G protein-coupled receptor kinases (GRKs) act to desensitize G protein-coupled receptors (GPCRs). In addition to this role at the plasma membrane, a nuclear function for GRK5, a member of the GRK4 subfamily of GRKs, has been reported. GRK5 phosphorylates and promotes the nuclear export of the histone deacetylase, HDAC5. Here we demonstrate that the possession of a nuclear localization sequence (NLS) is a common feature of GRK4 subfamily members (GRKs 4, 5 and 6). However, the location of the NLS and the ability of these GRKs to bind DNA in vitro are different. The NLSs of GRK5 and 6 bind DNA in vitro, whilst the NLS of GRK4 does not. Using mutants of GRK5 we identify the regions of GRK5 required for DNA-binding in vitro and nuclear localization in cells. The DNA-binding ability of GRK5 requires both the NLS and an N-terminal calmodulin (CaM)-binding site. A functional nuclear export sequence (NES), required for CaM-dependent nuclear export of the kinase, is also identified. Based on our observations we propose a model to explain how nuclear localization of GRK5 may be regulated. Notably, the nuclear localization of GRK5 and 6 is differentially regulated. These results suggest subfamily specific nuclear functions for the GRK4 subfamily members. Identification of GRK specific small molecule inhibitors of nuclear localization and/or function for the GRK4 subfamily may thus be an achievable goal.

BackgroundPositive Youth Development (PYD) delivered outside school aims to enable young people to develop positive assets such as relationships and confidence, rather than to merely address risk. Existing reviews of PYD effects on substance use or violence are old and unsystematic.ObjectivesTo systematically review evidence to answer the following questions: what theories of change inform PYD interventions addressing substance use and violence? What characteristics of participants and contexts are identified as barriers to and facilitators of implementation and receipt in process evaluations of PYD? What is the effectiveness and cost-effectiveness of PYD in reducing substance use and violence? What characteristics of participants and contexts appear to moderate, or are necessary and sufficient for, PYD effectiveness?Data sourcesA total of 21 bibliographic databases; 35 websites and contacting authors.Review methodsWe included reports published in English since 1985 and reporting on theories of change, as well as process, outcome and economic evaluations of PYD targeting 11- to 18-year-olds and addressing substance use or violence. References were screened on title/abstract and, where appropriate, on full report. Data extraction and quality assessment used Critical Appraisal Skills Programme, Evidence for Policy and Practice Information and Co-ordinating Centre and Cochrane tools. Theories of change and process evaluations were qualitatively metasynthesised. Outcome evaluations were synthesised narratively and meta-analytically.Results32,394 unique references were identified and 48 were included. A total of 16 reports described theories, 13 (10 studies) evaluated processes and 25 (10 studies) evaluated outcomes.Theories of changePYD interventions aim to offer opportunities for young people to develop positive ‘assets’ such as skills and confidence. These are theorised to promote and be promoted by young people’s ‘intentional self-regulation’, which involves reflecting on behaviour; determining goals; using existing resources to pursue these; and redirecting effort when thwarted. This enables ‘developmental regulation’, namely individuals capitalising on other opportunities to promote personal development. Positive assets thus accrued reduce health risks by reducing the impact on individuals of environmental risk or by ameliorating the impact of such risks. The literature offers limited insights beyond these general ideas.Process evaluationsCommunity engagement ensured that programmes were accessible and appealing. Staff capacity and continuity were crucial factors but often challenging when programmes could not offer full-time jobs. Tensions arose between a desire to empower participants to choose activities and a requirement for them to undertake a breadth of activities.Outcome evaluationsMeta-analyses of all combined outcomes and of short-term alcohol use, illicit drug use and smoking found no significant effects. There were small, statistically significant, short-term effects for an omnibus measure of substance use and for violence. We could not undertake metaregression to assess sociodemographic moderators but narrative synthesis suggested no clear pattern of effects by sex. We found no economic evaluations.LimitationsInsufficient studies precluded qualitative comparative analyses.ConclusionsHow PYD might promote health is currently undertheorised. Implementation can be challenging. We found little evidence that current PYD interventions delivered outside school reduce substance use or violence. However, these may not constitute a test of the effectiveness of the PYD model, as some included interventions that, although meeting our inclusion criteria, were not exemplars of PYD.Future workFurther evaluations should assess interventions employing PYD theory of change.Study registrationThis study is registered as PROSPERO CRD42013005439.FundingThe National Institute for Health Research Public Health Research programme.

In order to maximise the learning potential of medical education programmes aimed at interdisciplinary or multidisciplinary teams, it is important to understand how the effectiveness of these programmes can vary between healthcare professionals from different specialities. Measuring the impact of educational activities between specialities may facilitate the development of future interdisciplinary and multidisciplinary education programmes, yielding enhanced learner outcomes and, ultimately, improving outcomes for patients. In this analysis, we report on a new approach to measuring change in knowledge and competence among learners from different physician specialities. We did this by tailoring post-activity competency assessments to three specialities – primary care physicians, pulmonologists and immunologists caring for patients with severe asthma. Our findings revealed that primary care physicians had markedly improved knowledge, measured using assessment questions, compared with the other specialities after completing the activity. We also report on differences between these specialities in intention to change clinical practice, confidence in clinical practice, and remaining educational gaps. Understanding how different members of the interdisciplinary team have benefited from an educational activity is essential for designing future educational activities and targeting resources.