HS 2325+8205 - an ideal laboratory for accretion disk physics

We identify HS 2325+8205 as an eclipsing, frequently outbursting dwarf nova with an orbital period of 279.841731(5) min. Spectroscopic observations are used to derive the radial velocity curve of the secondary star from absorption features and also from the H-alpha emission lines, originating from the accretion disc, yielding K_secondary = K_abs = 237 +- 28 km/s and K_emn = 145 +- 9 km/s respectively. The distance to the system is calculated to be 400 (+200, -140) pc. A photometric monitoring campaign reveals an outburst recurrence time of 12-14 d, The combination of magnitude range (17-14 mag), high declination, eclipsing nature and frequency of outbursts makes HS 2325+8205 the ideal system for "real-time" studies of the accretion disc evolution and behavior in dwarf nova outbursts.Comment: 20 pages, 7 figures. Accepted for Publications of the Astronomical Society of the Pacifi

Nudging down theft from insecure vehicles. A pilot study

This report presents the preliminary findings of a pilot study to reduce thefts from cars committed against insecure vehicles, using the behavioural insights or ‘nudge approach’. The recipients of the ‘nudges’ were potential victims of theft from insecure vehicles living in high rate areas for this crime, where a bespoke leaflet campaign was developed to nudge vehicle owners into thinking more carefully when leaving their vehicles unattended, particularly when left on their driveways overnight. Although somewhat tentative at this stage, the preliminary findings indicate that the percentage of thefts committed against insecure vehicles in the two treatment areas was reduced significantly when compared with the two control group areas where no nudge interventions were introduced. This demonstrates that if appropriate nudges (grounded in psychological theory) are coupled with and delivered by appropriate messengers, the prosocial behavioural change can be encouraged which can lead to a reduction in criminal behaviour and opportunities for crim

Routine activities and proactive police activity: a macro-scale analysis of police searches in London and New York City

This paper explored how city-level changes in routine activities were associated with changes in frequencies of police searches using six years of police records from the London Metropolitan Police Service and the New York City Police Department. Routine activities were operationalised through selecting events that potentially impacted on (a) the street population, (b) the frequency of crime or (c) the level of police activity. OLS regression results indicated that routine activity variables (e.g. day of the week, periods of high demand for police service) can explain a large proportion of the variance in search frequency throughout the year. A complex set of results emerged, revealing cross-national dissimilarities and the differential impact of certain activities (e.g. public holidays). Importantly, temporal frequencies in searches are not reducible to associations between searches and recorded street crime, nor changes in on-street population. Based on the routine activity approach, a theoretical police-action model is proposed

Functional solubilization of the β 2-adrenoceptor using diisobutylene maleic acid

The β2-adrenoceptor (β2AR) is a well-established target in asthma and a prototypical G protein-coupled receptor for biophysical studies. Solubilization of membrane proteins has classically involved the use of detergents. However, the detergent environment differs from the native membrane environment and often destabilizes membrane proteins. Use of amphiphilic copolymers is a promising strategy to solubilize membrane proteins within their native lipid environment in the complete absence of detergents. Here we show the isolation of the β 2AR in the polymer diisobutylene maleic acid (DIBMA). We demonstrate that β 2AR remains functional in the DIBMA lipid particle and shows improved thermal stability compared with the n-dodecyl-β-D-maltopyranoside detergent-solubilized β 2AR. This unique method of extracting β 2AR offers significant advantages over previous methods routinely employed such as the introduction of thermostabilizing mutations and the use of detergents, particularly for functional biophysical studies

Modulation of Glucagon Receptor Pharmacology by Receptor Activity-modifying Protein-2 (RAMP2).

The glucagon and glucagon-like peptide-1 (GLP-1) receptors play important, opposing roles in regulating blood glucose levels. Consequently, these receptors have been identified as targets for novel diabetes treatments. However, drugs acting at the GLP-1 receptor, although having clinical efficacy, have been associated with severe adverse side-effects, and targeting of the glucagon receptor has yet to be successful. Here we use a combination of yeast reporter assays and mammalian systems to provide a more complete understanding of glucagon receptor signaling, considering the effect of multiple ligands, association with the receptor-interacting protein receptor activity-modifying protein-2 (RAMP2), and the role of individual G protein α-subunits. We demonstrate that RAMP2 alters both ligand selectivity and G protein preference of the glucagon receptor. Importantly, we also uncover novel cross-reactivity of therapeutically used GLP-1 receptor ligands at the glucagon receptor that is abolished by RAMP2 interaction. This study reveals the glucagon receptor as a previously unidentified target for GLP-1 receptor agonists and highlights a role for RAMP2 in regulating its pharmacology. Such previously unrecognized functions of RAMPs highlight the need to consider all receptor-interacting proteins in future drug development.This work was supported by a Warwick Impact Fund (C.W., G.L.), the BBSRC (G.L. - BB/G01227X/1), (T.S., G.R., D.R. - BB/F008392/1), (D.P. - BB/M007529/1 and BB/M000176/1), Warwick Research Development Fund (C.W., G.L.) grant number (RD13301) and the Birmingham Science City Research Alliance (G.L).This is the final version of the article. It first appeared from ASBMB at http://dx.doi.org/10.1074/jbc.M114.62460

hCALCRL mutation causes autosomal recessive nonimmune hydrops fetalis with lymphatic dysplasia

We report the first case of nonimmune hydrops fetalis (NIHF) associated with a recessive, in-frame deletion of V205 in the G protein–coupled receptor, Calcitonin Receptor-Like Receptor (hCALCRL). Homozygosity results in fetal demise from hydrops fetalis, while heterozygosity in females is associated with spontaneous miscarriage and subfertility. Using molecular dynamic modeling and in vitro biochemical assays, we show that the hCLR(V205del) mutant results in misfolding of the first extracellular loop, reducing association with its requisite receptor chaperone, receptor activity modifying protein (RAMP), translocation to the plasma membrane and signaling. Using three independent genetic mouse models we establish that the adrenomedullin–CLR–RAMP2 axis is both necessary and sufficient for driving lymphatic vascular proliferation. Genetic ablation of either lymphatic endothelial Calcrl or nonendothelial Ramp2 leads to severe NIHF with embryonic demise and placental pathologies, similar to that observed in humans. Our results highlight a novel candidate gene for human congenital NIHF and provide structure–function insights of this signaling axis for human physiology