Design of dual ligands using excessive pharmacophore query alignment : from 7th German Conference on Chemoinformatics: 25 CIC-Workshop Goslar, Germany, 6 - 8 November 2011

Dual- or multi-target ligands have gained increased attention in the past years due to several advantages, including more simple pharmacokinetic and phamarcodynamic properties compared to a combined application of several drugs. Furthermore multi-target ligands often possess improved efficacy. We present a new approach for the discovery of dual-target ligands using aligned pharmacophore models combined with a shape-based scoring. Starting with two sets of known active compounds for each target, a number of different pharmacophore models is generated and subjected to pairwise graph-based alignment using the Kabsch-Algorithm. Since a compound may be able to bind to different targets in different conformations, the algorithm aligns pairs of pharmacophore models sharing the same features which are not necessarily at the exactly same spatial distance. Using the aligned models, a pharmacophore search on a multi-conformation-database is performed to find compounds matching both models. The potentially “dual” ligands are scored by a shape-based comparison with the known active molecules using ShaEP. Using this approach, we performed a prospective fragment-based virtual screening for dual 5-LO/sEH inhibitors. Both enzymes play an important role in the arachidonic acid cascade and are involved in inflammatory processes, pain, cardiovascular diseases and allergic reactions. Beside several new selective inhibitors we were able to find a compound inhibiting both enzymes in low micromolar concentrations. The results indicate that the idea of aligned pharmacophore models can be successfully employed for the discovery of dual-target ligands

The relations between DISC-IV DSM diagnoses of ADHD and multi-informant CBCL-AP syndrome scores

Background: Previous studies have examined the relation between attention problems (APs) obtained with the Child Behavior Checklist (CBCL) and attention deficit hyperactivity disorder (ADHD) assessed with the Diagnostic and Statistical Manual of Mental Disorders (DSM). We will examine this relation across sex using multi-informant data. Methods: Parents of 12 538 twins, aged 7, 10, and 12 years, and teachers of twins, aged 10 years, completed the questionnaires. The mothers of a sample of 283 boys and 291 girls who scored either low or high on longitudinal maternal CBCL-AP were interviewed. Results: Children with a low AP score obtained a negative ADHD diagnosis in 96% of cases. Children with a high AP score obtained a positive diagnosis in 36% (girls) and 59% (boys) of cases. The association between paternal and maternal AP ratings and ADHD was the same, whereas the association between teacher AP ratings and ADHD was low. Conclusions: The association between AP and ADHD is higher in boys than girls, possibly because of a bias toward the male manifestation of ADHD. © 2006 Elsevier Inc. All rights reserved

Particle tracking in kaon electroproduction with cathode-charge sampling in multi-wire proportional chambers

Wire chambers are routinely operated as tracking detectors in magnetic spectrometers at high-intensity continuous electron beams. Especially in experiments studying reactions with small cross-sections the reaction yield is limited by the background rate in the chambers. One way to determine the track of a charged particle through a multi-wire proportional chamber (MWPC) is the measurement of the charge distribution induced on its cathodes. In practical applications of this read-out method, the algorithm to relate the measured charge distribution to the avalanche position is an important factor for the achievable position resolution and for the track reconstruction efficiency. An algorithm was developed for operating two large-sized MWPCs in a strong background environment with multiple-particle tracks. Resulting efficiencies were determined as a function of the electron beam current and on the signal amplitudes. Because of the different energy-losses of pions, kaons, and protons in the momentum range of the spectrometer the efficiencies depend also on the particle species

High-precision determination of the electric and magnetic form factors of the proton

New precise results of a measurement of the elastic electron-proton scattering cross section performed at the Mainz Microtron MAMI are presented. About 1400 cross sections were measured with negative four-momentum transfers squared up to Q^2=1 (GeV/c)^2 with statistical errors below 0.2%. The electric and magnetic form factors of the proton were extracted by fits of a large variety of form factor models directly to the cross sections. The form factors show some features at the scale of the pion cloud. The charge and magnetic radii are determined to be r_E=0.879(5)(stat.)(4)(syst.)(2)(model)(4)(group) fm and r_M=0.777(13)(stat.)(9)(syst.)(5)(model)(2)(group) fm.Comment: 5 pages, 2 figures, published in Phys. Rev. Lett. v3: added references, updated text, color figure

Reply to Comment on "High-Precision Determination of the Electric and Magnetic Form Factors of the Proton"

In arXiv:1108.3058v1 [nucl-ex], Arrington criticizes the Coulomb corrections we applied in the analysis of high precision form factor data (see Phys.Rev.Lett.105:242001, 2010, arXiv:1007.5076v3 [nucl-ex]). We show, by comparing different calculations cited in the Comment, that the criticism of the Comment neglects the large uncertainty of "more modern" TPE corrections. This uncertainty has also been seen in recent polarized measurements. We rerun our analysis using one of these calculations. The results show that the Comment exaggerates the quantitative effect at small Q^2.Comment: 1 page, 2 figure, To appear as a Reply Comment in Physical Review Letter

The electric and magnetic form factors of the proton

The paper describes a precise measurement of electron scattering off the proton at momentum transfers of $0.003 \lesssim Q^2 \lesssim 1$\ GeV$^2$. The average point-to-point error of the cross sections in this experiment is $\sim$ 0.37%. These data are used for a coherent new analysis together with all world data of unpolarized and polarized electron scattering from the very smallest to the highest momentum transfers so far measured. The extracted electric and magnetic form factors provide new insight into their exact shape, deviating from the classical dipole form, and of structure on top of this gross shape. The data reaching very low $Q^2$ values are used for a new determination of the electric and magnetic radii. An empirical determination of the Two-Photon-Exchange (TPE) correction is presented. The implications of this correction on the radii and the question of a directly visible signal of the pion cloud are addressed.Comment: 38 pages, 20 figures. Updated data files. PRC versio

A Large-Scale FPGA-Based Trigger and Dead-Time Free DAQ System for the Kaos Spectrometer at MAMI

The Kaos spectrometer is maintained by the A1 collaboration at the Mainz Microtron MAMI with a focus on the study of (e,e'K^+) coincidence reactions. For its electron-arm two vertical planes of fiber arrays, each comprising approximately 10 000 fibers, are operated close to zero degree scattering angle and in close proximity to the electron beam. A nearly dead-time free DAQ system to acquire timing and tracking information has been installed for this spectrometer arm. The signals of 144 multi-anode photomultipliers are collected by 96-channel front-end boards, digitized by double-threshold discriminators and the signal time is picked up by state-of-the-art F1 time-to-digital converter chips. In order to minimize background rates a sophisticated trigger logic was implemented in newly developed Vuprom modules. The trigger performs noise suppression, signal cluster finding, particle tracking, and coincidence timing, and can be expanded for kinematical matching (e'K^+) coincidences. The full system was designed to process more than 4 000 read-out channels and to cope with the high electron flux in the spectrometer and the high count rate requirement of the detectors. It was successfully in-beam tested at MAMI in 2009.Comment: Contributed to 17th IEEE Real Time Conference (RT10), Lisbon, 24-28 May 201

Design of dual ligands using excessive pharmacophore query alignment

Dual- or multi-target ligands have gained increased attention in the past years due to several advantages, including more simple pharmacokinetic and phamarcodynamic properties compared to a combined application of several drugs. Furthermore multi-target ligands often possess improved efficacy. We present a new approach for the discovery of dual-target ligands using aligned pharmacophore models combined with a shape-based scoring. Starting with two sets of known active compounds for each target, a number of different pharmacophore models is generated and subjected to pairwise graph-based alignment using the Kabsch-Algorithm. Since a compound may be able to bind to different targets in different conformations, the algorithm aligns pairs of pharmacophore models sharing the same features which are not necessarily at the exactly same spatial distance. Using the aligned models, a pharmacophore search on a multi-conformation-database is performed to find compounds matching both models. The potentially “dual” ligands are scored by a shape-based comparison with the known active molecules using ShaEP. Using this approach, we performed a prospective fragment-based virtual screening for dual 5-LO/sEH inhibitors. Both enzymes play an important role in the arachidonic acid cascade and are involved in inflammatory processes, pain, cardiovascular diseases and allergic reactions. Beside several new selective inhibitors we were able to find a compound inhibiting both enzymes in low micromolar concentrations. The results indicate that the idea of aligned pharmacophore models can be successfully employed for the discovery of dual-target ligands

Search for light massive gauge bosons as an explanation of the (g−2)μ(g-2)_\mu anomaly at MAMI

A massive, but light abelian U(1) gauge boson is a well motivated possible signature of physics beyond the Standard Model of particle physics. In this paper, the search for the signal of such a U(1) gauge boson in electron-positron pair-production at the spectrometer setup of the A1 Collaboration at the Mainz Microtron (MAMI) is described. Exclusion limits in the mass range of 40 MeV up to 300 MeV with a sensitivity in the mixing parameter of down to $\epsilon^2 = 8\times 10^{-7}$ are presented. A large fraction of the parameter space has been excluded where the discrepancy of the measured anomalous magnetic moment of the muon with theory might be explained by an additional U(1) gauge boson.Comment: 4 pages, 3 figure

Spotting Signs of Autism in 3-Year-Olds: Comparing Information from Parents and Preschool Staff

© 2018, The Author(s). Preschool informants may provide valuable information about symptoms of autism spectrum disorder (ASD) in young children. We compared the diagnostic accuracy of ratings by preschool staff with those by parents of 3-year-old children using the Achenbach System of Empirically Based Assessment Preschool Forms. The sample consisted of 32 children at familial risk for ASD without diagnosis, 10 children at risk for ASD with diagnosis, and 14 low-risk typically developing controls. Preschool staff ratings were more accurate than parent ratings at differentiating children with and without ASD, and more closely associated with clinician-rated symptoms. These results point to the value of information from preschool informants in early detection and diagnostic assessments