Mapping of possible prion protein self-interaction domains using peptide arrays

Background  

The common event in transmissible spongiform encephalopathies (TSEs) or prion diseases is the conversion of host-encoded protease sensitive cellular prion protein (PrP^C) into strain dependent isoforms of scrapie associated protease resistant isoform (PrP^Sc) of prion protein (PrP). These processes are determined by similarities as well as strain dependent variations in the PrP structure. Selective self-interaction between PrP molecules is the most probable basis for initiation of these processes, potentially influenced by chaperone molecules, however the mechanisms behind these processes are far from understood. We previously determined that polymorphisms do not affect initial PrP^C to PrP^Sc binding but rather modulate a subsequent step in the conversion process. Determining possible sites of self-interaction could elucidate which amino acid(s) or amino acid sequences contribute to binding and further conversion into other isoforms. To this end, ovine – and bovine PrP peptide-arrays consisting of 15-mer overlapping peptides were probed with recombinant sheep PrP^C fused to maltose binding protein (MBP-PrP).     

Nonpeptide inhibitors of cathepsin G: optimization of a novel beta-ketophosphonic acid lead by structure-based drug design

The serine protease cathepsin G (EC 3.4.21.20; Cat G), which is stored in the azurophilic granules of neutrophils (polymorphonuclear leukocytes) and released on degranulation, has been implicated in various pathological conditions associated with inflammation. By employing high-throughput screening, we identified beta-ketophosphonic acid 1 as a moderate inhibitor of Cat G (IC(50) = 4.1 microM). We were fortunate to obtain a cocrystal of 1 with Cat G and solve its structure by X-ray crystallography (3.5 A). Structural details from the X-ray analysis of 1.Cat G served as a platform for optimization of this lead compound by structure-based drug design. With the aid of molecular modeling, substituents were attached to the 3-position of the 2-naphthyl ring of 1, which occupies the S1 pocket of Cat G, to provide an extension into the hydrophobic S3 region. Thus, we arrived at analogue 7 with an 80-fold potency improvement over 1 (IC(50) = 53 nM). From these results, it is evident that the beta-ketophosphonic acid unit can form the basis for a novel class of serine protease inhibitors.     

Time-resolved gas-phase kinetic and quantum chemical studies of the reaction of silylene with nitric oxide

Time-resolved kinetic studies of the reaction of silylene, SiH2, generated by laser flash photolysis of phenylsilane, have been carried out to obtain rate constants for its bimolecular reaction with NO. The reaction was studied in the gas phase over the pressure range 1-100 Torr in SF6 bath gas at five temperatures in the range 299-592 K. The second-order rate constants at 10 Torr fitted the Arrhenius equation log(k/cm3 molecule(-1) s(-1)) = (-11.66 +/- 0.01) + (6.20 +/- 0.10 kJ mol(-1))/RT ln 10 The rate constants showed a variation with pressure of a factor of ca. 2 over the available range, almost independent of temperature. The data could not be fitted by RRKM calculations to a simple third body assisted association reaction alone. However, a mechanistic model with an additional (pressure independent) side channel gave a reasonable fit to the data. Ab initio calculations at the G3 level supported a mechanism in which the initial adduct, bent H2SiNO, can ring close to form cyclo-H2SiNO, which is partially collisionally stabilized. In addition, bent H2SiNO can undergo a low barrier isomerization reaction leading, via a sequence of steps, ultimately to dissociation products of which the lowest energy pair are NH2 + SiO. The rate controlling barrier for this latter pathway is only 16 kJ mol(-1) below the energy of SiH2 + NO. This is consistent with the kinetic findings. A particular outcome of this work is that, despite the pressure dependence and the effects of the secondary barrier (in the side reaction), the initial encounter of SiH2 with NO occurs at the collision rate. Thus, silylene can be as reactive with odd electron molecules as with many even electron species. Some comparisons are drawn with the reactions of CH2 + NO and SiCl2 + NO.     

The mass-shell and gauge-fixing conditions for the free relativistic massive quantum particle

Working in the context of the Weyl group, which describes off-mass-shell relativistic particles, we impose “gauge-fixing” constraints involvingR ⁰,R ⁺, andD as matrix element conditions to be satisfied by the on-mass-shell states of a massive particle. We evaluate the matrix elements inp-space using five sets of co-ordinates: (p ²,p), (p ²,p ⁺,p _T ), (p ²,p ^?,p _T ), (p ²,π), and (p ²,π ⁺,π _T ) where \(\pi ^\mu \equiv p^\mu /(p^2 )^{\tfrac{1}{2}} \) . We find that, only in the case ofR ⁰ with (p ²,p) coordinates,R ⁺ with (p ²,p ⁺,p _T ) coordinates, andD with (p ², π) or (p ²,π ⁺,π _T ) coordinates, can the condition be satisfied by arbitrary on-mass-shell states. In all other cases, the condition can be satisfied only by states belonging to a subset of subspaces of the on-mass-shell Hilbert space, i.e it forces a violation of the superposition principle. These results constitute thep-space quantum version of Shanmugadhasan's theorem for constrained classical systems which states that there exists, at least locally in phase space, a canonical transformation to a set of variables in which the second-class constraints become canonical pairs equal to zero with the other canonical coordinates independent of the second-class constraints.     

Novel Synthesis of (+/−)-cis-4-Amino-2-cyclopentene-1-methanol,a Key Intermediate in the Preparation of Carbocyclic 2′,3′-Didehydro-2′,3′-dideoxy Nucleosides

Abstract

Novel synthetic routes directed toward the preparation of (+/?)-cis -4-amino-2-cyclopentene-1-methanol are described. The routes investigated involve azide openings of chiral and non-chiral cyclopentyl epoxides.     

Search for a standard model Higgs boson in the H→ZZ→ℓ(+)ℓ(-)νν decay channel with the ATLAS detector

A search for a heavy standard model Higgs boson decaying via H→ZZ→→?(+)?(-)νν, where ?=e, μ, is presented. It is based on proton-proton collision data at √s=7 TeV, collected by the ATLAS experiment at the LHC in the first half of 2011 and corresponding to an integrated luminosity of 1.04 fb(-1). The data are compared to the expected standard model backgrounds. The data and the background expectations are found to be in agreement and upper limits are placed on the Higgs boson production cross section over the entire mass window considered; in particular, the production of a standard model Higgs boson is excluded in the region 340相似文献   

Synthesis of 3-vinylpiperidine

A novel synthesis of 3-vinylpiperidine from commercially available ethyl 3-pyridylacetate is described.     

Studies on photoinduced effects in pulse-electrodeposited Ag/Hg-1212/CdSe hetero-nanostructures

Metal/superconductor/semiconductor (Ag/Hg-1212/CdSe) hetero-nanostructures have been fabricated using pulse-electrodeposition technique and are characterized by X-ray diffraction (XRD), full-width at half-maximum (FWHM) and scanning electron microscopy (SEM) studies. The junction capacitance of Ag/Hg-1212, Hg-1212/CdSe and Ag/Hg-1212/CdSe heterojunctions is measured in dark and under laser irradiation at room temperature. The nature of the junction formed and built-in-junction potentials were determined. The increase in carrier concentration across the junction due to photo-irradiation has been observed.     

Effect of laser irradiation of C-V characteristics of electrodeposited Ag/Tl-2223/CdSe hetero-nanostructures

One of the innovative technological directions for the high-temperature superconductors has been persued by fabricating the heteroepitaxial multilayer structures such as superconductor-semiconductor heterostructures. In the present investigation, metal/superconductor/semiconductor (Ag/Tl-2223/CdSe) hetero-nanostructures have successfully been fabricated using dc electrodeposition technique and were characterized by X-ray diffraction (XRD), full-width at half-maximum (FWHM) and scanning electron microscopy (SEM) studies. The measurement of junction capacitance as a function of biasing voltage was used for the estimation of junction built-in-potential (V _D) and to study the charge distribution in a heterojunction. The Mott-Schottky plots were measured for each junction in dark and under the photo-irradiation. The effect of laser irradiation on C-V characteristics of hetero-nanostructure has been studied.