Scaffold searching: automated identification of similar ring systems for the design of combinatorial libraries

Rigid ring systems can be used to position receptor-binding functional groups in 3D space and they thus play an increasingly important role in the design of combinatorial libraries. This paper discusses the use of shape-similarity methods to identify ring systems that are structurally similar to, and aligned with, a user-defined target ring system. These systems can be used as alternative scaffolds for the construction of a combinatorial library

Policy Words and Policy Deeds: The ECB and the Euro

This paper examines the role of the ECB communication activities on daily Eurodollar exchange rate and interest rates. We estimate the relationship between monetary policy and the exchange rate using a technique that explicitly recognizes the joint determination of both the levels and volatilities of these variables. We also consider more traditional estimation strategies as a test of the robustness of our main results. We introduce a new indicator of ECB communications policies that focuses on what the ECB says about the future economic outlook for the euro area along five different economic dimensions. The impact of ECB communications policies is more apparent in the time series framework than in the heteroskedasticity estimator approach. Previous studies that conclude that news effects are significant at the daily frequency may have reached such a conclusion because the measurement of news was too highly aggregated. The endogeneity of the exchange rate – interest rate relationship is more apparent when the proxy for monetary policy is the euro area – US differential than when any other proxy for monetary policy is employed. Finally, interest rate changes generally have a much larger impact on exchange rate movements, and their volatility, than do ECB verbal pronouncements.Central bank communication; Eurodollar exchange rate

The pp24 phosphoprotein of Mason-Pfizer monkey virus contributes to viral genome packaging

BACKGROUND: The Gag protein of Mason-Pfizer monkey virus, a betaretrovirus, contains a phosphoprotein that is cleaved into the Np24 protein and the phosphoprotein pp16/18 during virus maturation. Previous studies by Yasuda and Hunter (J. Virology. 1998. 72:4095–4103) have demonstrated that pp16/18 contains a viral late domain required for budding and that the Np24 protein plays a role during the virus life cycle since deletion of this N-terminal domain blocked virus replication. The function of the Np24 domain, however, is not known. RESULTS: Here we identify a region of basic residues (KKPKR) within the Np24 domain that is highly conserved among the phosphoproteins of various betaretroviruses. We show that this KKPKR motif is required for virus replication yet dispensable for procapsid assembly, membrane targeting, budding and release, particle maturation, or viral glycoprotein packaging. Additional experiments indicated that deletion of this motif reduced viral RNA packaging 6–8 fold and affected the transient association of Gag with nuclear pores. CONCLUSION: These results demonstrate that the Np24 domain plays an important role in RNA packaging and is in agreement with evidence that suggests that correct intracellular targeting of Gag to the nuclear compartment is an fundamental step in the retroviral life cycle

Measurement of the Effect on Single Bunch Stability of Changing Transition Energy in the CERN SPS

The SPS is the final accelerator in the chain which will be used to fill the Large Hadron Collider (LHC), at present under construction at CERN. The most critical limitation for single bunch intensity in the SPS comes from the longitudinal microwave instability. One of the ways to raise the instability threshold is to decrease the transition energy which can be obtained by perturbing the dispersion function. In order to test expectations an experiment was performed in the SPS using the existing lattice. By adjusting the betatron tune at 26 GeV to be close to a multiple of the machine super perio d, a situation not acceptable for regular operation, the transition energy was reduced from 22 to 19 GeV. The results of this change on the beam were measured directly from the bunch spectrum

A bacterial chloroform reductive dehalogenase: purification and biochemical characterization

© 2017 The Authors. Microbial Biotechnology published by John Wiley & Sons Ltd and Society for Applied Microbiology. We report herein the purification of a chloroform (CF)-reducing enzyme, TmrA, from the membrane fraction of a strict anaerobe Dehalobacter sp. strain UNSWDHB to apparent homogeneity with an approximate 23-fold increase in relative purity compared to crude lysate. The membrane fraction obtained by ultracentrifugation was solubilized in Triton X-100 in the presence of glycerol, followed by purification by anion exchange chromatography. The molecular mass of the purified TmrA was determined to be 44.5 kDa by SDS-PAGE and MALDI-TOF/TOF. The purified dehalogenase reductively dechlorinated CF to dichloromethane in vitro with reduced methyl viologen as the electron donor at a specific activity of (1.27 ± 0.04) × 103units mg protein−1. The optimum temperature and pH for the activity were 45°C and 7.2, respectively. The UV-visible spectrometric analysis indicated the presence of a corrinoid and two [4Fe-4S] clusters, predicted from the amino acid sequence. This is the first report of the production, purification and biochemical characterization of a CF reductive dehalogenase

Curvature-direction measures of self-similar sets

We obtain fractal Lipschitz-Killing curvature-direction measures for a large class of self-similar sets F in R^d. Such measures jointly describe the distribution of normal vectors and localize curvature by analogues of the higher order mean curvatures of differentiable submanifolds. They decouple as independent products of the unit Hausdorff measure on F and a self-similar fibre measure on the sphere, which can be computed by an integral formula. The corresponding local density approach uses an ergodic dynamical system formed by extending the code space shift by a subgroup of the orthogonal group. We then give a remarkably simple proof for the resulting measure version under minimal assumptions.Comment: 17 pages, 2 figures. Update for author's name chang

Proton acceleration by irradiation of isolated spheres with an intense laser pulse

We report on experiments irradiating isolated plastic spheres with a peak laser intensity of 2-3 x 10(20) W cm(-2). With a laser focal spot size of 10 mu m full width half maximum (FWHM) the sphere diameter was varied between 520 nm and 19.3 mu m. Maximum proton energies of similar to 25 MeV are achieved for targets matching the focal spot size of 10 mu m in diameter or being slightly smaller. For smaller spheres the kinetic energy distributions of protons become nonmonotonic, indicating a change in the accelerating mechanism from ambipolar expansion towards a regime dominated by effects caused by Coulomb repulsion of ions. The energy conversion efficiency from laser energy to proton kinetic energy is optimized when the target diameter matches the laser focal spot size with efficiencies reaching the percent level. The change of proton acceleration efficiency with target size can be attributed to the reduced cross-sectional overlap of subfocus targets with the laser. Reported experimental observations are in line with 3D3V particle in cell simulations. They make use of well-defined targets and point out pathways for future applications and experiments.DFG via the Cluster of Excellence Munich-Centre for Advanced Photonics (MAP) Transregio SFB TR18NNSA DE-NA0002008Super-MUC pr48meIvo CermakCGC Instruments in design and realization of the Paul trap systemIMPRS-APSLMUexcellent Junior Research FundDAAD|ToIFEEuropean Union's Horizon research and innovation programme 633053Physic

Medical Comorbidities and Functional Dependent Living Are Independent Risk Factors for Short-Term Complications Following Osteotomy Procedures about the Knee

© The Author(s) 2018. Objective: To characterize rates and risk factors for adverse events following distal femoral osteotomy (DFO), high tibial osteotomy (HTO), and tibial tubercle osteotomy (TTO) procedures. Design: Patients undergoing DFO, HTO, or TTO procedures during 2005 to 2016 were identified in the American College of Surgeons National Surgical Quality Improvement Program. Rates of adverse events were characterized for each procedure. Demographic, comorbidity, and procedural factors were tested for association with occurrence of any adverse events. Results: A total of 1,083 patients were identified. Of these, 305 (28%) underwent DFO, 273 (25%) underwent HTO, and 505 (47%) underwent TTO. Mean ages for patients undergoing each procedure were the following: DFO, 51 ± 23 years; HTO, 40 ± 13 years; and TTO, 31 ± 11 years. The most common comorbidities for DFO were hypertension (34%) and smoking (17%); for HTO, hypertension (22%) and smoking (21%); and for TTO, smoking (20%) and hypertension (11%). Independent risk factors for occurrence of any adverse event were age ⩾45 years for DFO (odds ratio [OR] = 3.1, P \u3c 0.001) and HTO (OR = 2.3, P = 0.029), and body mass index \u3e30 for HTO (OR = 2.5, 95% confidence interval = 1.1-5.7, P = 0.031). When all osteotomy procedures were analyzed collectively, additional variables including diabetes mellitus (OR = 2.2, P = 0.017), chronic obstructive pulmonary disease (OR = 5.5, P = 0.003), and dependent functional status (OR = 3.0, P = 0.004) were associated with adverse events. Conclusions: The total rate of adverse events was not independently associated with the type of osteotomy procedure. In addition, patients with age \u3e45, diabetes mellitus, chronic obstructive pulmonary disease, and dependent functional status have greater odds for adverse events and should be counseled and monitored accordingly

Identification of target-specific bioisosteric fragments from ligand-protein crystallographic data

Bioisosteres are functional groups or atoms that are structurally different but that can form similar intermolecular interactions. Potential bioisosteres were identified here from analysing the X-ray crystallographic structures for sets of different ligands complexed with a fixed protein. The protein was used to align the ligands with each other, and then pairs of ligands compared to identify substructural features with high volume overlap that occurred in approximately the same region of geometric space. The resulting pairs of substructural features can suggest potential bioisosteric replacements for use in lead-optimisation studies. Experiments with 12 sets of ligand-protein complexes from the Protein Data Bank demonstrate the effectiveness of the procedure