The SRSF4–GAS5-Glucocorticoid Receptor Axis Regulates Ventricular Hypertrophy.

RATIONALE: RBPs (RNA-binding proteins) play critical roles in human biology and disease. Aberrant RBP expression affects various steps in RNA processing, altering the function of the target RNAs. The RBP SRSF4 (serine/arginine-rich splicing factor 4) has been linked to neuropathies and cancer. However, its role in the heart is completely unknown. OBJECTIVE: To investigate the role of SRSF4 in the heart. METHODS AND RESULTS: Echocardiography of mice specifically lacking SRSF4 in the heart (SRSF4 KO) revealed left ventricular hypertrophy and increased cardiomyocyte area, which led to progressive diastolic dysfunction with age. SRSF4 KO mice showed altered electrophysiological activity under isoproterenol-induced cardiac stress, with a post-QRS depression and a longer QT interval, indicating an elevated risk of sudden cardiac death. RNA-Seq analysis revealed expression changes in several long noncoding RNAs, including GAS5 (growth arrest-specific 5), which we identified as a direct SRSF4 target in cardiomyocytes by individual-nucleotideresolution cross-linking and immuno-precipitation. GAS5 is a repressor of the GR (glucocorticoid receptor) and was downregulated in SRSF4 KO hearts. This corresponded with elevated GR transcriptional activity in cardiomyocytes, leading to increases in hypertrophy markers and cell size. Furthermore, hypertrophy in SRSF4 KO cardiomyocytes was reduced by overexpressing GAS5. CONCLUSIONS: Loss of SRSF4 expression results in cardiac hypertrophy, diastolic dysfunction, and abnormal repolarization. The molecular mechanism underlying this effect involves GAS5 downregulation and consequent elevation of GR transcriptional activity. Our findings may help to develop new therapeutic tools for the treatment of cardiac hypertrophy and myocardial pathology in patients with Cushing syndrome.post-print2695 K

The SRSF4–GAS5-Glucocorticoid Receptor Axis Regulates Ventricular Hypertrophy.

RATIONALE: RBPs (RNA-binding proteins) play critical roles in human biology and disease. Aberrant RBP expression affects various steps in RNA processing, altering the function of the target RNAs. The RBP SRSF4 (serine/arginine-rich splicing factor 4) has been linked to neuropathies and cancer. However, its role in the heart is completely unknown. OBJECTIVE: To investigate the role of SRSF4 in the heart. METHODS AND RESULTS: Echocardiography of mice specifically lacking SRSF4 in the heart (SRSF4 KO) revealed left ventricular hypertrophy and increased cardiomyocyte area, which led to progressive diastolic dysfunction with age. SRSF4 KO mice showed altered electrophysiological activity under isoproterenol-induced cardiac stress, with a post-QRS depression and a longer QT interval, indicating an elevated risk of sudden cardiac death. RNA-Seq analysis revealed expression changes in several long noncoding RNAs, including GAS5 (growth arrest-specific 5), which we identified as a direct SRSF4 target in cardiomyocytes by individual-nucleotideresolution cross-linking and immuno-precipitation. GAS5 is a repressor of the GR (glucocorticoid receptor) and was downregulated in SRSF4 KO hearts. This corresponded with elevated GR transcriptional activity in cardiomyocytes, leading to increases in hypertrophy markers and cell size. Furthermore, hypertrophy in SRSF4 KO cardiomyocytes was reduced by overexpressing GAS5. CONCLUSIONS: Loss of SRSF4 expression results in cardiac hypertrophy, diastolic dysfunction, and abnormal repolarization. The molecular mechanism underlying this effect involves GAS5 downregulation and consequent elevation of GR transcriptional activity. Our findings may help to develop new therapeutic tools for the treatment of cardiac hypertrophy and myocardial pathology in patients with Cushing syndrome.post-print2695 K

Television watching, videogames, and excess of body fat in Spanish adolescents: the AVENA study

Abstract OBJECTIVE: We assessed the individual association of sedentary behaviors with the risk of overweight and excess body fat (overfat) in adolescents. METHODS: A representative sample (1960 subjects, 1012 males, age 13-18.5 y) of Spanish adolescents was studied within the framework of the Alimentación y Valoración del Estado Nutricional de los Adolescentes (AVENA) study. Television (TV) watching, videogame and computer usage, doing homework, and the way students got to school, physical activity, and socioeconomic status were analyzed. Anthropometrics were measured to describe overweight (International Obesity Task Force cutoffs for body mass index) and overfat (body fat percentage >85th percentile). RESULTS: When all subjects were considered as an entire group, the overweight risk increased by 15.8% (P < 0.05) per increasing hour of TV watching. The overweight risks decreased by 32.5% in females, 22% per increasing year of age, and 12.5% by increasing socioeconomic status by 1 U (all Ps < 0.05). The obesity risks decreased with age by 17.8% per year in males and 27.1% in females (both Ps < 0.05). The overfat risks increased by 26.8% and 9.4% per increasing hour of TV and weekend videogame usage, respectively (both Ps < 0.05). In males, the overfat risk increased by 21.5% per increasing hour in weekend videogame usage (P < 0.05). Each hour of TV use increased the overfat risks by 22% in males and 28.3% in females (both Ps < 0.05). CONCLUSIONS: Time spent watching TV increased the risk of overweight and obesity in Spanish adolescents, but the effect was influenced by age, sex, and socioeconomic status. Moreover, an excess of body fat was more directly explained by the time spent watching TV and playing videogames during the weekend.Peer Reviewe

HuR/ELAVL1 drives malignant peripheral nerve sheath tumor growth and metastasis

Cancer cells can develop a strong addiction to discrete molecular regulators, which control the aberrant gene expression programs that drive and maintain the cancer phenotype. Here, we report the identification of the RNA-binding protein HuR/ELAVL1 as a central oncogenic driver for malignant peripheral nerve sheath tumors (MPNSTs), which are highly aggressive sarcomas that originate from cells of the Schwann cell lineage. HuR was found to be highly elevated and bound to a multitude of cancer-associated transcripts in human MPNST samples. Accordingly, genetic and pharmacological inhibition of HuR had potent cytostatic and cytotoxic effects on tumor growth, and strongly suppressed metastatic capacity in vivo. Importantly, we linked the profound tumorigenic function of HuR to its ability to simultaneously regulate multiple essential oncogenic pathways in MPNST cells, including the Wnt/β-catenin, YAP/TAZ, RB/E2F, and BET pathways, which converge on key transcriptional networks. Given the exceptional dependency of MPNST cells on HuR for survival, proliferation, and dissemination, we propose that HuR represents a promising therapeutic target for MPNST treatment

Surrounded by sound: noise, rights and environments

Noise was probably the first environmental pollutant (apart from human waste) in the Ancient world. Yet today, by comparison with other environmental matters, noise and protection from its effects are often overlooked, except in specialist fields such as architecture or planning. One major reason for this may be that noise does not possess the same ability to spread that is characteristic of other forms of pollution. Noise is also an unusual form of environmental pollution in having a physical impact – it is ‘heard’ and can be ‘felt’ – but is predominantly interpreted subjectively. The impact and consequences of anthropogenic noise for humans and biodiversity in general, are currently under-investigated in criminology and are under-addressed in both public and private international environmental law. Here we question why noise has not (so far) been explored within green criminology and only tentatively explored within cultural criminology. The objectives are to provide an overview of noise as a topic, connecting media, culture, anti- and pro-social behaviour, and to unearth interconnections between the matter of noise and its implications for the environment

The SRSF4–GAS5-Glucocorticoid Receptor Axis Regulates Ventricular Hypertrophy

Objective: To investigate the role of SRSF4 in the heart. Methods and Results: Echocardiography of mice specifically lacking SRSF4 in the heart (SRSF4 KO) revealed left ventricular hypertrophy and increased cardiomyocyte area, which led to progressive diastolic dysfunction with age. SRSF4 KO mice showed altered electrophysiological activity under isoproterenol-induced cardiac stress, with a post-QRS depression and a longer QT interval, indicating an elevated risk of sudden cardiac death. RNA-Seq analysis revealed expression changes in several long noncoding RNAs, including GAS5 (growth arrest-specific 5), which we identified as a direct SRSF4 target in cardiomyocytes by individual-nucleotide-resolution cross-linking and immuno-precipitation. GAS5 is a repressor of the GR (glucocorticoid receptor) and was downregulated in SRSF4 KO hearts. This corresponded with elevated GR transcriptional activity in cardiomyocytes, leading to increases in hypertrophy markers and cell size. Furthermore, hypertrophy in SRSF4 KO cardiomyocytes was reduced by overexpressing GAS5. Conclusions: Loss of SRSF4 expression results in cardiac hypertrophy, diastolic dysfunction, and abnormal repolarization. The molecular mechanism underlying this effect involves GAS5 downregulation and consequent elevation of GR transcriptional activity. Our findings may help to develop new therapeutic tools for the treatment of cardiac hypertrophy and myocardial pathology in patients with Cushing syndrome.European UnionMinisterio de Economía y CompetitividadInstituto de Salud Carlos IIIComunidad de MadridPlan Estatal I+D+I 2013-2016Ministerio de Ciencia, Innovación y UniversidadesFundación Pro-CNICSevero Ochoa Center de ExcellenceDepto. de Medicina y Cirugía AnimalFac. de VeterinariaTRUEpu

Diet quality index as a predictor of treatment efficacy in overweight and obese adolescents: The EVASYON study

The EVASYON Study Group.[Background & aim]: A diet quality index (DQI) is a tool that provides an overall score of an individual's dietary intake when assessing compliance with food-based dietary guidelines. A number of DQIs have emerged, albeit their associations with health-related outcomes are debated. The aim of the present study was to assess whether adherence to dietary intervention, and the overall quality of the diet, can predict body composition changes.[Methods]: To this purpose, overweight/obese adolescents (n = 117, aged: 13–16 years; 51 males, 66 females) were recruited into a multi-component (diet, physical activity and psychological support) family-based group treatment programme. We measured the adolescents' compliance and body composition at baseline and after 2 months (intensive phase) and 13 months (extensive phase) of follow-up. Also, at baseline, after 6 months, and at the end of follow-up we calculated the DQI.[Results]: Global compliance with the dietary intervention was 37.4% during the intensive phase, and 14.3% during the extensive phase. Physical activity compliance was 94.1% at 2-months and 34.7% at 13months and psychological support compliance were growing over the intervention period (10.3% intensive phase and 45.3% during extensive phase). Adolescents complying with the meal frequency criteria at the end of the extensive phase had greater reductions in FMI z-scores than those did not complying (Cohen's d = 0.53). A statistically significant association was observed with the diet quality index. DQI-A variation explained 98.1% of BMI z-score changes and 95.1% of FMI changes.[Conclusions]: We conclude that assessment of changes in diet quality could be a useful tool in predicting body composition changes in obese adolescents involved in a diet and physical activity intervention programme backed-up by psychological and family support.The study was supported by the Ministry of Health, Social Services and Equality via the Carlos III Institute of Health (FIS Grant PI051080, PI051579). The EVASYON study received the award for the best applied research project in 2009 from AESAN (Spanish Agency for Food Safety and Nutrition from the Spanish Ministry of Health and Consumer Affairs. The study was supported by Aragon's Regional Government (DGA, Diputación General de Aragón) and European Regional Development Fund.Peer reviewe