Accelerating array constraints in symbolic execution

Despite significant recent advances, the effectiveness of symbolic execution is limited when used to test complex, real-world software. One of the main scalability challenges is related to constraint solv- ing: large applications and long exploration paths lead to complex constraints, often involving big arrays indexed by symbolic expres- sions. In this paper, we propose a set of semantics-preserving trans- formations for array operations that take advantage of contextual information collected during symbolic execution. Our transforma- tions lead to simpler encodings and hence better performance in constraint solving. The results we obtain are encouraging: we show, through an extensive experimental analysis, that our transforma- tions help to significantly improve the performance of symbolic execution in the presence of arrays. We also show that our transfor- mations enable the analysis of new code, which would be otherwise out of reach for symbolic execution

The Sister-Chromatid Exchange Assay in Human Cells

The semiconservative nature of DNA replication allows the differential labeling of sister chromatids that isthe fundamental requirement to perform the sister-chromatid exchange (SCE) assay. SCE assay is apowerful technique to visually detect the physical exchange of DNA between sister chromatids. SCEscould result as a consequence of DNA damage repair by homologous recombination (HR) during DNAreplication. Here, we provide the detailed protocol to perform the SCE assay in cultured human cells. Cellsare exposed to the thymidine analog 5-bromo-20-deoxyuridine (BrdU) during two cell cycles, resulting inthe two sister chromatids having differential incorporation of the analog. After metaphase spreads prepara-tion and further processing, SCEs are nicely visualized under the microscope

Are there biological differences between screen-detected and interval colorectal cancers in the English Bowel Cancer Screening Programme?

Background: We measured biomarkers of tumour growth and vascularity in interval and screen-detected colorectal cancers (CRCs) in the English Bowel Cancer Screening Programme in order to determine whether rapid tumour growth might contribute to interval CRC (a CRC diagnosed between a negative guaiac stool test and the next scheduled screening episode). Methods: Formalin-fixed, paraffin-embedded sections from 71 CRCs (screen-detected 43, interval 28) underwent immunohistochemistry for CD31 and Ki-67, in order to measure the microvessel density (MVD) and proliferation index (PI), respectively, as well as microsatellite instability (MSI) testing. Results: Interval CRCs were larger (P=0.02) and were more likely to exhibit venous invasion (P=0.005) than screen-detected tumours. There was no significant difference in MVD or PI between interval and screen-detected CRCs. More interval CRCs displayed MSI-high (14%) compared with screen-detected tumours (5%). A significantly (P=0.005) higher proportion (51%) of screen-detected CRC resection specimens contained at least one polyp compared with interval CRC (18%) resections. Conclusions: We found no evidence of biological differences between interval and screen-detected CRCs, consistent with the low sensitivity of guaiac stool testing as the main driver of interval CRC. The contribution of synchronous adenomas to occult blood loss for screening requires further investigation

The role of childhood social position in adult type 2 diabetes: Evidence from the English Longitudinal Study of Ageing

Copyright @ 2014 Pikhartova et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.This article has been made available through the Brunel Open Access Publishing Fund.Background: Socioeconomic circumstances in childhood and early adulthood may influence the later onset of chronic disease, although such research is limited for type 2 diabetes and its risk factors at the different stages of life. The main aim of the present study is to examine the role of childhood social position and later inflammatory markers and health behaviours in developing type 2 diabetes at older ages using a pathway analytic approach. Methods. Data on childhood and adult life circumstances of 2,994 men and 4,021 women from English Longitudinal Study of Ageing (ELSA) were used to evaluate their association with diabetes at age 50 years and more. The cases of diabetes were based on having increased blood levels of glycated haemoglobin and/or self-reported medication for diabetes and/or being diagnosed with type 2 diabetes. Father's job when ELSA participants were aged 14 years was used as the measure of childhood social position. Current social characteristics, health behaviours and inflammatory biomarkers were used as potential mediators in the statistical analysis to assess direct and indirect effects of childhood circumstances on diabetes in later life. Results: 12.6 per cent of participants were classified as having diabetes. A disadvantaged social position in childhood, as measured by father's manual occupation, was associated at conventional levels of statistical significance with an increased risk of type 2 diabetes in adulthood, both directly and indirectly through inflammation, adulthood social position and a risk score constructed from adult health behaviours including tobacco smoking and limited physical activity. The direct effect of childhood social position was reduced by mediation analysis (standardised coefficient decreased from 0.089 to 0.043) but remained statistically significant (p = 0.035). All three indirect pathways made a statistically significantly contribution to the overall effect of childhood social position on adulthood type 2 diabetes. Conclusions: Childhood social position influences adult diabetes directly and indirectly through inflammatory markers, adulthood social position and adult health behaviours. © 2014Pikhartova et al.; licensee BioMed Central Ltd.Economic and Social Research Council-funded International Centre for Life Course Studies in Society and Health (RES-596-28-0001)

Imputation of variants from the 1000 Genomes Project modestly improves known associations and can identify low-frequency variant-phenotype associations undetected by HapMap based imputation

notes: PMCID: PMC3655956This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Genome-wide association (GWA) studies have been limited by the reliance on common variants present on microarrays or imputable from the HapMap Project data. More recently, the completion of the 1000 Genomes Project has provided variant and haplotype information for several million variants derived from sequencing over 1,000 individuals. To help understand the extent to which more variants (including low frequency (1% ≤ MAF <5%) and rare variants (<1%)) can enhance previously identified associations and identify novel loci, we selected 93 quantitative circulating factors where data was available from the InCHIANTI population study. These phenotypes included cytokines, binding proteins, hormones, vitamins and ions. We selected these phenotypes because many have known strong genetic associations and are potentially important to help understand disease processes. We performed a genome-wide scan for these 93 phenotypes in InCHIANTI. We identified 21 signals and 33 signals that reached P<5×10(-8) based on HapMap and 1000 Genomes imputation, respectively, and 9 and 11 that reached a stricter, likely conservative, threshold of P<5×10(-11) respectively. Imputation of 1000 Genomes genotype data modestly improved the strength of known associations. Of 20 associations detected at P<5×10(-8) in both analyses (17 of which represent well replicated signals in the NHGRI catalogue), six were captured by the same index SNP, five were nominally more strongly associated in 1000 Genomes imputed data and one was nominally more strongly associated in HapMap imputed data. We also detected an association between a low frequency variant and phenotype that was previously missed by HapMap based imputation approaches. An association between rs112635299 and alpha-1 globulin near the SERPINA gene represented the known association between rs28929474 (MAF = 0.007) and alpha1-antitrypsin that predisposes to emphysema (P = 2.5×10(-12)). Our data provide important proof of principle that 1000 Genomes imputation will detect novel, low frequency-large effect associations

Investigating the Accuracy of Quantitative Echocardiographic-Modified Task Force Criteria for Arrhythmogenic Ventricular Cardiomyopathy in Adolescent Male Elite Athletes

This is the final version. Available on open access from Springer via the DOI in this recordAthlete preparticipation screening focuses on preventing sudden cardiac death (SCD) by detecting diseases such as arrhythmogenic ventricular cardiomyopathy (AVC), which affects primarily the right ventricular myocardium. Diagnosis may be obscured by physiological remodeling of the athlete heart. Healthy athletes may meet the 2010 Task Force Criteria right ventricular outflow tract (RVOT) dimension cut-offs, questioning the suitability of the modified Task Force Criteria (mTFC) in adolescent athletes. In this study, 67 male adolescent footballers undergoing preparticipation screening were reviewed. All athletes underwent a screening for resting ECG and echocardiogram according to the English FA protocol, as well as cardiopulmonary exercise testing, stress ECG, and exercise echocardiography. Athletes' right ventricular outflow tract (RVOT) that met the major AVC diagnostic criteria for dilatation were identified. Of 67 evaluated athletes, 7 had RVOT dilatation that met the major criteria, all in the long axis parasternal view measurement. All had normal right ventricular systolic function, including normal free-wall longitudinal strain (ranging from - 21.5 to - 32.7%). Left ventricular ejection fraction ranged from 52 to 67%, without evidence of structural changes. Resting ECGs and cardiopulmonary exercise tests were normal in all individuals. In a series of healthy athletes meeting the major AVC diagnostic criteria for RVOT dilatation, none had any other pathological changes on a detailed screening including ECG, exercise testing, and echocardiography. This report highlights that current AVC echocardiographic diagnosis criteria have limitations in this population.National Institute for Health Research (NIHR)Medical Research Council (MRC

Silver hake tracks changes in Northwest Atlantic circulation

Author Posting. © The Author(s), 2011. This is the author's version of the work. It is posted here by permission of Nature Publishing Group for personal use, not for redistribution. The definitive version was published in Nature Communications 2 (2011): 412, doi:10.1038/ncomms1420.Recent studies documenting shifts in spatial distribution of many organisms in response to a warming climate highlight the need to understand the mechanisms underlying species distribution at large spatial scales. Here we present one noteworthy example of remote oceanographic processes governing the spatial distribution of adult silver hake, Merluccius bilinearis, a commercially important fish in the Northeast US shelf region. Changes in spatial distribution of silver hake over the last 40 years are highly correlated with the position of the Gulf Stream (GS). These changes in distribution are in direct response to local changes in bottom temperature on the continental shelf that are responding to the same large scale circulation change affecting the GS path, namely changes in the Atlantic Meridional Overturning Circulation (AMOC). If AMOC weakens as is suggested by global climate models, silver hake distribution will remain in a poleward position, the extent to which could be forecast at both decadal and multidecadal scales.J.A.N. was supported by the NOAA Fisheries and the Environment program (FATE). T.M.J. and Y.O.K. were supported by the WHOI Ocean Climate Change Institute and Ocean Life Institute

Replication of a whole school ethos-changing intervention: different context, similar effects, additional insights

Background Whole school, ethos-changing interventions reduce risk behaviours in middle adolescence, more than curriculum-based approaches. Effects on older ages are not known. We set out to replicate one of these interventions, Australia’s Gatehouse Project, in a rural Canadian high school. Methods A guided, whole school change process sought to make students feel more safe, connected, and valued by: changes in teaching practices, orientation processes, professional development of staff, recognition and reward mechanisms, elevating student voice, and strategies to involve greater proactivity and participation. We conducted risk behaviour surveys in grades 10 to 12 before the intervention and 2 years afterwards, and social network analyses with the staff. Changes in health and health risk behaviours were assessed using chi-square. Interactions between the intervention and gender and between the intervention and school engagement were assessed using interaction terms in logistic regression models. Changes in the density of relationships among staff were tested with methods analogous to paired t-tests. Results Like Gatehouse, there was no statistically significant reduction in depressive symptoms or bullying, though the trend was in that direction. Among girls, there was a statistically significant decrease in low school engagement (45% relative reduction), and decreases in drinking (46% relative reduction), unprotected sex (61% relative reduction) and poor health (relative reduction of 73%). The reduction in drinking matched the national trend. Reductions in unprotected sex and poor health went against the national trend. We found no statistically significant changes for boys. The effects coincided with statistically significant increases in the densities of staff networks, indicating that part of the mechanism may be through relationships at school. Conclusions A non-specific, risk protective intervention in the social environment of the school had a significant impact on a cluster of risk behaviours for girls. Results were remarkably like reports from similar school environment interventions elsewhere, albeit with different behaviours being affected. It may be that this type of intervention activates change processes that interact highly with context, impacting different risks differently, according to the prevalence, salience and distribution of the risk and the interconnectivity of relationships between staff and students. This requires further exploration.14 page(s

A comprehensive study on the role of the Yersinia pestis virulence markers in an animal model of pneumonic plague

We determined the role of Yersinia pestis virulence markers in an animal model of pneumonic plague. Eleven strains of Y. pestis were characterized using PCR assays to detect the presence of known virulence genes both encoded by the three plasmids as well as chromosomal markers. The virulence of all Y. pestis strains was compared in a mouse model for pneumonic plague. The presence of all known virulence genes correlated completely with virulence in the Balb/c mouse model. Strains which lacked HmsF initially exhibited visible signs of disease whereas all other strains (except wild-type strains) did not exhibit any disease signs. Forty-eight hours post-infection, mice which had received HmsF– strains regained body mass and were able to control infection; those infected with strains possessing a full complement of virulence genes suffered from fatal disease. The bacterial loads observed in the lung and other tissues reflected the observed clinical signs as did the cytokine changes measured in these animals. We can conclude that all known virulence genes are required for the establishment of pneumonic plague in mammalian animal models, the role of HmsF being of particular importance in disease progression