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  1. A Perturbed pK_a at the Binding Site of the Nicotinic Acetylcholine Receptor: Implications for Nicotine Binding

    Petersson, E. James; Choi, Anita; Dahan, David S.; Lester, Henry A.; Dougherty, Dennis A.
    A series of tethered quaternary ammonium derivatives of Tyr have been incorporated into the binding site of the nicotinic acetylcholine receptor (nAChR) using the in vivo nonsense suppression method, producing constitutively active (self-gating) receptors. We have incorporated primary, secondary, and tertiary amine tethered agonists to give receptors whose constitutive activity can be modulated by pH. Lowering the pH protonates the tethered amine, giving it a positive charge and allowing it to reversibly activate the receptor. Tertiary and secondary tethered amines, TyrO3T and TyrO3S, have been successfully incorporated at α149 in the nAChR. Constitutive currents at pH 5.5 are 6 times...

  2. The First Total Synthesis of Dragmacidin D

    Garg, Neil K.; Sarpong, Richmond; Stoltz, Brian M.
    The first total synthesis of the biologically significant bis-indole alkaloid dragmacidin D (5) has been achieved. Thermal and electronic modulation provides the key for a series of palladium-catalyzed Suzuki cross-coupling reactions that furnished the core structure of the complex guanidine- and aminoimidazole-containing dragmacidins. Following this crucial sequence, a succession of meticulously controlled final events was developed leading to the completion of the natural product.

  3. Structural Model for an Alkaline Form of Ferricytochrome c

    Assfalg, Michael; Bertini, Ivano; Dolfi, Alessandra; Turano, Paola; Mauk, A. Grant; Rosell, Federico I.; Gray, Harry B.
    An ^(15)N-enriched sample of the yeast iso-1-ferricytochrome c triple variant (Lys72Ala/Lys79Ala/Cys102Thr) in an alkaline conformation was examined by NMR spectroscopy. The mutations were planned to produce a cytochrome c with a single conformer. Despite suboptimal conditions for the collection of spectra (i.e., pH ≈ 11), NMR remains a suitable investigation technique capable of taking advantage of paramagnetism. 76% of amino acids and 49% of protons were assigned successfully. The assignment was in part achieved through standard methods, in part through the identification of groups maintaining the same conformation as in the native protein at pH 7 and, for a few...

  4. Gold Electrodes Wired for Coupling with the Deeply Buried Active Site of Arthrobacter globiformis Amine Oxidase

    Hess, Corinna R.; Juda, Gregory A.; Dooley, David M.; Amii, Ricky N.; Hill, Michael G.; Winkler, Jay R.; Gray, Harry B.
    Diethylaniline-terminated oligo(phenyl-ethynyl)-thiol (DEA-OPE-SH) wires on Au-bead electrodes facilitate electron tunneling to and from the deeply buried topaquinone (TPQ) cofactor in Arthrobacter globiformis amine oxidase (AGAO). Reversible cyclic voltammograms were observed when AGAO was adsorbed onto this DEA-OPE-SAu surface:  the 2e^-/2H^+ reduction potential is −140 mV versus SCE.

  5. In Vitro Selection of mRNA Display Libraries Containing an Unnatural Amino Acid

    Li, Shuwei; Millward, Steven; Roberts, Richard
    The incorporation of unnatural amino acid into selectable, amplifiable peptide and protein libraries expands the chemical diversity of such libraries, thus considerably facilitating the process of obtaining ligands with improved properties (affinity, specificity, and function), particularly against therapeutically interesting targets. Here, we report that biocytin, a biotin derivative of lysine, can be inserted into an mRNA−protein fusion molecule through amber stop codon suppression. We also demonstrate that templates containing the codon corresponding to the biocytin tRNA (a UAG stop codon) can be enriched by iterative cycles of selection against a streptavidin agarose matrix.

  6. Interhemispheric relationships: the neocortical commissures; syndromes of hemisphere disconnection

    Sperry, R. W.; Gazzaniga, M. S.; Bogen, J. E.
    [Introduction] Until a few years ago, prevailing views regarding the syndrome of the corpus callosum in man were based very largely on the studies of Akelaitis and his co-workers (Akelaitis et al. 1942; Akelaitis 1944). Using a wide variety of tests Akelaitis examined a series of more than two dozen patients with partial and complete surgical sections of the corpus callosum and anterior commissure and was unable to find any consistent neurological or psychological dysfunctions that could be reliably attributed to the commissural sections. Symptoms such as unilateral astereognosis, alexia, agraphia, ideo-motor apraxia (Sweet 1941), as well as apathy, amnesia,...

  7. The Enantioselective Organocatalytic 1,4-Addition of Electron-Rich Benzenes to α,β-Unsaturated Aldehydes

    Paras, Nick A.; MacMillan, David W. C.
    The first enantioselective organocatalytic alkylation of electron-rich benzene rings with α,β-unsaturated aldehydes has been accomplished. The use of iminium catalysis has provided a new strategy for the enantioselective construction of benzylic stereogenicity, an important chiral synthon for natural product and medicinal agent synthesis. The (2S,5S)-5-benzyl-2-tert-butylimidazolidinone amine catalyst has been found to mediate the conjugate addition of a wide variety of substituted and unsubstituted anilines to unsaturated aldehydes. A diverse spectrum of aldehyde substrates can also be accommodated in this new organocatalytic transformation. While catalyst quantities of 10 mol % were generally employed in this study, successful alkylations conducted with catalyst...

  8. Designed Arginine-Rich RNA-Binding Peptides with Picomolar Affinity

    Austin, Ryan J.; Xia, Tianbing; Ren, Jinsong; Takahashi, Terry T.; Roberts, Richard W.
    Arginine-rich peptide motifs (ARMs) capable of binding unique RNA structures play critical roles in transcription, translation, RNA trafficking, and RNA packaging. Bacteriophage ARMs necessary for transcription antitermination bind to distinct boxB RNA hairpin sequences with a characteristic induced α-helical structure. Characterization of ARMs from lambdoid phages reveals that the dissociation constant of the P22 bacteriophage model−antitermination complex (P22_(N21)−P22boxB) is 200 ± 56 pM in free solution at physiologic concentrations of monovalent cation, significantly stronger than previously determined by gel mobility shift and polyacrylamide gel coelectophoresis, and 2 orders of magnitude stronger than the tightest known native ARM−RNA interaction at physiological...

  9. Probing Microplasticity in Small-Scale FCC Crystals via Dynamic Mechanical Analysis

    Ni, Xiaoyue; Papanikolaou, Stefanos; Vajente, Gabriele; Adhikari, Rana X.; Greer, Julia R.
    In small-scale metallic systems, collective dislocation activity has been correlated with size effects in strength and with a steplike plastic response under uniaxial compression and tension. Yielding and plastic flow in these samples is often accompanied by the emergence of multiple dislocation avalanches. Dislocations might be active preyield, but their activity typically cannot be discerned because of the inherent instrumental noise in detecting equipment. We apply alternate current load perturbations via dynamic mechanical analysis during quasistatic uniaxial compression experiments on single crystalline Cu nanopillars with diameters of 500 nm and compute dynamic moduli at frequencies 0.1, 0.3, 1, and 10...

  10. Synthesis and Activity of Ruthenium Alkylidene Complexes Coordinated with Phosphine and N-Heterocyclic Carbene Ligands

    Trnka, Tina M.; Morgan, John P.; Sanford, Melanie S.; Wilhelm, Thomas E.; Scholl, Matthias; Choi, Tae-Lim; Ding, Sheng; Day, Michael W.; Grubbs, Robert H.
    This paper reports the synthesis and characterization of a variety of ruthenium complexes coordinated with phosphine and N-heterocyclic carbene (NHC) ligands. These complexes include several alkylidene derivatives of the general formula (NHC)(PR_3)(Cl)_2Ru═CHR', which are highly active olefin metathesis catalysts. Although these catalysts can be prepared adequately by the reaction of bis(phosphine) ruthenium alkylidene precursors with free NHCs, we have developed an alternative route that employs NHC-alcohol or -chloroform adducts as “protected” forms of the NHC ligands. This route is advantageous because NHC adducts are easier to handle than their free carbene counterparts. We also demonstrate that sterically bulky bis(NHC) complexes...

  11. Novel Reactivity of Ruthenium Alkylidenes in Protic Solvents: Degenerate Alkylidene Proton Exchange

    Lynn, David M.; Grubbs, Robert H.
    A novel organometallic transformation is reported in which the alkylidene protons of water-soluble ruthenium alkylidenes 1 and 2 undergo nondestructive, degenerate exchange with solvent-derived deuterons in perdeuterated protic solvents such as D_2O and CD_3OD. Deuterated alkylidene complex (1-D) was isolated from a solution of alkylidene 1 in D_2O, and the new alkylidene was fully characterized by ^1H, ^2H, ^(13)C, and ^(31)P NMR spectroscopy and fast-atom bombardment mass spectroscopy (FAB-MS). The rate of alkylidene proton exchange for this transformation was found to correlate with the bulk dielectric constant of the solvent or solvent mixtures employed. The data support a mechanism for...

  12. The Electronic Influence of Ring Substituents and Ansa Bridges in Zirconocene Complexes as Probed by Infrared Spectroscopic, Electrochemical, and Computational Studies

    Zachmanoglou, Cary E.; Docrat, Arefa; Bridgewater, Brian M.; Parkin, Gerard; Brandow, Christopher G.; Bercaw, John E.; Jardine, Christian N.; Lyall, Mark; Green, Jennifer C.; Keister, Jerome B.
    The electronic influence of unbridged and ansa-bridged ring substituents on a zirconocene center has been studied by means of IR spectroscopic, electrochemical, and computational methods. With respect to IR spectroscopy, the average of the symmetric and asymmetric stretches (ν_(CO(av))) of a large series of dicarbonyl complexes (Cp^R)_2Zr(CO)_2 has been used as a probe of the electronic influence of a cyclopentadienyl ring substituent. For unbridged substituents (Me, Et, Pri, But, SiMe_3), ν_(CO(av)) on a per substituent basis correlates well with Hammett σ_(meta) parameters, thereby indicating that the influence of these substituents is via a simple inductive effect. In contrast, the reduction...

  13. A Large Throughput High Resolution Fourier Transform Spectrometer for Submillimeter Applications

    Bin, M.; Benford, D. J.; Gaidis, M. C.; Büttgenbach, T. H.; Zmuidzinas, J.; Serabyn, E.; Phillips, T. G.
    We have designed and constructed a Fourier Transform Spectrometer (FTS) for the study of submillimeter-wave mixers and optical components. The FTS has a large aperture (up to 25.4 cm) and small focal ratio (as fast as f/2.5) to achieve a large throughput. It operates in the 100-3750 GHz (3.3-125 cm^(−1)) frequency range with a resolution of up to 75 MHz (0.0025 cm^(−1)). Here we discuss the design goals and provide a detailed description of the construction of the FTS. In addition, we highlight the variety of studies which have been conducted with this instrument, which include characterizing SIS mixers through...

  14. The Golden Standard Type Ia Supernova 2005cf: Observations from the Ultraviolet to the Near-Infrared Wavebands

    Wang, X.; Li, W.; Filippenko, A. V.; Foley, R. J.; Kirshner, R. P.; Modjaz, M.; Bloom, J.; Brown, P. J.; Carter, D.; Friedman, A. S.; Gal-Yam, A.; Ganeshalingam, M.; Hicken, M.; Krisciunas, K.; Milne, P.; Silverman, J. M.; Suntzeff, N. B.; Wood-Vasey, W. M.; Cenko, S. B.; Challis, P.; Fox, D. B.; Kirkman, D.; Li, J. Z.; Li, T. P.; Malkan, M. A.; Moore, M. R.; Reitzel, D. B.; Rich, R. M.; Serduke, F. J. D.; Shang, R. C.; Steele, T. N.; Swift, B. J.; Tao, C.; Wong, D. S.; Zhang, S. N.
    We present extensive photometry at ultraviolet (UV), optical, and near-infrared (NIR) wavelengths, as well as dense sampling of optical spectra, for the normal Type Ia supernova (SN Ia) 2005cf. The optical photometry, performed at eight different telescopes, shows a 1σ scatter of ≾0.03 mag after proper corrections for the instrument responses. From the well-sampled light curves, we find that SN 2005cf reached a B-band maximum at 13.63 ± 0.02 mag, with an observed luminosity decline rate Δm _(15)(B) = 1.05 ± 0.03 mag. The correlations between the decline rate and various color indexes, recalibrated on the basis of an expanded...

  15. The Distance to NGC 6397 by M-Subdwarf Main-Sequence Fitting

    Reid, I. Neill; Gizis, John E.
    Recent years have seen a substantial improvement both in photometry of low-luminosity stars in globular clusters and in modeling the stellar atmospheres of late-type dwarfs. We build on these observational and theoretical advances in undertaking the first determination of the distance to a globular cluster by main-sequence fitting using stars on the lower main sequence. The calibrating stars are extreme M subdwarfs, as classified by Gizis, with parallaxes measured to a precision of better than 10%. Matching against King et al.'s deep [V, (V-I)] photometry of NGC 6397, and adopting E_(B-V) = 0.18 mag, we derive a true distance modulus...

  16. Propagation of Thermonuclear Flames on Rapidly Rotating Neutron Stars: Extreme Weather during Type I X-Ray Bursts

    Spitkovsky, Anatoly; Levin, Yuri; Ushomirsky, Greg
    We analyze the global hydrodynamic flow in the ocean of an accreting, rapidly rotating, nonmagnetic neutron star in a low-mass X-ray binary during a type I X-ray burst. We use both analytical arguments and numerical simulations of simplified models for ocean burning. Our analysis extends previous work by taking into account the rapid rotation of the star and the lift-up of the burning ocean during the burst. We find a new regime for the spreading of a nuclear burning front, where the flame is carried along a coherent shear flow across the front. If turbulent viscosity is weak, the speed...

  17. Movement Intention Is Better Predicted than Attention in the Posterior Parietal Cortex

    Quiroga, Rodrigo Quian; Snyder, Lawrence H.; Batista, Aaron P.; Cui, He; Andersen, Richard A.
    We decoded on a trial-by-trial basis the location of visual targets, as a marker of the locus of attention, and intentions to reach and to saccade in different directions using the activity of neurons in the posterior parietal cortex of two monkeys. Predictions of target locations were significantly worse than predictions of movement plans for the same target locations. Moreover, neural signals in the parietal reach region (PRR) gave better predictions of reaches than saccades, whereas signals in the lateral intraparietal area (LIP) gave better predictions of saccades than reaches. Taking together the activity of both areas, the prediction of...

  18. Co-infection Weakens Selection Against Epistatic Mutations in RNA Viruses

    Froissart, Rémy; Wilke, Claus O.; Montville, Rebecca; Remold, Susanna K.; Chao, Lin; Turner, Paul E.
    Co-infection may be beneficial in large populations of viruses because it permits sexual exchange between viruses that is useful in combating the mutational load. This advantage of sex should be especially substantial when mutations interact through negative epistasis. In contrast, co-infection may be detrimental because it allows virus complementation, where inferior genotypes profit from superior virus products available within the cell. The RNA bacteriophage φ6 features a genome divided into three segments. Co-infection by multiple φ6 genotypes produces hybrids containing reassorted mixtures of the parental segments. We imposed a mutational load on φ6 populations by mixing the wild-type virus with...

  19. Bankruptcy prediction for credit risk using neural networks: A survey and new results

    Atiya, Amir F.
    The prediction of corporate bankruptcies is an important and widely studied topic since it can have significant impact on bank lending decisions and profitability. This work presents two contributions. First we review the topic of bankruptcy prediction, with emphasis on neural-network (NN) models. Second, we develop an NN bankruptcy prediction model. Inspired by one of the traditional credit risk models developed by Merton (1974), we propose novel indicators for the NN system. We show that the use of these indicators in addition to traditional financial ratio indicators provides a significant improvement in the (out-of-sample) prediction accuracy (from 81.46% to 85.5%...

  20. On the Age Estimation of LBDS 53W091

    Yi, Sukyoung; Brown, Thomas M.; Heap, Sara; Hubeny, Ivan; Landsman, Wayne; Lanz, Thierry; Sweigart, Allen
    The recent spectral analysis of LBDS 53W091 by Spinrad and his collaborators has suggested that this red galaxy at z = 1.552 is at least 3.5 Gyr old. This imposes an important constraint on cosmology, suggesting that this galaxy formed at z ≳ 6.5, assuming recent estimates of cosmological parameters. While their analysis was heavily focused on the use of some UV spectral breaks as age indicators, we have performed χ2 tests to the continuum of this galaxy using its UV spectrum and photometric data (R, J, H, and K: 2000-9000 Å in rest frame). We have used the updated...

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