Mixture effects at very low doses with combinations of anti-androgenic pesticides, antioxidants, industrial pollutant and chemicals used in personal care products

This article has been made available through the Brunel Open Access Publishing Fund.Many xenobiotics have been identified as in vitro androgen receptor (AR) antagonists, but information about their ability to produce combined effects at low concentrations ismissing. Such data can reveal whether joint effects at the receptor are induced at low levels andmay support the prioritisation of in vivo evaluations and provide orientations for the grouping of anti-androgens in cumulative risk assessment. Combinations of 30 AR antagonists from a wide range of sources and exposure routes (pesticides, antioxidants, parabens, UV-filters, synthetic musks, bisphenol-A, benzo(a)pyrene, perfluorooctane sulfonate and pentabromodiphenyl ether) were tested using a reporter gene assay (MDA-kb2). Chemicalswere combined at threemixture ratios, equivalent to single components' effect concentrations that inhibit the action of dihydrotesterone by 1%, 10% or 20%. Concentration addition (CA) and independent action were used to calculate additivity expectations. We observed complete suppression of dihydrotestosterone effects when chemicals were combined at individual concentrations eliciting 1%, 10% or 20% AR antagonistic effect. Due to the large number of mixture components, the combined AR antagonistic effects occurred at very low concentrations of individual mixture components. CA slightly underestimated the combined effects at all mixture ratios. In conclusion, large numbers of AR antagonists froma wide variety of sources and exposure routes have the ability of acting together at the receptor to produce joint effects at very low concentrations. Significant mixture effects are observed when chemicals are combined at concentrations that individually do not induce observable AR antagonistic effects. Cumulative risk assessment for AR antagonists should apply grouping criteria based on effects where data are available, rather than on criteria of chemical similarity

Active labour market policy in the UK : at a (local) crossroads?

Active labour market policy (ALMP) has developed into a widely used and seemingly embedded approach to addressing worklessness, both in the UK and internationally. But the future of UK ALMP looks far from certain. Some recent developments suggest demise and diminution. But at the same time there is also evidence of more positive points, including increasing recognition of the importance of employer involvement and activity a t local level. Possible future trajectories are considered in the light of emerging developments, and two potential scenarios for future UK ALMP are posited: ‘less support, more sticks’ and an ‘active local labour markets approach’

Far infrared and submillimeter brightness temperatures of the giant planets

The brightness temperatures of Jupiter, Saturn, Uranus, and Neptune in the range 35 to 1000 micron. The effective temperatures derived from the measurements, supplemented by shorter wavelength Voyager data for Jupiter and Saturn, are 126.8 + or - 4.5 K, 93.4 + or - 3.3 K, 58.3 + or - 2.0 K, and 60.3 + or - 2.0 K, respectively. The implications of the measurements for bolometric output and for atmospheric structure and composition are discussed. The temperature spectrum of Jupiter shows a strong peak at approx. 350 microns followed by a deep valley at approx. 450 to 500 microns. Spectra derived from model atmospheres qualitatively reproduced these features but do not fit the data closely

Evaluation of modelling approaches for predicting the spatial distribution of soil organic carbon stocks at the national scale

Soil organic carbon (SOC) plays a major role in the global carbon budget. It can act as a source or a sink of atmospheric carbon, thereby possibly influencing the course of climate change. Improving the tools that model the spatial distributions of SOC stocks at national scales is a priority, both for monitoring changes in SOC and as an input for global carbon cycles studies. In this paper, we compare and evaluate two recent and promising modelling approaches. First, we considered several increasingly complex boosted regression trees (BRT), a convenient and efficient multiple regression model from the statistical learning field. Further, we considered a robust geostatistical approach coupled to the BRT models. Testing the different approaches was performed on the dataset from the French Soil Monitoring Network, with a consistent cross-validation procedure. We showed that when a limited number of predictors were included in the BRT model, the standalone BRT predictions were significantly improved by robust geostatistical modelling of the residuals. However, when data for several SOC drivers were included, the standalone BRT model predictions were not significantly improved by geostatistical modelling. Therefore, in this latter situation, the BRT predictions might be considered adequate without the need for geostatistical modelling, provided that i) care is exercised in model fitting and validating, and ii) the dataset does not allow for modelling of local spatial autocorrelations, as is the case for many national systematic sampling schemes

Employer participation in active labour market policy : from reactive gatekeepers to proactive strategic partners

Active labour market policy (ALMP) is a well-established strategy but one aspect is greatly neglected – employer participation – about which there is a lack of systematic evidence. The question of why and how employers participate in ALMP, and whether there may be some shift from employers solely being passive recipients of job-ready candidates to having a more proactive and strategic role, is addressed by drawing on new research into Talent Match, a contemporary UK employability programme which places particular emphasis on employer involvement. The research findings point to a conceptual distinction between employers’ roles as being reactive gatekeepers to jobs and/or being proactive strategic partners, with both evident. It is argued that the Talent Match programme demonstrates potential to benefit employers, jobseekers and programme providers, with devolution of policy to the local level a possible way forward. The conclusion, however, is that the barrier to wider replication is not necessarily a problem of practice but of centralised control of policy and, in particular, commitment to a supply-side approach. Empirical, conceptual and policy contributions are made to this under-researched topic

Fundamental properties of the mammalian innate immune system revealed by multispecies comparison of type I interferon responses

The host innate immune response mediated by type I interferon (IFN) and the resulting up-regulation of hundreds of interferon-stimulated genes (ISGs) provide an immediate barrier to virus infection. Studies of the type I ‘interferome’ have mainly been carried out at a single species level, often lacking the power necessary to understand key evolutionary features of this pathway. Here, using a single experimental platform, we determined the properties of the interferomes of multiple vertebrate species and developed a webserver to mine the dataset. This approach revealed a conserved ‘core’ of 62 ISGs, including genes not previously associated with IFN, underscoring the ancestral functions associated with this antiviral host response. We show that gene expansion contributes to the evolution of the IFN system and that interferomes are shaped by lineage-specific pressures. Consequently, each mammal possesses a unique repertoire of ISGs, including genes common to all mammals and others unique to their specific species or phylogenetic lineages. An analysis of genes commonly down-regulated by IFN suggests that epigenetic regulation of transcription is a fundamental aspect of the IFN response. Our study provides a resource for the scientific community highlighting key paradigms of the type I IFN response

EVOLUTION OF THE STRATOSPHERIC TEMPERATURE AND CHEMICAL COMPOSITION OVER ONE TITANIAN YEAR

Since the Voyager 1 (V1) flyby in 1980, Titans exploration from space and the ground has been ongoing for more than a full revolution of Saturn around the Sun (one Titan year or 29.5 Earth years was completed in May 2010). In this study we search for temporal variations affecting Titans atmospheric thermal and chemical structure within that year. We process Cassini CIRS data taken during the Titan flybys from 2006-2013 and compare them to the 1980 V1IRIS spectra (re-analyzed here). We also consider data from Earth-based and -orbiting observatories (such as from the ISO, re-visited). When we compare the CIRS 2010 and the IRIS data we find limited inter-annual variations, below the 25 or35 levels for the lower and middle, or the high latitudes, respectively. A return to the 1980 stratospheric temperatures and abundances is generally achieved from 50degN to 50degS, indicative of the solar radiation being the dominating energy source at 10 AU, as for the Earth, as predicted by GCM and photochemical models. However, some exceptions exist among the most complex hydrocarbons (C4H2 and C3H4), especially in the North. In the Southern latitudes, since 2012, we see a trend for an increase of several trace gases, possibly indicative of a seasonal atmospheric reversal. At the Northern latitudes we found enhanced abundances around the period of the northern spring equinox in mid-2009 (as in Bampasidis et al. 2012), which subsequently decreased (from 2010-2012) returning to values similar to those found in the V1 epoch a Titanian year before

Computational modelling of cancerous mutations in the EGFR/ERK signalling pathway

This article has been made available through the Brunel Open Access Publishing Fund - Copyright @ 2009 Orton et al.BACKGROUND: The Epidermal Growth Factor Receptor (EGFR) activated Extracellular-signal Regulated Kinase (ERK) pathway is a critical cell signalling pathway that relays the signal for a cell to proliferate from the plasma membrane to the nucleus. Deregulation of the EGFR/ERK pathway due to alterations affecting the expression or function of a number of pathway components has long been associated with numerous forms of cancer. Under normal conditions, Epidermal Growth Factor (EGF) stimulates a rapid but transient activation of ERK as the signal is rapidly shutdown. Whereas, under cancerous mutation conditions the ERK signal cannot be shutdown and is sustained resulting in the constitutive activation of ERK and continual cell proliferation. In this study, we have used computational modelling techniques to investigate what effects various cancerous alterations have on the signalling flow through the ERK pathway. RESULTS: We have generated a new model of the EGFR activated ERK pathway, which was verified by our own experimental data. We then altered our model to represent various cancerous situations such as Ras, B-Raf and EGFR mutations, as well as EGFR overexpression. Analysis of the models showed that different cancerous situations resulted in different signalling patterns through the ERK pathway, especially when compared to the normal EGF signal pattern. Our model predicts that cancerous EGFR mutation and overexpression signals almost exclusively via the Rap1 pathway, predicting that this pathway is the best target for drugs. Furthermore, our model also highlights the importance of receptor degradation in normal and cancerous EGFR signalling, and suggests that receptor degradation is a key difference between the signalling from the EGF and Nerve Growth Factor (NGF) receptors. CONCLUSION: Our results suggest that different routes to ERK activation are being utilised in different cancerous situations which therefore has interesting implications for drug selection strategies. We also conducted a comparison of the critical differences between signalling from different growth factor receptors (namely EGFR, mutated EGFR, NGF, and Insulin) with our results suggesting the difference between the systems are large scale and can be attributed to the presence/absence of entire pathways rather than subtle difference in individual rate constants between the systems.This work was funded by the Department of Trade and Industry (DTI), under their Bioscience Beacon project programme. AG was funded by an industrial PhD studentship from Scottish Enterprise and Cyclacel