A Monitor of Beam Polarization Profiles for the TRIUMF Parity Experiment

TRIUMF experiment E497 is a study of parity violation in pp scattering at an energy where the leading term in the analyzing power is expected to vanish, thus measuring a unique combination of weak-interaction flavour conserving terms. It is desired to reach a level of sensitivity of 2x10^-8 in both statistical and systematic errors. The leading systematic errors depend on transverse polarization components and, at least, the first moment of transverse polarization. A novel polarimeter that measures profiles of both transverse components of polarization as a function of position is described.Comment: 19 pages LaTeX, 10 PostScript figures. To appear in Nuclear Instruments and Methods in Physics Research, Section

Antitubercular specific activity of ibuprofen and the other 2-arylpropanoic acids using the HT-SPOTi whole-cell phenotypic assay

Objectives: Lead antituberculosis (anti-TB) molecules with novel mechanisms of action are urgently required to fuel the anti-TB drug discovery pipeline. The aim of this study was to validate the use of the high-throughput spot culture growth inhibition (HT-SPOTi) assay for screening libraries of compounds against Mycobacterium tuberculosis and to study the inhibitory effect of ibuprofen (IBP) and the other 2-arylpropanoic acids on the growth inhibition of M tuberculosis and other mycobacterial species. Methods: The HT-SPOTi method was validated not only with known drugs but also with a library of 47 confirmed anti-TB active compounds published in the ChEMBL database. Three over-the-counter non-steroidal anti-inflammatory drugs were also included in the screening. The 2-arylpropanoic acids, including IBP, were comprehensively evaluated against phenotypically and physiologically different strains of mycobacteria, and their cytotoxicity was determined against murine RAW264.7 macrophages. Furthermore, a comparative bioinformatic analysis was employed to propose a potential mycobacterial target. Results: IBP showed antitubercular properties while carprofen was the most potent among the 2-arylpropanoic class. A 3,5-dinitro-IBP derivative was found to be more potent than IBP but equally selective. Other synthetic derivatives of IBP were less active, and the free carboxylic acid of IBP seems to be essential for its anti-TB activity. IBP, carprofen and the 3,5-dinitro-IBP derivative exhibited activity against multidrug-resistant isolates and stationary phase bacilli. On the basis of the human targets of the 2-arylpropanoic analgesics, the protein initiation factor infB (Rv2839c) of M tuberculosis was proposed as a potential molecular target. Conclusions: The HT-SPOTi method can be employed reliably and reproducibly to screen the antimicrobial potency of different compounds. IBP demonstrated specific antitubercular activity, while carprofen was the most selective agent among the 2-arylpropanoic class. Activity against stationary phase bacilli and multidrug-resistant isolates permits us to speculate a novel mechanism of antimycobacterial action. Further medicinal chemistry and target elucidation studies could potentially lead to new therapies against TB

Visual assessment methods used by designers in industry

This thesis concerns visual assessment methods that occur in the dealings of the Consultant Industrial Designer with his industrial clients. The present situation of Industrial Design consultancy in the United Kingdom is outlined in the introduction. This is followed by information on visual assessments. This information is presented from field data in the form of case studies from the personal files of the author. There are twenty case studies from six different companies, all trading in electronic goods. There are thirteen case studies of engineering goods, and seven case studies of consumer goods. In all case studies presented, the author was the principal Industrial Designer involved. In the reporting of the case studies all occasions of visual assessment are prominently noted. Supplementary information is presented from desk data in the form of published works. This data is classified into subjects on designers, the design process and techniques of visualisation, presentation and assessment. This information is analysed into the main constituents that contribute to the visual assessment methods, organised into a simple form and summarised. This summary is then synthesised into a number of models that describe the contributing constituents of visual assessment. The conclusions are presented as a series of models that describe the visual assessment methods under consideration. In the appendices are listed the formal academic submissions that supplement this thesis (Figs. 1 and 2)

Novel HSPB1 mutation causes both motor neuronopathy and distal myopathy.

OBJECTIVE: To identify the cause of isolated distal weakness in a family with both neuropathic and myopathic features on EMG and muscle histology. METHODS: Case study with exome sequencing in 2 affected individuals, bioinformatic prioritization of genetic variants, and segregation analysis of the likely causal mutation. Functional studies included Western blot analysis of the candidate protein before and after heat shock treatment of primary skin fibroblasts. RESULTS: A novel HSPB1 variant (c.387C>G, p.Asp129Glu) segregated with the phenotype and was predicted to alter the conserved α-crystallin domain common to small heat shock proteins. At baseline, there was no difference in HSPB1 protein levels nor its binding partner αB-crystallin. Heat shock treatment increased HSPB1 protein levels in both patient-derived and control fibroblasts, but the associated increase in αB-crystallin expression was greater in patient-derived than control fibroblasts. CONCLUSIONS: The HSPB1 variant (c.387C>G, p.Asp129Glu) is the likely cause of distal neuromyopathy in this pedigree with pathogenic effects mediated through binding to its partner heat shock protein αB-crystallin. Mutations in HSBP1 classically cause a motor axonopathy, but this family shows that the distal weakness can be both myopathic and neuropathic. The traditional clinical classification of distal weakness into "myopathic" or "neuropathic" forms may be misleading in some instances, and future treatments need to address the pathology in both tissues.This study was funded by Wellcome Trust (101876/Z/13/Z and 096919Z/11/Z), Medical Research Council (UK) (G0601943), and Medical Research Council Mitochondrial Biology Unit (MC_UP_1501/2). Funding bodies had no influence on study design or data interpretation.This is the final version of the article. It first appeared from Wolters Kluwer via http://dx.doi.org/10.1212/NXG.000000000000011

Parity Violation in Proton-Proton Scattering

Measurements of parity-violating longitudinal analyzing powers (normalized asymmetries) in polarized proton-proton scattering provide a unique window on the interplay between the weak and strong interactions between and within hadrons. Several new proton-proton parity violation experiments are presently either being performed or are being prepared for execution in the near future: at TRIUMF at 221 MeV and 450 MeV and at COSY (Kernforschungsanlage Juelich) at 230 MeV and near 1.3 GeV. These experiments are intended to provide stringent constraints on the set of six effective weak meson-nucleon coupling constants, which characterize the weak interaction between hadrons in the energy domain where meson exchange models provide an appropriate description. The 221 MeV is unique in that it selects a single transition amplitude (3P2-1D2) and consequently constrains the weak meson-nucleon coupling constant h_rho{pp}. The TRIUMF 221 MeV proton-proton parity violation experiment is described in some detail. A preliminary result for the longitudinal analyzing power is Az = (1.1 +/-0.4 +/-0.4) x 10^-7. Further proton-proton parity violation experiments are commented on. The anomaly at 6 GeV/c requires that a new multi-GeV proton-proton parity violation experiment be performed.Comment: 13 Pages LaTeX, 5 PostScript figures, uses espcrc1.sty. Invited talk at QULEN97, International Conference on Quark Lepton Nuclear Physics -- Nonperturbative QCD Hadron Physics & Electroweak Nuclear Processes --, Osaka, Japan May 20--23, 199

Formulation of hydrophobic peptides for skin delivery via coated microneedles

Microneedles (MNs) have been investigated as a minimally-invasive delivery technology for a range of active pharmaceutical ingredients (APIs). Various formulations and methods for coating the surface of MNs with therapeutics have been proposed and exemplified, predominantly for hydrophilic drugs and particulates. The development of effective MN delivery formulations for hydrophobic drugs is more challenging with dosing restrictions and the use of organic solvents impacting on both the bioactivity and the kinetics of drug release. In this study we propose a novel formulation that is suitable for MN coating of hydrophobic auto-antigen peptides currently being investigated for antigen specific immunotherapy (ASI) of type 1 diabetes. The formulation, comprising three co-solvents (water, 2-methyl-2-butanol and acetic acid) and polyvinylalcohol 2000 (PVA2000) can dissolve both hydrophilic and hydrophobic peptide auto-antigens at relatively high, and clinically relevant, concentrations (25 mg/ml or 12.5 mg/ml). The drug:excipient ratio is restricted to 10:1 w/w to maximise dose whilst ensuring that the dry-coated payload does not significantly impact on MN skin penetration performance. The coating formulation and process does not adversely affect the biological activity of the peptide. The delivery efficiency of the coated peptide into skin is influenced by a number of parameters. Electropolishing the metal MN surface increases delivery efficiency from 2.0 ± 1.0% to 59.9 ± 6.7%. An increased mass of peptide formulation per needle, from 0.37 μg to 2 μg peptide dose, resulted in a thicker coating and a 20% reduction in the efficiency of skin delivery. Other important performance parameters for coated MNs include the role of excipients in assisting dissolution from the MNs, the intrinsic hydrophobicity of the peptide and the species of skin model used in laboratory studies. This study therefore both exemplifies the potential of a novel formulation for coating hydrophobic and hydrophilic peptides onto MN devices and provides new insight into the factors that influence delivery efficiency from coated MNs. Importantly, the results provide guidance for identifying critical attributes of the formulation, coating process and delivery device, that confer reproducible and effective delivery from coated MNs, and thus contribute to the requirements of the regulators appraising these devices

Discovery of potent and selective 5-azaindazole inhibitors of leucine-rich repeat kinase 2 (LRRK2) - Part 1

Parkinson’s disease is a relatively common neurological disorder with incidence increasing with age. Present treatments merely alleviate the symptoms and do not alter the course of the disease, thus identification of disease modifying therapies represents a significant unmet medical need. Mutations in the LRRK2 gene are risk-factors for developing PD and it has been hypothesized that the increased kinase activity of certain LRRK2 mutants are responsible for the damage of the dopaminergic neurons, thus LRRK2 inhibitors offer the potential to target an underlying cause of the disease. In this communication, we describe hit-to-lead medicinal chemistry program on a novel series of 5-azaindazoles. Compound 1, obtained from high-throughput screening was optimized to a highly potent, selective series of molecules with promising DMPK properties. Introduction of heterocycles at the 3-position were found to significantly increase the potency and kinase selectivity, whilst changes to the 4-chlorobenzyl group improved the physicochemical properties. Our series was licensed to a major pharmaceutical company for further developmen

Trouble at the top: The construction of a tenant identity in the governance of social housing organizations

The project of citizen governance has transformed the social housing sector in England where 20,000 tenants now sit as directors on the boards of housing associations, but the entrance of social housing tenants to the boardroom has aroused opposition from the chief executives of housing companies and triggered regulatory intervention from government inspectors. This paper investigates the cause of these tensions through a theoretical framework drawn from the work of feminist philosopher Judith Butler. It interprets housing governance as an identificatory project with the power to constitute tenant directors as regulated subjects, and presents evidence to suggest that this project of identity fails to completely enclose its subject, allowing tenant directors to engage in ‘identity work’ that threatens the supposed unity of the board. The paper charts the development of antagonism and political tension in the board rooms of housing companies to present an innovative account of the construction and contestation of identities in housing governance

Qweak: A Precision Measurement of the Proton's Weak Charge

The Qweak experiment at Jefferson Lab aims to make a 4% measurement of the parity-violating asymmetry in elastic scattering at very low $Q^2$ of a longitudinally polarized electron beam on a proton target. The experiment will measure the weak charge of the proton, and thus the weak mixing angle at low energy scale, providing a precision test of the Standard Model. Since the value of the weak mixing angle is approximately 1/4, the weak charge of the proton $Q_w^p = 1-4 \sin^2 \theta_w$ is suppressed in the Standard Model, making it especially sensitive to the value of the mixing angle and also to possible new physics. The experiment is approved to run at JLab, and the construction plan calls for the hardware to be ready to install in Hall C in 2007. The theoretical context of the experiment and the status of its design are discussed.Comment: 5 pages, 2 figures, LaTeX2e, to be published in CIPANP 2003 proceeding