The role of ECL2 in CGRP receptor activation: a combined modelling and experimental approach

The calcitonin gene-related peptide (CGRP) receptor is a complex of a calcitonin receptor-like receptor (CLR), which is a family B G-protein-coupled receptor (GPCR) and receptor activity modifying protein 1. The role of the second extracellular loop (ECL2) of CLR in binding CGRP and coupling to Gs was investigated using a combination of mutagenesis and modelling. An alanine scan of residues 271–294 of CLR showed that the ability of CGRP to produce cAMP was impaired by point mutations at 13 residues; most of these also impaired the response to adrenomedullin (AM). These data were used to select probable ECL2-modelled conformations that are involved in agonist binding, allowing the identification of the likely contacts between the peptide and receptor. The implications of the most likely structures for receptor activation are discussed.</jats:p

Mobile element scanning (ME-Scan) identifies thousands of novel Alu insertions in diverse human populations

Alu retrotransposons are the most numerous and active mobile elements in humans, causing genetic disease and creating genomic diversity. Mobile element scanning (ME-Scan) enables comprehensive and affordable identification of mobile element insertions (MEI) using targeted high-throughput sequencing of multiplexed MEI junction libraries. In a single experiment, ME-Scan identifies nearly all AluYb8 and AluYb9 elements, with high sensitivity for both rare and common insertions, in 169 individuals of diverse ancestry. ME-Scan detects heterozygous insertions in single individuals with 91% sensitivity. Insertion presence or absence states determined by ME-Scan are 95% concordant with those determined by locus-specific PCR assays. By sampling diverse populations from Africa, South Asia, and Europe, we are able to identify 5799 Alu insertions, including 2524 novel ones, some of which occur in exons. Sub-Saharan populations and a Pygmy group in particular carry numerous intermediate-frequency Alu insertions that are absent in non-African groups. There is a significant dearth of exon-interrupting insertions among common Alu polymorphisms, but the density of singleton Alu insertions is constant across exonic and nonexonic regions. In one case, a validated novel singleton Alu interrupts a proteincoding exon of FAM187B. This implies that exonic Alu insertions are generally deleterious and thus eliminated by natural selection, but not so quickly that they cannot be observed as extremely rare variants. © 2013, Published by Cold Spring Harbor Laboratory Press

Game theory of mind

This paper introduces a model of ‘theory of mind’, namely, how we represent the intentions and goals of others to optimise our mutual interactions. We draw on ideas from optimum control and game theory to provide a ‘game theory of mind’. First, we consider the representations of goals in terms of value functions that are prescribed by utility or rewards. Critically, the joint value functions and ensuing behaviour are optimised recursively, under the assumption that I represent your value function, your representation of mine, your representation of my representation of yours, and so on ad infinitum. However, if we assume that the degree of recursion is bounded, then players need to estimate the opponent's degree of recursion (i.e., sophistication) to respond optimally. This induces a problem of inferring the opponent's sophistication, given behavioural exchanges. We show it is possible to deduce whether players make inferences about each other and quantify their sophistication on the basis of choices in sequential games. This rests on comparing generative models of choices with, and without, inference. Model comparison is demonstrated using simulated and real data from a ‘stag-hunt’. Finally, we note that exactly the same sophisticated behaviour can be achieved by optimising the utility function itself (through prosocial utility), producing unsophisticated but apparently altruistic agents. This may be relevant ethologically in hierarchal game theory and coevolution

Non-pharmacological interventions to reduce psychological distress in patients undergoing diagnostic cardiac catheterization: a rapid review

Abstract Background: Cardiac catheterization is the standard procedure for the diagnosis of coronary heart disease. The threat physically and emotionally from this procedure can effect the patient’s perception of their health. The heightened psychological distress associated with this diagnostic procedure can cause adverse patient outcomes. Non-pharmacologic interventions have been implemented to reduce psychological distress associated with cardiac catheterization. Aims: The objective of this rapid review is to assess the efficacy of non-pharmacologic interventions (procedural education, relaxation techniques, psychological preparation) on psychological distress experienced by patients as they undergo a cardiac catheterization. Methods: Published, peer-reviewed, English-language intervention studies from 1981 to 2014 were identified in a search of CINAHL, Medline, and Cochrane Library. Eligible studies included adults undergoing cardiac catheterization. Studies included in this review used experimental and quasi-experimental designs and assessed at least one primary outcome: anxiety, depression, and pain to test non-pharmacologic interventions pre and post-cardiac catheterization. Researchers independently extracted data from included studies and completed a quality assessment using a published tool. Data was synthesised as a narrative. Results: There were 29 eligible experimental and quasi-experimental studies that tested the 3 interventions (n=2504). Findings suggest that non-pharmacologic interventions were able to effectively reduce psychological distress in some patients undergoing cardiac catheterization. Conclusion: Evidence is stronger in recent studies that non-pharmacologic interventions of procedural education and psychological preparation can reduce psychological distress in patients undergoing cardiac catheterization. Further research is needed to define the various relaxation techniques that can be effectively implemented for patients undergoing cardiac catheterization

Infliximab versus ciclosporin for steroid-resistant acute severe ulcerative colitis (CONSTRUCT):a mixed methods, open-label, pragmatic randomised trial

Infliximab and ciclosporin are of similar efficacy in treating acute severe ulcerative colitis, but there has been no comparative evaluation of their relative clinical effectiveness and cost-effectiveness.In this mixed methods, open-label, pragmatic randomised trial, we recruited consenting patients aged 18 years or older at 52 district general and teaching hospitals in England, Scotland, and Wales who had been admitted, unscheduled, with severe ulcerative colitis and failed to respond to intravenous hydrocortisone within about 5 days. Patients were randomly allocated (1:1) to receive either infliximab (5 mg/kg intravenous infusion given over 2 h at baseline, and again at 2 weeks and 6 weeks after the first infusion) or ciclosporin (2 mg/kg per day by continuous infusion for up to 7 days, followed by twice-daily tablets delivering 5·5 mg/kg per day for 12 weeks). Randomisation used a web-based password-protected site, with a dynamic algorithm to generate allocations on request, thus protecting against investigator preference or other subversion, while ensuring that each trial group was balanced by centre, which was the only stratification used. Local investigators and participants were aware of the treatment allocated, but the chief investigator and analysts were masked. Analysis was by treatment allocated. The primary outcome was quality-adjusted survival-ie, the area under the curve (AUC) of scores from the Crohn's and Ulcerative Colitis Questionnaire (CUCQ) completed by participants at baseline, 3 months, and 6 months, then every 6 months from 1 year to 3 years. This trial is registered with the ISRCTN Registry, number ISRCTN22663589.Between June 17, 2010, and Feb 26, 2013, 270 patients were recruited. 135 patients were allocated to the infliximab group and 135 to the ciclosporin group. 121 (90%) patients in each group were included in the analysis of the primary outcome. There was no significant difference between groups in quality-adjusted survival (mean AUC 564·0 [SD 241·9] in the infliximab group vs 587·0 [226·2] in the ciclosporin group; mean adjusted difference 7·9 [95% CI -22·0 to 37·8]; p=0·603). Likewise, there were no significant differences between groups in the secondary outcomes of CUCQ scores, EQ-5D, or SF-6D scores; frequency of colectomy (55 [41%] of 135 patients in the infliximab group vs 65 [48%] of 135 patients in the ciclosporin group; p=0·223); or mean time to colectomy (811 [95% CI 707-912] days in the infliximab group vs 744 [638-850] days in the ciclosporin group; p=0·251). There were no differences in serious adverse reactions (16 reactions in 14 participants receiving infliximab vs ten in nine patients receiving ciclosporin); serious adverse events (21 in 16 patients vs 25 in 17 patients); or deaths (three in the infliximab group vs none in the ciclosporin group).There was no significant difference between ciclosporin and infliximab in clinical effectiveness.NIHR Health Technology Assessment programme

Mycobacterium tuberculosis Rv2419c, the missing glucosyl-3-phosphoglycerate phosphatase for the second step in methylglucose lipopolysaccharide biosynthesis

Mycobacteria synthesize intracellular methylglucose lipopolysaccharides (MGLP) proposed to regulate fatty acid synthesis. Although their structures have been elucidated, the identity of most biosynthetic genes remains unknown. The first step in MGLP biosynthesis is catalyzed by a glucosyl-3-phosphoglycerate synthase (GpgS, Rv1208 in Mycobacterium tuberculosis H37Rv). However, a typical glucosyl-3-phosphoglycerate phosphatase (GpgP, EC3.1.3.70) for dephosphorylation of glucosyl-3-phosphoglycerate to glucosylglycerate, was absent from mycobacterial genomes. We purified the native GpgP from Mycobacterium vanbaalenii and identified the corresponding gene deduced from amino acid sequences by mass spectrometry. The M. tuberculosis ortholog (Rv2419c), annotated as a putative phosphoglycerate mutase (PGM, EC5.4.2.1), was expressed and functionally characterized as a new GpgP. Regardless of the high specificity for glucosyl-3-phosphoglycerate, the mycobacterial GpgP is not a sequence homolog of known isofunctional GpgPs. The assignment of a new function in M. tuberculosis genome expands our understanding of this organism's genetic repertoire and of the early events in MGLP biosynthesis

Pharmacokinetic Study of Rucaparib in Patients With Advanced Solid Tumors

The phase 1‐2 study CO‐338‐010 (Study 10; NCT01482715) is evaluating single‐agent rucaparib, a poly(ADP‐ribose) polymerase inhibitor, administered orally to patients with an advanced solid tumor. In the dose escalation phase (Part 1), we characterized the single‐dose and steady‐state pharmacokinetic profiles of rucaparib administered once daily (QD; dose range, 40‐500 mg; n = 16) or twice daily (BID; dose range, 240‐840 mg; n = 30). Across all dosing schedules examined, the plasma exposure of rucaparib was approximately dose proportional; half‐life was approximately 17 hours, and median time to maximum concentration (t_max) ranged from 1.5 to 6.0 hours after a single dose and 1.5 to 4.0 hours following repeated dosing. The steady‐state accumulation ratio ranged from 1.60 to 2.33 following QD dosing and 1.47 to 5.44 following BID dosing. No effect of food on rucaparib pharmacokinetics was observed with a single dose of 40 mg (n = 3) or 300 mg (n = 6). In a phase 2 portion of the study (Part 3), the pharmacokinetic profile of rucaparib was further evaluated at the recommended phase 2 dose of 600 mg BID (n = 26). The mean (coefficient of variation) steady‐state maximum concentration (C_max) and area under the concentration‐time curve from time zero to 12 hours (AUC_0-12h) were 1940 ng/mL (54%) and 16 900 ng ⋅ h/mL (54%), respectively. A high‐fat meal moderately increased rucaparib exposure. The fed‐to‐fasted geometric mean ratios (90% confidence interval [CI]) for AUC_0-24h and C_max were 138% (117%‐162%) and 120% (99.1%‐146%); the median (90%CI) t_max delay was 2.5 (0.5‐4.4) hours

Measurement of the running of the QED coupling in small-angle Bhabha scattering at LEP

Using the OPAL detector at LEP, the running of the effective QED coupling alpha(t) is measured for space-like momentum transfer from the angular distribution of small-angle Bhabha scattering. In an almost ideal QED framework, with very favourable experimental conditions, we obtain: Delta alpha(-6.07GeV^2) - Delta alpha(-1.81GeV^2) = (440 pm 58 pm 43 pm 30) X 10^-5, where the first error is statistical, the second is the experimental systematic and the third is the theoretical uncertainty. This agrees with current evaluations of alpha(t).The null hypothesis that alpha remains constant within the above interval of -t is excluded with a significance above 5sigma. Similarly, our results are inconsistent at the level of 3sigma with the hypothesis that only leptonic loops contribute to the running. This is currently the most significant direct measurment where the running alpha(t) is probed differentially within the measured t range.Comment: 43 pages, 12 figures, Submitted to Euro. Phys. J.