Base damage, local sequence context andTP53mutation hotspots: a molecular dynamics study of benzo[a]pyrene induced DNA distortion and mutability

The mutational pattern for the TP53 tumour suppressor gene in lung tumours differs to other cancer types by having a higher frequency of G:C>T:A transversions. The aetiology of this differing mutation pattern is still unknown. Benzo[a]pyrene,diol epoxide (BPDE) is a potent cigarette smoke carcinogen that forms guanine adducts at TP53 CpG mutation hotspot sites including codons 157, 158, 245, 248 and 273. We performed molecular modelling of BPDE-adducted TP53 duplex sequences to determine the degree of local distortion caused by adducts which could influence the ability of nucleotide excision repair. We show that BPDE adducted codon 157 has greater structural distortion than other TP53 G:C>T:A hotspot sites and that sequence context more distal to adjacent bases must influence local distortion. Using TP53 trinucleotide mutation signatures for lung cancer in smokers and non-smokers we further show that codons 157 and 273 have the highest mutation probability in smokers. Combining this information with adduct structural data we predict that G:C>T:A mutations at codon 157 in lung tumours of smokers are predominantly caused by BPDE. Our results provide insight into how different DNA sequence contexts show variability in DNA distortion at mutagen adduct sites that could compromise DNA repair at well characterized cancer related mutation hotspots

From carbon nanotubes and silicate layers to graphene platelets for polymer nanocomposites

In spite of extensive studies conducted on carbon nanotubes and silicate layers for their polymer-based nanocomposites, the rise of graphene now provides a more promising candidate due to its exceptionally high mechanical performance and electrical and thermal conductivities. The present study developed a facile approach to fabricate epoxy–graphene nanocomposites by thermally expanding a commercial product followed by ultrasonication and solution-compounding with epoxy, and investigated their morphologies, mechanical properties, electrical conductivity and thermal mechanical behaviour. Graphene platelets (GnPs) of 3.5

Fusion of secretory vesicles isolated from rat liver

Secretory vesicles isolated from rat liver were found to fuse after exposure to Ca2+. Vescle fusion is characterized by the occurrence of twinned vesicles with a continuous cleavage plane between two vesicles in freeze-fracture electron microscopy. The number of fused vesicles increases with increasing Ca2+-concentrations and is half maximal around 10–6 m. Other divalent cations (Ba2+, Sr2+, and Mg2+) were ineffective. Mg2+ inhibits Ca2+-induced fusion. Therefore, the fusion of secretory vesiclesin vitro is Ca2+ specific and exhibits properties similar to the exocytotic process of various secretory cells. Various substances affecting secretionin vivo (microtubular inhibitors, local anethetics, ionophores) were tested for their effect on membrane fusion in our system. The fusion of isolated secretory vesicles from liver was found to differ from that of pure phospholipid membranes in its temperature dependence, in its much lower requirement for Ca2+, and in its Ca2+-specificity. Chemical and enzymatic modifications of the vesicle membrane indicate that glycoproteins may account for these differences

Large time behavior and asymptotic stability of the two-dimensional Euler and linearized Euler equations

We study the asymptotic behavior and the asymptotic stability of the two-dimensional Euler equations and of the two-dimensional linearized Euler equations close to parallel flows. We focus on spectrally stable jet profiles $U(y)$ with stationary streamlines $y_{0}$ such that $U'(y_{0})=0$, a case that has not been studied previously. We describe a new dynamical phenomenon: the depletion of the vorticity at the stationary streamlines. An unexpected consequence, is that the velocity decays for large times with power laws, similarly to what happens in the case of the Orr mechanism for base flows without stationary streamlines. The asymptotic behaviors of velocity and the asymptotic profiles of vorticity are theoretically predicted and compared with direct numerical simulations. We argue on the asymptotic stability of these flow velocities even in the absence of any dissipative mechanisms.Comment: To be published in Physica D, nonlinear phenomena (accepted January 2010

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)

Response of soil fungal richness and composition to Lantana camara L. infestation in the Toowoomba region, South-East Queensland, Australia

Infestations by the weedy perennial plant Lantana camara L. (lantana) cause major disruptions to biodiversity; however, the effects of lantana on soil fungal communities are poorly understood, yet may interrupt important mutualisms in natural and semi-natural ecosystems. This research is aimed at understanding the impacts of lantana on the soil fungal community of five sites on contrasting soils in the Toowoomba region of south-east Queensland. Soil samples were collected from paired lantana infested and non-infested plots and the soil fungal community ascertained via analysis of terminal restriction fragments (TRFs) of isolated fungal DNA samples. Soils from these plots were also sampled for a range of chemical characteristics. Forty-eight identifiable fungal TRFs were recovered from the T-RFLP analysis. Mean fungal taxon richness showed no significant differences between lantana infested and non-infested plots across the range of sites examined. However, one site on nutrient-poor granitic soils had significantly higher (ANOVA, p<0.001) fungal taxon richness than other sites on other soils. While a number of fungal taxa were ubiquitous across all sites and lantana infested and non-infested plots, some taxa were exclusively found in either infested or non-infested plots at one site, suggesting some association between fungal composition and infestation. We conclude that there are no differences in the fungal taxon richness between lantana infested and non-infested plots, but a significant difference in mean fungal taxon richness between sites representing contrasting soil types. Further analysis of fungal composition may reveal more conclusive patterns regarding the possible effects of lantana invasion on soil fungal assemblages. Further research is required to confirm compositional differences with respect to lantana infestation and determine whether such effects are the direct effects of allelopathy or indirect effects of changes to soil properties

Performance of the CMS Cathode Strip Chambers with Cosmic Rays

The Cathode Strip Chambers (CSCs) constitute the primary muon tracking device in the CMS endcaps. Their performance has been evaluated using data taken during a cosmic ray run in fall 2008. Measured noise levels are low, with the number of noisy channels well below 1%. Coordinate resolution was measured for all types of chambers, and fall in the range 47 microns to 243 microns. The efficiencies for local charged track triggers, for hit and for segments reconstruction were measured, and are above 99%. The timing resolution per layer is approximately 5 ns

Sex-specific regulation of chemokine Cxcl5/6 controls neutrophil recruitment and tissue injury in acute inflammatory states

This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Barts and The London Trustees Studentship (SM), Marie Curie fellowships (MB, JD), Arthritis Research UK career development fellowship (JW), William Harvey Research Foundation grant (JW/RSS), Kidney Research UK fellowship (NSAP), Barts and The London Vacation Scholarship (ISN), Wellcome Trust senior fellowship (DWG), and a Wellcome Trust career development fellowship (RSS). This work forms part of the research themes contributing to the translational research portfolio of Barts and The London Cardiovascular Biomedical Research Unit, which is supported and funded by National Institute for Health Researc

Sequence-dependent DNA condensation as a driving force of DNA phase separation

The physical properties of DNA have been suggested to play a central role in spatio-temporal organization of eukaryotic chromosomes. Experimental correlations have been established between the local nucleotide content of DNA and the frequency of inter- and intra-chromosomal contacts but the underlying physical mechanism remains unknown. Here, we combine fluorescence resonance energy transfer (FRET) measurements, precipitation assays, and molecular dynamics simulations to characterize the effect of DNA nucleotide content, sequence, and methylation on inter-DNA association and its correlation with DNA looping. First, we show that the strength of DNA condensation mediated by poly-lysine peptides as a reduced model of histone tails depends on the DNA???s global nucleotide content but also on the local nucleotide sequence, which turns out to be qualitatively same as the condensation by spermine. Next, we show that the presence and spatial arrangement of C5 methyl groups determines the strength of inter-DNA attraction, partially explaining why RNA resists condensation. Interestingly, multi-color single molecule FRET measurements reveal strong anti-correlation between DNA looping and DNA-DNA association, suggesting that a common biophysical mechanism underlies them. We propose that the differential affinity between DNA regions of varying sequence pattern may drive the phase separation of chromatin into chromosomal subdomains