A Common Repressor Pool Results in Indeterminacy of Extrinsic Noise

For over a decade, noise in gene expression has been the focus of experimental and theoretical studies. It is currently accepted that gene expression noise can be decomposed into extrinsic and intrinsic components, which have orthogonal contributions to the total noise. Intrinsic noise stems from the random occurrence of biochemical reactions and is inherent to gene expression. Extrinsic noise originates from fluctuations in the concentrations of regulatory components or random transitions in the cell’s state and is imposed to the gene of interest by the intra- and extra-cellular environment. The basic assumption has been that extrinsic noise acts as a pure input on the gene of interest, which exerts no feedback on the extrinsic noise source. Consequently, multiple copies of a gene would be uniformly influenced by an extrinsic noise source. Here we report that this assumption falls short when multiple genes share a common pool of a regulatory molecule. Due to competitive utilization of the molecules existing in this pool, genes are no longer uniformly influenced by the extrinsic noise source. Rather, they exert negative feedbacks on each other. Thus, extrinsic noise calculated using the currently established method becomes ill-defined

DFT Benchmark Studies on Representative Species and Poisons of Methane Steam Reforming on Ni(111)

Ni catalysts used in Methane Steam Reforming (MSR) are highly susceptible to poisoning by carbon-based species, which poses a major impediment to the productivity of industrial operations. These graphitic carbon-like formations are typically modelled from first principles as graphene. Although numerous experimental investigations have been carried out, a conclusive mechanistic molecular-level understanding of graphene formation on Ni during the MSR reaction is still elusive. First principles-based approaches, such as Density Functional Theory (DFT) calculations, can provide valuable insight into the mechanism of graphene growth in the MSR reaction. It is, however, critical that a DFT model of this reaction can accurately describe the interactions of Ni(111) with the MSR intermediates as well as graphene. Crucially, these interactions include van der Waals forces, making the choice of a proper DFT functional a subject of debate, as there are several dispersion-inclusive functionals available in the literature. In this work, a systematic benchmark study has been carried out to identify a suitable DFT functional for the graphene and MSR system. The binding energies of graphene and important MSR species were computed on Ni(111) using GGA functionals, DFT-D3 and van der Waals density functionals (vdW-DF). Comparisons of these binding energies with published experimental data reveal that the GGA functionals are inadequate for the graphene-Ni(111) system. Among the vdW-DF, optB88-vdW predicts the binding energy of graphene with high accuracy; however, its predictions significantly deviate from the experimental binding energies of CO and O. Among DFT-D3 functionals, PBE-D3 was found to have a reasonable predictive accuracy for most MSR species (excluding the CO adsorbate). Overall, no single DFT functional could estimate the binding energies of all the species with equally high accuracy. Our benchmarks guide the selection of DFT functionals for simulations of MSR and could aid in the future development of predictive quality functionals

Psychological Distress and Risk of Accidental Death in the General Population.

SB is supported by grants from the European Research Council and the UK Medical Research Council/Alcohol Research UK.This is the author accepted manuscript. The final version is available from Wolters Kluwer via http://dx.doi.org/10.1097/EDE.000000000000054

Adaptive coarse-grained Monte Carlo simulation of reaction and diffusion dynamics in heterogeneous plasma membranes

Background: An adaptive coarse-grained (kinetic) Monte Carlo (ACGMC) simulation framework is applied to reaction and diffusion dynamics in inhomogeneous domains. The presented model is relevant to the diffusion and dimerization dynamics of epidermal growth factor receptor (EGFR) in the presence of plasma membrane heterogeneity and specifically receptor clustering. We perform simulations representing EGFR cluster dissipation in heterogeneous plasma membranes consisting of higher density clusters of receptors surrounded by low population areas using the ACGMC method. We further investigate the effect of key parameters on the cluster lifetime.Results: Coarse-graining of dimerization, rather than of diffusion, may lead to computational error. It is shown that the ACGMC method is an effective technique to minimize error in diffusion-reaction processes and is superior to the microscopic kinetic Monte Carlo simulation in terms of computational cost while retaining accuracy. The low computational cost enables sensitivity analysis calculations. Sensitivity analysis indicates that it may be possible to retain clusters of receptors over the time scale of minutes under suitable conditions and the cluster lifetime may depend on both receptor density and cluster size.Conclusions: The ACGMC method is an ideal platform to resolve large length and time scales in heterogeneous biological systems well beyond the plasma membrane and the EGFR system studied here. Our results demonstrate that cluster size must be considered in conjunction with receptor density, as they synergistically affect EGFR cluster lifetime. Further, the cluster lifetime being of the order of several seconds suggests that any mechanisms responsible for EGFR aggregation must operate on shorter timescales (at most a fraction of a second), to overcome dissipation and produce stable clusters observed experimentally. © 2010 Collins et al; licensee BioMed Central Ltd

Estimated cardiorespiratory fitness in childhood and cardiometabolic health in adulthood: 1970 British Cohort Study

BACKGROUND Associations of cardiorespiratory fitness in childhood and adulthood with adult cardiometabolic risk factors are poorly understood, not least because of the paucity of studies. OBJECTIVES We investigated associations between nonexercise testing cardiorespiratory fitness (NETCRF) in childhood/adulthood and cardiometabolic risk factors in adulthood. METHODS Based on an established algorithm comprising gender, age, body mass index, resting heart rate, and self‐reported physical activity at age 10, we computed NETCRF. Risk factors were assessed at age 46 in 5,009 participants when NETCRF was again calculated. Linear regression was used to summarise associations between NETCRF in childhood and risk factors in adulthood and, additionally, the relationship between NETCRF in adulthood and risk factors in adulthood after adjusting for childhood NETCRF. RESULTS Inconsistent associations were observed between childhood NETCRF and adult risk factors. NETCRF in adulthood was associated with blood pressure [‐5.8 (‐6.7, ‐4.9)], glycated haemoglobin [‐3.41 (‐4.06, ‐2.76)], total cholesterol [‐0.16 (‐0.24, ‐0.08)], HDL‐cholesterol [0.19 (0.16, 0.22)], triglycerides [‐0.68 (‐0.85, ‐0.50)] and C‐reactive protein [‐0.29 (‐0.35, ‐0.22)] in adult males. Similar associations were observed in adult females. Compared to those with low estimated fitness in both childhood and adulthood, participants with low fitness in childhood and high fitness in adulthood had a lower risk of two or more cardiometabolic risk factors (odds ratio: 0.22; 95% confidence interval: 0.16, 0.30). CONCLUSION Associations between estimated fitness and risk factors are stronger in adulthood than from childhood to adulthood. Adults with previously sedentary childhoods may still gain benefits from improving their fitness

Psychological distress in relation to site specific cancer mortality: pooling of unpublished data from 16 prospective cohort studies

OBJECTIVE:  To examine the role of psychological distress (anxiety and depression) as a potential predictor of site specific cancer mortality. DESIGN:  Pooling of individual participant data from 16 prospective cohort studies initiated 1994-2008. SETTING:  Nationally representative samples drawn from the health survey for England (13 studies) and the Scottish health survey (three studies). PARTICIPANTS:  163 363 men and women aged 16 or older at study induction, who were initially free of a cancer diagnosis, provided self reported psychological distress scores (based on the general health questionnaire, GHQ-12) and consented to health record linkage. MAIN OUTCOME MEASURE:  Vital status records used to ascertain death from 16 site specific malignancies; the three Scottish studies also had information on cancer registration (incidence). RESULTS:  The studies collectively contributed an average of 9.5 years of mortality surveillance during which there were 16 267 deaths (4353 from cancer). After adjustment for age, sex, education, socioeconomic status, body mass index (BMI), and smoking and alcohol intake, and with reverse causality (by left censoring) and missing data (by imputation) taken into account, relative to people in the least distressed group (GHQ-12 score 0-6), death rates in the most distressed group (score 7-12) were consistently raised for cancer of all sites combined (multivariable adjusted hazard ratio 1.32, 95% confidence interval 1.18 to 1.48) and cancers not related to smoking (1.45, 1.23 to 1.71), as well as carcinoma of the colorectum (1.84, 1.21 to 2.78), prostate (2.42, 1.29 to 4.54), pancreas (2.76, 1.47 to 5.19), oesophagus (2.59, 1.34 to 5.00), and for leukaemia (3.86, 1.42 to 10.5). Stepwise associations across the full range of distress scores were observed for colorectal and prostate cancer. CONCLUSION:  This study contributes to the growing evidence that psychological distress might have some predictive capacity for selected cancer presentations, in addition to other somatic diseases