzyme resulted in a substantial decrease in plaque formation by YN87448, XJ-160/E2, and XJ-160/E1E2, but had marginal effect on XJ-160 and XJ-160/E1, suggesting that E2 glycoprotein from YN87448 plays a more important role than does E1 in mediating cellular HS-related cell infection. In addition, the peptide containing 145–150 aa from E2 gene of YN87448 specifically bound to heparin, while the corresponding peptide from the E2 gene of XJ-160 essentially showed no binding to heparin. As a new dataset, these results clearly confirm an essential role of E2 glycoprotein, especially the domain of 145–150 aa, in SINV cellular infection through

  11. Early2 factor (E2F) deregulation is a prognostic and predictive biomarker in lung adenocarcinoma

    PubMed Central

    Chen, Lu; Kurtyka, Courtney A; Welsh, Eric A; Engel, Brienne E; Muñoz-Antonia, Teresita; Yoder, Sean J; Eschrich, Steven A; Creelan, Ben C; Chiappori, Alberto A; Gray, Jhanelle E; Ramirez, Jose Luis; Rosell, Rafael; Schabath, Matthew B; Haura, Eric B; Chen, Dung-Tsa; Cress, Douglas W

    2016-01-01

    Clinicians routinely prescribe adjuvant chemotherapy (ACT) for resected non-small cell lung cancer patients. However, ACT only improves five-year disease-free survival in stage I-III non-small cell lung cancer by 5-15%, with most patients deriving no benefit. Herein, deregulation of the E2F pathway was explored as a biomarker in lung adenocarcinoma patients. An E2F pathway scoring system, based on 74 E2F-regulated genes, was trained for RNA from two platforms: fresh-frozen (FF) or formalin-fixed paraffin-embedded (FFPE) tissues. The E2F score was tested as a prognostic biomarker in five FF-based cohorts and two FFPE-based cohorts. The E2F score was tested as a predictive biomarker in two randomized clinical trials; JBR10 and the NATCH (Neo-Adjuvant Taxol-Carboplatin Hope) trial. The E2F score was prognostic in untreated patients in all seven datasets examined (p < 0.05). Stage-specific analysis of combined cohorts demonstrated that the E2F score was prognostic in stage I patients (p = 0.0495 to <0.001; hazard ratio, HR, =2.04- 2.22) with a similar trend in other stages. The E2F score was strongly predictive in stage II patients from the two combined randomized clinical trials with a significant differential treatment effect (p = 0.015). Specifically, ACT improved survival in stage II patients with high E2F (p = 0.01; HR= 0.21). The 5-year survival increased from 18% to 81%. In contrast, in patients with low E2F, 5-year survival was 57% in untreated patients and 41% in ACT-treated patients with a HR of 1.55 (p = 0.47). In summary, the E2F score provides valuable prognostic information for Stage I and predictive information for Stage II lung adenocarcinoma patients and should be further explored as a decision support tool for their treatment. PMID:27756884

  12. Effects of E2HSA, a Long-Acting Glucagon Like Peptide-1 Receptor Agonist, on Glycemic Control and Beta Cell Function in Spontaneous Diabetic db/db Mice.

    PubMed

    Hou, Shaocong; Li, Caina; Huan, Yi; Liu, Shuainan; Liu, Quan; Sun, Sujuan; Jiang, Qian; Jia, Chunming; Shen, Zhufang

    2015-01-01

    Glucagon like peptide-1 (GLP-1) receptor agonists such as exendin-4 have been widely used but their short half-life limits their therapeutic value. The recombinant protein, E2HSA, is a novel, long-acting GLP-1 receptor agonist generated by the fusion of exendin-4 with human serum albumin. In mouse pancreatic NIT-1 cells, E2HSA activated GLP-1 receptor with similar efficacy as exendin-4. After single-dose administration in ICR mice, E2HSA showed prolonged glucose lowering effects which lasted up to four days and extended inhibition on gastric emptying for at least 72 hours. Chronic E2HSA treatment in db/db mice significantly improved glucose tolerance, reduced elevated nonfasting and fasting plasma glucose levels, and also decreased HbA1c levels. E2HSA also increased insulin secretion and decreased body weight and appetite. Furthermore, immunofluorescence analysis showed that E2HSA increased β-cell area, improved islet morphology, and reduced β-cell apoptosis. In accordance with the promotion of β-cell function and survival, E2HSA upregulated genes such as Irs2, Pdx-1, Nkx6.1, and MafA and downregulated the expression levels of FoxO1 and proapoptotic Bcl-2 family proteins. In conclusion, with prolonged glucose lowering effects and promoting β-cell function and survival, the fusion protein, E2HSA, is a promising new therapeutic for once weekly treatment of type 2 diabetes.

  13. Aberrant regulation of survivin by the RB/E2F family of proteins.

    PubMed

    Jiang, Yuying; Saavedra, Harold I; Holloway, Michael P; Leone, Gustavo; Altura, Rachel A

    2004-09-24

    Survivin is a putative oncogene that is aberrantly expressed in cancer cells. It has been hypothesized to play a central role in cancer progression and resistance to therapy in diverse tumor types. Although some of the transcriptional processes regulating its expression have been established, the diversity of genes that may be controlling the levels of its expression in both normal cells as well as in cancer cells has not been fully explored. The most common genetically mutated pathways in human malignancies are the p53 tumor suppressor pathway and the RB/E2F pathway. Both of these pathways, when intact, provide essential checkpoints in the maintenance of normal cell growth and protect the cell from DNA damage. Using non-transformed embryonic fibroblasts, we provide evidence of a molecular link between the regulation of survivin transcription and the RB/E2F family of proteins. We demonstrate that both pRB and p130 can interact with the survivin promoter and can repress survivin transcription. We also show that the E2F activators (E2F1, E2F2, and E2F3) can bind to the survivin promoter and induce survivin transcription. Genetically modified cells that harbor deletions in various members of the RB/E2F family confirm our data from the wild-type cells. Our findings implicate several members of the RB/E2F pathway in an intricate mechanism of survivin gene regulation that, when genetically altered during the process of tumorigenesis, may function within cancer cells to aberrantly alter survivin levels and enhance tumor progression.

  14. The E1-E2 center in gallium arsenide is the divacancy.

    PubMed

    Schultz, Peter A

    2015-02-25

    Based on defect energy levels computed from first-principles calculations, it is shown the E1-E2 center in irradiated GaAs cannot be due to an isolated arsenic vacancy. The only simple intrinsic defect with levels compatible with E1 and E2 is the divacancy. The arsenic monovacancy is reassigned to the E3 center in irradiated GaAs. These new assignments are shown to reconcile a number of seemingly contradictory experimental observations.

  15. Identification of Conserved Residues in Hepatitis C Virus Envelope Glycoprotein E2 That Modulate Virus Dependence on CD81 and SRB1 Entry Factors

    PubMed Central

    Lavie, Muriel; Sarrazin, Stéphane; Montserret, Roland; Descamps, Véronique; Baumert, Thomas F.; Duverlie, Gilles; Séron, Karin; Penin, François

    2014-01-01

    ABSTRACT In spite of the high variability of its sequence, hepatitis C virus (HCV) envelope glycoprotein E2 contains several conserved regions. In this study, we explored the structural and functional features of the highly conserved E2 segment from amino acid (aa) 502 to 520, which had been proposed as a fusion peptide and shown to strongly overlap a potential conserved neutralizing epitope. For this purpose, we used reverse genetics to introduce point mutations within this region, and we characterized the phenotypes of these mutants in the light of the recently published structure of E2. The functional analyses showed that their phenotypes are in agreement with the positions of the corresponding residues in the E2 crystal structure. In contrast, our data ruled out the involvement of this region in membrane fusion, and they indicate that alternative conformations would be necessary to expose the potential neutralizing epitope present in this segment. Of particular interest, we identified three specific mutations (Y507L, V514A, and V515A) located within this neutralizing epitope which only mildly reduced infectivity and showed no assembly defect. These mutations modulated HCV dependence on the viral receptor SRB1, and/or they also modulated virion sensitivity to neutralizing antibodies. Importantly, their characterization also showed that amino acids Y507, V514, and V515 contribute to E2 interaction with HCV receptor CD81. In conclusion, our data show that the highly conserved E2 segment from aa 502 to 520 plays a key role in cell entry by influencing the association of the viral particle with coreceptors and neutralizing antibodies. IMPORTANCE Hepatitis C virus (HCV) envelope proteins E1 and E2 exhibit sequence variability. However, some segments of the envelope proteins are highly conserved, suggesting that these sequences play a key role at some steps of the HCV life cycle. In this work, we characterized the function and structure of a highly conserved E2 region

  16. Investigation of the anomalously low B (E 2 ;41+→21+) /B (E 2 ;21+→01+) ratio in 134Ce through lifetime measurements

    NASA Astrophysics Data System (ADS)

    Zhu, B. J.; Li, C. B.; Wu, X. G.; Zhong, J.; Chen, Q. M.; Zheng, Y.; He, C. Y.; Zhou, W. K.; Deng, L. T.; Li, G. S.

    2017-01-01

    The existing experimental value of the ratio B4 /2≡B (E 2 ;41+→21+) /B (E 2 ;21+→01+) in 134Ce is less than unity, which is outside the range allowed by current collective models and is highly anomalous. In the present work, new lifetime measurements of excited states in 134Ce have been performed in order to clarify this discrepancy. Excited states of 134Ce were populated by the fusion-evaporation reaction 122Sn(16O,4 n )134Ce . The recoil distance doppler shift method was employed, and reliable lifetimes for the 21+, 41+, 102+, and 122+ states were derived from the differential decay curve method. The resulting B4 /2 value is larger than unity, resolving the disagreement with traditional collective models. The new experimental data is in very good agreement with the calculation in the framework of the interacting boson model. The systematic evolution in collectivity of the Ce isotopes is discussed.

  17. Structural basis for penetration of the glycan shield of hepatitis C virus E2 glycoprotein by a broadly neutralizing human antibody.

    PubMed

    Li, Yili; Pierce, Brian G; Wang, Qian; Keck, Zhen-Yong; Fuerst, Thomas R; Foung, Steven K H; Mariuzza, Roy A

    2015-04-17

    Hepatitis C virus (HCV) is a major cause of liver cirrhosis and hepatocellular carcinoma. A challenge for HCV vaccine development is to identify conserved epitopes able to elicit protective antibodies against this highly diverse virus. Glycan shielding is a mechanism by which HCV masks such epitopes on its E2 envelope glycoprotein. Antibodies to the E2 region comprising residues 412-423 (E2(412-423)) have broadly neutralizing activities. However, an adaptive mutation in this linear epitope, N417S, is associated with a glycosylation shift from Asn-417 to Asn-415 that enables HCV to escape neutralization by mAbs such as HCV1 and AP33. By contrast, the human mAb HC33.1 can neutralize virus bearing the N417S mutation. To understand how HC33.1 penetrates the glycan shield created by the glycosylation shift to Asn-415, we determined the structure of this broadly neutralizing mAb in complex with its E2(412-423) epitope to 2.0 Å resolution. The conformation of E2(412-423) bound to HC33.1 is distinct from the β-hairpin conformation of this peptide bound to HCV1 or AP33, because of disruption of the β-hairpin through interactions with the unusually long complementarity-determining region 3 of the HC33.1 heavy chain. Whereas Asn-415 is buried by HCV1 and AP33, it is solvent-exposed in the HC33.1-E2(412-423) complex, such that glycosylation of Asn-415 would not prevent antibody binding. Furthermore, our results highlight the structural flexibility of the E2(412-423) epitope, which may serve as an immune evasion strategy to impede induction of antibodies targeting this site by reducing its antigenicity.

  18. Long-Term Nitric Oxide Release and Elevated Temperature Stability with S-Nitroso-N-acetylpenicillamine (SNAP)-Doped Elast-eon E2As Polymer

    PubMed Central

    Brisbois, Elizabeth J.; Handa, Hitesh; Major, Terry C.; Bartlett, Robert H.; Meyerhoff, Mark E.

    2013-01-01

    Nitric oxide (NO) is known to be a potent inhibitor of platelet activation and adhesion. Healthy endothelial cells that line the inner walls of all blood vessels exhibit a NO flux of 0.5~4×10−10 mol cm−2 min−1 that helps prevent thrombosis. Materials with a NO flux that is equivalent to this level are expected to exhibit similar anti-thrombotic properties. In this study, five biomedical grade polymers doped with S-nitroso-N-acetylpenicillamine (SNAP) were investigated for their potential to control the release of NO from the SNAP within the polymers, and further control the release of SNAP itself. SNAP in the Elast-eon E2As polymer creates an inexpensive, homogeneous coating that can locally deliver NO (via thermal and photochemical reactions) as well slowly release SNAP. Furthermore, SNAP is surprisingly stable in the E2As polymer, retaining 82% of the initial SNAP after 2 months storage at 37°C. The E2As polymer containing SNAP was coated on the walls of extracorporeal circuits (ECC) and exposed to 4 h blood flow in a rabbit model of extracorporeal circulation to examine the effects on platelet count, platelet function, clot area, and fibrinogen adsorption. After 4 h, platelet count was preserved at 100±7% of baseline for the SNAP/E2As coated loops, compared to 60±6% for E2As control circuits (n=4). The SNAP/E2As coating also reduced the thrombus area when compared to the control (2.3±0.6 and 3.4±1.1 pixels/cm2, respectively). The results suggest that the new SNAP/E2As coating has potential to improve the thromboresistance of intravascular catheters, grafts, and other blood contacting medical devices, and exhibits excellent storage stability compared to previously reported NO release polymeric materials. PMID:23777908

  19. Temperature Dependent E2 Raman Modes in the ZnCoO Ternary Alloy

    NASA Technical Reports Server (NTRS)

    Samanta, K.; Bhattacharya, P.; Katiyar, R. S.

    2007-01-01

    The anharmonic properties of low and high frequency E2 modes of ZnO and Co doped ZnO were investigated using Raman scattering spectroscopy. We have determined the behavior of frequency, linewidths, and lifetime of E2 modes in the temperature range from 80 to 800 K. In the case of E2(high) mode the frequency shift towards the lower energy side was analyzed in light of the theory of anharmonic phonon-phonon interaction and thermal expansion of the lattice, and the linewidth behavior was analyzed in terms of anharmonic effect of three-phonon decay mechanism. But in the case of E2(low), the linewidth and frequency behaved practically harmonic with respect to temperature and independent of Co substitutions. It is found that the E2(high) phonon anharmonicity is higher for ZnCoO alloys than in pure ZnO and it increases with the compositional disorder. The low temperature lifetime of E2 phonon in ZnO, 1 % and 3% Co doped ZnO were found to be 1.S2, 1.74, and 1.54 ps, respectively.

  20. Cezanne regulates E2F1-dependent HIF2α expression

    PubMed Central

    Moniz, Sonia; Bandarra, Daniel; Biddlestone, John; Campbell, Kirsteen J.; Komander, David; Bremm, Anja; Rocha, Sonia

    2015-01-01

    ABSTRACT Mechanisms regulating protein degradation ensure the correct and timely expression of transcription factors such as hypoxia inducible factor (HIF). Under normal O2 tension, HIFα subunits are targeted for proteasomal degradation, mainly through vHL-dependent ubiquitylation. Deubiquitylases are responsible for reversing this process. Although the mechanism and regulation of HIFα by ubiquitin-dependent proteasomal degradation has been the object of many studies, little is known about the role of deubiquitylases. Here, we show that expression of HIF2α (encoded by EPAS1) is regulated by the deubiquitylase Cezanne (also known as OTUD7B) in an E2F1-dependent manner. Knockdown of Cezanne downregulates HIF2α mRNA, protein and activity independently of hypoxia and proteasomal degradation. Mechanistically, expression of the HIF2α gene is controlled directly by E2F1, and Cezanne regulates the stability of E2F1. Exogenous E2F1 can rescue HIF2α transcript and protein expression when Cezanne is depleted. Taken together, these data reveal a novel mechanism for the regulation of the expression of HIF2α, demonstrating that the HIF2α promoter is regulated by E2F1 directly and that Cezanne regulates HIF2α expression through control of E2F1 levels. Our results thus suggest that HIF2α is controlled transcriptionally in a cell-cycle-dependent manner and in response to oncogenic signalling. PMID:26148512

  1. Nucleotide polymorphism in colicin E2 gene clusters: evidence for nonneutral evolution.

    PubMed

    Tan, Y; Riley, M A

    1997-06-01

    To explore the molecular mechanisms behind the diversification of colicin gene clusters, we examined DNA sequence polymorphism for the colicin gene clusters of 14 colicin E2 (ColE2) plasmids obtained from natural isolates of Escherichia coli. Two types of ColE2 plasmids are revealed, with type II gene clusters generated by recombination between type I ColE2 and ColE7 gene clusters. The levels and patterns of DNA polymorphism are different between the two types. Type I polymorphism is distributed evenly along the gene cluster, while type II accumulates polymorphism at an elevated rate in the 5' end of the colicin gene. These differences may be explained by recombinational origins of type II gene clusters. The pattern of divergence between the ColE2 gene cluster and its close relative ColE9 is not correlated with the pattern of polymorphism within ColE2, suggesting that this gene cluster is not evolving in a neutral fashion. A statistical test confirms significant departures from the predictions of neutrality. These data lend further support to the hypothesis that colicin gene clusters may evolve under the influence of nonneutral forces.

  2. Physical and functional interactions of human papillomavirus E2 protein with nuclear receptor coactivators

    SciTech Connect

    Wu, M.-H.; Huang, C.-J.; Liu, S.-T.; Liu, P.-Y.; Ho, C.-L. . E-mail: shihming@ndmctsgh.edu.tw

    2007-05-11

    In addition to the human papillomavirus (HPV)-induced immortalization of epithelial cells, which usually requires integration of the viral DNA into the host cell genome, steroid hormone-activated nuclear receptors (NRs) are thought to bind to specific DNA sequences within transcriptional regulatory regions on the long control region to either increase or suppress transcription of dependent genes. In this study, our data suggest that the NR coactivator function of HPV E2 proteins might be mediated through physical and functional interactions with not only NRs but also the NR coactivators GRIP1 (glucocorticoid receptor-interacting protein 1) and Zac1 (zinc-finger protein which regulates apoptosis and cell cycle arrest 1), reciprocally regulating their transactivation activities. GRIP1 and Zac1 both were able to act synergistically with HPV E2 proteins on the E2-, androgen receptor-, and estrogen receptor-dependent transcriptional activation systems. GRIP1 and Zac1 might selectively function with HPV E2 proteins on thyroid receptor- and p53-dependent transcriptional activation, respectively. Hence, the transcriptional function of E2 might be mediated through NRs and NR coactivators to regulate E2-, NR-, and p53-dependent transcriptional activations.

  3. Transcriptional control of stem cell fate by E2Fs and pocket proteins

    PubMed Central

    Julian, Lisa M.; Blais, Alexandre

    2015-01-01

    E2F transcription factors and their regulatory partners, the pocket proteins (PPs), have emerged as essential regulators of stem cell fate control in a number of lineages. In mammals, this role extends from both pluripotent stem cells to those encompassing all embryonic germ layers, as well as extra-embryonic lineages. E2F/PP-mediated regulation of stem cell decisions is highly evolutionarily conserved, and is likely a pivotal biological mechanism underlying stem cell homeostasis. This has immense implications for organismal development, tissue maintenance, and regeneration. In this article, we discuss the roles of E2F factors and PPs in stem cell populations, focusing on mammalian systems. We discuss emerging findings that position the E2F and PP families as widespread and dynamic epigenetic regulators of cell fate decisions. Additionally, we focus on the ever expanding landscape of E2F/PP target genes, and explore the possibility that E2Fs are not simply regulators of general ‘multi-purpose’ cell fate genes but can execute tissue- and cell type-specific gene regulatory programs. PMID:25972892

  4. Temperature dependent E2 Raman modes in the ZnCoO ternary alloy

    NASA Astrophysics Data System (ADS)

    Samanta, K.; Bhattacharya, P.; Katiyar, R. S.

    2007-01-01

    The anharmonic properties of low and high frequency E2 modes of ZnO and Co doped ZnO were investigated using Raman scattering spectroscopy. We have determined the behavior of frequency, linewidths, and lifetime of E2 modes in the temperature range from 80 to 800K . In the case of E2high mode the frequency shift towards the lower energy side was analyzed in light of the theory of anharmonic phonon-phonon interaction and thermal expansion of the lattice, and the linewidth behavior was analyzed in terms of anharmonic effect of three-phonon decay mechanism. But in the case of E2low , the linewidth and frequency behaved practically harmonic with respect to temperature and independent of Co substitutions. It is found that the E2high phonon anharmonicity is higher for ZnCoO alloys than in pure ZnO and it increases with the compositional disorder. The low temperature lifetime of E2 phonon in ZnO , 1% and 3% Co doped ZnO were found to be 1.82, 1.74, and 1.54ps , respectively.

  5. Sequential E2s drive polyubiquitin chain assembly on APC targets.

    PubMed

    Rodrigo-Brenni, Monica C; Morgan, David O

    2007-07-13

    The anaphase-promoting complex (APC), or cyclosome, is an E3 ubiquitin-protein ligase that collaborates with E2 ubiquitin-conjugating enzymes to assemble polyubiquitin chains on proteins important for cell-cycle progression. It remains unclear how the APC - or many other E3s - promotes the multiple distinct reactions necessary for chain assembly. We addressed this problem by analyzing APC interactions with different E2s. We screened all budding yeast E2s as APC coenzymes in vitro and found that two, Ubc4 and Ubc1, are the key E2 partners for the APC. These proteins display strikingly different but complementary enzymatic behaviors: Ubc4 supports the rapid monoubiquitination of multiple lysines on APC targets, while Ubc1 catalyzes K48-linked polyubiquitin chain assembly on preattached ubiquitins. Mitotic APC function is lost in yeast strains lacking both Ubc1 and Ubc4. E2-25K, a human homolog of Ubc1, also promotes APC-dependent chain extension on preattached ubiquitins. We propose that sequential E2 proteins catalyze K48-linked polyubiquitination and thus proteasomal destruction of APC targets.

  6. Prostaglandin E2 impairs osteogenic and facilitates adipogenic differentiation of human bone marrow stromal cells.

    PubMed

    Noack, Carolin; Hempel, Ute; Preissler, Carolin; Dieter, Peter

    2015-03-01

    The synthetic glucocorticoid dexamethasone (dex) is a mandatory additive to induce osteogenic differentiation of bone marrow stromal cell (BMSC) in vitro; however it is also known to promote the pathogenesis of osteoporotic bone disease in vivo. In this study human (h)BMSC were cultured in osteogenic medium containing β-glycerophosphate and ascorbate (OM) and in OM containing dex (OM/D). It was seen that dex induced in human (h)BMSC both, osteogenic and adipogenic differentiation markers. Dex reveals its anti-inflammatory effect by reducing endogenous prostaglandin E2 (PGE2) formation and by suppressing the inducible enzymes cyclooxygenase 2 and microsomal PGE2 synthase 1. It was further seen that dex enhanced the expression of prostaglandin receptors, mainly EP2 and EP4 receptor subtypes. We thus hypothesized that dex enforces the susceptibility of hBMSC to respond to exogenous PGE2. Permanent exposure of hBMSC which were cultured in OM/D to PGE2, decreased osteogenic and increased adipogenic differentiation markers. The effects of PGE2 were preferentially mediated by receptor subtypes EP2 and EP4; EP1 was partially involved in pro-adipogenic effects, and EP3 was partially involved in anti-osteogenic effects. These results suggest that dex suppresses the formation of endogenous PGE2 but also enables hBMSC to respond to PGE2 due to the induction of PGE2 receptors EP2 and EP4. PGE2 then shifts in hBMSC the balance from osteogenic to adipogenic differentiation.

  7. Prostaglandin E2 receptor EP3 regulates both adipogenesis and lipolysis in mouse white adipose tissue

    PubMed Central

    Xu, Hu; Fu, Jia-Lin; Miao, Yi-Fei; Wang, Chun-Jiong; Han, Qi-Fei; Li, Sha; Huang, Shi-Zheng; Du, Sheng-Nan; Qiu, Yu-Xiang; Yang, Ji-Chun; Gustafsson, Jan-Åke; Breyer, Richard M.; Zheng, Feng; Wang, Nan-Ping; Zhang, Xiao-Yan; Guan, You-Fei

    2016-01-01

    Among the four prostaglandin E2 receptors, EP3 receptor is the one most abundantly expressed in white adipose tissue (WAT). The mouse EP3 gene gives rise to three isoforms, namely EP3α, EP3β, and EP3γ, which differ only at their C-terminal tails. To date, functions of EP3 receptor and its isoforms in WAT remain incompletely characterized. In this study, we found that the expression of all EP3 isoforms were downregulated in WAT of both db/db and high-fat diet-induced obese mice. Genetic ablation of three EP3 receptor isoforms (EP3−/− mice) or EP3α and EP3γ isoforms with EP3β intact (EP3β mice) led to an obese phenotype with increased food intake, decreased motor activity, reduced insulin sensitivity, and elevated serum triglycerides. Since the differentiation of preadipocytes and mouse embryonic fibroblasts to adipocytes was markedly facilitated by either pharmacological blockade or genetic deletion/inhibition of EP3 receptor via the cAMP/PKA/PPARγ pathway, increased adipogenesis may contribute to obesity in EP3−/− and EP3β mice. Moreover, both EP3−/− and EP3β mice had increased lipolysis in WAT mainly due to the activated cAMP/PKA/hormone-sensitive lipase pathway. Taken together, our findings suggest that EP3 receptor and its α and γ isoforms are involved in both adipogenesis and lipolysis and influence food intake, serum lipid levels, and insulin sensitivity. PMID:27436752

  8. Intrauterine Group A Streptococcal Infections are Exacerbated by Prostaglandin E2

    PubMed Central

    Mason, Katie L.; Rogers, Lisa M.; Soares, Elyara M.; Bani-Hashemi, Tara; Downward, John Erb; Agnew, Dalen; Peters-Golden, Marc; Weinberg, Jason B.; Crofford, Leslie J.; Aronoff, David M.

    2013-01-01

    Streptococcus pyogenes(Group A Streptococcus; GAS) is a major cause of severe postpartum sepsis, a reemerging cause of maternal morbidity and mortality worldwide. Immunological alterations occur during pregnancy to promote maternofetal tolerance, which may increase the risk for puerperal infection. Prostaglandin E2 (PGE2) is an immunomodulatory lipid that regulates maternofetal tolerance, parturition, and innate immunity. The extent to which PGE2 regulates host immune responses to GAS infections in the context of endometritis is unknown. To address this, both an in vivo mouse intrauterine (i.u.) GAS infection model and an in vitro human macrophage-GAS interaction model were utilized. In C57BL/6 mice, i.u. GAS inoculation resulted in local and systemic inflammatory responses and triggered extensive changes in the expression of eicosanoid pathway genes. The i.u. administration of PGE2 increased the mortality of infected mice, suppressed local IL-6 and IL-17A levels, enhanced neutrophilic inflammation, reduced uterine macrophage populations, and increased bacterial dissemination. A role for endogenous PGE2 in modulating anti-streptococcal host defense was suggested because mice lacking the genes encoding the microsomal PGE2 synthase-1 or the EP2 receptor were protected from death, as were mice treated with the EP4 receptor antagonist GW627368X. PGE2 also regulated GAS-macrophage interactions. In GAS-infected human THP-1 (macrophage-like) cells, PGE2 inhibited the production of MCP-1 and TNF-α while augmenting IL-10 expression. PGE2 also impaired the phagocytic ability of human placental macrophages, THP-1 cells, and mouse peritoneal macrophages in vitro. Exploring the targeted disruption of PGE2 synthesis and signaling to optimize existing antimicrobial therapies against GAS may be warranted. PMID:23913961

  9. Serotonin modulates the cytokine network in the lung: involvement of prostaglandin E2

    PubMed Central

    Ménard, G; Turmel, V; Bissonnette, E Y

    2007-01-01

    Serotonin, well known for its role in depression, has been shown to modulate immune responses. Interestingly, the plasma level of serotonin is increased in symptomatic asthmatic patients and the use of anti-depressants, known to reduce serotonin levels, provokes a decrease in asthma symptoms and an increase in pulmonary function. Thus, we tested the hypothesis that serotonin affects alveolar macrophage (AM) cytokine production, altering the cytokine network in the lung and contributing to asthma pathogenesis. AMs were treated with different concentrations of serotonin (10-11−10-9 M) or 5-HT1 and 5-HT2 receptor agonists for 2 h prior stimulation. T helper 1 (Th1) and Th2 cytokines, prostaglandin-E2 (PGE2) and nitric oxide (NO) were measured in cell-free supernatants. Serotonin significantly inhibited the production of tumour necrosis factor (TNF) and interleukin (IL)-12, whereas IL-10, NO and PGE2 production were increased. These immunomodulatory effects of serotonin were mimicked by 5-HT2 receptor agonist but were not abrogated by 5-HT2 receptor antagonist, suggesting the implication of other 5-HT receptors. Inhibitors of cyclooxygenase and antibody to PGE2 abrogated the inhibitory and stimulatory effect of serotonin on TNF and IL-10 production, respectively, whereas NO synthase inhibitor eliminated serotonin-stimulated IL-10 increase. Furthermore, PGE2 significantly increased AM IL-10 and NO production. These results suggest that serotonin alters the cytokine network in the lung through the production of PGE2. The reduction of Th1-type cytokine by serotonin may contribute to asthma pathogenesis. PMID:17822443

  10. Prostaglandin E2 exerts the proapoptotic and antiproliferative effects on bovine NK cells.

    PubMed

    Maślanka, Tomasz; Chrostowska, Małgorzata; Otrocka-Domagała, Iwona; Snarska, Anna; Mikiewicz, Mateusz; Zuśka-Prot, Monika; Jasiecka, Agnieszka; Ziółkowski, Hubert; Markiewicz, Włodzimierz; Jaroszewski, Jerzy J

    2016-08-01

    The aim of this research was to determine whether prostaglandin E2 (PGE2) affects bovine NK cells in respect of their counts, apoptosis and proliferation, and if it does, then which of the PGE2 receptor (EP) subtype(s) mediate(s) these effects. We here report that long-term, but not short-term, exposure of bovine peripheral blood mononuclear cells to PGE2 at 10(-5)M, 10(-6)M and 10(-7)M, but not at 10(-8)M, caused a significant increase in the percentage of early apoptotic cells among NK cell subset. Moreover, PGE2 at 10(-5)M and 10(-6)M, but not at 10(-7)M and 10(-8)M, induced a considerable decrease in the absolute count of NK cells. The magnitude of these effects increased with an increasing concentration of PGE2. The blockade of EP1, EP2, EP3 and EP4 receptors did not prevent the PGE2-induced apoptosis and depletion of NK cells. The results suggest that the proapoptotic effect of PGE2 is secondary in character and the induction of this effect is not mediated through EP receptors. Furthermore, the studies demonstrated that PGE2 at 10(-5)M and 10(-6)M, but not at 10(-7)M and 10(-8)M, highly significantly reduced the percentage of proliferating NK cells. The EP1, EP1/2 and EP3 receptor antagonists were unable to block this effect significantly, whereas the selective blockade of EP4 receptors prevented the PGE2-induced inhibition of NK cells proliferation. These results indicate that PGE2 at certain concentrations may impair the proliferation of NK cells and this effect is mediated via the EP4 receptor.

  11. Regulation of sulfated glycosaminoglycan production by prostaglandin E2 in cultured lung fibroblasts

    SciTech Connect

    Karlinsky, J.B.; Goldstein, R.H. )

    1989-08-01

    Prostaglandin E2 (PGE2) has been shown to increase the synthesis of hyaluronic acid in cultured fibroblasts by increasing the activity of hyaluronate synthetase, a group of plasma membrane-bound synthetic enzymes. We examined whether PGE2 also increased the activity of those enzyme systems involved in the synthesis of sulfated glycosaminoglycan in the human embryonic lung fibroblast. Exposure of cells to PGE2 resulted in dose-dependent increases in glucosamine incorporation into all sulfated glycosaminoglycan subtypes. PGE2 at 10(-7) mol/L increased total glycosaminoglycan per dish to 21.6 +/- 3.1 micrograms versus 12.0 +/- 2.5 micrograms in control untreated cultures. Stimulation of endogenous PGE2 production by bradykinin had a similar effect on glycosaminoglycan synthesis. To examine whether PGE2 affected sulfated glycosaminoglycan protein core production, cells were labeled with tritiated glucosamine in the presence of cycloheximide. Under these conditions, incorporation of radiolabel into all glycosaminoglycan subtypes was reduced. However, when exogenous sulfated glycosaminoglycan chain initiator (p-nitrophenyl beta-D-xyloside) was added, incorporation of tritiated glucosamine into sulfated glycosaminoglycan increased but not to levels found in control cultures. Application of PGE2 to cultures treated with cycloheximide alone, or to cultures treated with cycloheximide plus xyloside, increased tritiated glucosamine incorporation into chondroitin, dermatan sulfate, and to a lesser extent into heparan sulfate. We conclude that PGE2 stimulates synthesis of all sulfated glycosaminoglycan even in the absence of new protein core production, probably by increasing activities of sulfated glycosaminoglycan synthetase enzymes. PGE2 stimulation of heparan sulfate synthesis is partially dependent on the availability of heparan sulfate-specific protein core.

  12. Low and high dose UVB regulation of transcription factor NF-E2-related factor 2.

    PubMed

    Kannan, Sankaranarayanan; Jaiswal, Anil K

    2006-09-01

    Transcription factor NF-E2-related factor 2 (Nrf2) regulates antioxidant response element (ARE)-mediated expression and coordinated induction of chemoprotective proteins in response to chemical stress. In this report, we investigated Nrf2 response to low and high dose UVB irradiation. Low dose (7.5 J/m(2)) UVB exposure of mouse hepatoma, mouse keratinocyte, and human skin fibroblast cells led to the nuclear accumulation of Nrf2 and up-regulation of ARE-mediated gene expression. On the contrary, and intriguingly, high dose (20 J/m(2)) UVB exposure of cells led to the nuclear exclusion of Nrf2 and down-regulation of chemoprotective gene expression with possible implications in UVB carcinogenesis. We investigated the mechanism by which high dose UVB induced the nuclear exclusion of Nrf2. Prior treatment with nuclear export inhibitor, leptomycin B, abrogated the UVB-induced nuclear exclusion of Nrf2, indicating that the decrease of Nrf2 in the nucleus was due to the nuclear export of Nrf2. High dose UVB increased the phosphorylation of Nrf2Y568 which stimulated the nuclear export of Nrf2. Mutation of Nrf2Y568 to phenylalanine and src kinase inhibitor PP2 abrogated/reduced the UVB-induced phosphorylation of Nrf2Y568 and nuclear exclusion of Nrf2. Transfection with src family member Fyn small interfering RNA resulted in the nuclear accumulation of Nrf2 and an increase in the expression and UVB induction of ARE-mediated gene expression. UVB exposure also induced the nuclear localization of Fyn. These results suggest that high dose UVB induced the activation/nuclear localization of Fyn which led to increased phosphorylation of Nrf2Y568 and enhanced nuclear export of Nrf2. This resulted in nuclear exclusion of Nrf2 and down-regulation of ARE-mediated chemoprotective gene expression.

  13. Prostaglandin E2 regulates angiogenesis via activation of fibroblast growth factor receptor-1.

    PubMed

    Finetti, Federica; Solito, Raffaella; Morbidelli, Lucia; Giachetti, Antonio; Ziche, Marina; Donnini, Sandra

    2008-01-25

    Prostaglandin E(2) (PGE(2)) behaves as a mitogen in epithelial tumor cells as well as in many other cell types. We investigated the actions of PGE(2) on microvascular endothelial cells (capillary venular endothelial cells) with the purpose of delineating the signaling pathway leading to the acquisition of the angiogenic phenotype and to new vessel formation. PGE(2) (100 nM) produced activation of the fibroblast growth factor receptor 1 (FGFR-1), as measured by its phosphorylation, but not of vascular endothelial growth factor receptor 2. PGE(2) stimulated the EP3 subtype receptor, as deduced by abrogation of EP3 Galpha(i) subunit activity through pertussis toxin. Consistent with this result, in human umbilical venular endothelial cells missing the EP3 receptor, PGE(2) did not phosphorylate FGFR-1. Upon binding to its receptor, PGE(2) initiated an autocrine/paracrine signaling cascade involving the intracellular activation of c-Src, activation of matrix metalloproteinase (predominantly MMP2), which in turn caused the mobilization of membrane-anchored fibroblast growth factor-2 (FGF-2). In fact, in cells unable to release FGF-2 the transfection with both FGFR-1 and EP3 did not result in FGFR-1 phosphorylation in response to PGE(2). Relevance for the FGF2-FGFR-1 system was highlighted by confocal analysis, showing receptor internalization after cell exposure to the prostanoid. ERK1/2 appeared to be the distal signal involved, its phosphorylation being sensitive to either cSrc inhibitor or FGFR-1 blocker. Finally, PGE(2) stimulated cell migration and capillary formation in aortic rings, which were severely reduced by inhibitors of signaling molecules or by receptor antagonist. In conclusion, this study provides evidence for the involvement of FGFR-1 through FGF2 in eliciting PGE(2) angiogenic responses. This signaling pattern is similar to the autocrine-paracrine mechanism which operates in endothelial cells to support neovascular growth.

  14. Hp-41CV flight performance advisory system (FPAS) for the E-2c, E-2B, and C-2A aircraft. Final technical report Apr-Jun 82

    SciTech Connect

    Ferrell, D.R.

    1982-06-01

    This report describes follow-on work performed under the auspices of AE 4900, Directed Studies in Aeronautical Engineering at the Naval Postgraduate School, to complement the original design of a Flight Performance Advisory System (FPAS) for the E-2C aircraft. The original design fulfilled the requirements of AE 3001, Aircraft Energy Conservation. AE 3001, offered in the Fall Quarter 1981, and conducted by Professor Allen E. Fuhs, was sponsored in part by the Naval Air Development Center (NADC). NADC desired to obtain the input of several fleet experienced aviators in order to design program code for the HP-41CV handheld, programmable calculator that would benefit pilots by providing them with fuel efficiency parameters in flight. Calculators were made available to the participants with the proviso that a completed and operable code for each aircraft be submitted by the end of the academic quarter, September 1981. Upon completion of the E-2C program, attempts were made to use the calculator in flight. One test was conducted informally in an E-2C at RVAW-110, NAS Miramar. Unfortunately, the voltage field induced in the cockpit by the main lobe of the radar passing over the cockpit caused the calculator to cease functioning. The need to devise shielding for the calculator, plus the desire to simplify and improve the existing code lead to this effort.

  15. E2F4 and ribonucleotide reductase mediate S-phase arrest in colon cancer cells treated with chlorophyllin.

    PubMed

    Chimploy, Korakod; Díaz, G Dario; Li, Qingjie; Carter, Orianna; Dashwood, Wan-Mohaiza; Mathews, Christopher K; Williams, David E; Bailey, George S; Dashwood, Roderick H

    2009-11-01

    Chlorophyllin (CHL) is a water-soluble derivative of chlorophyll that exhibits cancer chemopreventive properties, but which also has been studied for its possible cancer therapeutic effects. We report here that human colon cancer cells treated with CHL accumulate in S-phase of the cell cycle, and this is associated with reduced expression levels of p53, p21, and other G(1)/S checkpoint controls. At the same time, E2F1 and E2F4 transcription factors become elevated and exhibit increased DNA binding activity. In CHL-treated colon cancer cells, bromodeoxyuridine pulse-chase experiments provided evidence for the inhibition of DNA synthesis. Ribonucleotide reductase (RR), a pivotal enzyme for DNA synthesis and repair, was reduced at the mRNA and protein level after CHL treatment, and the enzymatic activity was inhibited in a concentration-dependent manner both in vitro and in vivo. Immunoblotting revealed that expression levels of RR subunits R1, R2, and p53R2 were reduced by CHL treatment in HCT116 (p53(+/+)) and HCT116 (p53(-/-)) cells, supporting a p53-independent mechanism. Prior studies have shown that reduced levels of RR small subunits can increase the sensitivity of colon cancer cells to clinically used DNA-damaging agents and RR inhibitors. We conclude that by inhibiting R1, R2, and p53R2, CHL has the potential to be effective in the clinical setting, when used alone or in combination with currently available cancer therapeutic agents.

  16. NATURE OF W51e2: MASSIVE CORES AT DIFFERENT PHASES OF STAR FORMATION

    SciTech Connect

    Shi Hui; Han, J. L.; Zhao Junhui E-mail: hjl@nao.cas.c

    2010-02-10

    We present high-resolution continuum images of the W51e2 complex processed from archival data of the Submillimeter Array (SMA) at 0.85 and 1.3 mm and the Very Large Array at 7 and 13 mm. We also made line images and profiles of W51e2 for three hydrogen radio recombination lines (RRLs; H26alpha, H53alpha, and H66alpha) and absorption of two molecular lines of HCN(4-3) and CO(2-1). At least four distinct continuum components have been detected in the 3'' region of W51e2 from the SMA continuum images at 0.85 and 1.3 mm with resolutions of 0.''3 x 0.''2 and 1.''4 x 0.''7, respectively. The west component, W51e2-W, coincides with the ultracompact H II region reported from previous radio observations. The H26alpha line observation reveals an unresolved hyper-compact ionized core (<0.''06 or <310 AU) with a high electron temperature of 1.2 x 10{sup 4} K, with the corresponding emission measure EM>7 x 10{sup 10} pc cm{sup -6} and the electron density N{sub e} >7 x 10{sup 6} cm{sup -3}. The inferred Lyman continuum flux implies that the H II region W51e2-W requires a newly formed massive star, an O8 star or a cluster of B-type stars, to maintain the ionization. W51e2-E, the brightest component at 0.85 mm, is located 0.''9 east from the hyper-compact ionized core. It has a total mass of {approx}140 M{sub sun} according to our spectral energy distribution analysis and a large infall rate of >1.3 x 10{sup -3} M{sub sun} yr{sup -1} inferred from the absorption of HCN. W51e2-E appears to be the accretion center in W51e2. Given the fact that no free-free emission and no RRLs have been detected, the massive core of W51e2-E appears to host one or more growing massive proto-stars. Located 2'' northwest from W51e2-E, W51e2-NW is detected in the continuum emission at 0.85 and 1.3 mm. No continuum emission has been detected at lambda>= 7 mm. Along with the maser activities previously observed, our analysis suggests that W51e2-NW is at an earlier phase of star formation. W51e2-N is

  17. Perspective on the reactions between F- and CH3CH2F: the free energy landscape of the E2 and SN2 reaction channels.

    PubMed

    Ensing, Bernd; Klein, Michael L

    2005-05-10

    Recently, we computed the 3D free energy surface of the base-induced elimination reaction between F(-) and CH(3)CH(2)F by using a powerful technique within Car-Parrinello molecular dynamics simulation. Here, the set of three order parameters is expanded to six, which allows the study of the competing elimination and substitution reactions simultaneously. The power of the method is exemplified by the exploration of the six-dimensional free energy landscape, sampling, and mapping out the eight stable states as well as the connecting bottlenecks. The free energy profile and barrier along the E2 and S(N)2 reaction channels are refined by using umbrella sampling. The two mechanisms do not share a common "E2C-like" transition state. Comparison with the zero temperature profiles shows a particularly significant entropy contribution to the S(N)2 channel.

  18. Gestational diabetes leads to down-regulation of CDK4-pRB-E2F1 pathway genes in pancreatic islets of rat offspring

    PubMed Central

    Nazari, Zahra; Nabiuni, Mohammad; Saeidi, Mohsen; Golalipour, Mohammad Jafar

    2017-01-01

    Objective(s): The link between a hyperglycemic intrauterine environment and the development of diabetes later in life has been observed in offspring exposed to gestational diabetes mellitus (GDM), but the underlying mechanisms for this phenomenon are still not clear. Reduced β-cells mass is a determinant in the development of diabetes (type 1 and type 2 diabetes). Some recent studies have provided evidence that the CDK4-pRB-E2F1 regulatory pathway is involved in β-cells proliferation. Therefore, we postulated that GDM exposure impacts the offspring’s β-cells by disruption in the CDK4-pRB-E2F1 pathway. Materials and Methods: Adult Wistar rats were randomly allocated in control and diabetic group. The experimental group received 40 mg/kg/body weight of streptozotocin (STZ) on day zero of gestation. After delivery, diabetic offspring of GDM mothers and control dams at the age of 15 week were randomly scarified and pancreases were harvested. Langerhans islets of diabetic and control groups were digested by collagenase digestion technique. After RNA extraction, we investigated the expressions of the kir 6.2 and CDK4-pRB-E2F1 pathway genes by quantitative real-time PCR. Results: GDM reduced the expression of CDK4-pRB-E2F1 pathway genes in Langerhans islets cells of offspring. CDK4, pRB and E2F1 pathway genes were downregulated in diabetic islets by 51%, 35% and 84%, respectively. Also, the expression of Kir 6.2 was significantly decreased in diabetic islets by 88%. Conclusion: We suggest that the effect of gestational diabetes on offspring’s β-cells may be primarily caused by the suppression of CDK4-pRB-E2F1 pathway. PMID:28293391

  19. Eliminating Transitions

    ERIC Educational Resources Information Center

    Gallick, Barb; Lee, Lisa

    2010-01-01

    Adults often find themselves transitioning from one activity to another in a short time span. Most of the time, they do not feel they have a lot of control over their schedules, but wish that they could carve out extended time to relax and focus on one project. Picture a group of children in the block area who have spent 15 or 20 minutes building…

  20. Dissecting the Role of E2 Protein Domains in Alphavirus Pathogenicity

    PubMed Central

    Weger-Lucarelli, James; Aliota, Matthew T.; Wlodarchak, Nathan; Kamlangdee, Attapon; Swanson, Ryan

    2015-01-01

    ABSTRACT Alphaviruses represent a diverse set of arboviruses, many of which are important pathogens. Chikungunya virus (CHIKV), an arthritis-inducing alphavirus, is the cause of a massive ongoing outbreak in the Caribbean and South America. In contrast to CHIKV, other related alphaviruses, such as Venezuelan equine encephalitis virus (VEEV) and Semliki Forest virus (SFV), can cause encephalitic disease. E2, the receptor binding protein, has been implicated as a determinant in cell tropism, host range, pathogenicity, and immunogenicity. Previous reports also have demonstrated that E2 contains residues important for host range expansions and monoclonal antibody binding; however, little is known about what role each protein domain (e.g., A, B, and C) of E2 plays on these factors. Therefore, we constructed chimeric cDNA clones between CHIKV and VEEV or SFV to probe the effect of each domain on pathogenicity in vitro and in vivo. CHIKV chimeras containing each of the domains of the E2 (ΔDomA, ΔDomB, and ΔDomC) from SFV, but not VEEV, were successfully rescued. Interestingly, while all chimeric viruses were attenuated compared to CHIKV in mice, ΔDomB virus showed similar rates of infection and dissemination in Aedes aegypti mosquitoes, suggesting differing roles for the E2 protein in different hosts. In contrast to CHIKV; ΔDomB, and to a lesser extent ΔDomA, caused neuron degeneration and demyelination in mice infected intracranially, suggesting a shift toward a phenotype similar to SFV. Thus, chimeric CHIKV/SFV provide insights on the role the alphavirus E2 protein plays on pathogenesis. IMPORTANCE Chikungunya virus (CHIKV) has caused large outbreaks of acute and chronic arthritis throughout Africa and Southeast Asia and has now become a massive public health threat in the Americas, causing an estimated 1.2 million human cases in just over a year. No approved vaccines or antivirals exist for human use against CHIKV or any other alphavirus. Despite the threat

  1. Conservation of the E8 CDS of the E8^E2 protein among mammalian papillomaviruses.

    PubMed

    Puustusmaa, Mikk; Abroi, Aare

    2016-09-01

    Papillomaviridae are small dsDNA viruses with a limited coding capacity. To fulfill all of the functional requirements for propagation and spreading, papillomaviruses use double coding and alternative protein isoforms. E8 ^ E2 is an alternative E2 protein isoform that is generated by fusing the short E8 CDS that completely overlaps E1 to the 'hinge' and the DNA-binding region of the E2 protein via alternative transcription/splicing. The papillomaviruses in which E8 ^ E2 mRNA sequences have been described exhibit a sparse phylogenomic distribution. Thus, it is not clear whether E8 ^ E2 is an ancestral protein that has not been described for other papillomavirus types or whether it randomly appears because of the conservation of the E1 protein and occurs only coincidentally. We searched for potential E8 coding sequences in a non-redundant set of papillomaviruses and applied SynPlot2 and an in-house-developed algorithm (cRegions) to determine the most plausible of the above-mentioned scenarios. Beginning with nine experimentally described E8 ^ E2 mRNAs, we predicted the potential E8 CDSs for more than 300 mammalian papillomavirus genomes. According to our analysis, E8 ^ E2 is not a result of E1 coding and represents a protein in its own right, and it most likely has an ancestral origin that precedes the divergence of major mammalian papillomavirus genera.

  2. Structure-function analysis of hepatitis C virus envelope glycoproteins E1 and E2.

    PubMed

    Nayak, Aparajita; Pattabiraman, Nagarajan; Fadra, Numrah; Goldman, Radoslav; Kosakovsky Pond, Sergei L; Mazumder, Raja

    2015-01-01

    Hepatitis C virus (HCV) is the leading cause of chronic liver disease in humans. The envelope proteins of HCV are potential candidates for vaccine development. The absence of three-dimensional (3D) structures for the functional domain of HCV envelope proteins [E1.E2] monomer complex has hindered overall understanding of the virus infection, and also structure-based drug design initiatives. In this study, we report a 3D model containing both E1 and E2 proteins of HCV using the recently published structure of the core domain of HCV E2 and the functional part of E1, and investigate immunogenic implications of the model. HCV [E1.E2] molecule is modeled by using aa205-319 of E1 to aa421-716 of E2. Published experimental data were used to further refine the [E1.E2] model. Based on the model, we predict 77 exposed residues and several antigenic sites within the [E1.E2] that could serve as vaccine epitopes. This study identifies eight peptides which have antigenic propensity and have two or more sequentially exposed amino acids and 12 singular sites are under negative selection pressure that can serve as vaccine or therapeutic targets. Our special interest is 285FLVGQLFTFSPRRHW299 which has five negatively selected sites (L286, V287, G288, T292, and G303) with three of them sequential and four amino acids exposed (F285, L286, T292, and R296). This peptide in the E1 protein maps to dengue envelope vaccine target identified previously by our group. Our model provides for the first time an overall view of both the HCV envelope proteins thereby allowing researchers explore structure-based drug design approaches.

  3. Inactivation of Rb and E2f8 synergizes to trigger stressed DNA replication during erythroid terminal differentiation.

    PubMed

    Ghazaryan, Seda; Sy, Chandler; Hu, Tinghui; An, Xiuli; Mohandas, Narla; Fu, Haiqing; Aladjem, Mirit I; Chang, Victor T; Opavsky, Rene; Wu, Lizhao

    2014-08-01

    Rb is critical for promoting cell cycle exit in cells undergoing terminal differentiation. Here we show that during erythroid terminal differentiation, Rb plays a previously unappreciated and unorthodox role in promoting DNA replication and cell cycle progression. Specifically, inactivation of Rb in erythroid cells led to stressed DNA replication, increased DNA damage, and impaired cell cycle progression, culminating in defective terminal differentiation and anemia. Importantly, all of these defects associated with Rb loss were exacerbated by the concomitant inactivation of E2f8. Gene expression profiling and chromatin immunoprecipitation (ChIP) revealed that Rb and E2F8 cosuppressed a large array of E2F target genes that are critical for DNA replication and cell cycle progression. Remarkably, inactivation of E2f2 rescued the erythropoietic defects resulting from Rb and E2f8 deficiencies. Interestingly, real-time quantitative PCR (qPCR) on E2F2 ChIPs indicated that inactivation of Rb and E2f8 synergizes to increase E2F2 binding to its target gene promoters. Taken together, we propose that Rb and E2F8 collaborate to promote DNA replication and erythroid terminal differentiation by preventing E2F2-mediated aberrant transcriptional activation through the ability of Rb to bind and sequester E2F2 and the ability of E2F8 to compete with E2F2 for E2f-binding sites on target gene promoters.

  4. Inactivation of Rb and E2f8 Synergizes To Trigger Stressed DNA Replication during Erythroid Terminal Differentiation

    PubMed Central

    Ghazaryan, Seda; Sy, Chandler; Hu, Tinghui; An, Xiuli; Mohandas, Narla; Fu, Haiqing; Aladjem, Mirit I.; Chang, Victor T.; Opavsky, Rene

    2014-01-01

    Rb is critical for promoting cell cycle exit in cells undergoing terminal differentiation. Here we show that during erythroid terminal differentiation, Rb plays a previously unappreciated and unorthodox role in promoting DNA replication and cell cycle progression. Specifically, inactivation of Rb in erythroid cells led to stressed DNA replication, increased DNA damage, and impaired cell cycle progression, culminating in defective terminal differentiation and anemia. Importantly, all of these defects associated with Rb loss were exacerbated by the concomitant inactivation of E2f8. Gene expression profiling and chromatin immunoprecipitation (ChIP) revealed that Rb and E2F8 cosuppressed a large array of E2F target genes that are critical for DNA replication and cell cycle progression. Remarkably, inactivation of E2f2 rescued the erythropoietic defects resulting from Rb and E2f8 deficiencies. Interestingly, real-time quantitative PCR (qPCR) on E2F2 ChIPs indicated that inactivation of Rb and E2f8 synergizes to increase E2F2 binding to its target gene promoters. Taken together, we propose that Rb and E2F8 collaborate to promote DNA replication and erythroid terminal differentiation by preventing E2F2-mediated aberrant transcriptional activation through the ability of Rb to bind and sequester E2F2 and the ability of E2F8 to compete with E2F2 for E2f-binding sites on target gene promoters. PMID:24865965

  5. Oxygen-reducing catalyst layer

    DOEpatents

    O'Brien, Dennis P [Maplewood, MN; Schmoeckel, Alison K [Stillwater, MN; Vernstrom, George D [Cottage Grove, MN; Atanasoski, Radoslav [Edina, MN; Wood, Thomas E [Stillwater, MN; Yang, Ruizhi [Halifax, CA; Easton, E Bradley [Halifax, CA; Dahn, Jeffrey R [Hubley, CA; O'Neill, David G [Lake Elmo, MN

    2011-03-22

    An oxygen-reducing catalyst layer, and a method of making the oxygen-reducing catalyst layer, where the oxygen-reducing catalyst layer includes a catalytic material film disposed on a substrate with the use of physical vapor deposition and thermal treatment. The catalytic material film includes a transition metal that is substantially free of platinum. At least one of the physical vapor deposition and the thermal treatment is performed in a processing environment comprising a nitrogen-containing gas.

  6. HER2 Signaling Drives DNA Anabolism and Proliferation through SRC-3 Phosphorylation and E2F1-Regulated Genes.

    PubMed

    Nikolai, Bryan C; Lanz, Rainer B; York, Brian; Dasgupta, Subhamoy; Mitsiades, Nicholas; Creighton, Chad J; Tsimelzon, Anna; Hilsenbeck, Susan G; Lonard, David M; Smith, Carolyn L; O'Malley, Bert W

    2016-03-15

    Approximately 20% of early-stage breast cancers display amplification or overexpression of the ErbB2/HER2 oncogene, conferring poor prognosis and resistance to endocrine therapy. Targeting HER2(+) tumors with trastuzumab or the receptor tyrosine kinase (RTK) inhibitor lapatinib significantly improves survival, yet tumor resistance and progression of metastatic disease still develop over time. Although the mechanisms of cytosolic HER2 signaling are well studied, nuclear signaling components and gene regulatory networks that bestow therapeutic resistance and limitless proliferative potential are incompletely understood. Here, we use biochemical and bioinformatic approaches to identify effectors and targets of HER2 transcriptional signaling in human breast cancer. Phosphorylation and activity of the Steroid Receptor Coactivator-3 (SRC-3) is reduced upon HER2 inhibition, and recruitment of SRC-3 to regulatory elements of endogenous genes is impaired. Transcripts regulated by HER2 signaling are highly enriched with E2F1 binding sites and define a gene signature associated with proliferative breast tumor subtypes, cell-cycle progression, and DNA replication. We show that HER2 signaling promotes breast cancer cell proliferation through regulation of E2F1-driven DNA metabolism and replication genes together with phosphorylation and activity of the transcriptional coactivator SRC-3. Furthermore, our analyses identified a cyclin-dependent kinase (CDK) signaling node that, when targeted using the CDK4/6 inhibitor palbociclib, defines overlap and divergence of adjuvant pharmacologic targeting. Importantly, lapatinib and palbociclib strictly block de novo synthesis of DNA, mostly through disruption of E2F1 and its target genes. These results have implications for rational discovery of pharmacologic combinations in preclinical models of adjuvant treatment and therapeutic resistance.

  7. Differential Effects of E2 on MAPK Activity in the Brain and Heart of Aged Female Rats

    PubMed Central

    Shults, Cody L.; Rao, Yathindar S.; Pak, Toni R.

    2016-01-01

    Aging and the coincident loss of circulating estrogens at menopause lead to increased risks for neurological and cardiovascular pathologies. Clinical studies show that estrogen therapy (ET) can be beneficial in mitigating these negative effects, in both the brain and heart, when it is initiated shortly after the perimenopausal transition. However, this same therapy is detrimental when initiated >10 years postmenopause. Importantly, the molecular mechanisms underlying this age-related switch in ET efficacy are unknown. Estrogen receptors (ERs) mediate the neuroprotective and cardioprotective functions of estrogens by modulating gene transcription or, non-genomically, by activating second messenger signaling pathways, such as mitogen activated protein kinases (MAPK). These kinases are critical regulators of cell signaling pathways and have widespread downstream effects. Our hypothesis is that age and estrogen deprivation following menopause alters the expression and activation of the MAPK family members p38 and ERK in the brain and heart. To test this hypothesis, we used a surgically induced model of menopause in 18 month old rats through bilateral ovariectomy (OVX) followed by an acute dose of 17β-estradiol (E2) administered at varying time points post-OVX (1 week, 4 weeks, 8 weeks, or 12 weeks). Age and E2 treatment differentially regulated kinase activity in both the brain and heart, and the effects were also brain region specific. MAPK signaling plays an integral role in aging, and the aberrant regulation of those signaling pathways might be involved in age-related disorders. Clinical studies show benefits of ET during early menopause but detrimental effects later, which might be reflective of changes in kinase expression and activation status. PMID:27487271

  8. E2F6 Impairs Glycolysis and Activates BDH1 Expression Prior to Dilated Cardiomyopathy

    PubMed Central

    Major, Jennifer L.; Dewan, Aaraf; Salih, Maysoon; Leddy, John J.; Tuana, Balwant S.

    2017-01-01

    Rationale The E2F pathway plays a critical role in cardiac growth and development, yet its role in cardiac metabolism remains to be defined. Metabolic changes play important roles in human heart failure and studies imply the ketogenic enzyme β-hydroxybutyrate dehydrogenase I (BDH1) is a potential biomarker. Objective To define the role of the E2F pathway in cardiac metabolism and dilated cardiomyopathy (DCM) with a focus on BDH1. Methods and Results We previously developed transgenic (Tg) mice expressing the transcriptional repressor, E2F6, to interfere with the E2F/Rb pathway in post-natal myocardium. These Tg mice present with an E2F6 dose dependent DCM and deregulated connexin-43 (CX-43) levels in myocardium. Using the Seahorse platform, a 22% decrease in glycolysis was noted in neonatal cardiomyocytes isolated from E2F6-Tg hearts. This was associated with a 39% reduction in the glucose transporter GLUT4 and 50% less activation of the regulator of glucose metabolism AKT2. The specific reduction of cyclin B1 (70%) in Tg myocardium implicates its importance in supporting glycolysis in the postnatal heart. No changes in cyclin D expression (known to regulate mitochondrial activity) were noted and lipid metabolism remained unchanged in neonatal cardiomyocytes from Tg hearts. However, E2F6 induced a 40-fold increase of the Bdh1 transcript and 890% increase in its protein levels in hearts from Tg pups implying a potential impact on ketolysis. By contrast, BDH1 expression is not activated until adulthood in normal myocardium. Neonatal cardiomyocytes from Wt hearts incubated with the ketone β-hydroxybutyrate (β-OHB) showed a 100% increase in CX-43 protein levels, implying a role for ketone signaling in gap junction biology. Neonatal cardiomyocyte cultures from Tg hearts exhibited enhanced levels of BDH1 and CX-43 and were not responsive to β-OHB. Conclusions The data reveal a novel role for the E2F pathway in regulating glycolysis in the developing myocardium

  9. ModelE2-TOMAS development and evaluation using aerosol optical depths, mass and number concentrations

    NASA Astrophysics Data System (ADS)

    Lee, Y. H.; Adams, P. J.; Shindell, D. T.

    2014-09-01

    The TwO-Moment Aerosol Sectional microphysics model (TOMAS) has been integrated into the state-of-the-art general circulation model, GISS ModelE2. TOMAS has the flexibility to select a size resolution as well as the lower size cutoff. A computationally efficient version of TOMAS is used here, which has 15 size bins covering 3 nm to 10 μm aerosol dry diameter. For each bin, it simulates the total aerosol number concentration and mass concentrations of sulphate, pure elementary carbon (hydrophobic), mixed elemental carbon (hydrophilic), hydrophobic organic matter, hydrophilic organic matter, sea salt, mineral dust, ammonium, and aerosol-associated water. This paper provides a detailed description of the ModelE2-TOMAS model and evaluates the model against various observations including aerosol precursor gas concentrations, aerosol mass and number concentrations, and aerosol optical depths. Additionally, global budgets in ModelE2-TOMAS are compared with those of other global aerosol models, and the TOMAS model is compared to the default aerosol model in ModelE2, which is a bulk aerosol model. Overall, the ModelE2-TOMAS predictions are within the range of other global aerosol model predictions, and the model has a reasonable agreement with observations of sulphur species and other aerosol components as well as aerosol optical depth. However, ModelE2-TOMAS (as well as the bulk aerosol model) cannot capture the observed vertical distribution of sulphur dioxide over the Pacific Ocean possibly due to overly strong convective transport. The TOMAS model successfully captures observed aerosol number concentrations and cloud condensation nuclei concentrations. Anthropogenic aerosol burdens in the bulk aerosol model running in the same host model as TOMAS (ModelE2) differ by a few percent to a factor of 2 regionally, mainly due to differences in aerosol processes including deposition, cloud processing, and emission parameterizations. Larger differences are found for naturally

  10. Aberrant Retinoblastoma (RB)-E2F Transcriptional Regulation Defines Molecular Phenotypes of Osteosarcoma.

    PubMed

    Scott, Milcah C; Sarver, Aaron L; Tomiyasu, Hirotaka; Cornax, Ingrid; Van Etten, Jamie; Varshney, Jyotika; O'Sullivan, M Gerard; Subramanian, Subbaya; Modiano, Jaime F

    2015-11-20

    We previously identified two distinct molecular subtypes of osteosarcoma through gene expression profiling. These subtypes are associated with distinct tumor behavior and clinical outcomes. Here, we describe mechanisms that give rise to these molecular subtypes. Using bioinformatic analyses, we identified a significant association between deregulation of the retinoblastoma (RB)-E2F pathway and the molecular subtype with worse clinical outcomes. Xenotransplantation models recapitulated the corresponding behavior for each osteosarcoma subtype; thus, we used cell lines to validate the role of the RB-E2F pathway in regulating the prognostic gene signature. Ectopic RB resets the patterns of E2F regulated gene expression in cells derived from tumors with worse clinical outcomes (molecular phenotype 2) to those comparable with those observed in cells derived from tumors with less aggressive outcomes (molecular phenotype 1), providing a functional association between RB-E2F dysfunction and altered gene expression in osteosarcoma. DNA methyltransferase and histone deacetylase inhibitors similarly reset the transcriptional state of the molecular phenotype 2 cells from a state associated with RB deficiency to one seen with RB sufficiency. Our data indicate that deregulation of RB-E2F pathway alters the epigenetic landscape and biological behavior of osteosarcoma.

  11. PCOS women show significantly higher homocysteine level, independent to glucose and E2 level

    PubMed Central

    Eskandari, Zahra; Sadrkhanlou, Rajab-Ali; Nejati, Vahid; Tizro, Gholamreza

    2016-01-01

    Background: It is reasonable to think that some biochemical characteristics of follicular fluid (FF) surrounding the oocyte may play a critical role in determining the quality of oocyte and the subsequent potential needed to achieve fertilization and embryo development. Objective: This study was carried out to evaluate the levels of FF homocysteine (Hcy) in IVF candidate polycystic ovary syndrome (PCOS) women and any relationships with FF glucose and estradiol (E2) levels. Materials and Methods: In this case control study which was performed in Dr. Tizro Day Care and IVF Center 70 infertile patients were enrolled in two groups: comprising 35 PCOS and 35 non PCOS women. Long protocol was performed for all patients. FF Hcy, glucose and E2 levels were analyzed at the time of oocyte retrieval. Results: It was observed that FF Hcy level was significantly higher in PCOS patients compared with non PCOSs (p<0.01). Observations demonstrated that in PCOS group, the Hcy level increased independent to E2, glucose levels, BMI and age, while the PCOS group showed significantly higher BMI compared with non-PCOS group (p=0.03). However, no significant differences were revealed between groups for FF glucose and E2 levels. Conclusion: Present data showed that although FF glucose and E2 levels were constant in PCOS and non PCOS patients, but the FF Hcy levels in PCOS were significantly increased (p=0.01). PMID:27679823

  12. Identification of conjugation specificity determinants unmasks vestigial preference for ubiquitin within the NEDD8 E2.

    PubMed

    Huang, Danny T; Zhuang, Min; Ayrault, Olivier; Schulman, Brenda A

    2008-03-01

    Ubiquitin-like proteins (UBLs) modify targets via related E1-E2-E3 cascades. How is UBL conjugation fidelity established? Here we report the basis for UBL selection by UBL conjugating enzyme 12 (Ubc12), which is specific for the neural precursor cell expressed, developmentally down-regulated protein 8 (NEDD8), and does not form a thioester-linked conjugate with ubiquitin. We systematically identified Ubc12 surfaces impeding Ubc12 approximately ubiquitin conjugate formation and found that several structurally dispersed E1 binding elements, rather than UBL-interacting surfaces, determine E2 approximately UBL specificity. In addition to roles for conserved E1 and E2 domains, unique structures contribute UBL specificity to the NEDD8 and ubiquitin pathways. By removing surface elements, without substituting corresponding sequences from ubiquitin E2s, we unmasked Ubc12's vestigial preference for ubiquitin over NEDD8 by approximately 10(10)-fold. This has implications for the evolution of specific functions among ubiquitin E2s. We also find that Ubc12 sequences dictating UBL selection map to the E3 binding site, thus providing a molecular mechanism preventing inappropriate modification of targets.

  13. Identification of E2F1 as a positive transcriptional regulator for {delta}-catenin

    SciTech Connect

    Kim, Kwonseop; Oh, Minsoo; Ki, Hyunkyoung; Wang Tao; Bareiss, Sonja; Fini, M. Elizabeth.; Li Dawei; Lu Qun

    2008-05-02

    {delta}-Catenin is upregulated in human carcinomas. However, little is known about the potential transcriptional factors that regulate {delta}-catenin expression in cancer. Using a human {delta}-catenin reporter system, we have screened several nuclear signaling modulators to test whether they can affect {delta}-catenin transcription. Among {beta}-catenin/LEF-1, Notch1, and E2F1, E2F1 dramatically increased {delta}-catenin-luciferase activities while {beta}-catenin/LEF-1 induced only a marginal increase. Rb suppressed the upregulation of {delta}-catenin-luciferase activities induced by E2F1 but did not interact with {delta}-catenin. RT-PCR and Western blot analyses in 4 different prostate cancer cell lines revealed that regulation of {delta}-catenin expression is controlled mainly at the transcriptional level. Interestingly, the effects of E2F1 on {delta}-catenin expression were observed only in human cancer cells expressing abundant endogenous {delta}-catenin. These studies identify E2F1 as a positive transcriptional regulator for {delta}-catenin, but further suggest the presence of strong negative regulator(s) for {delta}-catenin in prostate cancer cells with minimal endogenous {delta}-catenin expression.

  14. Atomic data from the Iron Project. XVII. Radiative transition probabilities for dipole allowed and forbidden transitions in Fe III.

    NASA Astrophysics Data System (ADS)

    Nahar, S. N.; Pradhan, A. K.

    1996-11-01

    Transition probabilities are obtained for both the dipole allowed (E1) fine structure transitions and the forbidden electric quadrupole and magnetic dipole (E2, M1) transitions in Fe III. For the E1 transitions, ab initio calculations in the close coupling (CC) approximation using the R-matrix method are carried out in LS coupling with a 49-term eigenfunction expansion for Fe IV. The fine structure components are obtained through algebraic transformation of the LS line strengths, and the oscillator strengths and A-coefficients are computed using spectroscopic energies of the observed levels. Radiative transition probabilities for 9797 fine structure E1 transitions corresponding to 1408 LS multiplets among 200 bound states of Fe III are reported. Forbidden E2 and M1 transition probabilities are computed for 362 transitions among the 34 fine structure levels of all 16 LS terms dominated by the 3d^6^ configuration using optimised configuration-interaction wavefunctions from the SUPERSTRUCTURE program in the Breit-Pauli approximation. Comparison of the present results is made with previous calculations and significant differences are found. Theoretical line ratios computed using the present E2 and M1 A-coefficients show better agreement with observations for some prominent Fe III lines in the infra-red than those using the earlier data by Garstang (1957MNRAS.117..393G). This work is carried out as part of the Iron Project to obtain accurate radiative and collisional data for the Iron group elements.

  15. Enzyme E2 from Chinese white shrimp inhibits replication of white spot syndrome virus and ubiquitinates its RING domain proteins.

    PubMed

    Chen, An-Jing; Wang, Shuai; Zhao, Xiao-Fan; Yu, Xiao-Qiang; Wang, Jin-Xing

    2011-08-01

    Recent studies have shown that the ubiquitin (Ub) proteasome pathway (UPP) is closely related to immune defense. We have identified a ubiquitin-conjugating enzyme, E2, from the Chinese white shrimp, Fenneropenaeus chinensis (FcUbc). Injection of recombinant FcUbc protein (rFcUbc) reduced the mortality of shrimp infected with white spot syndrome virus (WSSV) and inhibited replication of WSSV. rFcUbc, but not a mutant FcUbc (mFcUbc), bound to WSSV RING domains (WRDs) from four potential E3 ligase proteins of WSSV in vitro. Importantly, rFcUbc could ubiquitinate the RING domains (named WRD2 and WRD3) of WSSV277 and WSSV304 proteins in vitro and the two proteins in WSSV-infected Drosophila melanogaster Schneider 2 (S2) cells. Furthermore, overexpression of FcUbc increased ubiquitination of WSSV277 and WSSV304 during WSSV infection. In summary, our study demonstrates that FcUbc from Chinese white shrimp inhibited WSSV replication and could ubiquitinate WSSV RING domain-containing proteins. This is the first report about antiviral function of Ubc E2 in shrimp.

  16. The E2 Ubiquitin-conjugating Enzyme UBE2J1 Is Required for Spermiogenesis in Mice*

    PubMed Central

    Koenig, Paul-Albert; Nicholls, Peter K.; Schmidt, Florian I.; Hagiwara, Masatoshi; Maruyama, Takeshi; Frydman, Galit H.; Watson, Nicki; Page, David C.; Ploegh, Hidde L.

    2014-01-01

    ER-resident proteins destined for degradation are dislocated into the cytosol by components of the ER quality control machinery for proteasomal degradation. Dislocation substrates are ubiquitylated in the cytosol by E2 ubiquitin-conjugating/E3 ligase complexes. UBE2J1 is one of the well-characterized E2 enzymes that participate in this process. However, the physiological function of Ube2j1 is poorly defined. We find that Ube2j1−/− mice have reduced viability and fail to thrive early after birth. Male Ube2j1−/− mice are sterile due to a defect in late spermatogenesis. Ultrastructural analysis shows that removal of the cytoplasm is incomplete in Ube2j1−/− elongating spermatids, compromising the release of mature elongate spermatids into the lumen of the seminiferous tubule. Our findings identify an essential function for the ubiquitin-proteasome-system in spermiogenesis and define a novel, non-redundant physiological function for the dislocation step of ER quality control. PMID:25320092

  17. On the equivalence of experimental B(E2) values determined by various techniques

    SciTech Connect

    Birch, M.; Pritychenko, B.; Singh, B.

    2016-06-30

    In this paper, we establish the equivalence of the various techniques for measuring B(E2) values using a statistical analysis. Data used in this work come from the recent compilation by B. Pritychenko et al. (2016). We consider only those nuclei for which the B(E2) values were measured by at least two different methods, with each method being independently performed at least twice. Our results indicate that most prevalent methods of measuring B(E2) values are equivalent, with some weak evidence that Doppler-shift attenuation method (DSAM) measurements may differ from Coulomb excitation (CE) and nuclear resonance fluorescence (NRF) measurements. However, such an evidence appears to arise from discrepant DSAM measurements of the lifetimes for 60Ni and some Sn nuclei rather than a systematic deviation in the method itself.

  18. Glucose regulates RMI1 expression through the E2F pathways in adipose cells.

    PubMed

    Suwa, Akira; Yoshino, Masayasu; Kurama, Takeshi; Shimokawa, Teruhiko; Aramori, Ichiro

    2011-08-01

    RecQ-mediated genome instability 1 (RMI1) has been identified as a novel energy homeostasis-related molecule. While recent studies have suggested that change in RMI1 expression levels in adipose tissue may affect the body's energy balance, no reports have identified the mechanism behind this expression regulation. In the present study, we found that RMI1 expression increased on differentiation of 3T3-L1 fibroblasts to adipocytes. In addition, glucose stimulation induced RMI1 expression to approximately eight times the baseline level. Further, knockdown of either E2F5 or E2F8 mRNA using siRNA suppressed this glucose-induced up-regulation of RMI1 expression. These results suggest that RMI1 expression may be regulated by glucose, at least in part, via E2F expression.

  19. Purification, crystallization and initial crystallographic characterization of brazil-nut allergen Ber e 2

    SciTech Connect

    Guo, Feng; Jin, Tengchuan; Howard, Andrew; Zhang, Yu-Zhu

    2007-11-01

    The crystallization of the brazil nut allergen Ber e 2 is reported. Peanut and tree-nut allergies have attracted considerable attention because of their frequency and their lifelong persistence. Brazil-nut (Bertholletia excelsa) allergies have been well documented and the 11S legumin-like seed storage protein Ber e 2 (excelsin) is one of the two known brazil-nut allergens. In this study, Ber e 2 was extracted from brazil-nut kernels and purified to high purity by crystalline precipitation and gel-filtration chromatography. Well diffracting single crystals were obtained using the hanging-drop vapour-diffusion method. A molecular-replacement structural solution has been obtained. Refinement of the structure is currently under way.

  20. On the equivalence of experimental B(E2) values determined by various techniques

    DOE PAGES

    Birch, M.; Pritychenko, B.; Singh, B.

    2016-06-30

    In this paper, we establish the equivalence of the various techniques for measuring B(E2) values using a statistical analysis. Data used in this work come from the recent compilation by B. Pritychenko et al. (2016). We consider only those nuclei for which the B(E2) values were measured by at least two different methods, with each method being independently performed at least twice. Our results indicate that most prevalent methods of measuring B(E2) values are equivalent, with some weak evidence that Doppler-shift attenuation method (DSAM) measurements may differ from Coulomb excitation (CE) and nuclear resonance fluorescence (NRF) measurements. However, such anmore » evidence appears to arise from discrepant DSAM measurements of the lifetimes for 60Ni and some Sn nuclei rather than a systematic deviation in the method itself.« less

  1. The Yale Interactive terrestrial Biosphere model: description, evaluation and implementation into NASA GISS ModelE2

    NASA Astrophysics Data System (ADS)

    Yue, X.; Unger, N.

    2015-04-01

    The land biosphere, atmospheric chemistry and climate are inextricably interconnected. We describe the Yale Interactive terrestrial Biosphere (YIBs) model, a land carbon cycle model that has been developed for coupling to the NASA Goddard Institute for Space Studies (GISS) ModelE2 global chemistry-climate model. The YIBs model adapts routines from the mature TRIFFID and CASA models to simulate interactive carbon assimilation, allocation, and autotrophic and heterotrophic respiration. Dynamic daily leaf area index is simulated based on carbon allocation and temperature- and drought-dependent prognostic phenology. YIBs incorporates a semi-mechanistic ozone vegetation damage scheme. Here, we validate the present day YIBs land carbon fluxes for three increasingly complex configurations: (i) off-line local site-level (ii) off-line global forced with WFDEI (WATCH Forcing Data methodology applied to ERA-Interim data) meteorology (iii) on-line coupled to the NASA ModelE2 (NASA ModelE2-YIBs). Off-line YIBs has hourly and on-line YIBs has half-hourly temporal resolution. The large observational database used for validation includes carbon fluxes from 145 flux tower sites and multiple satellite products. At the site level, YIBs simulates reasonable seasonality (correlation coefficient R > 0.8) of gross primary productivity (GPP) at 121 out of 145 sites with biases in magnitude ranging from -19 to 7% depending on plant function type. On the global scale, the off-line model simulates an annual GPP of 125 ± 3 petagrams of carbon (Pg C) and net ecosystem exchange (NEE) of -2.5 ± 0.7 Pg C for 1982-2011, with seasonality and spatial distribution consistent with the satellite observations. We assess present day global ozone vegetation damage using the off-line YIBs configuration. Ozone damage reduces global GPP by 2-5% annually with regional extremes of 4-10% in East Asia. The on-line model simulates annual GPP of 123 ± 1 Pg C and NEE of -2.7 ± 0.7 Pg C. NASA ModelE2-YIBs is a

  2. Salicylic acid binding of mitochondrial alpha-ketoglutarate dehydrogenase E2 affects mitochondrial oxidative phosphorylation and electron transport chain components and plays a role in basal defense against tobacco mosaic virus in tomato.

    PubMed

    Liao, Yangwenke; Tian, Miaoying; Zhang, Huan; Li, Xin; Wang, Yu; Xia, Xiaojian; Zhou, Jie; Zhou, Yanhong; Yu, Jingquan; Shi, Kai; Klessig, Daniel F

    2015-02-01

    Salicylic acid (SA) plays a critical role in plant defense against pathogen invasion. SA-induced viral defense in plants is distinct from the pathways mediating bacterial and fungal defense and involves a specific pathway mediated by mitochondria; however, the underlying mechanisms remain largely unknown. The SA-binding activity of the recombinant tomato (Solanum lycopersicum) alpha-ketoglutarate dehydrogenase (Slα-kGDH) E2 subunit of the tricarboxylic acid (TCA) cycle was characterized. The biological role of this binding in plant defenses against tobacco mosaic virus (TMV) was further investigated via Slα-kGDH E2 silencing and transient overexpression in plants. Slα-kGDH E2 was found to bind SA in two independent assays. SA treatment, as well as Slα-kGDH E2 silencing, increased resistance to TMV. SA did not further enhance TMV defense in Slα-kGDH E2-silenced tomato plants but did reduce TMV susceptibility in Nicotiana benthamiana plants transiently overexpressing Slα-kGDH E2. Furthermore, Slα-kGDH E2-silencing-induced TMV resistance was fully blocked by bongkrekic acid application and alternative oxidase 1a silencing. These results indicated that binding by Slα-kGDH E2 of SA acts upstream of and affects the mitochondrial electron transport chain, which plays an important role in basal defense against TMV. The findings of this study help to elucidate the mechanisms of SA-induced viral defense.

  3. ApoE2 Exaggerates PTSD-Related Behavioral, Cognitive, and Neuroendocrine Alterations

    PubMed Central

    Johnson, Lance A; Zuloaga, Damian G; Bidiman, Erin; Marzulla, Tessa; Weber, Sydney; Wahbeh, Helane; Raber, Jacob

    2015-01-01

    Apolipoprotein E (apoE) is an essential component of lipoprotein particles in both the brain and periphery, and exists in three isoforms in the human population: E2, E3, and E4. ApoE has numerous, well-established roles in neurobiology. Most notably, E4 is associated with earlier onset and increased risk of Alzheimer's disease (AD). Although possession of E2 is protective in the context of AD, E2 appears to confer an increased incidence and severity of posttraumatic stress disorder (PTSD). However, the biological processes underlying this link remain unclear. In this study, we began to elucidate these associations by examining the effects of apoE on PTSD severity in combat veterans, and on PTSD-like behavior in mice with human apoE. In a group of 92 veterans with PTSD, we observed significantly higher Clinician-Administered PTSD Scale and PTSD Checklist scores in E2+ individuals, as well as alterations in salivary cortisol levels. Furthermore, we measured behavioral and biological outcomes in mice expressing human apoE after a single stressful event as well as following a period of chronic variable stress, a model of combat-related trauma. Mice with E2 showed impairments in fear extinction, and behavioral, cognitive, and neuroendocrine alterations following trauma. To the best of our knowledge, these data constitute the first translational demonstration of PTSD severity in men and PTSD-like symptoms in mice with E2, and point to apoE as a novel biomarker of susceptibility, and potential therapeutic target, for PTSD. PMID:25857685

  4. The challenges of classical swine fever control: modified live and E2 subunit vaccines.

    PubMed

    Huang, Yu-Liang; Deng, Ming-Chung; Wang, Fun-In; Huang, Chin-Cheng; Chang, Chia-Yi

    2014-01-22

    Classical swine fever (CSF) is an economically important, highly contagious disease of swine worldwide. CSF is caused by classical swine fever virus (CSFV), and domestic pigs and wild boars are its only natural hosts. The two main strategies used to control CSF epidemic are systematic prophylactic vaccination and a non-vaccination stamping-out policy. This review compares the protective efficacy of the routinely used modified live vaccine (MLV) and E2 subunit vaccines and summarizes the factors that influence the efficacy of the vaccines and the challenges that both vaccines face to CSF control. Although MLV provide earlier and more complete protection than E2 subunit vaccines, it has the drawback of not allowing differentiation between infected and vaccinated animals (DIVA). The marker vaccine of E2 protein with companion discriminatory test to detect antibodies against E(rns) allows DIVA and is a promising strategy for future control and eradication of CSF. Maternal derived antibody (MDA) is the critical factor in impairing the efficacy of both MLV and E2 subunit vaccines, so the well-designed vaccination programs of sows and piglets should be considered together. Because of the antigen variation among various genotypes of CSFV, antibodies raised by either MLV or subunit vaccine neutralize genotypically homologous strains better than heterologous ones. However, although this is not a major concern for MLV as the induced immune responses can protect pigs against the challenge of various genotypes of CSFVs, it is critical for E2 subunit vaccines. It is thus necessary to evaluate whether the E2 subunit vaccine can completely protect against the current prevalent strains in the field. An ideal new generation of vaccine should be able to maintain the high protective efficiency of MLV and overcome the problem of antigenic variations while allowing for DIVA.

  5. Inhibition of PDC-E2 human combinatorial autoantibodies by peptide mimotopes.

    PubMed

    Leung, P S; Cha, S; Joplin, R E; Galperin, C; Van de Water, J; Ansari, A A; Coppel, R L; Schatz, P J; Cwirla, S; Fabris, L E; Neuberger, J M; Gershwin, M E

    1996-12-01

    Immunohistochemical studies have shown that a unique immunoreactive molecule is present near the apical region of human biliary epithelial (BE) cells in patients with primary biliary cirrhosis (PBC). This can be visualized by confocal microscopy in PBC livers using a number of unique monoclonal antibodies to the E2 component of pyruvate dehydrogenase complex (PDC-E2), the autoantigen most commonly recognized by antimitochondrial antibodies (AMA). One such antibody, the murine mAb C355.1 was used to identify peptide mimotopes of PDC-E2 by screening a random dodecapeptide phage library ON 159.2 to identify the possible biochemical nature of this apical staining molecule. Out of 36 independent clones, 29 showed a common sequence and seven other sequences were singly represented. Three common amino acid motifs (SYP, TYVS and VRH) were found among these eight sequences. Similar to C355.1, the human combinatorial antibodies derived from a patient with PBC, SP1 and SP4, recognize the inner lipoyl domain of PDC-E2. However, when these antibodies are used to stain PBC BE cells, SP4 stains the apical region of PBC BE cells with high intensity whereas SP1 produces only cytoplasmic staining. Competitive inhibition of immunohistochemical staining using PDC-E2 specific human combinatorial antibodies SP1 and SP4 was performed using five of the above dodecapeptides. Interestingly, the peptides selected with C355.1 differentially inhibited the binding of SP1 and SP4 to PBC BE cells. Finally, rabbit sera raised against one such peptide (WMSYPDRTLRTS) stained BE cells from patients with PBC with a higher intensity than controls. Comparable data was obtained with immunoelectronmicroscopy. These data suggest that a molecular mimic of PDC-E2 is present at the external aspect of PBC BE cells.

  6. Comparative genomics reveals multistep pathogenesis of E2A-PBX1 acute lymphoblastic leukemia

    PubMed Central

    Duque-Afonso, Jesús; Feng, Jue; Scherer, Florian; Lin, Chiou-Hong; Wong, Stephen H.K.; Wang, Zhong; Iwasaki, Masayuki; Cleary, Michael L.

    2015-01-01

    Acute lymphoblastic leukemia (ALL) is the most common childhood cancer; however, its genetic diversity limits investigation into the molecular pathogenesis of disease and development of therapeutic strategies. Here, we engineered mice that conditionally express the E2A-PBX1 fusion oncogene, which results from chromosomal translocation t(1;19) and is present in 5% to 7% of pediatric ALL cases. The incidence of leukemia in these mice varied from 5% to 50%, dependent on the Cre-driving promoter (Cd19, Mb1, or Mx1) used to induce E2A-PBX1 expression. Two distinct but highly similar subtypes of B cell precursor ALLs that differed by their pre–B cell receptor (pre-BCR) status were induced and displayed maturation arrest at the pro-B/large pre–B II stages of differentiation, similar to human E2A-PBX1 ALL. Somatic activation of E2A-PBX1 in B cell progenitors enhanced self-renewal and led to acquisition of multiple secondary genomic aberrations, including prominent spontaneous loss of Pax5. In preleukemic mice, conditional Pax5 deletion cooperated with E2A-PBX1 to expand progenitor B cell subpopulations, increasing penetrance and shortening leukemia latency. Recurrent secondary activating mutations were detected in key signaling pathways, most notably JAK/STAT, that leukemia cells require for proliferation. These data support conditional E2A-PBX1 mice as a model of human ALL and suggest targeting pre-BCR signaling and JAK kinases as potential therapeutic strategies. PMID:26301816

  7. Expression of cyclins E1 and E2 during mouse development and in neoplasia

    PubMed Central

    Geng, Yan; Yu, Qunyan; Whoriskey, Wendy; Dick, Fred; Tsai, Kenneth Y.; Ford, Heide L.; Biswas, Debajit K.; Pardee, Arthur B.; Amati, Bruno; Jacks, Tyler; Richardson, Andrea; Dyson, Nicholas; Sicinski, Piotr

    2001-01-01

    Cyclin E1 (formerly called cyclin E) and the recently described cyclin E2 belong to the family of E-type cyclins that operate during the G1/S phase progression in mammalian cells. The two E-cyclins share a catalytic partner, cyclin-dependent kinase 2 (CDK2), and activate their associated kinase activities at similar times during cell cycle progression. Despite these similarities, it is unknown whether the two proteins perform distinct functions, or, alternatively, they control S-phase entry of different cell types in a tissue-specific fashion. To start addressing in vivo functions of E-cyclins, we determined the expression pattern of cyclins E1 and E2 during normal mouse development. We found that the two E-cyclins showed very similar patterns of expression; both were expressed within the proliferating compartment during embryo development. Analyses of cells and tissues lacking members of the retinoblastoma (pRB) family of proteins revealed that the expression of both cyclins is controlled in a pRB-dependent, but p107- and p130-independent fashion, likely through the pRB-dependent E2F transcription factors. We also found that cyclins E1 and E2 are expressed at high levels in mouse breast tumors driven by the Myc oncogene. Last, we found that cyclin E2 is overexpressed in ≈24% of analyzed human mammary carcinomas. Collectively these findings suggest that the expression of cyclins E1 and E2 is governed by similar molecular circuitry. PMID:11687642

  8. Transcriptional regulation of subtilisin-like proprotein convertase PACE4 by E2F: possible role of E2F-mediated upregulation of PACE4 in tumor progression.

    PubMed

    Yuasa, Keizo; Suzue, Kaori; Nagahama, Masami; Matsuda, Yoshiko; Tsuji, Akihiko

    2007-11-01

    PACE4, a member of the subtilisin-like proprotein convertase (SPC) family, is expressed at high levels in certain tumor cells and plays a role in metastatic progression through activation of matrix metalloproteinases. The mechanism leading to overexpression of PACE4 in tumor cells remains unclear. In this study, we show that the E2F1 transcription factor, which is implicated in carcinoma invasiveness, upregulates the expression of PACE4. HT1080 (highly tumorigenic and invasive) cells expressed much higher levels of PACE4 and E2F family (E2F1 and E2F2) transcripts than IMR90 (normal fibroblast) cells. Expression levels of other SPCs (furin and PC6) remained unchanged in these cells. Promoter analysis indicated that two E2F consensus binding sites (-117/-110 and -86/-79) in the 5'-flanking region of the human PACE4 gene function as positive regulatory elements. Mutation of these sites abolished PACE4 promoter response to E2F1 as well as binding of E2F1 in electrophoretic mobility-shift assays. Other E2F members, E2F2 and E2F3, also activated PACE4 expression, as in the case of E2F1. These results indicate a novel mechanism for E2F family-mediated promotion of carcinoma invasiveness through PACE4.

  9. Purification, crystallization and initial crystallographic characterization of brazil-nut allergen Ber e 2.

    PubMed

    Guo, Feng; Jin, Tengchuan; Howard, Andrew; Zhang, Yu Zhu

    2007-11-01

    Peanut and tree-nut allergies have attracted considerable attention because of their frequency and their lifelong persistence. Brazil-nut (Bertholletia excelsa) allergies have been well documented and the 11S legumin-like seed storage protein Ber e 2 (excelsin) is one of the two known brazil-nut allergens. In this study, Ber e 2 was extracted from brazil-nut kernels and purified to high purity by crystalline precipitation and gel-filtration chromatography. Well diffracting single crystals were obtained using the hanging-drop vapour-diffusion method. A molecular-replacement structural solution has been obtained. Refinement of the structure is currently under way.

  10. Discovery and Classification of the z=1.86 SLSNe: DES15E2mlf

    NASA Astrophysics Data System (ADS)

    Pan, Y.-C.; Foley, R. J.; Galbany, L.; Gonzalez-Gaitan, S.; Forster, F.; Hamuy, M.; Prieto, J. L.; Yuan, F.; Tucker, B. E.; Lidman, C.; Martini, P.; Gshwend, Julia; Moller, A.; Zhang, B.; Desai, S.; Paech, K.; Smith, R. C.; Schubnell, M.; Kessler, R.; Lasker, J.; Scolnic, D.; Brout, D. J.; Gladney, L.; Sako, M.; Wolf, R. C.; Brown, P. J.; Krisciunas, K.; Suntzeff, N.; Nichol, R.; Papadopoulos, A.; Childress, M.; D'Andrea, C.; Prajs, S.; Smith, M.; Sullivan, M.; Maartens, R.; Gupta, R.; Kovacs, E.; Kuhlmann, S.; Spinka, H.; Ahn, E.; Finley, D. A.; Frieman, J.; Marriner, J.; Wester, W.; Aldering, G.; Kim, A. G.; Thomas, R. C.; Barbary, K.; Bloom, J. S.; Goldstein, D.; Nugent, P.; Perlmutter, S.; Casas, R.; Castander, F. J.

    2015-12-01

    We report the spectroscopic classification of DES15E2mlf as a superluminous supernova (SLSN) discovered by the Dark Energy Survey (ATEL #4668). DES15E2mlf was discovered on 7 November 2015 at R.A. = 00:41:33.40, Decl = -43:27:17.2 with r = 24.1 mag. We obtained spectra using GMOS on Gemini-South (520-990nm) on 06 December 2015 which indicated a redshift of z = 1.86 from Mg II 2800 absorption.

  11. US NDC Modernization Iteration E2 Prototyping Report: User Interface Framework

    SciTech Connect

    Lewis, Jennifer E.; Palmer, Melanie A.; Vickers, James Wallace; Voegtli, Ellen M.

    2014-12-01

    During the second iteration of the US NDC Modernization Elaboration phase (E2), the SNL US NDC Modernization project team completed follow-on Rich Client Platform (RCP) exploratory prototyping related to the User Interface Framework (UIF). The team also developed a survey of browser-based User Interface solutions and completed exploratory prototyping for selected solutions. This report presents the results of the browser-based UI survey, summarizes the E2 browser-based UI and RCP prototyping work, and outlines a path forward for the third iteration of the Elaboration phase (E3).

  12. 77 FR 21782 - International Conference on Harmonisation; Draft Guidance for Industry on E2C(R2) Periodic...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-04-11

    ... and combines two ICH guidances, ``E2C Clinical Safety Data Management: Periodic Safety Update Reports for Marketed Drugs'' (E2C guidance) and ``Addendum to E2C Clinical Safety Data Management: Periodic... Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852....

  13. 26 CFR 1.401(e)-2 - General rules relating to plans covering self-employed individuals.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ..., Stock Bonus Plans, Etc. § 1.401(e)-2 General rules relating to plans covering self-employed individuals... 26 Internal Revenue 5 2013-04-01 2013-04-01 false General rules relating to plans covering self-employed individuals. 1.401(e)-2 Section 1.401(e)-2 Internal Revenue INTERNAL REVENUE SERVICE,...

  14. 26 CFR 1.401(e)-2 - General rules relating to plans covering self-employed individuals.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ..., Stock Bonus Plans, Etc. § 1.401(e)-2 General rules relating to plans covering self-employed individuals... 26 Internal Revenue 5 2012-04-01 2011-04-01 true General rules relating to plans covering self-employed individuals. 1.401(e)-2 Section 1.401(e)-2 Internal Revenue INTERNAL REVENUE SERVICE,...

  15. 26 CFR 1.401(e)-2 - General rules relating to plans covering self-employed individuals.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ..., Stock Bonus Plans, Etc. § 1.401(e)-2 General rules relating to plans covering self-employed individuals... 26 Internal Revenue 5 2014-04-01 2014-04-01 false General rules relating to plans covering self-employed individuals. 1.401(e)-2 Section 1.401(e)-2 Internal Revenue INTERNAL REVENUE SERVICE,...

  16. 26 CFR 1.401(e)-2 - General rules relating to plans covering self-employed individuals.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ..., Stock Bonus Plans, Etc. § 1.401(e)-2 General rules relating to plans covering self-employed individuals... 26 Internal Revenue 5 2011-04-01 2011-04-01 false General rules relating to plans covering self-employed individuals. 1.401(e)-2 Section 1.401(e)-2 Internal Revenue INTERNAL REVENUE SERVICE,...

  17. Precise Calculations of Astrophysically Important Allowed and Forbidden Transitions of Xe VIII

    NASA Astrophysics Data System (ADS)

    Bhowmik, Anal; Nath Dutta, Narendra; Roy, Sourav

    2017-02-01

    The present work reports transition line parameters for Xe viii, which are potentially important for astrophysics in view of recent observations of multiply ionized xenon in hot white dwarfs. The relativistic coupled-cluster method is employed here to calculate the E1, E2, and M1 transition line parameters with high accuracy. The E1 oscillator strengths and probabilities of E2 and M1 transitions are determined using theoretical amplitudes and experimental energy values. The calculated branching ratios and the lifetimes are supplemented to the transition parameters. The accurate presentation of these calculated data is crucial for density estimation in several stellar and interstellar media.

  18. Organization of the cores of the mammalian pyruvate dehydrogenase complex formed by E2 and E2 plus the E3-binding protein and their capacities to bind the E1 and E3 components.

    PubMed

    Hiromasa, Yasuaki; Fujisawa, Tetsuro; Aso, Yoichi; Roche, Thomas E

    2004-02-20

    The subunits of the dihydrolipoyl acetyltransferase (E2) component of mammalian pyruvate dehydrogenase complex can form a 60-mer via association of the C-terminal I domain of E2 at the vertices of a dodecahedron. Exterior to this inner core structure, E2 has a pyruvate dehydrogenase component (E1)-binding domain followed by two lipoyl domains, all connected by mobile linker regions. The assembled core structure of mammalian pyruvate dehydrogenase complex also includes the dihydrolipoyl dehydrogenase (E3)-binding protein (E3BP) that binds the I domain of E2 by its C-terminal I' domain. E3BP similarly has linker regions connecting an E3-binding domain and a lipoyl domain. The composition of E2.E3BP was thought to be 60 E2 plus approximately 12 E3BP. We have prepared homogenous human components. E2 and E2.E3BP have s(20,w) values of 36 S and 31.8 S, respectively. Equilibrium sedimentation and small angle x-ray scattering studies indicate that E2.E3BP has lower total mass than E2, and small angle x-ray scattering showed that E3 binds to E2.E3BP outside the central dodecahedron. In the presence of saturating levels of E1, E2 bound approximately 60 E1 and maximally sedimented 64.4 +/- 1.5 S faster than E2, whereas E1-saturated E2.E3BP maximally sedimented 49.5 +/- 1.4 S faster than E2.E3BP. Based on the impact on sedimentation rates by bound E1, we estimate fewer E1 (approximately 12) were bound by E2.E3BP than by E2. The findings of a smaller E2.E3BP mass and a lower capacity to bind E1 support the smaller E3BP substituting for E2 subunits rather than adding to the 60-mer. We describe a substitution model in which 12 I' domains of E3BP replace 12 I domains of E2 by forming 6 dimer edges that are symmetrically located in the dodecahedron structure. Twelve E3 dimers were bound per E248.E3BP12 mass, which is consistent with this model.

  19. TGF{beta}-mediated formation of pRb-E2F complexes in human myeloid leukemia cells

    SciTech Connect

    Hu Xiaotang

    2008-05-02

    TGF{beta} is well known for its inhibitory effect on cell cycle G1 checkpoint kinases. However, its role in the control of pRb-E2F complexes is not well established. TGF{beta} inhibits phosphorylation of pRb at several serine and threonine residues and regulates the association of E2F transcription factors with pRb family proteins. Recent studies found that predominantly E2F-4, p130, and histone deacetylase (HDAC) are found to bind to corresponding E2F-responsive promoters in G0/G1 phase. As cells progress through mid-G1, p130-E2F4 complex are replaced by p107-E2F4 followed by activators E2F1, 2, and 3. pRb was not detectable in the promoters containing the E2F-responsive site in cycling cells but was associated with E2F4-p130 complexes or E2F4-p107 complexes during G0/G1 phase. In human myeloid leukemia cell line, MV4-11, TGF{beta} upregulated pRb-E2F-4 and p130-E2F-4, and downregulated p107-E2F-4 complexes. However, pRB-E2F1 and pRb-E2F3 complexes were found in proliferating cells but not in TGF{beta} arrested G1 cells. In addition, electrophoretic gel mobility shift assay (EMSA) could not detect pRb-E2F DNA-binding activities either in S or G1 phase but exhibited the existence of p107-E2F4 in proliferating cells and p130-E2F4 complexes in TGF{beta}-arrested G1 cells, respectively. Our data suggest that p107 and p130, but not pRb, and the repressor E2F, but not activator E2Fs, play a critical role in regulating E2F-responsive gene expression in TGF{beta}-mediated cell cycle control in human myeloid leukemia cells.

  20. DOE Challenge Home Case Study: e2 Homes – Winter Park, Florida

    SciTech Connect

    none,

    2013-01-01

    This Challenge Home case study describes the first certified DOE Challenge Home as constructed by e2 Homes. Completed in May 2012, the “Wilson Residence” in Winter Park, Florida, is a 4,305-ft2 custom home that scores a HERS 57 without solar and a better than zero net-energy HERS -7 with solar.

  1. LXCXE-independent chromatin remodeling by Rb/E2f mediates neuronal quiescence.

    PubMed

    Andrusiak, Matthew G; Vandenbosch, Renaud; Dick, Fred A; Park, David S; Slack, Ruth S

    2013-05-01

    Neuronal survival is dependent upon the retinoblastoma family members, Rb1 (Rb) and Rb2 (p130). Rb is thought to regulate gene repression, in part, through direct recruitment of chromatin modifying enzymes to its conserved LXCXE binding domain. We sought to examine the mechanisms that Rb employs to mediate cell cycle gene repression in terminally differentiated cortical neurons. Here, we report that Rb loss converts chromatin at the promoters of E2f-target genes to an activated state. We established a mouse model system in which Rb-LXCXE interactions could be induciblely disabled. Surprisingly, this had no effect on survival or gene silencing in neuronal quiescence. Absence of the Rb LXCXE-binding domain in neurons is compatible with gene repression and long-term survival, unlike Rb deficiency. Finally, we are able to show that chromatin activation following Rb deletion occurs at the level of E2fs. Blocking E2f-mediated transcription downstream of Rb loss is sufficient to maintain chromatin in an inactive state. Taken together our results suggest a model whereby Rb-E2f interactions are sufficient to maintain gene repression irrespective of LXCXE-dependent chromatin remodeling.

  2. Rb knockdown accelerates bladder cancer progression through E2F3 activation.

    PubMed

    Wang, Jiang-Ping; Jiao, Yong; Wang, Cheng-Yuan; Xu, Zhi-Bin; Zhang, Bo

    2017-01-01

    Bladder cancer is one of the most common cancers diagnosed in the world and leads to significant mortality and morbidity among affected patients. The retinoblastoma (Rb) protein is a main tumor suppressor, controlling cellular responses to potentially oncogenic stimulation. E2F3 was invariably disrupted in different human cancers for its central role in the control of cellular proliferation. Here, we investigated how Rb is integrated to control bladder cancer progression through E2F3 and p53 regulation. The results exhibit that Rb expression is lower in patients with bladder tumor, while E2F3 level is high. Rb knockdown enhanced bladder tumor cell proliferation and migration, aggravated with p53 silence. Interestingly, Rb silence results in E2F3, Myc and mTOR signaling pathway activation, contributing to bladder cancer cell proliferation and apoptosis suppression mainly through caspase-3 inhibition in vitro and in vivo. Immunohistochemical analysis revealed that Rb is highly expressed in normal bladder cells, but was repressed in tumor tissues of the bladder completely, suggesting a possible role of Rb as a tumor suppressor.

  3. The E2 Domains of APP and APLP1 Share a Conserved Mode of Dimerization

    SciTech Connect

    S Lee; Y Xue; J Hulbert; Y Wang; X Liu; B Demeler; Y Ha

    2011-12-31

    Amyloid precursor protein (APP) is genetically linked to Alzheimer's disease. APP is a type I membrane protein, and its oligomeric structure is potentially important because this property may play a role in its function or affect the processing of the precursor by the secretases to generate amyloid {beta}-peptide. Several independent studies have shown that APP can form dimers in the cell, but how it dimerizes remains controversial. At least three regions of the precursor, including a centrally located and conserved domain called E2, have been proposed to contribute to dimerization. Here we report two new crystal structures of E2, one from APP and the other from APLP1, a mammalian APP homologue. Comparison with an earlier APP structure, which was determined in a different space group, shows that the E2 domains share a conserved and antiparallel mode of dimerization. Biophysical measurements in solution show that heparin binding induces E2 dimerization. The 2.1 {angstrom} resolution electron density map also reveals phosphate ions that are bound to the protein surface. Mutational analysis shows that protein residues interacting with the phosphate ions are also involved in heparin binding. The locations of two of these residues, Arg-369 and His-433, at the dimeric interface suggest a mechanism for heparin-induced protein dimerization.

  4. Lesion of the tuberomammillary nucleus E2-region attenuates postictal seizure protection in rats.

    PubMed

    Jin, Chun-Lei; Zhuge, Zheng-Bing; Wu, Deng-Chang; Zhu, Yuan-Yuan; Wang, Shuang; Luo, Jian-Hong; Chen, Zhong

    2007-03-01

    Postictal seizure protection (PSP) is an endogenous anticonvulsant phenomenon that follows an epileptic seizure and inhibits the induction of further seizures. The tuberomammillary nucleus (TM), located in the posterior hypothalamus, consists of five subregions and is the sole source of histaminergic neurons in the brain. To determine whether the TM is involved in PSP in rats, we tested the effects of bilateral electrolytic lesions of the TM E2-region on seizures induced by intermittent maximal electroshock (MES). The TM E2-region lesions significantly attenuated PSP during the intermittent MES procedure. Furthermore, intracerebroventricular injection of alpha-fluoromethylhistidine (100 microg), a selective and irreversible histidine decarboxylase inhibitor, mimicked the attenuation of PSP induced by the lesion of TM E2-region. In addition, neurochemical experiments revealed that the TM E2-region lesions markedly decreased basal histamine levels in the cortex, hippocampus, brainstem and hypothalamus, but had no significant effect on basal glutamate and GABA levels. Moreover, intermittent MES induced a persistent decrease of brain histamine levels in both sham-operated and lesioned rats. These results indicate that through its intrinsic histaminergic system, the TM may exert powerful inhibitory function during the intermittent MES procedure and actively participate in the mechanisms of PSP.

  5. 40 CFR Figure E-2 to Subpart E of... - Product Manufacturing Checklist

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 6 2013-07-01 2013-07-01 false Product Manufacturing Checklist E Figure E-2 to Subpart E of Part 53 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED...—Product Manufacturing Checklist PRODUCT MANUFACTURING CHECKLIST AuditeeAuditor signatureDate...

  6. Stages of Change – Continuous Measure (URICA-E2): psychometrics of a Norwegian version

    PubMed Central

    Lerdal, Anners; Moe, Britt; Digre, Elin; Harding, Thomas; Kristensen, Frode; Grov, Ellen K; Bakken, Linda N; Eklund, Marthe L; Ruud, Ireen; Rossi, Joseph S

    2009-01-01

    Title Stages of Change – Continuous Measure (URICA-E2): psychometrics of a Norwegian version. Aim This paper is a report of research to translate the English version of the Stages of Change continuous measure questionnaire (URICA-E2) into Norwegian and to test the validity of the questionnaire and its usefulness in predicting behavioural change. Background While the psychometric properties of the Stages of Change categorical measure have been tested extensively, evaluation of the psychometric properties of the continuous questionnaire has not been described elsewhere in the literature. Method Cross-sectional data were collected with a convenience sample of 198 undergraduate nursing students in 2005 and 2006. The English version of URICA-E2 was translated into Norwegian according to standardized procedures. Findings Principal components analysis clearly confirmed five of the dimensions of readiness to change (Precontemplation Non-Believers, Precontemplation Believers, Contemplation, Preparation and Maintenance), while the sixth dimension, Action, showed the lowest Eigenvalue (0·93). Findings from the cluster analysis indicate distinct profiles among the respondents in terms of readiness to change their exercise behaviour. Conclusion The URICA-E2 was for the most part replicated from Reed’s original work. The result of the cluster analysis of the items associated with the factor ‘Action’ suggests that these do not adequately measure the factor. PMID:19032513

  7. LXCXE-independent chromatin remodeling by Rb/E2f mediates neuronal quiescence

    PubMed Central

    Andrusiak, Matthew G.; Vandenbosch, Renaud; Dick, Fred A.; Park, David S.; Slack, Ruth S.

    2013-01-01

    Neuronal survival is dependent upon the retinoblastoma family members, Rb1 (Rb) and Rb2 (p130). Rb is thought to regulate gene repression, in part, through direct recruitment of chromatin modifying enzymes to its conserved LXCXE binding domain. We sought to examine the mechanisms that Rb employs to mediate cell cycle gene repression in terminally differentiated cortical neurons. Here, we report that Rb loss converts chromatin at the promoters of E2f-target genes to an activated state. We established a mouse model system in which Rb-LXCXE interactions could be induciblely disabled. Surprisingly, this had no effect on survival or gene silencing in neuronal quiescence. Absence of the Rb LXCXE-binding domain in neurons is compatible with gene repression and long-term survival, unlike Rb deficiency. Finally, we are able to show that chromatin activation following Rb deletion occurs at the level of E2fs. Blocking E2f-mediated transcription downstream of Rb loss is sufficient to maintain chromatin in an inactive state. Taken together our results suggest a model whereby Rb-E2f interactions are sufficient to maintain gene repression irrespective of LXCXE-dependent chromatin remodeling. PMID:23574720

  8. "Expectations to Change" ((E2C): A Participatory Method for Facilitating Stakeholder Engagement with Evaluation Findings

    ERIC Educational Resources Information Center

    Adams, Adrienne E.; Nnawulezi, Nkiru A.; Vandenberg, Lela

    2015-01-01

    From a utilization-focused evaluation perspective, the success of an evaluation is rooted in the extent to which the evaluation was used by stakeholders. This paper details the "Expectations to Change" (E2C) process, an interactive, workshop-based method designed to engage primary users with their evaluation findings as a means of…

  9. Half-life of the 15 /2+ state of 135I: A test of E 2 seniority relations

    NASA Astrophysics Data System (ADS)

    Spagnoletti, P.; Simpson, G. S.; Carroll, R.; Régis, J.-M.; Blanc, A.; Jentschel, M.; Köster, U.; Mutti, P.; Soldner, T.; de France, G.; Ur, C. A.; Urban, W.; Bruce, A. M.; Drouet, F.; Fraile, L. M.; Gaffney, L. P.; Ghitǎ, D. G.; Ilieva, S.; Jolie, J.; Korten, W.; Kröll, T.; Larijarni, C.; Lalkovski, S.; Licǎ, R.; Mach, H.; Mǎrginean, N.; Paziy, V.; Podolyák, Zs.; Regan, P. H.; Scheck, M.; Saed-Samii, N.; Thiamova, G.; Townsley, C.; Vancraeyenest, A.; Vedia, V.; Gargano, A.; Van Isacker, P.

    2017-02-01

    The half-life of the 15 /21+ state of the 3-valence-proton nucleus 135I has been measured to be 1.74(8) ns using the EXILL-FATIMA mixed array of Ge and LaBr3 detectors. The nuclei were produced following the cold neutron-induced fission of a 235U target at the PF1B beam line of the Institut Laue-Langevin. The extracted B (E 2 ;15 /2+→11 /2+) value enabled a test of seniority relations for the first time between E 2 transition rates. Large-scale shell-model calculations were performed for 134Te and 135I, and reinterpreted in a single-orbit approach. The results show that the two-body component of the E 2 operator can be large whereas energy shifts due to the three-body component of the effective interaction are small.

  10. Hypervariable antigenic region 1 of classical swine fever virus E2 protein impacts antibody neutralization.

    PubMed

    Liao, Xun; Wang, Zuohuan; Cao, Tong; Tong, Chao; Geng, Shichao; Gu, Yuanxing; Zhou, Yingshan; Li, Xiaoliang; Fang, Weihuan

    2016-07-19

    Envelope glycoprotein E2 of classical swine fever virus (CSFV) is the major antigen that induces neutralizing antibodies and confers protection against CSFV infection. There are three hypervariable antigenic regions (HAR1, HAR2 and HAR3) of E2 that are different between the group 1 vaccine C-strain and group 2 clinical isolates. This study was aimed to characterize the antigenic epitope region recognized by monoclonal antibody 4F4 (mAb-4F4) that is present in the group 2 field isolate HZ1-08, but not in the C-strain, and examine its impact on neutralization titers when antisera from different recombinant viruses were cross-examined. Indirect ELISA with C-strain E2-based chimeric proteins carrying the three HAR regions showed that the mAb-4F4 bound to HAR1 from HZ1-08 E2, but not to HAR2 or HAR3, indicating that the specific epitope is located in the HAR1 region. Of the 6 major residues differences between C-strain and field isolates, Glu713 in the HAR1 region of strain HZ1-08 is critical for mAb-4F4 binding either at the recombinant protein level or using intact recombinant viruses carrying single mutations. C-strain-based recombinant viruses carrying the most antigenic part of E2 or HAR1 from strain HZ1-08 remained non-pathogenic to pigs and induced good antibody responses. By cross-neutralization assay, we observed that the anti-C-strain serum lost most of its neutralization capacity to RecC-HZ-E2 and QZ-14 (subgroup 2.1d field isolate in 2014), and vice versa. More importantly, the RecC-HAR1 virus remained competent in neutralizing ReC-HZ-E2 and QZ-14 strains without compromising the neutralization capability to the recombinant C-strain. Thus, we propose that chimeric C-strain carrying the HAR1 region of field isolates is a good vaccine candidate for classical swine fever.

  11. Deregulation of the pRb-E2F4 axis alters epidermal homeostasis and favors tumor development

    PubMed Central

    Costa, Clotilde; Santos, Mirentxu; Martínez-Fernández, Mónica; Lorz, Corina; Lázaro, Sara; Paramio, Jesús M.

    2016-01-01

    E2F/RB activity is altered in most human tumors. The retinoblastoma family of proteins plays a key role in regulating the progression of the cell cycle from the G1 to S phases. This is achieved through negative regulation of E2F transcription factors, important positive regulators of cell cycle entry. E2F family members are divided into two groups: activators (E2F1-E2F3a) and repressors (E2F3b-E2F8). E2F4 accounts for a large part of the E2F activity and is a main E2F repressor member in vivo. Perturbations in the balance from quiescence towards proliferation contribute to increased mitotic gene expression levels frequently observed in cancer. We have previously reported that combined Rb1-Rbl1 or Rb1-E2f1 ablation in epidermis produces important alterations in epidermal proliferation and differentiation, leading to tumor development. However, the possible roles of E2F4 in this context are still to be determined. Here, we show the absence of any discernible phenotype in the skin of mice lacking of E2f4. In contrast, the inducible loss of Rb1 in the epidermis of E2F4-null mice produced multiple skin abnormalities including altered differentiation and proliferation, spontaneous wounds, carcinoma in situ development and stem cell perturbations. All these phenotypic alterations are associated with extensive gene expression changes, the induction of c-myc and the Akt activation. Moreover the whole transcriptome analyses in comparison with previous models generated also revealed extensive changes in multiple repressive complexes and in transcription factor activity. These results point to E2F4 as a master regulator in multiple steps of epidermal homeostasis in Rb1 absence. PMID:27708231

  12. Endogenous prostaglandin E2 potentiates anti-inflammatory phenotype of macrophage through the CREB-C/EBP-β cascade.

    PubMed

    Na, Yi Rang; Jung, Daun; Yoon, Bo Ruem; Lee, Won Woo; Seok, Seung Hyeok

    2015-09-01

    Macrophages have important functions in tissue homeostasis, but the exact mechanisms regarding wide spectrum of macrophage phenotype remain unresolved. In this study, we report that mouse bone marrow derived naïve macrophages produce prostaglandin E2 (PGE2 ) endogenously, resulting in anti-inflammatory gene expression upon differentiation induced by macrophage colony stimulating factor (M-CSF). Cyclooxygenase (COX) inhibition by indomethacin reduced endogenous PGE2 production of macrophages and subsequently reduced arg1, IL10 and Mrc1, YmI and FizzI gene expressions. Of note, PGE2 phosphorylates CREB via EP2 and EP4 receptor ligation, thereby transcriptionally increasing C/EBP-β expression in BALB/c bone marrow derived macrophages. Activated CREB directly binds to the CREB-responsive element of the C/EBP-β promoter, such that PGE2 ultimately reinforces arg1, IL10 and Mrc1 gene expression. Cyclic AMP activator forskolin also phosphorylated CREB and induced the C/EBP-β cascade, but this was completely blocked by the PKA inhibitor, H89. Consequently, M-CSF grown macrophages inhibited T-cell proliferation but the inhibition ability was reduced when the COX is inhibited by indomethacin or macrophage C/EBP-β expression was decreased by siRNA transduction. Our results collectively describe the molecular basis for homeostatic macrophage differentiation by endogenous PGE2 .

  13. Host cell factor-1 recruitment to E2F-bound and cell-cycle-control genes is mediated by THAP11 and ZNF143.

    PubMed

    Parker, J Brandon; Yin, Hanwei; Vinckevicius, Aurimas; Chakravarti, Debabrata

    2014-11-06

    Host cell factor-1 (HCF-1) is a metazoan transcriptional coregulator essential for cell-cycle progression and cell proliferation. Current models suggest a mechanism whereby HCF-1 functions as a direct coregulator of E2F proteins, facilitating the expression of genes necessary for cell proliferation. In this report, we show that HCF-1 recruitment to numerous E2F-bound promoters is mediated by the concerted action of zinc finger transcription factors THAP11 and ZNF143, rather than E2F proteins directly. THAP11, ZNF143, and HCF-1 form a mutually dependent complex on chromatin, which is independent of E2F occupancy. Disruption of the THAP11/ZNF143/HCF-1 complex results in altered expression of cell-cycle control genes and leads to reduced cell proliferation, cell-cycle progression, and cell viability. These data establish a model in which a THAP11/ZNF143/HCF-1 complex is a critical component of the transcriptional regulatory network governing cell proliferation.

  14. Abrogation of a mitotic checkpoint by E2 proteins from oncogenic human papillomaviruses correlates with increased turnover of the p53 tumor suppressor protein.

    PubMed Central

    Frattini, M G; Hurst, S D; Lim, H B; Swaminathan, S; Laimins, L A

    1997-01-01

    Human papillomavirus (HPV) E2 and E1 proteins are required for the replication of viral genomes in vivo. We have examined the effects of increasing the level of E2 on viral and cellular replication using recombinant adenoviruses. Infection of cells which maintain HPV 31 DNA episomally with E2 recombinant adenoviruses resulted in a 5-fold increase in genome copy number as well as an S phase arrest allowing for the continued replication of cellular DNA. Similar effects on cell cycle progression were seen following infection of normal human foreskin keratinocytes, the natural host cell. The DNA content of these cells increased beyond 4N indicating that multiple rounds of replication had occurred without an intervening mitotic event. In addition, increased cyclin A and E associated kinase activity was observed, while no change was detected in cyclin B associated kinase activity or in the activation state of cdc2 kinase. Interestingly, the levels of the p53 tumor suppresser protein were dramatically reduced through a post-transcriptional mechanism following infection. These data suggest a role for E2 in regulating viral and cellular replication by abrogation of a mitotic checkpoint, which is, at least in part, controlled by p53. PMID:9029152

  15. Research on Methods of Processing Transit IC Card Information and Constructing Transit OD Matrix

    NASA Astrophysics Data System (ADS)

    Han, Xiuhua; Li, Jin; Peng, Han

    Transit OD matrix is of vital importance when planning urban transit system. Traditional transit OD matrix constructing method needs a large range of spot check survey. It is expensive and needs long cycle time to process information. Recently transit IC card charging systems have been widely applied in big cities. Being processed reasonably, transit passenger information stored in IC card database can turn into information resource. It will reduce survey cost a lot. The concept of transit trip chain is put forward in this paper. According to the characteristics of closed transit trip chain, it discusses how to process IC card information and construct transit OD matrix. It also points out that urban transit information platform and data warehouse should be constructed, and how to integrate IC card information.

  16. Brd4 is required for e2-mediated transcriptional activation but not genome partitioning of all papillomaviruses.

    PubMed

    McPhillips, M G; Oliveira, J G; Spindler, J E; Mitra, R; McBride, A A

    2006-10-01

    Bromodomain protein 4 (Brd4) has been identified as the cellular binding target through which the E2 protein of bovine papillomavirus type 1 links the viral genome to mitotic chromosomes. This tethering ensures retention and efficient partitioning of genomes to daughter cells following cell division. E2 is also a regulator of viral gene expression and a replication factor, in association with the viral E1 protein. In this study, we show that E2 proteins from a wide range of papillomaviruses interact with Brd4, albeit with variations in efficiency. Moreover, disruption of the E2-Brd4 interaction abrogates the transactivation function of E2, indicating that Brd4 is required for E2-mediated transactivation of all papillomaviruses. However, the interaction of E2 and Brd4 is not required for genome partitioning of all papillomaviruses since a number of papillomavirus E2 proteins associate with mitotic chromosomes independently of Brd4 binding. Furthermore, mutations in E2 that disrupt the interaction with Brd4 do not affect the ability of these E2s to associate with chromosomes. Thus, while all papillomaviruses attach their genomes to cellular chromosomes to facilitate genome segregation, they target different cellular binding partners. In summary, the E2 proteins from many papillomaviruses, including the clinically important alpha genus human papillomaviruses, interact with Brd4 to mediate transcriptional activation function but not all depend on this interaction to efficiently associate with mitotic chromosomes.

  17. Structure of the human FANCL RING-Ube2T complex reveals determinants of cognate E3-E2 selection.

    PubMed

    Hodson, Charlotte; Purkiss, Andrew; Miles, Jennifer Anne; Walden, Helen

    2014-02-04

    The combination of an E2 ubiquitin-conjugating enzyme with an E3 ubiquitin-ligase is essential for ubiquitin modification of a substrate. Moreover, the pairing dictates both the substrate choice and the modification type. The molecular details of generic E3-E2 interactions are well established. Nevertheless, the determinants of selective, specific E3-E2 recognition are not understood. There are ∼40 E2s and ∼600 E3s giving rise to a possible ∼24,000 E3-E2 pairs. Using the Fanconi Anemia pathway exclusive E3-E2 pair, FANCL-Ube2T, we report the atomic structure of the FANCL RING-Ube2T complex, revealing a specific and extensive network of additional electrostatic and hydrophobic interactions. Furthermore, we show that these specific interactions are required for selection of Ube2T over other E2s by FANCL.

  18. Mechanisms by Which 17β-Estradiol (E2) Suppress Neuronal cox-2 Gene Expression

    PubMed Central

    Stacey, Winfred; Bhave, Shreyas; Uht, Rosalie M.

    2016-01-01

    E2 attenuates inflammatory responses by suppressing expression of pro-inflammatory genes. Given that inflammation is increasingly being associated with neurodegenerative and psychiatric processes, we sought to elucidate mechanisms by which E2 down-regulates a component of an inflammatory response, cyclooxygenase– 2 (COX-2) expression. Although inflammatory processes in the brain are usually associated with microglia and astrocytes, we found that the COX-2 gene (cox-2) was expressed in a neuronal context, specifically in an amygdalar cell line (AR-5). Given that COX-2 has been reported to be in neurons in the brain, and that the amygdala is a site involved in neurodegenerative and neuropsychiatric processes, we investigated mechanisms by which E2 could down-regulate cox-2 expression in the AR-5 line. These cells express estrogen receptors alpha (ERα) and beta (ERβ), and as shown here cox-2. At the level of RNA, E2 and the ERβ selective ligand diarylpropionitrile (DPN) both attenuated gene expression, whereas the ERα selective ligand propyl pyrazole triol (PPT) had no effect. Neither ligand increased ERβ at the cox-2 promoter. Rather, DPN decreased promoter occupancy of NF-κB p65 and histone 4 (H4) acetylation. Treatment with the non-specific HDAC inhibitor Trichostatin A (TSA) counteracted DPN’s repressive effects on cox-2 expression. In keeping with the TSA effect, E2 and DPN increased histone deacetylase one (HDAC1) and switch-independent 3A (Sin3A) promoter occupancy. Lastly, even though E2 increased CpG methylation, DPN did not. Taken together, the pharmacological data indicate that ERβ contributes to neuronal cox-2 expression, as measured by RNA levels. Furthermore, ER ligands lead to increased recruitment of HDAC1, Sin3A and a concomitant reduction of p65 occupancy and Ac-H4 levels. None of the events, however, are associated with a significant recruitment of ERβ at the promoter. Thus, ERβ directs recruitment to the cox-2 promoter, but does so in

  19. Rubus idaeus L Inhibits Invasion Potential of Human A549 Lung Cancer Cells by Suppression Epithelial-to-Mesenchymal Transition and Akt Pathway In Vitro and Reduces Tumor Growth In Vivo.

    PubMed

    Chu, Shu-Chen; Hsieh, Yih-Shou; Hsu, Li-Sung; Chen, Kuo-Shuen; Chiang, Chien-Cheng; Chen, Pei-Ni

    2014-05-01

    The metastasis of lung cancer is the most prevalent cause of patient death. Various treatment strategies have targeted the prevention of the occurrence of metastasis. The epithelial-mesenchymal transition (EMT) in lung cancer cells is considered a prerequisite to acquire the invasive/migratory phenotype and to subsequently achieve metastasis. However, the effects ofRubus idaeuson cancer invasion and the EMT of the human lung carcinoma remain unclear. In this article, we test the hypothesis thatR idaeusethyl acetate (RIAE) possesses an antimetastatic effect and reverses the EMT potential of human lung A549 cells. We extract the raspberryR idaeuswith methanol (RIME), chloroform (RICE), ethyl acetate (RIAE),n-butanol (RIBE), and water (RIWE). The RIAE treatment obviously inhibits the invasive (P< .001), motility (P< .001), spreading, and migratory potential (P< .001) of highly metastatic human lung cancer A549 cells. The zymography and promoter luciferase analysis reveals that RIAE decreases the proteinase and transcription activities of MMP-2 and u-PA. Molecular analyses show that RIAE increases the E-cadherin level that is mainly localized at the cellular membrane. This result was also verified through confocal analyses. RIAE also induces the upregulation of an epithelial marker, such as α-catenin, and decreases mesenchymal markers, such as snail-1 and N-cadherin, that promote cell invasion and metastasis. RIAE inhibits MMP-2 and u-PA by attenuating the NF-κB and p-Akt expression. The inhibition of RIAE on the growth of A549 cells in vivo was also verified using a cancer cell xenograft nude mice model. Our results show the anti-invasive/antitumor effects of RIAE and associated mechanisms, which suggest that RIAE should be further tested in clinically relevant models to exploit its potential benefits against metastatic lung cancer cells.

  20. Genotypical Differences in Aluminum Resistance of Maize Are Expressed in the Distal Part of the Transition Zone. Is Reduced Basipetal Auxin Flow Involved in Inhibition of Root Elongation by Aluminum?1

    PubMed Central

    Kollmeier, Malte; Felle, Hubert H.; Horst, Walter J.

    2000-01-01

    Short-term Al treatment (90 μm Al at pH 4.5 for 1 h) of the distal transition zone (DTZ; 1–2 mm from the root tip), which does not contribute significantly to root elongation, inhibited root elongation in the main elongation zone (EZ; 2.5–5 mm from the root tip) to the same extent as treatment of the entire maize (Zea mays) root apex. Application of Al to the EZ had no effect on root elongation. Higher genotypical resistance to Al applied to the entire root apex, and specifically to the DTZ, was expressed by less inhibition of root elongation, Al accumulation, and Al-induced callose formation, primarily in the DTZ. A characteristic pH profile along the surface of the root apex with a maximum of pH 5.3 in the DTZ was demonstrated. Al application induced a substantial flattening of the pH profile moreso in the Al-sensitive than in the Al-resistant cultivar. Application of indole-3-acetic acid to the EZ but not to the meristematic zone significantly alleviated the inhibition of root elongation induced by the application of Al to the DTZ. Basipetal transport of exogenously applied [3H]indole-3-acetic acid to the meristematic zone was significantly inhibited by Al application to the DTZ in the Al-sensitive maize cv Lixis. Our results provide evidence that the primary mechanisms of genotypical differences in Al resistance are located within the DTZ, and suggest a signaling pathway in the root apex mediating the Al signal between the DTZ and the EZ through basipetal auxin transport. PMID:10712559