Molecular architecture of Gαo and the structural basis for RGS16-mediated deactivation

Heterotrimeric G proteins relay extracellular cues from heptahelical transmembrane receptors to downstream effector molecules. Composed of an α subunit with intrinsic GTPase activity and a βγ heterodimer, the trimeric complex dissociates upon receptor-mediated nucleotide exchange on the α subunit, enabling each component to engage downstream effector targets for either activation or inhibition as dictated in a particular pathway. To mitigate excessive effector engagement and concomitant signal transmission, the Gα subunit's intrinsic activation timer (the rate of GTP hydrolysis) is regulated spatially and temporally by a class of GTPase accelerating proteins (GAPs) known as the regulator of G protein signaling (RGS) family. The array of G protein-coupled receptors, Gα subunits, RGS proteins and downstream effectors in mammalian systems is vast. Understanding the molecular determinants of specificity is critical for a comprehensive mapping of the G protein system. Here, we present the 2.9 Å crystal structure of the enigmatic, neuronal G protein Gαo in the GTP hydrolytic transition state, complexed with RGS16. Comparison with the 1.89 Å structure of apo-RGS16, also presented here, reveals plasticity upon Gαo binding, the determinants for GAP activity, and the structurally unique features of Gαo that likely distinguish it physiologically from other members of the larger Gαi family, affording insight to receptor, GAP and effector specificity

Success for All in England: Results From the Third Year of a National Evaluation

This article reports the third-year findings of a longitudinal evaluation in England of Success for All (SFA), a comprehensive literacy program. Eighteen SFA schools across England and 18 control schools, matched on prior achievement and demographics, were included in this quasi-experimental study. The results of hierarchical linear modeling analysis reveal a statistically significant positive school-level effect for SFA schools compared with control schools on standardized reading measures of word-level and decoding skills, and there were directionally positive but nonsignificant school-level effects on measures of comprehension and fluency. Practical and policy implications of these findings are discussed, particularly as they relate to recent English government policies encouraging schools to implement research-proven approaches

Adherence to 24-Hour Movement Guidelines for the Early Years and associations with social-cognitive development among Australian preschool children

Background: The new Australian 24-Hour Movement Guidelines for the Early Years recommend that, for preschoolers, a healthy 24-h includes: i) ≥180 min of physical activity, including ≥60 min of energetic play, ii) ≤1 h of sedentary screen time, and iii) 10–13 h of good quality sleep. Using an Australian sample, this study reports the proportion of preschool children meeting these guidelines and investigates associations with social-cognitive development. Methods: Data from 248 preschool children (mean age = 4.2 ± 0.6 years, 57% boys) participating in the PATH-ABC study were analyzed. Children completed direct assessments of physical activity (accelerometry) and social cognition (the Test of Emotional Comprehension (TEC) and Theory of Mind (ToM)). Parents reported on children’s screen time and sleep. Children were categorised as meeting/not meeting: i) individual guidelines, ii) combinations of two guidelines, or iii) all three guidelines. Associations were examined using linear regression adjusting for child age, sex, vocabulary, area level socio-economic status and childcare level clustering. Results: High proportions of children met the physical activity (93.1%) and sleep (88.7%) guidelines, whereas fewer met the screen time guideline (17.3%). Overall, 14.9% of children met all three guidelines. Children meeting the sleep guideline performed better on TEC than those who did not (mean difference [MD] = 1.41; 95% confidence interval (CI) = 0.36, 2.47). Children meeting the sleep and physical activity or sleep and screen time guidelines also performed better on TEC (MD = 1.36; 95% CI = 0.31, 2.41) and ToM (MD = 0.25; 95% CI = −0.002, 0.50; p = 0.05), respectively, than those who did not. Meeting all three guidelines was associated with better ToM performance (MD = 0.28; 95% CI = −0.002, 0.48, p = 0.05), while meeting a larger number of guidelines was associated with better TEC (3 or 2 vs. 1/none, p < 0.02) and ToM performance (3 vs. 2, p = 0.03). Conclusions: Strategies to promote adherence to the 24-Hour Movement Behaviour Guidelines for the Early Years among preschool children are warranted. Supporting preschool children to meet all guidelines or more guidelines, particularly the sleep and screen time guidelines, may be beneficial for their social-cognitive development

Dystrophin deficiency in canine X-linked muscular dystrophy in Japan (CXMDJ) alters myosin heavy chain expression profiles in the diaphragm more markedly than in the tibialis cranialis muscle

<p>Abstract</p> <p>Background</p> <p>Skeletal muscles are composed of heterogeneous collections of muscle fiber types, the arrangement of which contributes to a variety of functional capabilities in many muscle types. Furthermore, skeletal muscles can adapt individual myofibers under various circumstances, such as disease and exercise, by changing fiber types. This study was performed to examine the influence of dystrophin deficiency on fiber type composition of skeletal muscles in canine X-linked muscular dystrophy in Japan (CXMD_J), a large animal model for Duchenne muscular dystrophy.</p> <p>Methods</p> <p>We used tibialis cranialis (TC) muscles and diaphragms of normal dogs and those with CXMD_Jat various ages from 1 month to 3 years old. For classification of fiber types, muscle sections were immunostained with antibodies against fast, slow, or developmental myosin heavy chain (MHC), and the number and size of these fibers were analyzed. In addition, MHC isoforms were detected by gel electrophoresis.</p> <p>Results</p> <p>In comparison with TC muscles of CXMD_J, the number of fibers expressing slow MHC increased markedly and the number of fibers expressing fast MHC decreased with growth in the affected diaphragm. In populations of muscle fibers expressing fast and/or slow MHC(s) but not developmental MHC of CXMD_Jmuscles, slow MHC fibers were predominant in number and showed selective enlargement. Especially, in CXMD_Jdiaphragms, the proportions of slow MHC fibers were significantly larger in populations of myofibers with non-expression of developmental MHC. Analyses of MHC isoforms also indicated a marked increase of type I and decrease of type IIA isoforms in the affected diaphragm at ages over 6 months. In addition, expression of developmental (embryonic and/or neonatal) MHC decreased in the CXMD_Jdiaphragm in adults, in contrast to continuous high-level expression in affected TC muscle.</p> <p>Conclusion</p> <p>The CXMD_Jdiaphragm showed marked changes in fiber type composition unlike TC muscles, suggesting that the affected diaphragm may be effectively adapted toward dystrophic stress by switching to predominantly slow fibers. Furthermore, the MHC expression profile in the CXMD_Jdiaphragm was markedly different from that in <it>mdx </it>mice, indicating that the dystrophic dog is a more appropriate model than a murine one, to investigate the mechanisms of respiratory failure in DMD.</p

Single Molecule Imaging Reveals Differences in Microtubule Track Selection Between Kinesin Motors

Molecular motors differentially recognize and move cargo along discrete microtubule subpopulations in cells, resulting in preferential transport and targeting of subcellular cargoes

Social, emotional, and behavioral functioning of secondary school students with low academic and language performance: perspectives from students, teachers, and parents

Adolescence is a time of transition when young people with language difficulties are at increased risk of experiencing social, emotional, and behavioral difficulties (SEBD). Most studies of social, emotional, and behavioral functioning (SEBF) in individuals with language difficulties focus on children with a clinical diagnosis of language impairment. This study explores SEBF in a nonclinical group of 12-year-old students with low educational and language performance from their own perspectives and those of their parents and teachers

An Investigation to Validate the Grammar and Phonology Screening (GAPS) Test to Identify Children with Specific Language Impairment

The extraordinarily high incidence of grammatical language impairments in developmental disorders suggests that this uniquely human cognitive function is "fragile". Yet our understanding of the neurobiology of grammatical impairments is limited. Furthermore, there is no "gold-standard" to identify grammatical impairments and routine screening is not undertaken. An accurate screening test to identify grammatical abilities would serve the research, health and education communities, further our understanding of developmental disorders, and identify children who need remediation, many of whom are currently un-diagnosed. A potential realistic screening tool that could be widely administered is the Grammar and Phonology Screening (GAPS) test--a 10 minute test that can be administered by professionals and non-professionals alike. Here we provide a further step in evaluating the validity and accuracy (sensitivity and specificity) of the GAPS test in identifying children who have Specific Language Impairment (SLI)

Relative deprivation and inequalities in social and political activism

In this paper we analyse whether relative deprivation has divergent effects on different types of social and political action. We expect that it will depress volunteering with parties as well as different types of conventional political participation more generally while stimulating volunteering with anti-cuts organisations and engagement in various kinds of protest activism. There is little research into how relative deprivation impacts on different types of social and political action from the wide range of activities available to citizens in contemporary democracies as well as into how this relationship might vary based on the wider economic context. While many studies construct scales, we examine participation in specific activities and associations, such as parties or anti-cuts organisations, voting, contacting, demonstrating and striking to show that deprivation has divergent effects that depart from what is traditionally argued. We apply random effects models with cross-level interactions utilizing an original cross-national European dataset collected in 2015 (N = 17,667) within a collaborative funded-project. We show that a negative economic context has a mobilizing effect by both increasing the stimulating effect of relative deprivation on protest activism as well as by closing or reversing the gap between resource-poor and resource-rich groups for volunteering with parties and voting