Coarse-grained model of entropic allostery

Many signaling functions in molecular biology require proteins to bind to substrates such as DNA in response to environmental signals such as the simultaneous binding to a small molecule. Examples are repressor proteins which may transmit information via a conformational change in response to the ligand binding. An alternative entropic mechanism of "allostery" suggests that the inducer ligand changes the intramolecular vibrational entropy, not just the mean static structure. We present a quantitative, coarse-grained model of entropic allostery, which suggests design rules for internal cohesive potentials in proteins employing this effect. It also addresses the issue of how the signal information to bind or unbind is transmitted through the protein. The model may be applicable to a wide range of repressors and also to signaling in trans-membrane proteins

Swimming using surface acoustic waves

Microactuation of free standing objects in fluids is currently dominated by the rotary propeller, giving rise to a range of potential applications in the military, aeronautic and biomedical fields. Previously, surface acoustic waves (SAWs) have been shown to be of increasing interest in the field of microfluidics, where the refraction of a SAW into a drop of fluid creates a convective flow, a phenomenon generally known as SAW streaming. We now show how SAWs, generated at microelectronic devices, can be used as an efficient method of propulsion actuated by localised fluid streaming. The direction of the force arising from such streaming is optimal when the devices are maintained at the Rayleigh angle. The technique provides propulsion without any moving parts, and, due to the inherent design of the SAW transducer, enables simple control of the direction of travel

Genome-Wide Association Study and Gene Expression Analysis Identifies CD84 as a Predictor of Response to Etanercept Therapy in Rheumatoid Arthritis

Anti-tumor necrosis factor alpha (anti-TNF) biologic therapy is a widely used treatment for rheumatoid arthritis (RA). It is unknown why some RA patients fail to respond adequately to anti-TNF therapy, which limits the development of clinical biomarkers to predict response or new drugs to target refractory cases. To understand the biological basis of response to anti-TNF therapy, we conducted a genome-wide association study (GWAS) meta-analysis of more than 2 million common variants in 2,706 RA patients from 13 different collections. Patients were treated with one of three anti-TNF medications: etanercept (n = 733), infliximab (n = 894), or adalimumab (n = 1,071). We identified a SNP (rs6427528) at the 1q23 locus that was associated with change in disease activity score (ΔDAS) in the etanercept subset of patients (P = 8×10-8), but not in the infliximab or adalimumab subsets (P>0.05). The SNP is predicted to disrupt transcription factor binding site motifs in the 3′ UTR of an immune-related gene, CD84, and the allele associated with better response to etanercept was associated with higher CD84 gene expression in peripheral blood mononuclear cells (P = 1×10-11 in 228 non-RA patients and P = 0.004 in 132 RA patients). Consistent with the genetic findings, higher CD84 gene expression correlated with lower cross-sectional DAS (P = 0.02, n = 210) and showed a non-significant trend for better ΔDAS in a subset of RA patients with gene expression data (n = 31, etanercept-treated). A small, multi-ethnic replication showed a non-significant trend towards an association among etanercept-treated RA patients of Portuguese ancestry (n = 139, P = 0.4), but no association among patients of Japanese ancestry (n = 151, P = 0.8). Our study demonstrates that an allele associated with response to etanercept therapy is also associated with CD84 gene expression, and further that CD84 expression correlates with disease activity. These findings support a model in which CD84 genotypes and/or expression may serve as a useful biomarker for response to etanercept treatment in RA patients of European ancestry. © 2013 Cui et al

Association between maternal education and objectively measured physical activity and sedentary time in adolescents

Investigating socioeconomic variation in physical activity (PA) and sedentary time is important as it may represent a pathway by which socioeconomic position (SEP) leads to ill health. Findings on the association between children's SEP and objectively assessed PA and/or sedentary time are mixed, and few studies have included international samples.Examine the associations between maternal education and adolescent's objectively assessed PA and sedentary time.This is an observational study of 12 770 adolescents (10-18 years) pooled from 10 studies from Europe, Australia, Brazil and the USA. Original PA data were collected between 1997 and 2009. The associations between maternal education and accelerometer variables were examined using robust multivariable regression, adjusted for a priori confounders (ie, body mass index, monitor wear time, season, age and sex) and regression coefficients combined across studies using random effects meta-analyses. Analyses were conducted in March 2014.Adolescents of university educated mothers spent more time sedentary (9.5 min/day, p=0.005) and less time in light activity (10 min/day, p<0.001) compared with adolescents of high school educated mothers. Pooled analysis across two studies from Brazil and Portugal (analysed separately because of the different coding of maternal education) showed that children of higher educated mothers (tertiary vs primary/secondary) spent less time in moderate to vigorous PA (MVPA) (6.6 min/day, p=0.001) and in light PA (39.2 min/day: p<0.001), and more time sedentary (45.9 min/day, p<0.001).Across a number of international samples, adolescents of mothers with lower education may not be at a disadvantage in terms of overall objectively measured PA

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

General practitioner workforce planning: assessment of four policy directions

<p>Abstract</p> <p>Background</p> <p>Estimating the supply of GPs into the future is important in forecasting shortages. The lengthy training process for medicine means that adjusting supply to meet demand in a timely fashion is problematic. This study uses Ireland as a case study to determine the future demand and supply of GPs and to assess the potential impact of several possible interventions to address future shortages.</p> <p>Methods</p> <p>Demand was estimated by applying GP visit rates by age and sex to national population projections. Supply was modelled using a range of parameters derived from two national surveys of GPs. A stochastic modelling approach was adopted to determine the probable future supply of GPs. Four policy interventions were tested: increasing vocational training places; recruiting GPs from abroad; incentivising later retirement; increasing nurse substitution to enable practice nurses to deliver more services.</p> <p>Results</p> <p>Relative to most other European countries, Ireland has few GPs per capita. Ireland has an ageing population and demand is estimated to increase by 19% by 2021. Without intervention, the supply of GPs will be 5.7% less than required in 2021. Increasing training places will enable supply to meet demand but only after 2019. Recruiting GPs from overseas will enable supply to meet demand continuously if the number recruited is approximately 0.8 per cent of the current workforce per annum. Later retirement has only a short-term impact. Nurse substitution can enable supply to meet demand but only if large numbers of practice nurses are recruited and allowed to deliver a wide range of GP services.</p> <p>Conclusions</p> <p>A significant shortfall in GP supply is predicted for Ireland unless recruitment is increased. The shortfall will have numerous knock-on effects including price increases, longer waiting lists and an increased burden on hospitals. Increasing training places will not provide an adequate response to future shortages. Foreign recruitment has ethical considerations but may provide a rapid and effective response. Increased nurse substitution appears to offer the best long-term prospects of addressing GP shortages and presents the opportunity to reshape general practice to meet the demands of the future.</p

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes

US Cosmic Visions: New Ideas in Dark Matter 2017: Community Report

This white paper summarizes the workshop "U.S. Cosmic Visions: New Ideas in Dark Matter" held at University of Maryland on March 23-25, 2017.Comment: 102 pages + reference

Alcohol-related blackouts among college students: impact of low level of response to alcohol, ethnicity, sex, and environmental characteristics

Objective: To explore how a genetically-influenced characteristic (the level of response to alcohol [LR]), ethnicity, and sex relate to environmental and attitudinal characteristics (peer drinking [PEER], drinking to cope [COPE], and alcohol expectancies [EXPECT]) regarding future alcohol-related blackouts (ARBs). Methods: Structural equation models (SEMs) were used to evaluate how baseline variables related to ARB patterns in 462 college students over 55 weeks. Data were extracted from a longitudinal study of heavy drinking and its consequences at a U.S. university. Results: In the SEM analysis, female sex and Asian ethnicity directly predicted future ARBs (beta weights 0.10 and -0.11, respectively), while all other variables had indirect impacts on ARBs through alcohol quantities (beta weights ~ 0.23 for European American ethnicity and low LR, 0.21 for cannabis use and COPE, and 0.44 for PEER). Alcohol quantities then related to ARBs with beta = 0.44. The SEM explained 23% of the variance. Conclusion: These data may be useful in identifying college students who are more likely to experience future ARBs over a 1-year period. They enhance our understanding of whether the relationships of predictors to ARBs are direct or mediated through baseline drinking patterns, information that may be useful in prevention strategies for ARBs