Parameter inference in mechanistic models of cellular regulation and signalling pathways using gradient matching

A challenging problem in systems biology is parameter inference in mechanistic models of signalling pathways. In the present article, we investigate an approach based on gradient matching and nonparametric Bayesian modelling with Gaussian processes. We evaluate the method on two biological systems, related to the regulation of PIF4/5 in Arabidopsis thaliana, and the JAK/STAT signal transduction pathway

Time-dependent models of dense PDRs with complex molecules

We present a study of the chemistry of a dense photon-dominated region (PDR) using a time-dependent chemical model. Our major interest is to study the spatial distribution of complex molecules such as hydrocarbons and cyanopolyynes in the cool dense material bordering regions where star formation has taken place. Our standard model uses a homogeneous cloud of density 2x10e4 cm-3 and temperature T=40 K, which is irradiated by a far-ultraviolet radiation field of intermediate intensity, given by X=100. We find that over a range of times unsaturated hydrocarbons (e.g., C2H, C4H, C3H2) have relatively high fractional abundances in the more external layers of the PDR, whereas their abundances in the innermost layers are several orders of magnitudes lower. On the other hand, molecules that are typical of late-time chemistry are usually more abundant in the inner parts of the PDR. We also present results for models with different density, temperature, intensity of the radiation field and initial fractional abundances. Our results are compared with both high- and moderate-angular resolution observations of the Horsehead nebula. Our standard model is partially successful in reproducing the observations. Additional models run with different physical parameters are able to reproduce the abundance of many of the observed molecules, but we do not find a single model that fits all the observations at the same time. We discuss the suitability of a time-dependent model of a dense PDR such as ours as an estimator of the age of a PDR, provided that enough observational data exist.Comment: 15 pages, 12 figures, 8 tables, to be published in MNRA

Regulation of vascular endothelial growth factor bioactivity in patients with acute lung injury

Background: Reduced bioactive vascular endothelial growth factor (VEGF) has been demonstrated in several inflammatory lung conditions including the acute respiratory distress syndrome (ARDS). sVEGFR-1, a soluble form of VEGF-1 receptor, is a potent natural inhibitor of VEGF. We hypothesised that sVEGFR-1 plays an important role in the regulation of the bioactivity of VEGF within the lung in patients with ARDS. Methods: Forty one patients with ARDS, 12 at risk of developing ARDS, and 16 normal controls were studied. Bioactive VEGF, total VEGF, and sVEGFR-1 were measured by ELISA in plasma and bronchoalveolar lavage (BAL) fluid. Reverse transcriptase polymerase chain reaction for sVEGFR-1 was performed on BAL cells. Results: sVEGFR-1 was detectable in the BAL fluid of 48% (20/41) of patients with early ARDS (1.4– 54.8 ng/ml epithelial lining fluid (ELF)) compared with 8% (1/12) at risk patients (p = 0.017) and none of the normal controls (p = 0.002). By day 4 sVEGFR-1 was detectable in only 2/18 ARDS patients (p = 0.008). Patients with detectable sVEGFR-1 had lower ELF median (IQR) levels of bioactive VEGF than those without detectable sVEGFR-1 (1415.2 (474.9–3192) pg/ml v 4761 (1349–7596.6) pg/ml, median difference 3346 pg/ml (95% CI 305.1 to 14711.9), p = 0.016), but there was no difference in total VEGF levels. BAL cells expressed mRNA for sVEGFR-1 and produced sVEGFR-1 protein which increased following incubation with tumour necrosis factor a. Conclusion: This study shows for the first time the presence of sVEGFR-1 in the BAL fluid of patients with ARDS. This may explain the presence of reduced bioactive VEGF in patients early in the course of ARDS

Activation workers’ perceptions of their long-term unemployed clients’ attitudes towards employment

The Work Programme’s use of severe social security benefit sanctions reflects British coalition ministers’ belief that many people on out-of-work benefits do not want a job. While a substantial empirical literature has repeatedly demonstrated that in fact unemployed benefit claimants possess the same work values as the employed and that the vast majority want paid work, it has ignored some conservative authors’ pleas to consider the views and experiences of people who work with the unemployed. Forty employees of agencies contracted to help unemployed people into employment were interviewed in summer 2011. Respondents had spent an estimated combined total of 147,000 hours in the presence of people who have claimed Jobseeker’s Allowance (JSA) for over six months. Most said that between a quarter and half of their present clients did not want employment. This finding does not contradict existing research, given that most JSA claimants re-enter employment within six months. However, all forty agreed that many others remained unemployed because they were choosy in the jobs they were willing to undertake, and,most strikingly, respondents overwhelmingly endorsed the view that a ‘dependency culture’ exists in households and neighbourhoods that have experienced joblessness for several generations

Cloth & memory

This book was published to accompany an exhibition of the same name at Salts Mills, Saltaire, Yorkshire, UK, in summer 2012, conceived and directed by Lesley Millar MBE, Professor of Textile Culture at the University for the Creative Arts. The exhibition and accompanying publication includes work by the artists Beverley Ayling-Smith, Carol Quarini, and Bob White. All visited Salts Mills and Saltaire and have created their work as a response to the history of the place: the memory of cloth and the making of cloth that has seeped into the fabric of the building. This exhibition is the first of two; Cloth and Memory 2 taking place in 2013

IL-21 receptor expression in human tendinopathy

The pathogenetic mechanisms underlying tendinopathy remain unclear, with much debate as to whether inflammation or degradation has the prominent role. Increasing evidence points toward and early inflammatory infiltrate and associated inflammatory cytokine production in human and animal models of tendon disease. The IL-21/IL-21R axis is a proinflammatory cytokine complex that has been associated with chronic inflammatory diseases including rheumatoid arthritis and inflammatory bowel disease. This project aimed to investigate the role and expression of the cytokine/receptor pair IL-21/IL-21R in human tendinopathy. We found significantly elevated expression of IL-21 receptor message and protein in human tendon samples but found no convincing evidence of the presence of IL-21 at message or protein level. The level of expression of IL-21R message/protein in human tenocytes was significantly up regulated by proinflammatory cytokines (TNFα/IL-1β) in vitro. These findings demonstrate that IL-21R is present in early human tendinopathy mainly expressed by tenocytes and macrophages. Despite a lack of IL-21 expression these data again suggest that early tendinopathy has an inflammatory/cytokine phenotype, which may provide novel translational targets in the treatment of tendinopathy

The UMIST Database for Astrochemistry 2012

We present the fifth release of the UMIST Database for Astrochemistry (UDfA). The new reaction network contains 6173 gas-phase reactions, involving 467 species, 47 of which are new to this release. We have updated rate coefficients across all reaction types. We have included 1171 new anion reactions and updated and reviewed all photorates. In addition to the usual reaction network, we also now include, for download, state-specific deuterated rate coefficients, deuterium exchange reactions and a list of surface binding energies for many neutral species. Where possible, we have referenced the original source of all new and existing data. We have tested the main reaction network using a dark cloud model and a carbon-rich circumstellar envelope model. We present and briefly discuss the results of these models

Wind Circulation in Selected Rotating Magnetic Early-B Stars

The rotating magnetic B stars have oblique dipolar magnetic fields and often anomalous helium and metallic compositions. These stars develop co-rotating torus-shaped clouds by channelling winds from their magnetic poles to an anchored planar disk over the magnetic equator. The line absorptions from the cloud can be studied as the complex rotates and periodically occults the star. We describe an analysis of the clouds of four stars (HD184927, beta Cep, sigma Ori E, and HR6684). From line synthesis models, we find that the metallic compositions are spatially uniform over the stars' surfaces. Next, using the Hubeny CIRCUS code, we demonstate that periodic UV continuum fluxes can be explained by the absorption of low-excitation lines. The analysis also quantifies the cloud temperatures, densities, and turbulences, which appear to increase inward toward the stars. The temperatures range from about 12,000K for the weak Fe lines up to temperatures of 33,000K for N V absorptions, which is in excess of temperatures expected from radiative equilibrium. The spectroscopic hallmark of this stellar class is the presence of strong C IV and N V resonance line absorptions at occultation phases and of redshifted emissions at magnetic pole-on phases. The emissions have characteristics which seem most compatible with the generation of high-energy shocks at the wind-cloud interface, as predicted by Babel.Comment: 19 pages, Latex plus 6 figures A&A single-spaced, accepted by Astronomy & Astrophysics. Files available by ftp at nobel.stsci.edu/pub/aapaper