A covalent antagonist for the human adenosine A2A receptor

The structure of the human A2A adenosine receptor has been elucidated by X-ray crystallography with a high affinity non-xanthine antagonist, ZM241385, bound to it. This template molecule served as a starting point for the incorporation of reactive moieties that cause the ligand to covalently bind to the receptor. In particular, we incorporated a fluorosulfonyl moiety onto ZM241385, which yielded LUF7445 (4-((3-((7-amino-2-(furan-2-yl)-[1, 2, 4]triazolo[1,5-a][1, 3, 5]triazin-5-yl)amino)propyl)carbamoyl)benzene sulfonyl fluoride). In a radioligand binding assay, LUF7445 acted as a potent antagonist, with an apparent affinity for the hA2A receptor in the nanomolar range. Its apparent affinity increased with longer incubation time, suggesting an increasing level of covalent binding over time. An in silico A2A-structure-based docking model was used to study the binding mode of LUF7445. This led us to perform site-directed mutagenesis of the A2A receptor to probe and validate the target lysine amino acid K153 for covalent binding. Meanwhile, a functional assay combined with wash-out experiments was set up to investigate the efficacy of covalent binding of LUF7445. All these experiments led us to conclude LUF7445 is a valuable molecular tool for further investigating covalent interactions at this receptor. It may also serve as a prototype for a therapeutic approach in which a covalent antagonist may be needed to counteract prolonged and persistent presence of the endogenous ligand adenosine.KEYWORDS: A2A adenosine receptor; Adenosine; Covalent antagonist; G protein-coupled receptors; Radioligand bindin

Brane fluctuation and the electroweak chiral Lagrangian

We use the external field method to study the electroweak chiral Lagrangian of the extra dimension model with brane fluctuation. Under the assumption that the contact terms between the matters of the standard model and KK excitations are heavily suppressed, we use the standard procedure to integrate out the quantum fields of KK excitations and the equation of motion to eliminate the classic fields of KK excitations. At one-loop level, we find that up to the order $O(p^4)$, due to the momentum conservation of the fifth dimension and the gauge symmetry of the zero modes, there is no constraint on the size of extra dimension. This result is consistent with the decoupling theorem. However, meaningful constraints can come from those operators in $O(p^6)$, which can contribute considerably to some anomalous vector couplings and can be accessible in the LC and LHC.Comment: Revised version, 20 pages in ReVTeX, to appear in PR

A covalent antagonist for the human adenosine A_2A receptor

The structure of the human A(2A) adenosine receptor has been elucidated by X-ray crystallography with a high affinity non-xanthine antagonist, ZM241385, bound to it. This template molecule served as a starting point for the incorporation of reactive moieties that cause the ligand to covalently bind to the receptor. In particular, we incorporated a fluorosulfonyl moiety onto ZM241385, which yielded LUF7445 (4-((3-((7-amino-2-(furan-2-yl)-[1, 2, 4]triazolo[1,5-a][1, 3, 5]triazin-5-yl)amino)propyl)carbamoyl)benzene sulfonyl fluoride). In a radioligand binding assay, LUF7445 acted as a potent antagonist, with an apparent affinity for the hA(2A) receptor in the nanomolar range. Its apparent affinity increased with longer incubation time, suggesting an increasing level of covalent binding over time. An in silico A(2A)-structure-based docking model was used to study the binding mode of LUF7445. This led us to perform site-directed mutagenesis of the A(2A) receptor to probe and validate the target lysine amino acid K153 for covalent binding. Meanwhile, a functional assay combined with wash-out experiments was set up to investigate the efficacy of covalent binding of LUF7445. All these experiments led us to conclude LUF7445 is a valuable molecular tool for further investigating covalent interactions at this receptor. It may also serve as a prototype for a therapeutic approach in which a covalent antagonist may be needed to counteract prolonged and persistent presence of the endogenous ligand adenosine.Medicinal Chemistr

Flavor Singlet Axial Vector Coupling of the Proton with Dynamical Wilson Fermions

We present the results of a full QCD lattice calculation of the flavor singlet axial vector coupling $G_A^1$ of the proton. The simulation has been carried out on a $16^3\times 32$ lattice at $\beta=5.6$ with $n_f=2$ dynamical Wilson fermions. It turns out that the statistical quality of the connected contribution to $G_A^1$ is excellent, whereas the disconnected part is accessible but suffers from large statistical fluctuations. Using a 1st order tadpole improved renormalization constant $Z_A$, we estimate $G_A^1 = 0.20(12)$.Comment: 13 pages, 5 eps figures, minor changes to text and citation

Interface engineering of graphene/copper matrix composites decorated with tungsten carbide for enhanced physico-mechanical properties

For metal matrix composites (MMCs), introduction of low-dimensional nano-carbon materials (NCMs) into three dimensional metallic matrix is commonly applied to enhance mechanical and physical properties of metals and thus significantly extend their wide range applications. However, the interfaces between the NCMs and metal matrix are always a major issue for achieving the best enhancement effects. In this paper, we investigated interfacial structures of graphene nanoplates (GNPs) reinforced Cu matrix composites fabricated using a simple and industrially scalable strategy, through integration of interface engineering design methodology and a spark plasma sintering (SPS) process. We then systematically evaluated their physico-mechanical properties, interfacial characteristics and strengthening mechanisms. The in-situ formed WxCy nano-layers and carbide nanoparticles on the surfaces of GNPs and near the interfaces of Cu grains promote strong interfacial bonding and improves the cohesive strength of Cu based nanocomposites. The GNPs-W/Cu composites show a good balance between strength and electrical conductivity. Their 0.2% yield strength and ultimate tensile strength have been improved up to 239.13% (112.73%) and 197.76% (72.51%), respectively, when compared with those of pure copper (or GNPs/Cu composites). Electrical conductivity of GNPs-W/Cu composites shows no apparent changes after the addition of the GNPs. The dislocation strengthening, refinement strengthening and load transfer strengthening were achieved simultaneously through the engineered interfaces in GNPs-W/Cu matrix composites. This work has provided a new strategy to fabricate high-performance NCMs enhanced MMCs by using the interface engineering methodology

A Lattice Study of the Magnetic Moment and the Spin Structure of the Nucleon

Using an approach free from momentum extrapolation, we calculate the nucleon magnetic moment and the fraction of the nucleon spin carried by the quark angular momentum in the quenched lattice QCD approximation. Quarks with three values of lattice masses, 210, 124 and 80 MeV, are formulated on the lattice using the standard Wilson approach. At every mass, 100 gluon configurations on 16^3 x 32 lattice with \beta=6.0 are used for statistical averaging. The results are compared with the previous calculations with momentum extrapolation. The contribution of the disconnected diagrams is studied at the largest quark mass using noise theory technique.Comment: 14 pages, 3 figures, Talk given at Lattice2001, Berlin, German

Measurements of J/psi Decays into 2(pi+pi-)eta and 3(pi+pi-)eta

Based on a sample of 5.8X 10^7 J/psi events taken with the BESII detector, the branching fractions of J/psi--> 2(pi+pi-)eta and J/psi-->3(pi+pi-)eta are measured for the first time to be (2.26+-0.08+-0.27)X10^{-3} and (7.24+-0.96+-1.11)X10^{-4}, respectively.Comment: 11 pages, 6 figure

BESII Detector Simulation

A Monte Carlo program based on Geant3 has been developed for BESII detector simulation. The organization of the program is outlined, and the digitization procedure for simulating the response of various sub-detectors is described. Comparisons with data show that the performance of the program is generally satisfactory.Comment: 17 pages, 14 figures, uses elsart.cls, to be submitted to NIM

Measurement of branching fractions for the inclusive Cabibbo-favored ~K*0(892) and Cabibbo-suppressed K*0(892) decays of neutral and charged D mesons

The branching fractions for the inclusive Cabibbo-favored ~K*0 and Cabibbo-suppressed K*0 decays of D mesons are measured based on a data sample of 33 pb-1 collected at and around the center-of-mass energy of 3.773 GeV with the BES-II detector at the BEPC collider. The branching fractions for the decays D+(0) -> ~K*0(892)X and D0 -> K*0(892)X are determined to be BF(D0 -> \~K*0X) = (8.7 +/- 4.0 +/- 1.2)%, BF(D+ -> ~K*0X) = (23.2 +/- 4.5 +/- 3.0)% and BF(D0 -> K*0X) = (2.8 +/- 1.2 +/- 0.4)%. An upper limit on the branching fraction at 90% C.L. for the decay D+ -> K*0(892)X is set to be BF(D+ -> K*0X) < 6.6%