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Valentin Soulard, Giorgio Villa, Denis Patrick Vollmar, Philippe Renaud
Selective incorporation of deuterium atoms into molecules is of high interest for labeling purposes and for optimizing properties of drug candidates. A mild and environmentally benign method for the deuteration of alkyl iodides via radical pathway using D2O as source of deuterium has been developed. The reaction is initiated and mediated by triethylborane in the presence of dodecanethiol as a catalyst. This method is compatible with a wide range of functional groups and provides the monodeuterated products in good yields and high level of deuterium incorporation...
December 14, 2017: Journal of the American Chemical Society
Camille Martin, Claire Kizlik-Masson, André Pèlegrin, Hervé Watier, Marie-Claude Viaud-Massuard, Nicolas Joubert
The annual "Antibody Industrial Symposium", co organized by LabEx MAbImprove, MabDesign and Polepharma, was held in Tours, France on June 27-28, 2017. The focus was on antibody-drug-conjugates (ADCs), new entities which realize the hope of Paul Ehrlich's magic bullet. ADCs result from the bioconjugation of a highly cytotoxic drug to a selective monoclonal antibody, which acts as a vector. Building on knowledge gained during the development of three approved ADCs, brentuximab vedotin (Adcetris®), ado trastuzumab emtansine (Kadcyla®) and inotuzumab ozogamicin (Besponsa®), and the many ADCs in development, this meeting addressed strategies and the latest innovations in the field from fundamental research to manufacturing...
December 14, 2017: MAbs
Rama S Akondy, Mark Fitch, Srilatha Edupuganti, Shu Yang, Haydn T Kissick, Kelvin W Li, Ben A Youngblood, Hossam A Abdelsamed, Donald J McGuire, Kristen W Cohen, Gabriela Alexe, Shashi Nagar, Megan M McCausland, Satish Gupta, Pramila Tata, W Nicholas Haining, M Juliana McElrath, David Zhang, Bin Hu, William J Greenleaf, Jorg J Goronzy, Mark J Mulligan, Marc Hellerstein, Rafi Ahmed
The differentiation of human memory CD8 T cells is not well understood. Here we address this issue using the live yellow fever virus (YFV) vaccine, which induces long-term immunity in humans. We used in vivo deuterium labelling to mark CD8 T cells that proliferated in response to the virus and then assessed cellular turnover and longevity by quantifying deuterium dilution kinetics in YFV-specific CD8 T cells using mass spectrometry. This longitudinal analysis showed that the memory pool originates from CD8 T cells that divided extensively during the first two weeks after infection and is maintained by quiescent cells that divide less than once every year (doubling time of over 450 days)...
December 13, 2017: Nature
Bruno Figadére, Tangyuan Cao, Thomas H Morton
The Hofmann elimination of ammonium ions having a single positive charge is demonstrated to exhibit stereospecificity with regard to expulsion of neutral alkene. For the 3-hexyl series of threo and erythro 4-monodeuterated ions (3-hexylammonium ion; N,N,N-trimethyl- d3-3-hexylammonium ion; N-ethyl-3-hexylammonium ion; N-methyl, N-ethyl-3-hexylammonium ion; N,N-dimethyl, N-ethyl-3-hexylammonium ion), the upper limit of the E:Z ratio of the expelled alkene (r) approaches 2 (the stereospecificity) with a deuterium isotope effect close to 2...
January 1, 2017: European Journal of Mass Spectrometry
M Soledade C Pedras, Q Huy To
The syntheses of perdeuterated phytoalexins nasturlexins A and C, and putative biosynthetic precursors, including phenylethyl isothiocyanates and phenylethyl dithiocarbamates, using commercially available [2,3,4,5,6-D5 ]phenylalanine, [2,3,4,5,6-D5 ]nitrobenzene and [2,3,4,5,6-D5 ]benzaldehyde are described. In addition, application of an efficient deuterium-hydrogen exchange transformation to non-labeled starting materials allowed access to new deuterated compounds, including 3-hydroxyphenylethyl glucosinolate...
December 12, 2017: Journal of Labelled Compounds & Radiopharmaceuticals
Paola Cavaliere, Sébastien Brier, Petr Filipenko, Christina Sizun, Bertrand Raynal, Françoise Bonneté, Fabienne Levi-Acobas, Jacques Bellalou, Patrick England, Julia Chamot-Rooke, Claudine Mayer, Françoise Norel
In bacteria, one primary and multiple alternative σ factors associate with the RNA polymerase core enzyme (E) to form holoenzymes (Eσ) with different promoter recognition specificities. The alternative σ factor RpoS/σS is produced in stationary phase and under stress conditions and reprograms global gene expression to promote bacterial survival. To date, the three-dimensional structure of a full-length free σ factor remains elusive. The current model suggests that extensive interdomain contacts in a free σ factor result in a compact conformation that masks the DNA-binding determinants of σ, explaining why a free σ factor does not bind double stranded promoter DNA efficiently...
December 11, 2017: Biochemical Journal
Michael C Pirrung, Allyson Dorsey, Natalie De Howitt, Jiayu Liao
A 5,5-d2 -luciferin was prepared to measure isotope effects on reactions of two intermediates in firefly bioluminescence: emission by oxyluciferin and elimination of a putative luciferyl adenylate hydroperoxide to dehydroluciferin. A negligible isotope effect on bioluminescence provides further support for the belief that the emitting species is the keto-phenolate of oxyluciferin and rules out its excited-state tautomerization, one potential contribution to a bioluminescence quantum yield less than unity. A small isotope effect on dehydroluciferin formation supports a single-electron-transfer mechanism for reaction of the luciferyl adenylate enolate with oxygen to form the hydroperoxide or dehydroluciferin...
December 2017: ChemistryOpen
Zheng Li, Chunxia Liu, Xue Xu, Wei Shi, Huilan Li, Yuxuan Dai, Xingguang Cai, Wenlong Huang, Hai Qian
The free fatty acid receptor 1 (FFA1) is a potential target due to its function in enhancement of glucose-stimulated insulin secretion. Takeda's compound 1 has robustly in vitro activity for FFA1, but it has been suffered from poor pharmacokinetic (PK) profiles because the phenylpropanoic acid is vulnerable to β-oxidation. To identify orally available agonists, we tried to interdict the metabolically labile group by incorporating two deuterium atoms at the α-position of phenylpropionic acid. Interestingly, the differences of physicochemical properties between hydrogen and deuterium are quite small, but there are many differences in the structure-activity relationship between phenylpropionic acid series and present deuterated series...
December 5, 2017: Bioorganic Chemistry
A DeGrush, A Maschinot, T Akdogan, R Alarcon, W Bertozzi, E Booth, T Botto, J R Calarco, B Clasie, C Crawford, K Dow, M Farkhondeh, R Fatemi, O Filoti, W Franklin, H Gao, E Geis, S Gilad, D K Hasell, P Karpius, M Kohl, H Kolster, T Lee, J Matthews, K McIlhany, N Meitanis, R Milner, J Rapaport, R Redwine, J Seely, A Shinozaki, A Sindile, S Širca, E Six, T Smith, B Tonguc, C Tschalär, E Tsentalovich, W Turchinetz, Y Xiao, W Xu, Z-L Zhou, V Ziskin, T Zwart
We report the measurement of the beam-vector and tensor asymmetries A_{ed}^{V} and A_{d}^{T} in quasielastic (e[over →],e^{'}p) electrodisintegration of the deuteron at the MIT-Bates Linear Accelerator Center up to missing momentum of 500  MeV/c. Data were collected simultaneously over a momentum transfer range 0.1<Q^{2}<0.5  (GeV/c)^{2} with the Bates Large Acceptance Spectrometer Toroid using an internal deuterium gas target polarized sequentially in both vector and tensor states. The data are compared with calculations...
November 3, 2017: Physical Review Letters
Susan Krueger
Solution small-angle neutron scattering (SANS) combined with contrast variation provides information about the size and shape of individual components of a multi-component biological assembly, as well as the spatial arrangements between the components. The large difference in the neutron scattering properties between hydrogen and deuterium is key to the method. Isotopic substitution of deuterium for some or all of the hydrogen in either the molecule or the solvent can greatly alter the scattering properties of the biological assembly, often with little or no change to its biochemical properties...
2017: Advances in Experimental Medicine and Biology
Małgorzata Pająk, Marianna Kańska
The kinetic (KIE) and solvent (SIE) isotope effect methods were used to investigate the mechanism of enzymatic hydroxylation of halogenated derivatives of l-tyrosine to l-DOPA catalyzed by the enzyme tyrosinase (EC The values of deuterium KIE and SIE were obtained using the non-competitive method with spectrophotometric measurements. The Lineweaver-Burk plots were used for determination of the inhibition mode of 3'-iodo-l-tyrosine. Based upon kinetic effects values the mechanism of action of enzyme tyrosinase was proposed...
2017: Journal of Radioanalytical and Nuclear Chemistry
A J Hupfer, E V Monakhov, B G Svensson, I Chaplygin, E V Lavrov
Uniaxial-stress experiments have been performed for the 3287- and 2445-cm-1 local vibrational modes assigned to the positive charge state of interstitial hydrogen [Formula: see text] and deuterium [Formula: see text], respectively, occurring in mono-crystalline rutile TiO2. The onset of the defect alignment under the stress applied perpendicular to the [001] axis is detected at 165 K (185 K), which corresponds to the activation energy of 0.53 eV (0.58 eV) for interstitial hydrogen (deuterium). Based on these findings the diffusion constants of [Formula: see text] and [Formula: see text] along the [001] axis of TiO2 are determined...
December 6, 2017: Scientific Reports
Kuizhi Chen, Maryam Abdolrhamani, Eric Sheets, Jeremy Freeman, Garrett Ward, Jeffery L White
Direct observation of multiple reactive sites in the zeolite HZSM-5, a member of the MFI family of zeolite structures, contradicts the traditional view of only one type of active protonic species in industrially-important zeolites. In addition to the well-known Bronsted acid site proton, two other protonic species undergo room-temperature hydrogen-deuterium exchange with an alkane hydrocarbon reagent, including one zeolite moiety characterized by a broad 1H chemical shift at ca. 12-15 ppm that is reported here for the first time...
December 6, 2017: Journal of the American Chemical Society
Jianhui Xie, Po-Kam Lo, Chow-Shing Lam, Kai-Chung Lau, Tai-Chu Lau
The ferrate(vi) ion, [FeO4]2-, has attracted much interest in recent years because of its potential use as a green oxidant in organic synthesis and water treatment. Although there have been several reports on the use of ferrate(vi) for the oxidation of alcohols to the corresponding carbonyl compounds, the mechanism remains unclear. In this work, the kinetics of the oxidation of a series of alcohols with α-C-H bond dissociation energies ranging from 81 to 95 kcal mol-1 have been studied by UV/Vis spectrophotometry...
December 6, 2017: Dalton Transactions: An International Journal of Inorganic Chemistry
Aaron R Navratil, Mikhail S Shchepinov, Edward A Dennis
Arachidonic acid (AA, 20:4) is an omega-6 polyunsaturated fatty acid (PUFA) and the main precursor to the class of lipid mediators known as eicosanoids. The enzymes that catalyze the oxygenation of AA begin by abstracting hydrogen from one of three bis-allylic carbons within 1,4- cis,cis-diene units. Substitution of deuterium for hydrogen has been shown to lead to massive kinetic isotope effects (KIE) for soybean lipoxygenase (sLOX) oxygenation of linoleic acid (LA, 18:2). Yet, experimental determination of the KIE during oxygenation of AA and LA by mammalian enzymes including cyclooxygenase (COX) and lipoxygenase (LOX) has revealed far lower values...
December 5, 2017: Journal of the American Chemical Society
Xiaofeng Li, Yeqing Tao, James W Murphy, Alexander N Scherer, TuKiet T Lam, Alan G Marshall, Anthony J Koleske, Titus J Boggon
The multi-domain protein, cortactin, contains a 37-residue repeating motif that binds to actin filaments. This cortactin repeat region comprises 6½ similar copies of the motif and binds actin filaments. To better understand this region of cortactin, and its fold, we conducted extensive biophysical analysis. Size exclusion chromatography with multi-angle light scattering (SEC-MALS) reveals that neither constructs of the cortactin repeats alone or together with the adjacent helical region homo-oligomerize. Using circular dichroism (CD) we find that in solution the cortactin repeats resemble a coil-like intrinsically disordered protein...
December 1, 2017: Scientific Reports
N Pu, T Nishitani, M Isobe, K Ogawa, H Kawase, T Tanaka, S Y Li, S Yoshihashi, A Uritani
In situ calibration of the neutron activation system on the Large Helical Device (LHD) was performed by using an intense 252Cf neutron source. To simulate a ring-shaped neutron source, we installed a railway inside the LHD vacuum vessel and made a train loaded with the 252Cf source run along a typical magnetic axis position. Three activation capsules loaded with thirty pieces of indium foils stacked with total mass of approximately 18 g were prepared. Each capsule was irradiated over 15 h while the train was circulating...
November 2017: Review of Scientific Instruments
J C Valenzuela, I Krasheninnikov, F Conti, F Wessel, V Fadeev, J Narkis, M P Ross, H U Rahman, E Ruskov, F N Beg
We present the design of a gas-puff injector for liner-on-target experiments. The injector is composed of an annular high atomic number (e.g., Ar and Kr) gas and an on-axis plasma gun that delivers an ionized deuterium target. The annular supersonic nozzle injector has been studied using Computational Fluid Dynamics (CFD) simulations to produce a highly collimated (M > 5), ∼1 cm radius gas profile that satisfies the theoretical requirement for best performance on ∼1-MA current generators. The CFD simulations allowed us to study output density profiles as a function of the nozzle shape, gas pressure, and gas composition...
November 2017: Review of Scientific Instruments
Martin Taubert, Stephan Stöckel, Patricia Geesink, Sophie Girnus, Nico Jehmlich, Martin von Bergen, Petra Rösch, Jürgen Popp, Kirsten Küsel
Microbial activity is key in understanding the contribution of microbial communities to ecosystem functions. Metabolic labeling with heavy water (D2 O) leads to the formation of carbon-deuterium bonds in active microorganisms. We illustrated how D2 O labeling allows monitoring of metabolic activity combined with a functional characterization of active populations in complex microbial communities. First, we demonstrated by single cell Raman microspectroscopy that all measured bacterial cells from groundwater isolates growing in complex medium with D2 O were labeled...
December 1, 2017: Environmental Microbiology
Alessandro Piai, Jyoti Dev, Qingshan Fu, James J Chou
HIV-1 envelope spike (Env) is a type I membrane protein that mediates viral entry. Recent studies showed that its transmembrane domain (TMD) forms a trimer in lipid bilayer whose structure has several peculiar features that remain difficult to explain. One is the presence of an arginine R696 in the middle of the TM helix. Additionally, the N- and C-terminal halves of the TM helix form trimeric cores of opposite nature (hydrophobic and hydrophilic, respectively). Here we determined the membrane partition and solvent accessibility of the TMD in bicelles that mimic a lipid bilayer...
December 1, 2017: Journal of the American Chemical Society
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