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

Family Resemblances? Ligand Binding and Activation of Family A and B G-Protein-Coupled Receptors Ligand binding and activation of the CGRP receptor

Abstract The receptor for CGRP (calcitonin gene-related peptide) is a heterodimer between a GPCR (G-proteincoupled receptor), CLR (calcitonin receptor-like receptor) and an accessory protein, RAMP1 (receptor activitymodifying protein 1). Models have been produced of RAMP1 and CLR. It is likely that the C-terminus of CGRP interacts with the extracellular N-termini of CLR and RAMP1; the extreme N-terminus of CLR is particularly important and may interact directly with CGRP and also with RAMP1. The N-terminus of CGRP interacts with the TM (transmembrane) portion of the receptor; the second ECL (extracellular loop) is especially important. Receptor activation is likely to involve the relative movements of TMs 3 and 6 to create a G-protein-binding pocket, as in Family A GPCRs. Pro 321 in TM6 appears to act as a pivot. At the base of TMs 2 and 3, Arg 151 , His 155 and Glu 211 may form a loose equivalent of the Family A DRY (Asp-Arg-Tyr) motif. Although the details of this proposed activation mechanism clearly do not apply to all Family B GPCRs, the broad outlines may be conserved

Can cutaneous telangiectasiae as late normal-tissue injury predict cardiovascular disease in women receiving radiotherapy for breast cancer?

Background: Overall, ~5% of patients show late normal-tissue damage after radiotherapy with a smaller number having a risk of radiation-induced heart disease. Although the data are conflicting, large studies have shown increased risks of cardiovascular disease (CVD) for irradiated patients compared with non-irradiated ones, or for those treated to the left breast or chest wall compared with those treated to the right. Cutaneous telangiectasiae as late normal-tissue injury have so far only been regarded as a cosmetic burden. Methods: The relationship between late normal-tissue radiation injury phenotypes in 149 irradiated breast cancer patients and the presence of cardiovascular disease were examined. Results: A statistically significant association between the presence of skin telangiectasiae and the long-term risk of CVD was shown in these patients (P=0.017; Fisher's exact test). Interpretation: This association may represent initial evidence that telangiectasiae can be used as a marker of future radiation-induced cardiac complications. It could also suggest a common biological pathway for the development of both telangiectasiae and CVD on the basis of a genetically predisposed endothelium. To our knowledge this is the first reported study looking at this association

A Hybrid Approach to Parallel Pattern Discovery in C++

Funding: EU Horizon 2020 project, TeamPlay, grant number 779882, and UK EPSRC Discovery, grant number EP/P020631/1.Parallel pattern libraries offer a strong combination of abstraction and performance. However, discovering places in sequential code where parallel patterns should be introduced is still highly non-trivial, often requiring expert manual analysis and profiling. We present a hybrid discovery technique to detect instances of parallel patterns in sequential code. This employs both static and dynamic trace-based analysis, together with hotspot detection. We evaluate our pattern discovery mechanism on a number of representative benchmarks. We evaluate the performance of the resulting parallelised benchmarks on a 24-core parallel machine.Postprin

Prostate Cancer Risk by BRCA2 Genomic Regions.

A BRCA2 prostate cancer cluster region (PCCR) was recently proposed (c.7914 to 3') wherein pathogenic variants (PVs) are associated with higher prostate cancer (PCa) risk than PVs elsewhere in the BRCA2 gene. Using a prospective cohort study of 447 male BRCA2 PV carriers recruited in the UK and Ireland from 1998 to 2016, we estimated standardised incidence ratios (SIRs) compared with population incidences and assessed variation in risk by PV location. Carriers of PVs in the PCCR had a PCa SIR of 8.33 (95% confidence interval [CI] 4.46-15.6) and were at a higher risk of PCa than carriers of other BRCA2 PVs (SIR = 3.31, 95% CI 1.97-5.57; hazard ratio = 2.34, 95% CI 1.09-5.03). PCCR PV carriers had an estimated cumulative PCa risk of 44% (95% CI 23-72%) by the age of 75 yr and 78% (95% CI 54-94%) by the age of 85 yr. Our results corroborate the existence of a PCCR in BRCA2 in a prospective cohort. PATIENT SUMMARY: In this report, we investigated whether the risk of prostate cancer for men with a harmful mutation in the BRCA2 gene differs based on where in the gene the mutation is located. We found that men with mutations in one region of BRCA2 had a higher risk of prostate cancer than men with mutations elsewhere in the gene

Corrigendum to: Cohort profile: Extended Cohort for E-health, Environment and DNA (EXCEED)

This is a correction to: International Journal of Epidemiology, Volume 48, Issue 3, June 2019, Pages 678–679j, https://doi.org/10.1093/ije/dyz07

The Missing Link! A New Skeleton for Evolutionary Multi-agent Systems in Erlang

Evolutionary multi-agent systems (EMAS) play a critical role in many artificial intelligence applications that are in use today. In this paper, we present a new generic skeleton in Erlang for parallel EMAS computations. The skeleton enables us to capture a wide variety of concrete evolutionary computations that can exploit the same underlying parallel implementation. We demonstrate the use of our skeleton on two different evolutionary computing applications: (1) computing the minimum of the Rastrigin function; and (2) solving an urban traffic optimisation problem. We show that we can obtain very good speedups (up to 142.44 ×× the sequential performance) on a variety of different parallel hardware, while requiring very little parallelisation effort.Publisher PDFPeer reviewe

Discovery and physical characterization as the first response to a potential asteroid collision: The case of 2023 DZ2

Near-Earth asteroids (NEAs) that may evolve into impactors deserve detailed threat assessment studies. Early physical characterization of a would-be impactor may help in optimizing impact mitigation plans. We first detected NEA 2023~DZ$_{2}$ on 27--February--2023. After that, it was found to have a Minimum Orbit Intersection Distance (MOID) with Earth of 0.00005~au as well as an unusually high initial probability of becoming a near-term (in 2026) impactor. We aim to perform a rapid but consistent dynamical and physical characterization of 2023~DZ$_{2}$ as an example of a key response to mitigate the consequences of a potential impact. We use a multi-pronged approach, drawing from various methods (observational/computational) and techniques (spectroscopy/photometry from multiple instruments), and bringing the data together to perform a rapid and robust threat assessment.} The visible reflectance spectrum of 2023~DZ$_{2}$ is consistent with that of an X-type asteroid. Light curves of this object obtained on two different nights give a rotation period $P$=6.2743$\pm$0.0005 min with an amplitude $A$=0.57$\pm$0.14~mag. We confirm that although its MOID is among the smallest known, 2023~DZ$_{2}$ will not impact Earth in the foreseeable future as a result of secular near-resonant behaviour. Our investigation shows that coordinated observation and interpretation of disparate data provides a robust approach from discovery to threat assessment when a virtual impactor is identified. We prove that critical information can be obtained within a few days after the announcement of the potential impactor.Comment: Accepted for publication in Astronomy and Astrophysics, 15 page

Receptor activity-modifying proteins 2 and 3 generate adrenomedullin receptor subtypes with distinct molecular properties

Adrenomedullin (AM) is a peptide hormone with numerous effects in the vascular systems. AM signals through the AM1 and AM2 receptors formed by the obligate heterodimerization of a G protein-coupled receptor, the calcitonin receptor-like receptor (CLR), and receptor activity-modifying proteins (RAMP) 2 and 3, respectively. These different CLR-RAMP interactions yield discrete receptor pharmacology and physiological effects. The effective design of therapeutics that target the individual AM receptors is dependent on understanding the molecular details of the effects of RAMPs on CLR. To understand the role of RAMPs 2 and 3 on the activation and conformation of the CLR subunit of AM receptors we mutated 68 individual amino acids in the juxtamembrane region of CLR, a key region for activation of AM receptors and determined the effects on cAMP signalling. Sixteen CLR mutations had differential effects between the AM1 and AM2 receptors. Accompanying this, independent molecular modelling of the full-length AM-bound AM1 and AM2 receptors predicted differences in the binding pocket, and differences in the electrostatic potential of the two AM receptors. Druggability analysis indicated unique features that could be used to develop selective small molecule ligands for each receptor. The interaction of RAMP2 or RAMP3 with CLR induces conformational variation in the juxtamembrane region, yielding distinct binding pockets, probably via an allosteric mechanism. These subtype-specific differences have implications for the design of therapeutics aimed at specific AM receptors and for understanding the mechanisms by which accessory proteins affect G protein-coupled receptor function