The Atypical Stimulant and Nootropic Modafinil Interacts with the Dopamine Transporter in a Different Manner than Classical Cocaine-Like Inhibitors

Modafinil is a mild psychostimulant with pro-cognitive and antidepressant effects. Unlike many conventional stimulants, modafinil has little appreciable potential for abuse, making it a promising therapeutic agent for cocaine addiction. The chief molecular target of modafinil is the dopamine transporter (DAT); however, the mechanistic details underlying modafinil's unique effects remain unknown. Recent studies suggest that the conformational effects of a given DAT ligand influence the magnitude of the ligand's reinforcing properties. For example, the atypical DAT inhibitors benztropine and GBR12909 do not share cocaine's notorious addictive liability, despite having greater binding affinity. Here, we show that the binding mechanism of modafinil is different than cocaine and similar to other atypical inhibitors. We previously established two mutations (W84L and D313N) that increase the likelihood that the DAT will adopt an outward-facing conformational state—these mutations increase the affinity of cocaine-like inhibitors considerably, but have little or opposite effect on atypical inhibitor binding. Thus, a compound's WT/mutant affinity ratio can indicate whether the compound preferentially interacts with a more outward- or inward-facing conformational state. Modafinil displayed affinity ratios similar to those of benztropine, GBR12909 and bupropion (which lack cocaine-like effects in humans), but far different than those of cocaine, β-CFT or methylphenidate. Whereas treatment with zinc (known to stabilize an outward-facing transporter state) increased the affinity of cocaine and methylphenidate two-fold, it had little or no effect on the binding of modafinil, benztropine, bupropion or GBR12909. Additionally, computational modeling of inhibitor binding indicated that while β-CFT and methylphenidate stabilize an “open-to-out” conformation, binding of either modafinil or bupropion gives rise to a more closed conformation. Our findings highlight a mechanistic difference between modafinil and cocaine-like stimulants and further demonstrate that the conformational effects of a given DAT inhibitor influence its phenomenological effects

The Lick AGN Monitoring Project: Broad-Line Region Radii and Black Hole Masses from Reverberation Mapping of Hbeta

We have recently completed a 64-night spectroscopic monitoring campaign at the Lick Observatory 3-m Shane telescope with the aim of measuring the masses of the black holes in 12 nearby (z < 0.05) Seyfert 1 galaxies with expected masses in the range ~10^6-10^7 M_sun and also the well-studied nearby active galactic nucleus (AGN) NGC 5548. Nine of the objects in the sample (including NGC 5548) showed optical variability of sufficient strength during the monitoring campaign to allow for a time lag to be measured between the continuum fluctuations and the response to these fluctuations in the broad Hbeta emission. We present here the light curves for the objects in this sample and the subsequent Hbeta time lags for the nine objects where these measurements were possible. The Hbeta lag time is directly related to the size of the broad-line region, and by combining the lag time with the measured width of the Hbeta emission line in the variable part of the spectrum, we determine the virial mass of the central supermassive black hole in these nine AGNs. The absolute calibration of the black hole masses is based on the normalization derived by Onken et al. We also examine the time lag response as a function of velocity across the Hbeta line profile for six of the AGNs. The analysis of four leads to ambiguous results with relatively flat time lags as a function of velocity. However, SBS 1116+583A exhibits a symmetric time lag response around the line center reminiscent of simple models for circularly orbiting broad-line region (BLR) clouds, and Arp 151 shows an asymmetric profile that is most easily explained by a simple gravitational infall model. Further investigation will be necessary to fully understand the constraints placed on physical models of the BLR by the velocity-resolved response in these objects.Comment: 24 pages, 16 figures and 13 tables, submitted to Ap

PhMYB4 fine-tunes the floral volatile signature of Petunia×hybrida through PhC4H

In Petunia×hybrida cv ‘Mitchell Diploid’ (MD), floral volatile benzenoid/phenylpropanoid (FVBP) biosynthesis is controlled spatially, developmentally, and daily at molecular, metabolic, and biochemical levels. Multiple genes have been shown to encode proteins that either directly catalyse a biochemical reaction yielding FVBP compounds or are involved in metabolite flux prior to the formation of FVBP compounds. It was hypothesized that multiple transcription factors are involved in the precise regulation of all necessary genes, resulting in the specific volatile signature of MD flowers. After acquiring all available petunia transcript sequences with homology to Arabidopsis thaliana R2R3-MYB transcription factors, PhMYB4 (named for its close identity to AtMYB4) was identified, cloned, and characterized. PhMYB4 transcripts accumulate to relatively high levels in floral tissues at anthesis and throughout open flower stages, which coincides with the spatial and developmental distribution of FVBP production and emission. Upon RNAi suppression of PhMYB4 (ir-PhMYB4) both petunia CINNAMATE-4-HYDROXYLASE (PhC4H1 and PhC4H2) gene transcript levels were significantly increased. In addition, ir-PhMYB4 plants emit higher levels of FVBP compounds derived from p-coumaric acid (isoeugenol and eugenol) compared with MD. Together, these results indicate that PhMYB4 functions in the repression of C4H transcription, indirectly controlling the balance of FVBP production in petunia floral tissue (i.e. fine-tunes)

Beam-Induced Nuclear Depolarisation in a Gaseous Polarised Hydrogen Target

Spin-polarised atomic hydrogen is used as a gaseous polarised proton target in high energy and nuclear physics experiments operating with internal beams in storage rings. When such beams are intense and bunched, this type of target can be depolarised by a resonant interaction with the transient magnetic field generated by the beam bunches. This effect has been studied with the HERA positron beam in the HERMES experiment at DESY. Resonances have been observed and a simple analytic model has been used to explain their shape and position. Operating conditions for the experiment have been found where there is no significant target depolarisation due to this effect.Comment: REVTEX, 6 pages, 5 figure

Measurement of the Spin Asymmetry in the Photoproduction of Pairs of High-pT Hadrons at HERMES

We present a measurement of the longitudinal spin asymmetry A_|| in photoproduction of pairs of hadrons with high transverse momentum p_T. Data were accumulated by the HERMES experiment using a 27.5 GeV polarized positron beam and a polarized hydrogen target internal to the HERA storage ring. For h+h- pairs with p_T^h_1 > 1.5 GeV/c and p_T^h_2 > 1.0 GeV/c, the measured asymmetry is A_|| = -0.28 +/- 0.12 (stat.) +/- 0.02 (syst.). This negative value is in contrast to the positive asymmetries typically measured in deep inelastic scattering from protons, and is interpreted to arise from a positive gluon polarization.Comment: 5 pages (latex), 4 figures (eps

The Flavor Asymmetry of the Light Quark Sea from Semi-inclusive Deep-inelastic Scattering

The flavor asymmetry of the light quark sea of the nucleon is determined in the kinematic range 0.02<x<0.3 and 1 GeV^2<Q^2<10 GeV^2, for the first time from semi-inclusive deep-inelastic scattering. The quantity (dbar(x)-ubar(x))/(u(x)-d(x)) is derived from a relationship between the yields of positive and negative pions from unpolarized hydrogen and deuterium targets. The flavor asymmetry dbar-ubar is found to be non-zero and x dependent, showing an excess of dbar over ubar quarks in the proton.Comment: 7 Pages, 2 figures, RevTeX format; slight revision in text, small change in extraction of dbar-ubar and comparison with a high q2 parameterizatio

Measurement of the Proton Spin Structure Function g1p with a Pure Hydrogen Target

A measurement of the proton spin structure function g1p(x,Q^2) in deep-inelastic scattering is presented. The data were taken with the 27.6 GeV longitudinally polarised positron beam at HERA incident on a longitudinally polarised pure hydrogen gas target internal to the storage ring. The kinematic range is 0.021<x<0.85 and 0.8 GeV^2<Q^2<20 GeV^2. The integral Int_{0.021}^{0.85} g1p(x)dx evaluated at Q0^2 of 2.5 GeV^2 is 0.122+/-0.003(stat.)+/-0.010(syst.).Comment: 7 pages, 3 figures, 1 table, RevTeX late

Observation of a Single-Spin Azimuthal Asymmetry in Semi-Inclusive Pion Electro-Production

Single-spin asymmetries for semi-inclusive pion production in deep-inelastic scattering have been measured for the first time. A significant target-spin asymmetry of the distribution in the azimuthal angle phi of the pion relative to the lepton scattering plane was observed for pi+ electro-production on a longitudinally polarized hydrogen target. The corresponding analyzing power in the sin(phi) moment of the cross section is 0.022 +/- 0.005 +/- 0.003. This result can be interpreted as the effect of terms in the cross section involving chiral-odd spin distribution functions in combination with a time-reversal-odd fragmentation function that is sensitive to the transverse polarization of the fragmenting quark.Comment: 5 pages of RevTex, 3 ps figures, 2 table

Exclusive Leptoproduction of rho^0 Mesons from Hydrogen at Intermediate Virtual Photon Energies

Measurements of the cross section for exclusive virtual-photoproduction of rho^0 mesons from hydrogen are reported. The data were collected by the HERMES experiment using 27.5 GeV positrons incident on a hydrogen gas target in the HERA storage ring. The invariant mass W of the photon-nucleon system ranges from 4.0 to 6.0 GeV, while the negative squared four-momentum Q^2 of the virtual photon varies from 0.7 to 5.0 GeV^2. The present data together with most of the previous data at W > 4 GeV are well described by a model that infers the W-dependence of the cross section from the dependence on the Bjorken scaling variable x of the unpolarized structure function for deep-inelastic scattering. In addition, a model calculation based on Off-Forward Parton Distributions gives a fairly good account of the longitudinal component of the rho^0 production cross section for Q^2 > 2 GeV^2.Comment: 10 pages, 6 embedded figures, LaTeX for SVJour(epj) document class. Revisions: curves added to Fig. 1, several clarifications added to tex

Measurement of Longitudinal Spin Transfer to Lambda Hyperons in Deep-Inelastic Lepton Scattering

Spin transfer in deep-inelastic Lambda electroproduction has been studied with the HERMES detector using the 27.6 GeV polarized positron beam in the HERA storage ring. For an average fractional energy transfer = 0.45, the longitudinal spin transfer from the virtual photon to the Lambda has been extracted. The spin transfer along the Lambda momentum direction is found to be 0.11 +/- 0.17 (stat) +/- 0.03 (sys); similar values are found for other possible choices for the longitudinal spin direction of the Lambda. This result is the most precise value obtained to date from deep-inelastic scattering with charged lepton beams, and is sensitive to polarized up quark fragmentation to hyperon states. The experimental result is found to be in general agreement with various models of the Lambda spin content, and is consistent with the assumption of helicity conservation in the fragmentation process.Comment: 8 pages, 3 figures; new version has an expanded discussion and small format change