Ryanodine receptor mutations: in sickness and in health

Ryanodine Receptors (RyR) are large ion channels necessary for Ca2+ release from intracellular stores in many cell types. Since RyR was discovered nearly 30 years ago, a fruitful research field has devoted to understanding the physiological regulation of the three protein isoforms in health, and the mechanisms underlying their dysfunction in sickness. This minireview discusses the structural characteristics of RyR2, the cardiac isoform, its regulation during cardiac function and the clinical significance of specific mutations. While hundreds of RyR2 mutations are associated with cardiac disease with different levels of confidence, close to 1500 variants appear in the general population without inducing harmful phenotypes. Hence, studying RyR2 mutations variants may shed light on overall protein regulation and the mechanisms that compensate for constitutive changes in RyR2 function.Sociedad Argentina de Fisiologí

Genetic ablation of ryanodine receptor 2 phosphorylation at Ser‐2808 aggravates Ca 2+ ‐dependent cardiomyopathy by exacerbating diastolic Ca 2+ release

Phosphorylation of the cardiac ryanodine receptor (RyR2) by protein kinase A (PKA) at Ser‐2808 is suggested to mediate the physiological ‘fight or flight’ response and contribute to heart failure by rendering the sarcoplasmic reticulum (SR) leaky for Ca 2+ . In the present study, we examined the potential role of RyR2 phosphorylation at Ser‐2808 in the progression of Ca 2+ ‐dependent cardiomyopathy (CCM) by using mice genetically modified to feature elevated SR Ca 2+ leak while expressing RyR2s that cannot be phosphorylated at this site (S2808A). Surprisingly, rather than alleviating the disease phenotype, constitutive dephosphorylation of Ser‐2808 aggravated CCM as manifested by shortened survival, deteriorated in vivo cardiac function, exacerbated SR Ca 2+ leak and mitochondrial injury. Notably, the deteriorations of cardiac function, myocyte Ca 2+ handling, and mitochondria integrity were consistently worse in mice with heterozygous ablation of Ser‐2808 than in mice with complete ablation. Wild‐type (WT) and CCM myocytes expressing unmutated RyR2s exhibited a high level of baseline phosphorylation at Ser‐2808. Exposure of these CCM cells to protein phosphatase 1 caused a transitory increase in Ca 2+ leak attributable to partial dephosphorylation of RyR2 tetramers at Ser‐2808 from more fully phosphorylated state. Thus, exacerbated Ca 2+ leak through partially dephosphorylated RyR2s accounts for the prevalence of the disease phenotype in the heterozygous S2808A CCM mice. These results do not support the importance of RyR2 hyperphosphorylation in Ca 2+ ‐dependent heart disease, and rather suggest roles for the opposite process, the RyR2 dephosphorylation at this residue in physiological and pathophysiological Ca 2+ signalling.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/106986/1/tjp6067.pd

Malformations of the craniocervical junction (chiari type I and syringomyelia: classification, diagnosis and treatment)

Chiari disease (or malformation) is in general a congenital condition characterized by an anatomic defect of the base of the skull, in which the cerebellum and brain stem herniate through the foramen magnum into the cervical spinal canal. The onset of Chiari syndrome symptoms usually occurs in the second or third decade (age 25 to 45 years). Symptoms may vary between periods of exacerbation and remission. The diagnosis of Chiari type I malformation in patients with or without symptoms is established with neuroimaging techniques. The most effective therapy for patients with Chiari type I malformation/syringomyelia is surgical decompression of the foramen magnum, however there are non-surgical therapy to relieve neurophatic pain: either pharmacological and non-pharmacological. Pharmacological therapy use drugs that act on different components of pain. Non-pharmacological therapies are primarly based on spinal or peripheral electrical stimulation

A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci.

We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P = 8 × 10⁻¹²) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 × 10⁻¹¹) on 19q12 maps to CCNE1 and rs11892031 (P = 1 × 10⁻⁷) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P = 4 × 10⁻¹¹) and a tag SNP for NAT2 acetylation status (P = 4 × 10⁻¹¹), and found interactions with smoking in both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into the mechanisms of carcinogenesis

School Effects on the Wellbeing of Children and Adolescents

Well-being is a multidimensional construct, with psychological, physical and social components. As theoretical basis to help understand this concept and how it relates to school, we propose the Self-Determination Theory, which contends that self-determined motivation and personality integration, growth and well-being are dependent on a healthy balance of three innate psychological needs of autonomy, relatedness and competence. Thus, current indicators involve school effects on children’s well-being, in many diverse modalities which have been explored. Some are described in this chapter, mainly: the importance of peer relationships; the benefits of friendship; the effects of schools in conjunction with some forms of family influence; the school climate in terms of safety and physical ecology; the relevance of the teacher input; the school goal structure and the implementation of cooperative learning. All these parameters have an influence in promoting optimal functioning among children and increasing their well-being by meeting the above mentioned needs. The empirical support for the importance of schools indicates significant small effects, which often translate into important real-life effects as it is admitted at present. The conclusion is that schools do make a difference in children’s peer relationships and well-being

Ecos de la academia: Revista de la Facultad de Educación, Ciencia y Tecnología - FECYT Nro 6

Ecos de la academia, Revista de la Facultad de Educación Ciencia y Tecnología es una publicación científica de la Universidad Técnica del Norte, con revisión por pares a doble ciego que publica artículos en idioma español, quichua, portugués e inglés. Se edita con una frecuencia semestral con dos números por año.En ella se divulgan trabajos originales e inéditos generados por los investigadores, docentes y estudiantes de la FECYT, y contribuciones de profesionales de instituciones docentes e investigativas dentro y fuera del país, con calidad, originalidad y relevancia en las áreas de ciencias sociales y tecnología aplicada.Modelos multidimensionales del bienestar en contextos de enseñanza- aprendizaje: una revisión sistemática. Nuevas tendencias para el área académica de la Publicidad en la zona 1 del Ecuador. Propuesta de un curso de escritura académica bajo la base de modelos experienciales. Aproximación al estudio de las emociones. Seguimiento a egresados y graduados para actualizar el perfil de egreso y profesional. Impacto de la Gerencia de Calidad en el clima organizacional en Educación Básica. Comunicación efectiva del gerente educativo orientada al manejo de conflictos en el personal docente. Meritocracia: Democratización o exclusión en el acceso a la educación superior en Ecuador. Asertividad y desempeño académico en estudiantes universitarios. La creatividad en la formación profesional. Aspectos metodológicos en el proceso de enseñanza- aprendizaje de la gimnasia en estudiantes de Educación Física. English Language Learning Interaction through Web 2.0 Technologies. La sistematización de la práctica educativa y su relación con la metodología de la investigación. El ozono y la oxigenación hiperbárica: una vía para mejorar la recuperación en lesiones deportivas. La labor tutorial: Independencia del aprendizaje en el contexto universitario. Motivación hacia la profesión docente en la Enseñanza Secundaria. El uso académico de Facebook y WhatsApp en estudiantes universitarios... La educación superior en Ecuador: situación actual y factores de mejora de la calidad. El Proyecto de Investigación “Imbabura Étnica”

Disease Caused by Mutations in NaV-β Subunit Genes

NaV-b subunits associate with the NaV-a or pore-forming subunit of the voltage-dependent sodium channel and play critical roles in channel expression, voltage dependence of the channel gating, cell adhesion, signal transduction, and channel pharmacology. Five NaV-b subunits have been identified in humans, all of them implicated in many primary arrhythmia syndromes that cause sudden death or neurologic disorders, including long QT syndrome, Brugada syndrome, cardiac conduction disorders, idiopathic ventricular fibrillation, epilepsy, neurodegenerative diseases, and neuropsychiatric disorders