Nuclear translocation of cardiac G protein-Coupled Receptor kinase 5 downstream of select Gq-activating hypertrophic ligands is a calmodulin-dependent process.

G protein-Coupled Receptors (GPCRs) kinases (GRKs) play a crucial role in regulating cardiac hypertrophy. Recent data from our lab has shown that, following ventricular pressure overload, GRK5, a primary cardiac GRK, facilitates maladaptive myocyte growth via novel nuclear localization. In the nucleus, GRK5\u27s newly discovered kinase activity on histone deacetylase 5 induces hypertrophic gene transcription. The mechanisms governing the nuclear targeting of GRK5 are unknown. We report here that GRK5 nuclear accumulation is dependent on Ca(2+)/calmodulin (CaM) binding to a specific site within the amino terminus of GRK5 and this interaction occurs after selective activation of hypertrophic Gq-coupled receptors. Stimulation of myocytes with phenylephrine or angiotensinII causes GRK5 to leave the sarcolemmal membrane and accumulate in the nucleus, while the endothelin-1 does not cause nuclear GRK5 localization. A mutation within the amino-terminus of GRK5 negating CaM binding attenuates GRK5 movement from the sarcolemma to the nucleus and, importantly, overexpression of this mutant does not facilitate cardiac hypertrophy and related gene transcription in vitro and in vivo. Our data reveal that CaM binding to GRK5 is a physiologically relevant event that is absolutely required for nuclear GRK5 localization downstream of hypertrophic stimuli, thus facilitating GRK5-dependent regulation of maladaptive hypertrophy

A school-based physical activity promotion intervention in children: rationale and study protocol for the PREVIENE Project

The lack of physical activity and increasing time spent in sedentary behaviours during childhood place importance on developing low cost, easy-toimplement school-based interventions to increase physical activity among children. The PREVIENE Project will evaluate the effectiveness of five innovative, simple, and feasible interventions (active commuting to/from school, active Physical Education lessons, active school recess, sleep health promotion, and an integrated program incorporating all 4 interventions) to improve physical activity, fitness, anthropometry, sleep health, academic achievement, and health-related quality of life in primary school children. The PREVIENE Project will provide the information about the effectiveness and implementation of different school-based interventions for physical activity promotion in primary school children.The PREVIENE Project was funded by the Spanish Ministry of Economy and Competitiveness (DEP2015-63988-R, MINECO-FEDER). MAG is supported by grants from the Spanish Ministry of Economy and Competitivenes

The CHIP-Family study to improve the psychosocial wellbeing of young children with congenital heart disease and their families: design of a randomized controlled trial

Background: Children with congenital heart disease (CHD) are at increased risk for behavioral, emotional, and cognitive problems. They often have reduced exercise capacity and participate less in sports, which is associated with a lower quality of life. Starting school may present more challenges for children with CHD and their families than for families with healthy children. Moreover, parents of children with CHD are at risk for psychosocial problems. Therefore, a family-centered psychosocial intervention for children with CHD when starting school is needed. Until now, the 'Congenital Heart Disease Intervention Program (CHIP) - School' is the only evidence-based intervention in this field. However, CHIP-School targeted parents only and resulted in non-significant, though positive, effects as to child psychosocial wellbeing. Hence, we expanded CHIP by adding a specific child module and including siblings, creating the CHIP-Family intervention. The CHIP-Family study aims to (1) test the effects of CHIP-Family on parental mental health and psychosocial wellbeing of CHD-children and to (2) identify baseline psychosocial and medical predictors for the e

Characterizing Creative Scientists in Nano-S&T: Productivity, Multidisciplinarity, and Network Brokerage in a Longitudinal Perspective

While some believe that publication and citation scores are key predictors of breakthroughs in science, others claim that people who work at the intersection of scientific communities are more likely to be familiar with selecting and synthesizing alternatives into novel ideas. This paper contributes to this controversy by presenting a longitudinal comparison of highly creative scientists with equally productive researchers. The sample of creative scientists is identified by combining information on science awards and nominations by international peers covering research accomplishments in the mid-1990s. Results suggest that it is not only the sheer quantity of publications that causes scientists to produce creative pieces of work. Rather, their ability to effectively communicate with otherwise disconnected peers and to address a broader work spectrum also enhances their chances to be widely cited and to develop novel ideas

GRK5 nuclear accumulation is diminished after treatment with a CaM inhibitor.

<p>(<b>A</b>) NRVM were infected with Ad-GRK5 and either Ad-LacZ or Ad-Gq-CAM. 48 hr after infection, cells were treated with DMSO or inhibitor: BIM1 (10 µM), Gö6976 (10 µM), CDZ (10 µM) and KN93 (10 µM) for 1 hr. The cells were harvested using subcellular fractionation and immunoblotted for GRK5. (<b>B</b>) Immunoblots were quantitated by densitometry, normalized to fibrillarin, and reported as fold change over baseline. * p<0.05 v. untreated baseline, # p<0.05 v. CDZ, one-way ANOVA with a Bonferroni correction, n = 4. (<b>C</b>) NRVM were infected with Ad-LacZ, Ad-GRK5 and Ad-Gq-CAM. 48 hr after infection, cells were treated with DMSO or CDZ (10 µM) for 1 hr. The cells were harvested using subcellular fractionation, and immunoblotted for GRK5. (<b>D</b>) Densitometric analysis for (<b>C</b>) with GRK5 normalized to fibrillarin and calculated as fold change over baseline. *p<0.01 v. DMSO GRK5, #p<0.01 v. DMSO GRK5+ Gq, one-way ANOVA with a Bonferroni correction, n = 4. (<b>E</b>) NRVM were infected with either Ad-LacZ or Ad-Gq-CAM. 48 hr after infection, cells were treated with DMSO or CDZ (10 µM). Immunofluorescence was detected using a polyclonal GRK5 antibody. (<b>F</b>) TIRF analysis of AdRbM infected with an adenovirus expressing GRK5-GFP and cultured overnight. Cells were imaged at 10 sec intervals for 700 sec. Cells were pre-treated with CDZ or DMSO for 30 min at 37°C prior to imaging. Baseline myocytes were untreated while stimulated myocytes were treated with PE (50 µM) at 120 sec. Fluorescence was normalized and reported to fold change versus baseline. n = 4. (<b>G</b>) Same experimental design as (<b>F</b>) except cells were stimulated with AngII (10 µM) at 120 s. n = 4.</p