New mutations at the imprinted Gnas cluster show gene dosage effects of Gsα in postnatal growth and implicate XLαs in bone and fat metabolism, but not in suckling

The imprinted Gnas cluster is involved in obesity, energy metabolism, feeding behavior, and viability. Relative contribution of paternally expressed proteins XLαs, XLN1, and ALEX or a double dose of maternally expressed Gsα to phenotype has not been established. In this study, we have generated two new mutants (Ex1A-T-CON and Ex1A-T) at the Gnas cluster. Paternal inheritance of Ex1A-T-CON leads to loss of imprinting of Gsα, resulting in preweaning growth retardation followed by catch-up growth. Paternal inheritance of Ex1A-T leads to loss of imprinting of Gsα and loss of expression of XLαs and XLN1. These mice have severe preweaning growth retardation and incomplete catch-up growth. They are fully viable probably because suckling is unimpaired, unlike mutants in which the expression of all the known paternally expressed Gnasxl proteins (XLαs, XLN1 and ALEX) is compromised. We suggest that loss of ALEX is most likely responsible for the suckling defects previously observed. In adults, paternal inheritance of Ex1A-T results in an increased metabolic rate and reductions in fat mass, leptin, and bone mineral density attributable to loss of XLαs. This is, to our knowledge, the first report describing a role for XLαs in bone metabolism. We propose that XLαs is involved in the regulation of bone and adipocyte metabolism

Slowing Heart Rate Protects Against Pathological Cardiac Hypertrophy.

We aimed to determine the pathophysiological impact of heart rate (HR) slowing on cardiac function. We have recently developed a murine model in which it is possible to conditionally delete the stimulatory heterotrimeric G-protein (Gαs) in the sinoatrial (SA) node after the addition of tamoxifen using cre-loxP technology. The addition of tamoxifen leads to bradycardia. We used this approach to examine the physiological and pathophysiological effects of HR slowing. We first looked at the impact on exercise performance by running the mice on a treadmill. After the addition of tamoxifen, mice with conditional deletion of Gαs in the SA node ran a shorter distance at a slower speed. Littermate controls preserved their exercise capacity after tamoxifen. Results consistent with impaired cardiac capacity in the mutants were also obtained with a dobutamine echocardiographic stress test. We then examined if HR reduction influenced pathological cardiac hypertrophy using two models: ligation of the left anterior descending coronary artery for myocardial infarction and abdominal aortic banding for hypertensive heart disease. In littermate controls, both procedures resulted in cardiac hypertrophy. However, induction of HR reduction prior to surgical intervention significantly ameliorated the hypertrophy. In order to assess potential protein kinase pathways that may be activated in the left ventricle by relative bradycardia, we used a phospho-antibody array and this revealed selective activation of phosphoinositide-3 kinase. In conclusion, HR reduction protects against pathological cardiac hypertrophy but limits physiological exercise capacity

Display of probability densities for data from a continuous distribution

Based on cumulative distribution functions, Fourier series expansion and Kolmogorov tests, we present a simple method to display probability densities for data drawn from a continuous distribution. It is often more efficient than using histograms.Comment: 5 pages, 4 figures, presented at Computer Simulation Studies XXIV, Athens, GA, 201

Search for Gravitational Waves from Primordial Black Hole Binary Coalescences in the Galactic Halo

We use data from the second science run of the LIGO gravitational-wave detectors to search for the gravitational waves from primordial black hole (PBH) binary coalescence with component masses in the range 0.2--$1.0 M_\odot$. The analysis requires a signal to be found in the data from both LIGO observatories, according to a set of coincidence criteria. No inspiral signals were found. Assuming a spherical halo with core radius 5 kpc extending to 50 kpc containing non-spinning black holes with masses in the range 0.2--$1.0 M_\odot$, we place an observational upper limit on the rate of PBH coalescence of 63 per year per Milky Way halo (MWH) with 90% confidence.Comment: 7 pages, 4 figures, to be submitted to Phys. Rev.

Psychometric properties of the Problematic Internet Use Questionnaire Short-Form (PIUQ-SF-6) in a nationally representative sample of adolescents

Despite the large number of measurement tools developed to assess problematic Internet use, numerous studies use measures with only modest investigation into their psychometric properties. The goal of the present study was to validate the short (6-item) version of the Problematic Internet Use Questionnaire (PIUQ) on a nationally representative adolescent sample (n = 5,005; mean age 16.4 years, SD = 0.87) and to determine a statistically established cut-off value. Data were collected within the framework of the European School Survey Project on Alcohol and Other Drugs project. Results showed an acceptable fit of the original three-factor structure to the data. In addition, a MIMIC model was carried out to justify the need for three distinct factors. The sample was divided into users at-risk of problematic Internet use and those with no-risk using a latent profile analysis. Two latent classes were obtained with 14.4% of adolescents belonging to the at-risk group. Concurrent and convergent validity were tested by comparing the two groups across a number of variables (i.e., time spent online, academic achievement, self-esteem, depressive symptoms, and preferred online activities). Using the at-risk latent profile analysis class as the gold standard, a cut-off value of 15 (out of 30) was suggested based on sensitivity and specificity analyses. In conclusion, the brief version of the (6-item) PIUQ also appears to be an appropriate measure to differentiate between Internet users at risk of developing problematic Internet use and those not at risk. Furthermore, due to its brevity, the shortened PIUQ is advantageous to utilize within large-scale surveys assessing many different behaviors and/or constructs by reducing the overall number of survey questions, and as a consequence, likely increasing completion rates

The empirical analysis of non-problematic video gaming and cognitive skills: a systematic review

Videogames have become one of the most popular leisure activities worldwide, including multiple game genres with different characteristics and levels of involvement required. Although a small minority of excessive players suffer detrimental consequences including impairment of several cognitive skills (e.g., inhibition, decision-making), it has also been demonstrated that playing videogames can improve different cognitive skills. Therefore, the current paper systematically reviewed the empirical studies experimentally investigating the positive impact of videogames on cognitive skills. Following a number of inclusion and exclusion criteria, a total of 32 papers were identified as empirically investigating three specific skills: taskswitching (eight studies), attentional control (22 studies), and sub-second time perception (two studies). Results demonstrated that compared to control groups, non-problematic use of videogames can lead to improved task-switching, more effective top-down attentional control and processing speed and increased sub-second time perception. Two studies highlighted the impact of gaming on cognitive skills differs depends upon game genre. The studies reviewed suggest that videogame play can have a positive impact on cognitive processes for players

The ric-8b protein (resistance to inhibitors of cholinesterase 8b) is key to preserving contractile function in the adult heart.

Resistance to inhibitors of cholinesterases (ric-8 proteins) are involved in modulating G-protein function, but little is known of their potential physiological importance in the heart. In the present study, we assessed the role of resistance to inhibitors of cholinesterase 8b (Ric-8b) in determining cardiac contractile function. We developed a murine model in which it was possible to conditionally delete ric-8b in cardiac tissue in the adult animal after the addition of tamoxifen. Deletion of ric-8b led to severely reduced contractility as measured using echocardiography days after administration of tamoxifen. Histological analysis of the ventricular tissue showed highly variable myocyte size, prominent fibrosis, and an increase in cellular apoptosis. RNA sequencing revealed transcriptional remodeling in response to cardiac ric-8b deletion involving the extracellular matrix and inflammation. Phosphoproteomic analysis revealed substantial downregulation of phosphopeptides related to myosin light chain 2. At the cellular level, the deletion of ric-8b led to loss of activation of the L-type calcium channel through the β-adrenergic pathways. Using fluorescence resonance energy transfer-based assays, we showed ric-8b protein selectively interacts with the stimulatory G-protein, Gαs. We explored if deletion of Gnas (the gene encoding Gαs) in cardiac tissue using a similar approach in the mouse led to an equivalent phenotype. The conditional deletion of the Gαs gene in the ventricle led to comparable effects on contractile function and cardiac histology. We conclude that ric-8b is essential to preserve cardiac contractile function likely through an interaction with the stimulatory G-protein and downstream phosphorylation of myosin light chain 2

Reductions in hypothalamic Gfap expression, glial cells and α-tanycytes in lean and hypermetabolic Gnasxl-deficient mice

BACKGROUND: Neuronal and glial differentiation in the murine hypothalamus is not complete at birth, but continues over the first two weeks postnatally. Nutritional status and Leptin deficiency can influence the maturation of neuronal projections and glial patterns, and hypothalamic gliosis occurs in mouse models of obesity. Gnasxl constitutes an alternative transcript of the genomically imprinted Gnas locus and encodes a variant of the signalling protein Gαs, termed XLαs, which is expressed in defined areas of the hypothalamus. Gnasxl-deficient mice show postnatal growth retardation and undernutrition, while surviving adults remain lean and hypermetabolic with increased sympathetic nervous system (SNS) activity. Effects of this knock-out on the hypothalamic neural network have not yet been investigated. RESULTS: RNAseq analysis for gene expression changes in hypothalami of Gnasxl-deficient mice indicated Glial fibrillary acid protein (Gfap) expression to be significantly down-regulated in adult samples. Histological analysis confirmed a reduction in Gfap-positive glial cell numbers specifically in the hypothalamus. This reduction was observed in adult tissue samples, whereas no difference was found in hypothalami of postnatal stages, indicating an adaptation in adult Gnasxl-deficient mice to their earlier growth phenotype and hypermetabolism. Especially noticeable was a loss of many Gfap-positive α-tanycytes and their processes, which form part of the ependymal layer that lines the medial and dorsal regions of the 3(rd) ventricle, while β-tanycytes along the median eminence (ME) and infundibular recesses appeared unaffected. This was accompanied by local reductions in Vimentin and Nestin expression. Hypothalamic RNA levels of glial solute transporters were unchanged, indicating a potential compensatory up-regulation in the remaining astrocytes and tanycytes. CONCLUSION: Gnasxl deficiency does not directly affect glial development in the hypothalamus, since it is expressed in neurons, and Gfap-positive astrocytes and tanycytes appear normal during early postnatal stages. The loss of Gfap-expressing cells in adult hypothalami appears to be a consequence of the postnatal undernutrition, hypoglycaemia and continued hypermetabolism and leanness of Gnasxl-deficient mice, which contrasts with gliosis observed in obese mouse models. Since α-tanycytes also function as adult neural progenitor cells, these findings might indicate further developmental abnormalities in hypothalamic formations of Gnasxl-deficient mice, potentially including neuronal composition and projections

Hyperthyroidism related to McCune-Albright syndrome: report of two cases and review of the literature

INTRODUCTION: McCune-Albright syndrome is a sporadic disease clinicaly characterized by polyostotic fibrous dysplasia, café-au-lait cutaneous spots and hyperfunctional endocrinopathies, such as precocious puberty, hyperthyroidism, acromegaly and others. The biologic physiopathology of the disease is based on an activating mutation of the gene for the Gs protein which mediates the activation of adenyl cyclase and subsequent gland autonomous secretion. The thyroid gland is usually involved in this disease, being hyperthyroidism the second most common endocrinopathy seen after precocious puberty. OBJECTIVE: Revision of the literature since 1937 to 1997, adding our casuistic and discussing the adequate treatment for the hyperthyroidism in the syndrome. RESULTS: Among 85 cases identified with the syndrome, hyperthyroidism treatment was described in 26 of them. Fifteen were submitted to surgery (total thyroidectomy), 6 were submitted to iodotherapy and 5 were treated with antithyroid drugs (ATD - propylthiouracil, carbimazole or methimazole). In some cases, treatment association was done. CONCLUSION: McCune-Albright syndrome is a rare disease, combining polyostotic fibrous dysplasia, café-au-lait cutaneous spots and hyperfunctional endocrinopathies. Cases with hyperthyroidism are treated iniatially clinically, but definitive ablation with surgery or radioiodine treatment is the most indicated option.INTRODUÇÃO: A síndrome de McCune Albright é uma doença rara, clinicamente definida pela combinação de displasia fibrosa poliostótica, manchas café-com-leite e endocrinopatias com hiperfunção, como puberdade precoce, hipertireoidismo, acromegalia e outras. A fisiopatologia biomolecular baseia-se em uma mutação ativadora do gene para a subunidade alfa da proteína de membrana Gs, que estimula a produção intracelular de AMPc, conferindo secreção autônoma à glândula em particular. A glândula tireóide é freqüentemente envolvida nesta doença, sendo o hipertireoidismo a segunda endocrinopatia mais comum após a puberdade precoce. OBJETIVO: Realizar uma revisão da literatura no período de 1937 a 1997, incluindo nossa casuística, e discutir o tratamento utilizado para o hipertireoidismo nesta síndrome. RESULTADOS: Do total de 85 casos, em 26 com hipertireoidismo se descreve o tipo de tratamento utilizado. Entre esses, 15 foram submetidos à cirurgia (tireoidectomia total), seis foram submetidos à iodoterapia e cinco foram submetidos a tratamento com drogas antitireoidianas (DAT - propiltiuracil, carbimazol ou metimazol), pois em alguns houve associação dos tratamentos citados anteriormente. CONCLUSÃO: A síndrome de McCune-Albright é uma doença rara, que inclui displasia fibrosa poliostótica, manchas café-com-leite e endocrinopatias com hiperfunção. Os casos acompanhados com hipertireoidismo são inicialmente tratados clinicamente com DAT, porém a ablação cirúrgica ou com radioiodoterapia é a opção definitiva mais indicada.Universidade Federal de São Paulo (UNIFESP) Departamento de Otorrinolaringologia e Cirurgia de Cabeça e PescoçoUNIFESP, Depto. de Otorrinolaringologia e Cirurgia de Cabeça e PescoçoSciEL

QCD and strongly coupled gauge theories : challenges and perspectives

We highlight the progress, current status, and open challenges of QCD-driven physics, in theory and in experiment. We discuss how the strong interaction is intimately connected to a broad sweep of physical problems, in settings ranging from astrophysics and cosmology to strongly coupled, complex systems in particle and condensed-matter physics, as well as to searches for physics beyond the Standard Model. We also discuss how success in describing the strong interaction impacts other fields, and, in turn, how such subjects can impact studies of the strong interaction. In the course of the work we offer a perspective on the many research streams which flow into and out of QCD, as well as a vision for future developments.Peer reviewe