Neurochondrin is an atypical RIIα-specific A-kinase anchoring protein.

Protein kinase activity is regulated not only by direct strategies affecting activity but also by spatial and temporal regulatory mechanisms. Kinase signaling pathways are coordinated by scaffolding proteins that orchestrate the assembly of multi-protein complexes. One family of such scaffolding proteins are the A-kinase anchoring proteins (AKAPs). AKAPs share the commonality of binding cAMP-dependent protein kinase (PKA). In addition, they bind further signaling proteins and kinase substrates and tether such multi-protein complexes to subcellular locations. The A-kinase binding (AKB) domain of AKAPs typically contains a conserved helical motif that interacts directly with the dimerization/docking (D/D) domain of the regulatory subunits of PKA. Based on a pull-down proteomics approach, we identified neurochondrin (neurite-outgrowth promoting protein) as a previously unidentified AKAP. Here, we show that neurochondrin interacts directly with PKA through a novel mechanism that involves two distinct binding regions. In addition, we demonstrate that neurochondrin has strong isoform selectivity towards the RIIα subunit of PKA with nanomolar affinity. This article is part of a Special Issue entitled: Inhibitors of Protein Kinases.

Vaccine coverage of children in care of the child welfare system.

OBJECTIVE: To assess vaccine coverage for a cohort of children who have been in the care of the child welfare system compared to children in the general population. METHODS: This retrospective cohort study used population-based administrative health data for a 2008 birth cohort of children from Alberta, Canada. We assessed coverage at ages 2 (n = 44,206) and 7 (n = 42,241) for three vaccines with different administration schedules for children in care (at any period before the age of assessment) and those who had never been in care, comparing them using risk differences and relative risks (RRs). We similarly assessed coverage for children not in care who shared characteristics of children in care. RESULTS: At age two, vaccination coverage for children in care ranged from 54.3% to 81.4%, depending on vaccine. In comparison, coverage for those not in care ranged from 74.2% to 87.4%. At age seven, coverage for children in care ranged from 53.1% to 65.3%, compared to 76.6% to 83.4% for those not in care. For all vaccines at both ages, the risk for being under-vaccinated was higher for children in care (e.g., diphtheria, pertussis, tetanus, polio, Haemophilus influenzae type b at age 7: RR 2.01, 95% confidence interval [CI] (1.74-2.32). Even for children not in care who had characteristics similar to children in care, we found children in care had lower coverage. CONCLUSION: Children in care have consistently lower vaccine coverage than children not in care. Policies and practices should promote optimal access to vaccination for these children.

Immunization Coverage of Children in Care of the Child Welfare System in High-Income Countries: A Systematic Review.

CONTEXT: Children in care of the child welfare system tend to underutilize preventive health services compared with other children. The purpose of this systematic review was to assess current knowledge regarding immunization coverage levels for children in the child welfare system and to determine barriers and supports to them utilizing immunization services. EVIDENCE ACQUISITION: Articles published in Medline, Embase, Cochrane Library, CINAHL, SocINDEX, and ERIC from January 1, 2000 to October 13, 2017 were searched. Thesis and conference databases and relevant websites were also examined. Studies were included if written in English, from high-income countries, and addressed immunizations for children in the child welfare system. Independent dual screening, extraction, and quality appraisal were conducted between October 2016 and December 2017, followed by narrative synthesis. EVIDENCE SYNTHESIS: Of 2,906 records identified, 33 met inclusion criteria: 21 studied coverage, two studied barriers/supports, and ten studied both. Nineteen studies were moderate or high quality and thus included in the narrative synthesis; 15 studied coverage, one studied barriers/supports, and three studied both. Most studies found lower coverage among children in child welfare. The few studies that explicitly studied barriers/supports to immunization identified that a collaborative and coordinated approach between health and social services was key to service delivery to this population. CONCLUSIONS: This review highlights that children in care of the child welfare system are at risk of poor immunization coverage. There is a need for high-quality studies on this issue, with a focus on assessing supports/barriers to immunization in this population.

Immunisation coverage of children in the child welfare system: a systematic review protocol.

INTRODUCTION: Children may be placed in the care of the child welfare system when they require additional supports or intervention to ensure their safety and security. Transitions in living arrangements (eg, home to foster care and return to home) and other difficult circumstances for these children may result in interruptions in routine preventive healthcare, such as childhood immunisations. The purpose of this systematic literature review is to determine whether immunisation coverage is a problem among children in the child welfare system and identify any known supports and/or barriers to vaccine uptake in this population. METHODS AND ANALYSIS: This systematic review will encompass published and unpublished primary research studies that assess (A) immunisation coverage of children in the child welfare system, (B) how this coverage compares to the general population and/or children not in the child welfare system, and (C) supports and barriers affecting immunisation status of these children. Vaccines in the recommended childhood immunisation schedule for each study setting will be considered. Medline, Embase, Cochrane Library, CINAHL, SocINDEX and ERIC will be comprehensively searched. We will also search ProQuest dissertations and theses, the Conference Proceedings Citation Index for Science and Social Science & Humanities, and a sample of relevant provincial, national and international websites. References of included studies will be manually searched for relevant studies. English language primary studies from 2000 to current focused on immunisations of children (age 0-17 years) in the child welfare system, in a high-income country, will be included. A narrative analysis of key findings from included studies will be performed and presented. ETHICS AND DISSEMINATION: This protocol does not require ethics approval. Planned dissemination includes peer-reviewed publication, conference presentations and briefs for policy makers. TRIAL REGISTRATION NUMBER: This protocol is registered in the PROSPERO International Prospective Register of Systematic Reviews, registration number CRD42016047319.

PKA-type I selective constrained peptide disruptors of AKAP complexes.

A-Kinase Anchoring Proteins (AKAPs) coordinate complex signaling events by serving as spatiotemporal modulators of cAMP-dependent protein kinase activity in cells. Although AKAPs organize a plethora of diverse pathways, their cellular roles are often elusive due to the dynamic nature of these signaling complexes. AKAPs can interact with the type I or type II PKA holoenzymes by virtue of high-affinity interactions with the R-subunits. As a means to delineate AKAP-mediated PKA signaling in cells, we sought to develop isoform-selective disruptors of AKAP signaling. Here, we report the development of conformationally constrained peptides named RI-STapled Anchoring Disruptors (RI-STADs) that target the docking/dimerization domain of the type 1 regulatory subunit of PKA. These high-affinity peptides are isoform-selective for the RI isoforms, can outcompete binding by the classical AKAP disruptor Ht31, and can selectively displace RIα, but not RIIα, from binding the dual-specific AKAP149 complex. Importantly, these peptides are cell-permeable and disrupt Type I PKA-mediated phosphorylation events in the context of live cells. Hence, RI-STAD peptides are versatile cellular tools to selectively probe anchored type I PKA signaling events.