The effects of RAMPs upon cell signalling.

G protein-coupled receptors (GPCRs) play a vital role in signal transduction. It is now clear that numerous other molecules within the cell and at the cell surface interact with GPCRs to modulate their signalling properties. Receptor activity modifying proteins (RAMPs) are a group of single transmembrane domain proteins which have been predominantly demonstrated to interact with Family B GPCRs, but interactions with Family A and C receptors have recently begun to emerge. These interactions can influence cell surface expression, ligand binding preferences and G protein-coupling, thus modulating GPCR signal transduction. There is still a great deal of research to be conducted into the effects of RAMPs on GPCR signalling; their effects upon Family B GPCRs are still not fully documented, in addition to their potential interactions with Family A and C GPCRs. New interactions could have a significant impact on the development of therapeutics

G55.0+0.3: A Highly Evolved Supernova Remnant

Multi-frequency analysis has revealed the presence of a new supernova remnant, G55.0+0.3, in the Galactic plane. A kinematic distance of 14 kpc has been measured from HI spectral line data. The faint, clumpy half-shell is non-thermal and has a physical radius of 70 pc. Using an evolutionary model, the age of the remnant is estimated to be on the order of one million years, which exceeds conventional limits by a factor of five. The remnant may be associated with the nearby pulsar J1932+2020, which has a spin-down age of 1.1 million years. This work implies that the radiative lifetimes of remnants could be much longer than previously suggested.Comment: 27 pages, 7 figures in 9 files (figures 1 and 2 require 2 files each), Accepted for publication in The Astrophysical Journal (Jan. 20, 1998 volume

CIRCE: Coordinated Ionospheric Reconstruction Cubesat Experiment

The Coordinated Ionospheric Reconstruction Cubesat Experiment (CIRCE) is a collaborative space mission between the UK Defence Science and Technology Laboratory (Dstl), and the US Naval Research Laboratory (NRL) in developing small satellite ionospheric physics capability. CIRCE will characterise space weather effects on a regional scale in the ionosphere/thermosphere system. Properly characterising the dynamic ionosphere is important for a wide range of both civil and defence applications such as GPS, communications, and sensing technology. Consisting of two near-identical 6U (2x3U) CubeSat buses, the CIRCE nanosatellites will fly in a lead-follow tandem configuration in co-planar near-polar orbits at 500km altitude. Provided by Blue Canyon Technologies (BCT), the two buses will use differential drag to achieve and maintain an in-track separation of between 250 and 500km, allowing short time-scale dynamics to be observed in-situ. These nanosatellites each carry a complement of 5 individual scientific instruments, contributed from academic, industrial, and government partners across the UK and US. Scheduled to launch in 2021 via the US Department of Defence Space Test Program, the two CIRCE satellites will provide observations to enable a greater understanding of the driving processes of geophysical phenomena in the ionosphere/thermosphere system, distributed across a wide range of latitudes, and altitudes, as the mission progresses

The Role of ICL1 and H8 in Class B1 GPCRs; Implications for Receptor Activation.

The first intracellular loop (ICL1) of G protein-coupled receptors (GPCRs) has received little attention, although there is evidence that, with the 8th helix (H8), it is involved in early conformational changes following receptor activation as well as contacting the G protein β subunit. In class B1 GPCRs, the distal part of ICL1 contains a conserved R12.48KLRCxR2.46b motif that extends into the base of the second transmembrane helix; this is weakly conserved as a [R/H]12.48KL[R/H] motif in class A GPCRs. In the current study, the role of ICL1 and H8 in signaling through cAMP, iCa2+ and ERK1/2 has been examined in two class B1 GPCRs, using mutagenesis and molecular dynamics. Mutations throughout ICL1 can either enhance or disrupt cAMP production by CGRP at the CGRP receptor. Alanine mutagenesis identified subtle differences with regard elevation of iCa2+, with the distal end of the loop being particularly sensitive. ERK1/2 activation displayed little sensitivity to ICL1 mutation. A broadly similar pattern was observed with the glucagon receptor, although there were differences in significance of individual residues. Extending the study revealed that at the CRF1 receptor, an insertion in ICL1 switched signaling bias between iCa2+ and cAMP. Molecular dynamics suggested that changes in ICL1 altered the conformation of ICL2 and the H8/TM7 junction (ICL4). For H8, alanine mutagenesis showed the importance of E3908.49b for all three signal transduction pathways, for the CGRP receptor, but mutations of other residues largely just altered ERK1/2 activation. Thus, ICL1 may modulate GPCR bias via interactions with ICL2, ICL4 and the Gβ subunit

Influence of operating parameters on the biodegradation of steroid estrogens and nonylphenolic compounds during biological wastewater treatment processes

This document is the unedited author's version of a Submitted Work that was subsequently accepted for publication in Environmental Science & Technology, copyright © American Chemical Society after peer review. To access the final edited and published work see http://pubs.acs.org/doi/abs/10.1021/es901612v.This study investigated operational factors influencing the removal of steroid estrogens and nonylphenolic compounds in two sewage treatment works, one a nitrifying/denitrifying activated sludge plant and the other a nitrifying/denitrifying activated sludge plant with phosphorus removal. Removal efficiencies of >90% for steroid estrogens and for longer chain nonylphenol ethoxylates (NP4−12EO) were observed at both works, which had equal sludge ages of 13 days. However, the biological activity in terms of milligrams of estrogen removed per day per tonne of biomass was found to be 50−60% more efficient in the nitrifying/denitrifying activated sludge works compared to the works which additionally incorporated phosphorus removal. A temperature reduction of 6 °C had no impact on the removal of free estrogens, but removal of the conjugated estrone-3-sulfate was reduced by 20%. The apparent biomass sorption (LogKp) values were greater in the nitrifying/denitrifying works than those in the nitrifying/denitrifying works with phosphorus removal for both steroid estrogens and nonylphenolic compounds possibly indicating a different cell surface structure and therefore microbial population. The difference in biological activity (mg tonne−1 d−1) identified in this study, of up to seven times, suggests that there is the potential for enhancing the removal of estrogens and nonylphenols if more detailed knowledge of the factors responsible for these differences can be identified and maximized, thus potentially improving the quality of receiving waters.Public Utilities Board (Singapore), Anglian Water Ltd, Severn Trent Water Ltd, Thames Water Utilities Ltd, United Utilities 393 Plc and Yorkshire Water Services

A perspective on radical transformations to sustainability: resistances, movements and alternatives

A transformation to sustainability calls for radical and systemic societal shifts. Yet what this entails in practice and who the agents of this radical transformation are require further elaboration. This article recenters the role of environmental justice movements in transformations, arguing that the systemic, multi-dimensional and intersectional approach inherent in EJ activism is uniquely placed to contribute to the realization of equitable sustainable futures. Based on a perspective of conflict as productive, and a “conflict transformation” approach that can address the root issues of ecological conflicts and promote the emergence of alternatives, we lay out a conceptual framework for understanding transformations through a power analysis that aims to confront and subvert hegemonic power relations; that is, multi-dimensional and intersectional; balancing ecological concerns with social, economic, cultural and democratic spheres; and is multi-scalar, and mindful of impacts across place and space. Such a framework can help analyze and recognize the contribution of grassroots EJ movements to societal transformations to sustainability and support and aid radical transformation processes. While transitions literature tends to focus on artifacts and technologies, we suggest that a resistance-centred perspective focuses on the creation of new subjectivities, power relations, values and institutions. This recenters the agency of those who are engaged in the creation and recuperation of ecological and new ways of being in the world in the needed transformation

Modelling the impact of larviciding on the population dynamics and biting rates of Simulium damnosum (s.l.): implications for vector control as a complementary strategy for onchocerciasis elimination in Africa

Background: In 2012, the World Health Organization set goals for the elimination of onchocerciasis transmission by 2020 in selected African countries. Epidemiological data and mathematical modelling have indicated that elimination may not be achieved with annual ivermectin distribution in all endemic foci. Complementary and alternative treatment strategies (ATS), including vector control, will be necessary. Implementation of vector control will require that the ecology and population dynamics of Simulium damnosum sensu lato be carefully considered. Methods: We adapted our previous SIMuliid POPulation dynamics (SIMPOP) model to explore the impact of larvicidal insecticides on S. damnosum (s.l.) biting rates in different ecological contexts and to identify how frequently and for how long vector control should be continued to sustain substantive reductions in vector biting. SIMPOP was fitted to data from large-scale aerial larviciding trials in savannah sites (Ghana) and small-scale ground larviciding trials in forest areas (Cameroon). The model was validated against independent data from Burkina Faso/Côte d’Ivoire (savannah) and Bioko (forest). Scenario analysis explored the effects of ecological and programmatic factors such as pre-control daily biting rate (DBR) and larviciding scheme design on reductions and resurgences in biting rates. Results: The estimated efficacy of large-scale aerial larviciding in the savannah was greater than that of ground-based larviciding in the forest. Small changes in larvicidal efficacy can have large impacts on intervention success. At 93% larvicidal efficacy (a realistic value based on field trials), 10 consecutive weekly larvicidal treatments would reduce DBRs by 96% (e.g. from 400 to 16 bites/person/day). At 70% efficacy, and for 10 weekly applications, the DBR would decrease by 67% (e.g. from 400 to 132 bites/person/day). Larviciding is more likely to succeed in areas with lower water temperatures and where blackfly species have longer gonotrophic cycles. Conclusions: Focal vector control can reduce vector biting rates in settings where a high larvicidal efficacy can be achieved and an appropriate duration and frequency of larviciding can be ensured. Future work linking SIMPOP with onchocerciasis transmission models will permit evaluation of the impact of combined anti-vectorial and anti-parasitic interventions on accelerating elimination of the disease

A Placebo-Controlled Trial of Percutaneous Coronary Intervention for Stable Angina.

Percutaneous coronary intervention (PCI) is frequently performed to reduce the symptoms of stable angina. Whether PCI relieves angina more than a placebo procedure in patients who are not receiving antianginal medication remains unknown. We conducted a double-blind, randomized, placebo-controlled trial of PCI in patients with stable angina. Patients stopped all antianginal medications and underwent a 2-week symptom assessment phase before randomization. Patients were then randomly assigned in a 1:1 ratio to undergo PCI or a placebo procedure and were followed for 12 weeks. The primary end point was the angina symptom score, which was calculated daily on the basis of the number of angina episodes that occurred on a given day, the number of antianginal medications prescribed on that day, and clinical events, including the occurrence of unblinding owing to unacceptable angina or acute coronary syndrome or death. Scores range from 0 to 79, with higher scores indicating worse health status with respect to angina. A total of 301 patients underwent randomization: 151 to the PCI group and 150 to the placebo group. The mean (±SD) age was 64±9 years, and 79% were men. Ischemia was present in one cardiac territory in 242 patients (80%), in two territories in 52 patients (17%), and in three territories in 7 patients (2%). In the target vessels, the median fractional flow reserve was 0.63 (interquartile range, 0.49 to 0.75), and the median instantaneous wave-free ratio was 0.78 (interquartile range, 0.55 to 0.87). At the 12-week follow-up, the mean angina symptom score was 2.9 in the PCI group and 5.6 in the placebo group (odds ratio, 2.21; 95% confidence interval, 1.41 to 3.47; P<0.001). One patient in the placebo group had unacceptable angina leading to unblinding. Acute coronary syndromes occurred in 4 patients in the PCI group and in 6 patients in the placebo group. Among patients with stable angina who were receiving little or no antianginal medication and had objective evidence of ischemia, PCI resulted in a lower angina symptom score than a placebo procedure, indicating a better health status with respect to angina. (Funded by the National Institute for Health and Care Research Imperial Biomedical Research Centre and others; ORBITA-2 ClinicalTrials.gov number, NCT03742050.). [Abstract copyright: Copyright © 2023 Massachusetts Medical Society.

Receptor component protein, an endogenous allosteric modulator of family B G protein coupled receptors.

Receptor component protein (RCP) is a 148 amino acid intracellular peripheral membrane protein, previously identified as promoting the coupling of CGRP to cAMP production at the CGRP receptor, a heterodimer of calcitonin receptor like-receptor (CLR), a family B G protein-coupled receptor (GPCR) and receptor activity modifying protein 1 (RAMP1). We extend these observations to show that it selectively enhances CGRP receptor coupling to Gs but not Gq or pERK activation. At other family B GPCRs, it enhances cAMP production at the calcitonin, corticotrophin releasing factor type 1a and glucagon-like peptide type 2 receptors with their cognate ligands but not at the adrenomedullin type 1 (AM1), gastric inhibitory peptide and glucagon-like peptide type 1 receptors, all expressed in transfected HEK293S cells. However, there is also cell-line variability as RCP did not enhance cAMP production at the endogenous calcitonin receptor in HEK293T cells and it has previously been reported that it is active on the AM1 receptor expressed on NIH3T3 cells. RCP appears to behave as a positive allosteric modulator at coupling a number of family B GPCRs to Gs, albeit in a manner that is regulated by cell-specific factors. It may exert its effects at the interface between the 2nd intracellular loop of the GPCR and Gs, although there is likely to be some overlap between this location and that occupied by the C-terminus of RAMPs if they bind to the GPCRs