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RIC‐3 is a transmembrane protein which acts as a molecular chaperone of nicotinic acetylcholine receptors (nAChRs). For some nAChR subtypes (such as homomeric α7 neuronal nAChRs), RIC‐3 is required for efficient receptor folding, assembly and functional expression. In contrast, for other nAChR subtypes (such as heteromeric α4β2 neuronal nAChRs) there have been reports that RIC‐3 can both enhance and reduce levels of functional expression. There is also evidence that RIC‐3 can modulate maturation of the closely related 5‐hydroxytryptamine (5‐HT) receptor (5‐HT3R). As with heteromeric nAChRs, apparently contradictory results have been reported for the influence of RIC‐3 on 5‐HT3R maturation in different expression systems. Recent evidence indicates that these differences in RIC‐3 chaperone activity may be influenced by the host cell, suggesting that other proteins may play an important role in modulating the effects of RIC‐3 as a chaperone. RIC‐3 was originally identified in the nematode Caenorhabditis elegans as the protein encoded by the gene ric‐3 (resistance to inhibitors of cholinesterase) and has subsequently been cloned and characterized from mammalian and insect species. This review provides a brief history of RIC‐3; from the identification of the ric‐3 gene in C. elegans in 1995 to the more recent demonstration of its activity as a nAChR chaperone. British Journal of Pharmacology (2008) 153, S177–S183; doi:10.1038/sj.bjp.0707661; published online 4 February 2008

Sustainable intensification is an emerging model for agriculture designed to reconcile accelerating global demand for agricultural products with long-term environmental stewardship. Defined here as increasing agricultural production while maintaining or improving environmental quality, sustainable intensification hinges upon decision-making by agricultural producers, consumers, and policy-makers. The Long-Term Agroecosystem Research (LTAR) network was established to inform these decisions. Here we introduce the LTAR Common Experiment, through which scientists and partnering producers in US croplands, rangelands, and pasturelands are conducting 21 independent but coordinated experiments. Each local effort compares the outcomes of a predominant, conventional production system in the region ('business as usual') with a system hypothesized to advance sustainable intensification ('aspirational'). Following the logic of a conceptual model of interactions between agriculture, economics, society, and the environment, we identified commonalities among the 21 experiments in terms of (a) concerns about business-as-usual production, (b) 'aspirational outcomes' motivating research into alternatives, (c) strategies for achieving the outcomes, (d) practices that support the strategies, and (e) relationships between practice outreach and adoption. Network-wide, concerns about business as usual include the costs of inputs, opportunities lost to uniform management approaches, and vulnerability to accelerating environmental changes. Motivated by environmental, economic, and societal outcomes, scientists and partnering producers are investigating 15 practices in aspirational treatments to sustainably intensify agriculture, from crop diversification to ecological restoration. Collectively, the aspirational treatments reveal four general strategies for sustainable intensification: (1) reducing reliance on inputs through ecological intensification, (2) diversifying management to match land and economic potential, (3) building adaptive capacity to accelerating environmental changes, and (4) managing agricultural landscapes for multiple ecosystem services. Key to understanding the potential of these practices and strategies are informational, economic, and social factors-and trade-offs among them-that limit their adoption. LTAR is evaluating several actions for overcoming these barriers, including finding financial mechanisms to make aspirational production systems more profitable, resolving uncertainties about trade-offs, and building collaborative capacity among agricultural producers, stakeholders, and scientists from a broad range of disciplines.

A holistic understanding of tissue and organ structure and function requires the detection of molecular constituents in their original three-dimensional (3D) context. Imaging mass cytometry (IMC) enables simultaneous detection of up to 40 antigens and transcripts using metal-tagged antibodies but has so far been restricted to two-dimensional imaging. Here we report the development of 3D IMC for multiplexed 3D tissue analysis at single-cell resolution and demonstrate the utility of the technology by analysis of human breast cancer samples. The resulting 3D models reveal cellular and microenvironmental heterogeneity and cell-level tissue organization not detectable in two dimensions. 3D IMC will prove powerful in the study of phenomena occurring in 3D space such as tumor cell invasion and is expected to provide invaluable insights into cellular microenvironments and tissue architecture.

Genomic alterations shape cell phenotypes and the structure of tumor ecosystems in poorly defined ways. To investigate these relationships, we used imaging mass cytometry to quantify the expression of 37 proteins with subcellular spatial resolution in 483 tumors from the METABRIC cohort. Single-cell analysis revealed cell phenotypes spanning epithelial, stromal and immune types. Distinct combinations of cell phenotypes and cell-cell interactions were associated with genomic subtypes of breast cancer. Epithelial luminal cell phenotypes separated into those predominantly impacted by mutations and those affected by copy number aberrations. Several features of tumor ecosystems, including cellular neighborhoods, were linked to prognosis, illustrating their clinical relevance. In summary, systematic analysis of single-cell phenotypic and spatial correlates of genomic alterations in cancer revealed how genomes shape both the composition and architecture of breast tumor ecosystems and will enable greater understanding of the phenotypic impact of genomic alterations.

Background Prescribing medicines for older adults in care homes is known to be sub-optimal. Whilst trials testing interventions to optimise prescribing in this setting have been published, heterogeneity in outcome reporting has hindered comparison of interventions, thus limiting evidence synthesis. The aim of this study was to develop a core outcome set (COS), a list of outcomes which should be measured and reported, as a minimum, for all effectiveness trials involving optimising prescribing in care homes. The COS was developed as part of the Care Homes Independent Pharmacist Prescribing Study (CHIPPS). Methods A long-list of outcomes was identified through a review of published literature and stakeholder input. Outcomes were reviewed and refined prior to entering a two-round online Delphi exercise and then distributed via a web link to the CHIPPS Management Team, a multidisciplinary team including pharmacists, doctors and Patient Public Involvement representatives (amongst others), who comprised the Delphi panel. The Delphi panellists ( n  = 19) rated the importance of outcomes on a 9-point Likert scale from 1 (not important) to 9 (critically important). Consensus for an outcome being included in the COS was defined as ≥70% participants scoring 7–9 and <15% scoring 1–3. Exclusion was defined as ≥70% scoring 1–3 and <15% 7–9. Individual and group scores were fed back to participants alongside the second questionnaire round, which included outcomes for which no consensus had been achieved. Results A long-list of 63 potential outcomes was identified. Refinement of this long-list of outcomes resulted in 29 outcomes, which were included in the Delphi questionnaire (round 1). Following both rounds of the Delphi exercise, 13 outcomes (organised into seven overarching domains: medication appropriateness, adverse drug events, prescribing errors, falls, quality of life, all-cause mortality and admissions to hospital (and associated costs)) met the criteria for inclusion in the final COS. Conclusions We have developed a COS for effectiveness trials aimed at optimising prescribing in older adults in care homes using robust methodology. Widespread adoption of this COS will facilitate evidence synthesis between trials. Future work should focus on evaluating appropriate tools for these key outcomes to further reduce heterogeneity in outcome measurement in this context.

Empirical and modelled data were used to examine the influence of the Leeuwin Current on larval fish assemblages along the Western Australian continental shelf and adjacent eastern Indian Ocean (22°S–34°S) during the late austral autumn. Larval fish assemblages, comprising >200 taxa from 114 neritic and oceanic teleost families, displayed significantly distinct latitudinal and cross-shelf variability, which was linked to meso-scale features of the Leeuwin Current, specifically anticyclonic eddies. Results of Lagrangian particle back-tracking showed good connection between the shelf and a developing eddy situated at 27°S; connectivity was highest in the 0–20 m depth stratum where >80% of the particles entering the eddy were derived from the shelf. This was supported by the high abundance (mean: 84 larvae m–2) of larval neritic taxa, especially small anchovyEngraulis australislarvae in the eddy. The lack of a significant difference in the size structure of these larvae between the shelf and eddy indicated continuous connection between these waters. In contrast, connectivity between the shelf and an older eddy further south was much lower (<40% of particles in the 0–20 m stratum) and the larval fish assemblage was dominated by meso-pelagic species. Further, the distribution of Myctophidae larvae (Diaphusspp.) highlighted areas of enhanced onshore transport in the south. The study has shown that, in the alongshore dominated Leeuwin Current system, cross-shelf transport can be similarly important in dispersal processes.

Neonicotinoids, such as imidacloprid, are nicotinic acetylcholine receptor (nAChR) agonists with potent insecticidal activity. Since its introduction in the early 1990s, imidacloprid has become one of the most extensively used insecticides for both crop protection and animal health applications. As with other classes of insecticides, resistance to neonicotinoids is a significant threat and has been identified in several pest species, including the brown planthopper, Nilaparvata lugens, a major rice pest in many parts of Asia. In this study, radioligand binding experiments have been conducted with whole-body membranes prepared from imidacloprid-susceptible and imidacloprid-resistant strains of N. lugens. The results reveal a much higher level of [3H]imidacloprid-specific binding to the susceptible strain than to the resistant strain (16.7 ± 1.0 and 0.34 ± 0.21 fmol/mg of protein, respectively). With the aim of understanding the molecular basis of imidacloprid resistance, five nAChR subunits (Nlα1-Nlα4 and Nlβ1) have been cloned from N. lugens. A comparison of nAChR subunit genes from imidacloprid-sensitive and imidacloprid-resistant populations has identified a single point mutation at a conserved position (Y151S) in two nAChR subunits, Nlα1 and Nlα3. A strong correlation between the frequency of the Y151S point mutation and the level of resistance to imidacloprid has been demonstrated by allele-specific PCR. By expression of hybrid nAChRs containing N. lugens α and rat β2 subunits, evidence was obtained that demonstrates that mutation Y151S is responsible for a substantial reduction in specific [3H]imidacloprid binding. This study provides direct evidence for the occurrence of target-site resistance to a neonicotinoid insecticide.

Background and purpose: The aim of this study was to investigate the influence of the intracellular domain of nicotinic acetylcholine receptor (nAChR) subunits upon receptor assembly, targeting and functional properties. Experimental approach: Because most nAChR subunits form functional receptors only as heteromeric complexes, it can be difficult to examine the influence of individual subunits or subunit domains in isolation. A series of subunit chimaeras was constructed which contain the intracellular loop region (located between the M3 and M4 transmembrane domains) from nAChR subunits α1–α10 or β1–β4. All of these chimaeras contain common extracellular and transmembrane domains (from the nAChR α7 subunit and the 5‐hydroxytryptamine receptor 5‐HT3A subunit, respectively), thereby facilitating both homomeric receptor assembly and detection with radiolabelled or fluorescent α‐bungarotoxin. Key results: The nAChR M3–M4 intracellular loop domain had no significant effect upon levels of total subunit protein detected in transfected cells but had a significant influence upon levels of both cell surface and intracellular assembled receptors. Comparisons of functional properties revealed a significant influence of the intracellular loop domain upon both single‐channel conductance and receptor desensitization. In addition, studies conducted in polarized epithelial cells demonstrate that the nAChR loop can influence receptor targeting, resulting in either polarized (apical) or non‐polarized distribution. Conclusions and implications: Evidence has been obtained which demonstrates that the large intracellular loop domain of nAChR subunits can exert a profound influence upon receptor assembly, targeting and ion channel properties. British Journal of Pharmacology (2008) 153, 1474–1484; doi:10.1038/sj.bjp.0707676; published online 21 January 2008

Background According to the prevention paradox, the majority of alcohol-related harms in the population occur among low-to-moderate risk drinkers, simply because they are more numerous in the population, although high-risk drinkers have a higher individual risk of experiencing alcohol-related harms. In this study we explored the prevention paradox in the Irish population by comparing alcohol-dependent drinkers (high-risk) to low-risk drinkers and non-dependent drinkers who engage in heavy episodic drinking (HED). Methods Data were generated from the 2013 National Alcohol Diary Survey (NADS), a nationally representative cross-sectional survey of Irish adults aged 18–75. Data were available for 4338 drinkers. Respondents dependent on alcohol (as measured by DSM-IV criteria), respondents who engaged in monthly HED or occasional HED (1–11 times a year) and low-risk drinkers were compared for distribution of eight alcohol-related harms. Results Respondents who were dependent on alcohol had a greater individual risk of experiencing each harm ( p  < .0001). The majority of the harms in the population were accounted for by drinkers who were not dependent on alcohol. Together, monthly and occasional HED drinkers accounted for 62% of all drinkers, consumed 70% of alcohol and accounted for 59% of alcohol-related harms. Conclusions Our results indicate that the majority of alcohol consumption and related harms in the Irish population are accounted for by low- and moderate-risk drinkers, and specifically by those who engage in heavy episodic drinking. A population-based approach to reducing alcohol-related harm is most appropriate in the Irish context. Immediate implementation of the measures in the Public Health (Alcohol) Act (2018) is necessary to reduce alcohol-related harm in Ireland.