Distinct Functional Constraints Partition Sequence Conservation in a cis-Regulatory Element

Different functional constraints contribute to different evolutionary rates across genomes. To understand why some sequences evolve faster than others in a single cis-regulatory locus, we investigated function and evolutionary dynamics of the promoter of the Caenorhabditis elegans unc-47 gene. We found that this promoter consists of two distinct domains. The proximal promoter is conserved and is largely sufficient to direct appropriate spatial expression. The distal promoter displays little if any conservation between several closely related nematodes. Despite this divergence, sequences from all species confer robustness of expression, arguing that this function does not require substantial sequence conservation. We showed that even unrelated sequences have the ability to promote robust expression. A prominent feature shared by all of these robustness-promoting sequences is an AT-enriched nucleotide composition consistent with nucleosome depletion. Because general sequence composition can be maintained despite sequence turnover, our results explain how different functional constraints can lead to vastly disparate rates of sequence divergence within a promoter

Behavioural Risk Factors in Mid-Life Associated with Successful Ageing, Disability, Dementia and Frailty in Later Life: A Rapid Systematic Review.

BACKGROUND: Smoking, alcohol consumption, poor diet and low levels of physical activity significantly contribute to the burden of illness in developed countries. Whilst the links between specific and multiple risk behaviours and individual chronic conditions are well documented, the impact of these behaviours in mid-life across a range of later life outcomes has yet to be comprehensively assessed. This review aimed to provide an overview of behavioural risk factors in mid-life that are associated with successful ageing and the primary prevention or delay of disability, dementia, frailty and non-communicable chronic conditions. METHODS: A literature search was conducted to identify cohort studies published in English since 2000 up to Dec 2014. Multivariate analyses and a minimum follow-up of five years were required for inclusion. Two reviewers screened titles, abstracts and papers independently. Studies were assessed for quality. Evidence was synthesised by mid-life behavioural risk for a range of late life outcomes. FINDINGS: This search located 10,338 individual references, of which 164 are included in this review. Follow-up data ranged from five years to 36 years. Outcomes include dementia, frailty, disability and cardiovascular disease. There is consistent evidence of beneficial associations between mid-life physical activity, healthy ageing and disease outcomes. Across all populations studied there is consistent evidence that mid-life smoking has a detrimental effect on health. Evidence specific to alcohol consumption was mixed. Limited, but supportive, evidence was available relating specifically to mid-life diet, leisure and social activities or health inequalities. CONCLUSIONS: There is consistent evidence of associations between mid-life behaviours and a range of late life outcomes. The promotion of physical activity, healthy diet and smoking cessation in all mid-life populations should be encouraged for successful ageing and the prevention of disability and chronic disease.This work was funded by the National Institute for Health and Care Excellence (NICE), invitation to tender reference DDER 42013, and supported by the National Institute for Health Research School for Public Health Research. The scope of the work was defined by NICE and the protocol was agreed with NICE prior to the start of work. The funders had no role in data analysis, preparation of the manuscript or decision to publish.This is the final version of the article. It first appeared from PLOS via http://dx.doi.org/10.1371/journal.pone.014440

Economic Benefits Assessment of Accelerated Pavement Testing Research in California: Case Study

A cost-benefit analysis method for determining the economic benefits of heavy vehicle simulator testing was evaluated. The University of California and its research partners began conducting accelerated pavement testing in 1994 on behalf of the California Department of Transportation. The authors present the findings of a pilot project intended to define a method suitable for measuring the direct economic benefits of heavy vehicle simulator testing in California. The chosen method was based on a cost-benefit analysis initially developed in Australia and later enhanced and applied in South Africa to determine economic benefits of their respective accelerated pavement testing programs. Results of a case study applying the Australian-South African method to heavy vehicle simulator tests conducted in California are presented. The case study evaluated benefits (in cost savings) from heavy vehicle simulator tests performed to validate innovative pavement mixes and designs proposed for the rehabilitation of a high-traffic urban Interstate route in the Los Angeles, California, area. Although local conditions in these countries differed significantly, the method was successfully applied and consistently showed positive results, presented as discounted net present value and benefit-cost ratio. Sensitivity analysis is recommended to determine a range of savings instead of a single benefit-cost ratio.open1126sciescopu

Global Review of the Age Distribution of Rotavirus Disease in Children Aged < 5 Years Before the Introduction of Rotavirus Vaccination

International audienceWe sought datasets with granular age distributions of rotavirus-positive disease presentations among children <5 years of age, before the introduction of rotavirus vaccines. We identified 117 datasets and fit parametric age distributions to each country dataset and mortality stratum. We calculated the median age and the cumulative proportion of rotavirus gastroenteritis events expected to occur at ages between birth and 5.0 years. The median age of rotavirus-positive hospital admissions was 38 weeks (interquartile range [IQR], 25-58 weeks) in countries with very high child mortality and 65 weeks (IQR, 40-107 weeks) in countries with very low or low child mortality. In countries with very high child mortality, 69% of rotavirus-positive admissions in children <5 years of age were in the first year of life, with 3% by 10 weeks, 8% by 15 weeks, and 27% by 26 weeks. This information is critical for assessing the potential benefits of alternative rotavirus vaccination schedules in different countries and for monitoring program impact