Exposure to parabens at the concentration of maximal proliferative response increases migratory and invasive activity of human breast cancer cells in vitro

Alkyl esters of p–hydroxybenzoic acid (parabens) are widely used as preservatives in personal care products, foods and pharmaceuticals. Their oestrogenic activity, their measurement in human breast tissue and their ability to drive proliferation of oestrogen-responsive human breast cancer cells has opened a debate on their potential to influence breast cancer development. Since proliferation is not the only hallmark of cancer cells, we have investigated the effects of exposure to parabens at concentrations of maximal proliferative response on migratory and invasive properties using three oestrogen-responsive human breast cancer cell lines (MCF-7, T-47-D, ZR-75-1). Cells were maintained short-term (1 week) or long-term (20±2 weeks) in phenol-red-free medium containing 5% charcoal-stripped serum with no addition, 10-8M 17-oestradiol, 1-5x10-4M methylparaben, 10-5M n-propylparaben or 10-5M n-butylparaben. Long-term exposure (20±2 weeks) of MCF-7 cells to methylparaben, n-propylparaben or n-butylparaben increased migration as measured using a scratch assay, time-lapse microscopy and xCELLigence technology: invasive properties were found to increase in matrix degradation assays and migration through matrigel on xCELLigence. Western immunoblotting showed an associated downregulation of E-cadherin and -catenin in the long-term paraben-exposed cells which could be consistent with a mechanism involving epithelial to mesenchymal transition. Increased migratory activity was demonstrated also in long-term paraben-exposed T-47-D and ZR-75-1 cells using a scratch assay and time-lapse microscopy. This is the first report that in vitro, parabens can influence not only proliferation but also migratory and invasive properties of human breast cancer cells.

Incorporating toxicokinetics into an individual-based model for more realistic pesticide exposure estimates: A case study of the wood mouse

The potential risk of agricultural pesticides to mammals typically depends on internal concentrations within individuals, and these are determined by the amount ingested and by absorption, distribution, metabolism, and excretion (ADME). Pesticide residues ingested depend, amongst other things, on individual spatial choices which determine how much and when feeding sites and areas of pesticide application overlap, and can be calculated using individual-based models (IBMs). Internal concentrations can be calculated using toxicokinetic (TK) models, which are quantitative representations of ADME processes. Here we provide a population model for the wood mouse (Apodemus sylvaticus) in which TK submodels were incorporated into an IBM representation of individuals making choices about where to feed. This allows us to estimate the contribution of individual spatial choice and TK processes to risk. We compared the risk predicted by four IBMs: (i) “AllExposed-NonTK”: assuming no spatial choice so all mice have 100% exposure, no TK, (ii) “AllExposed-TK”: identical to (i) except that the TK processes are included where individuals vary because they have different temporal patterns of ingestion in the IBM, (iii) “Spatial-NonTK”: individual spatial choice, no TK, and (iv) “Spatial-TK”: individual spatial choice and with TK. The TK parameters for hypothetical pesticides used in this study were selected such that a conventional risk assessment would fail. Exposures were standardised using risk quotients (RQ; exposure divided by LD50 or LC50). We found that for the exposed sub-population including either spatial choice or TK reduced the RQ by 37–85%, and for the total population the reduction was 37–94%. However spatial choice and TK together had little further effect in reducing RQ. The reasons for this are that when the proportion of time spent in treated crop (PT) approaches 1, TK processes dominate and spatial choice has very little effect, and conversely if PT is small spatial choice dominates and TK makes little contribution to exposure reduction. The latter situation means that a short time spent in the pesticide-treated field mimics exposure from a small gavage dose, but TK only makes a substantial difference when the dose was consumed over a longer period. We concluded that a combined TK-IBM is most likely to bring added value to the risk assessment process when the temporal pattern of feeding, time spent in exposed area and TK parameters are at an intermediate level; for instance wood mice in foliar spray scenarios spending more time in crop fields because of better plant cover.

Rerum cognoscere causas: part II - opportunities generated by the agency/structure debate and suggestions for clarifying the social theoretic position of system dynamics

This is the second half of a two-part paper dealing with the social theoretic assumptions underlying system dynamics. In the first half it was concluded that analysing system dynamics using traditional, paradigm-based social theories is highly problematic. An innovative and potentially fruitful resolution is now proposed to these problems. In the first section it is argued that in order to find an appropriate social theoretic home for system dynamics it is necessary to look to a key exchange in contemporary social science: the agency/structure debate. This debate aims to move beyond both the theories based only on the actions of individual human agents, and those theories that emphasise only structural influences. Emerging from this debate are various theories that instead aim to unite the human agent view of the social realm with views that concentrate solely on system structure. It is argued that system dynamics is best viewed as being implicitly grounded in such theories. The main conclusion is therefore that system dynamics can contribute to an important part of social thinking by providing a formal approach for explicating social mechanisms. This conclusion is of general significance for system dynamics. However, the over-arching aim of the two-part paper is to increase the understanding of system dynamics in related disciplines. Four suggestions are therefore offered for how the system dynamics method might be extended further into the social sciences. It is argued that, presented in the right way, the formal yet contingent feedback causality thinking of system dynamics should diffuse widely in the social sciences and make a distinctive and important contribution to them. Felix qui potuit rerum cognoscere causas Happy is he who comes to know the causes of things Virgil - Georgics, Book II, line 490. 29 BCE

Should system dynamics be described as a 'hard' or 'deterministic' systems approach?

This paper explores the criticism that system dynamics is a ‘hard’ or ‘deterministic’ systems approach. This criticism is seen to have four interpretations and each is addressed from the perspectives of social theory and systems science. Firstly, system dynamics is shown to offer not prophecies but Popperian predictions. Secondly, it is shown to involve the view that system structure only partially, not fully, determines human behaviour. Thirdly, the field's assumptions are shown not to constitute a grand content theory—though its structural theory and its attachment to the notion of causality in social systems are acknowledged. Finally, system dynamics is shown to be significantly different from systems engineering. The paper concludes that such confusions have arisen partially because of limited communication at the theoretical level from within the system dynamics community but also because of imperfect command of the available literature on the part of external commentators. Improved communication on theoretical issues is encouraged, though it is observed that system dynamics will continue to justify its assumptions primarily from the point of view of practical problem solving. The answer to the question in the paper's title is therefore: on balance, no.

Time-dependent flows in the coupled solar wind-magnetosphere-ionosphere system

Concepts of time-dependent flow in the coupled solar wind-magnetosphere-ionosphere system are discussed and compared with the frequently-adopted steady-state paradigm. Flows are viewed as resulting from departures of the system from equilibrium excited by dayside and nightside reconnection processes, with the flows then taking the system back towards a new equilibrium configuration. The response of the system to reconnection impulses, continuous but unbalanced reconnection and balanced steady-state reconnection are discussed in these terms. It is emphasized that in the time-dependent case the ionospheric and interplanetary electric fields are generally inductively decoupled from each other; a simple mapping of the interplanetary electric field along equipotential field lines into the ionosphere occurs only in the electrostatic steady-state case.

Beneath a learning management system: understanding the human information interaction in information systems

Studies on learning management systems have largely been technical in nature with an emphasis on the evaluation of the human computer interaction (HCI) processes in using the LMS. This paper reports a study that evaluates the information interaction processes on an eLearning course used in teaching an applied Statistics course. The eLearning course is used as a synonym for information systems. The study explores issues of missing context in stored information in information systems. Using the semiotic framework as a guide, the researchers evaluated an existing eLearning course with the view to proposing a model for designing improved eLearning courses for future eLearning programmes. In this exploratory study, a survey questionnaire is used to collect data from 160 participants on an eLearning course in Statistics in Applied Climatology. The views of the participants are analysed with a focus on only the human information interaction issues. Using the semiotic framework as a guide, syntactic, semantic, pragmatic and social context gaps or problems were identified. The information interactions problems identified include ambiguous instructions, inadequate information, lack of sound, interface design problems among others. These problems affected the quality of new knowledge created by the participants. The researchers thus highlighted the challenges of missing information context when data is stored in an information system. The study concludes by proposing a human information interaction model for improving the information interaction quality issues in the design of eLearning course on learning management platforms and those other information systems.

The Syntax of Pronominal Subjects in L2 Spanish: Comparing Two L2 Populations with Different Exposure

The purpose of this article is two-fold. First, via a critical review of available studies on the adult L2 resetting of the Null-Subject Parameter (NSP) and in light of a typologically wide sampling of languages, we conclude that the NSP cluster is much narrower in scope than is reflected in the design and discussion of most L2 studies. Secondly, we present original research on the L2 resetting of the NSP by two groups of adult English intermediate learners of L2 Spanish: a study-abroad group and a class-room only group. We seek to quantify the extent to which study-abroad experience, that is, increased exposure to native input, is beneficial specifically as it relates to the acquisition of new functional features needed for parameter re-setting (cf. Isabelli 2004). Despite the observable and clandestine linguistic benefits to study-abroad, our data suggest that for the resetting of the NSP, at least, such exposure to native input is not particularly gainful.

The blended approach to real estate allocations: performance implications of combining an exposure to German Spezialfonds with Global Listed Real Estate Securities

This paper seeks to increase the understanding of the performance implications for investors who choose to combine an unlisted real estate portfolio (in this case German Spezialfonds) with a (global) listed real estate element. We call this a “blended” approach to real estate allocations. For the avoidance of doubt, in this paper we are dealing purely with real estate equity (listed and unlisted) allocations, and do not incorporate real estate debt (listed or unlisted) or direct property into the process. A previous paper (Moss and Farrelly 2014) showed the benefits of the blended approach as it applied to UK Defined Contribution Pension Schemes. The catalyst for this paper has been the recent attention focused on German pension fund allocations, which have a relatively low (real estate) equity content, and a high bond content. We have used the MSCI Spezialfonds Index as a proxy for domestic German institutional real estate allocations, and the EPRA Global Developed Index as a proxy for a global listed real estate allocation. We also examine whether a rules based trading strategy, in this case Trend Following, can improve the risk adjusted returns above those of a simple buy and hold strategy for our sample period 2004-2015. Our findings are that by blending a 30% global listed portfolio with a 70% allocation (as opposed to a typical 100% weighting) to Spezialfonds, the real estate allocation returns increase from 2.88% p.a. to 5.42% pa. Volatility increases, but only to 6.53%., but there is a noticeable impact on maximum drawdown which increases to 19.4%. By using a Trend Following strategy raw returns are improved from 2.88% to 6.94% p.a. , The Sharpe Ratio increases from 1.05 to 1.49 and the Maximum Drawdown ratio is now only 1.83% compared to 19.4% using a buy and hold strategy . Finally, adding this (9%) real estate allocation to a mixed asset portfolio allocation typical for German pension funds there is an improvement in both the raw return (from 7.66% to 8.28%) and the Sharpe Ratio (from 0.91 to 0.98).

Transcriptomic analysis of Enterohaemorrhagic Escherichia coli O157:H7 in response to plant extracts

Enterohaemorrhagic Escherichia coli (EHEC) are a group of food and contact-borne pathogens responsible for haemorrhagic colitis. The bacteria can be transmitted by contaminated meat, but importantly, also by plants. The bacteria can use plants as an alternative host, where they associate with both the leaves and the roots. Colonisation in the rhizosphere of plants is thought to be the main habitat for colonisation. Four different plant species, commonly associated with EHEC outbreaks, were infected with EHEC O157:H7 isolates Sakai and TUV 93-0 over ten days to assess the colonisation potential of the bacteria in both the phyllosphere and rhizosphere of plants. The rhizosphere was found to sustain a higher population level of bacteria over time in comparison to the phyllosphere, yet both strains were unable to utilize root exudates for growth. Global gene expression changes of EHEC O157:H7 strain Sakai were measured in response to plant extracts such as leaf lysates, root exudates and leaf cell wall polysaccharides from spinach cultivar Amazon and lettuce cultivar Salinas. Microarrays analysis showed a significant change in expression of 17 % of genes on exposure to leaf lysates of spinach. A more specific response was seen to spinach leaf cell wall polysaccharides with only a 1.5 % change. In contrast, when exposed to lettuce leaf cell wall polysaccharides a higher change of 4.8 % was seen. Genes that were differentially expressed belonged to multiple functional groups, including metabolism, indicating the utilization of plant-specific polysaccharides. Several areas of further investigation have been determined from this project, including the importance of culturing bacterial strains at a relevant temperature, the proposed lack of the type III secretion system in plant colonization by EHEC O157:H7 and the utilization of plant components for growth and persistence in the plant environment.

Differential uptake, partitioning and transfer of Cd and Zn in the soil-pea plant-aphid system

The biomagnification of trace metals during transfer from contaminated soil to higher trophic levels may potentially result in the exposure of predatory arthropods to toxic concentrations of these elements. This study examined the transfer of Cd and Zn in a soil−plant−arthropod system grown in series of field plots that had received two annual applications of municipal biosolids with elevated levels of Cd and Zn. Results showed that biosolids amendment significantly increased the concentration of Cd in the soil and the shoots of pea plants and the concentration of Zn in the soil, pea roots, shoots, and pods. In addition, the ratio of Cd to Zn concentration showed that Zn was preferentially transferred compared to Cd through all parts of the system. As a consequence, Zn was biomagnified by the system whereas Cd was biominimized. Cd and Zn are considered to exhibit similar behaviors in biological systems. However, the Cd/Zn ratios demonstrated that in this system, Cd is much less labile in the root−shoot−pod and shoot−aphid pathways than Zn.

Decadal predictability of regional-scale peak winds over Europe using the Earth System Model of the Max-Planck-Institute for Meteorology

The predictability of high impact weather events on multiple time scales is a crucial issue both in scientific and socio-economic terms. In this study, a statistical-dynamical downscaling (SDD) approach is applied to an ensemble of decadal hindcasts obtained with the Max-Planck-Institute Earth System Model (MPI-ESM) to estimate the decadal predictability of peak wind speeds (as a proxy for gusts) over Europe. Yearly initialized decadal ensemble simulations with ten members are investigated for the period 1979–2005. The SDD approach is trained with COSMO-CLM regional climate model simulations and ERA-Interim reanalysis data and applied to the MPI-ESM hindcasts. The simulations for the period 1990–1993, which was characterized by several windstorm clusters, are analyzed in detail. The anomalies of the 95 % peak wind quantile of the MPI-ESM hindcasts are in line with the positive anomalies in reanalysis data for this period. To evaluate both the skill of the decadal predictability system and the added value of the downscaling approach, quantile verification skill scores are calculated for both the MPI-ESM large-scale wind speeds and the SDD simulated regional peak winds. Skill scores are predominantly positive for the decadal predictability system, with the highest values for short lead times and for (peak) wind speeds equal or above the 75 % quantile. This provides evidence that the analyzed hindcasts and the downscaling technique are suitable for estimating wind and peak wind speeds over Central Europe on decadal time scales. The skill scores for SDD simulated peak winds are slightly lower than those for large-scale wind speeds. This behavior can be largely attributed to the fact that peak winds are a proxy for gusts, and thus have a higher variability than wind speeds. The introduced cost-efficient downscaling technique has the advantage of estimating not only wind speeds but also estimates peak winds (a proxy for gusts) and can be easily applied to large ensemble datasets like operational decadal prediction systems.

The financial and environmental performance of firms exposed to the EU Emissions Trading Scheme

This thesis is an empirical-based study of the European Union’s Emissions Trading Scheme (EU ETS) and its implications in terms of corporate environmental and financial performance. The novelty of this study includes the extended scope of the data coverage, as most previous studies have examined only the power sector. The use of verified emissions data of ETS-regulated firms as the environmental compliance measure and as the potential differentiating criteria that concern the valuation of EU ETS-exposed firms in the stock market is also an original aspect of this study. The study begins in Chapter 2 by introducing the background information on the emission trading system (ETS), which focuses on (i) the adoption of ETS as an environmental management instrument and (ii) the adoption of ETS by the European Union as one of its central climate policies. Chapter 3 surveys four databases that provide carbon emissions data in order to determine the most suitable source of the data to be used in the later empirical chapters. The first empirical chapter, which is also Chapter 4 of this thesis, investigates the determinants of the emissions compliance performance of the EU ETS-exposed firms through constructing the best possible performance ratio from verified emissions data and self-configuring models for a panel regression analysis. Chapter 5 examines the impacts on the EU ETS-exposed firms in terms of their equity valuation with customised portfolios and multi-factor market models. The research design takes into account the emissions allowance (EUA) price as an additional factor, as it has the most direct association with the EU ETS to control for the exposure. The final empirical Chapter 6 takes the investigation one step further, by specifically testing the degree of ETS exposure facing different sectors with sector-based portfolios and an extended multi-factor market model. The findings from the emissions performance ratio analysis show that the business model of firms significantly influences emissions compliance, as the capital intensity has a positive association with the increasing emissions-to-emissions cap ratio. Furthermore, different sectors show different degrees of sensitivity towards the determining factors. The production factor influences the performance ratio of the Utilities sector, but not the Energy or Materials sectors. The results show that the capital intensity has a more profound influence on the utilities sector than on the materials sector. With regard to the financial performance impact, ETS-exposed firms as aggregate portfolios experienced a substantial underperformance during the 2001–2004 period, but not in the operating period of 2005–2011. The results of the sector-based portfolios show again the differentiating effect of the EU ETS on sectors, as one sector is priced indifferently against its benchmark, three sectors see a constant underperformance, and three sectors have altered outcomes.

Assessment and improvement of biotransfer models to cow’s milk and beef used in exposure assessment tools for organic pollutants

The aim of this study was to assess and improve the accuracy of biotransfer models for the organic pollutants (PCBs, PCDD/Fs, PBDEs, PFCAs, and pesticides) into cow’s milk and beef used in human exposure assessment. Metabolic rate in cattle is known as a key parameter for this biotransfer, however few experimental data and no simulation methods are currently available. In this research, metabolic rate was estimated using existing QSAR biodegradation models of microorganisms (BioWIN) and fish (EPI-HL and IFS-HL). This simulated metabolic rate was then incorporated into the mechanistic cattle biotransfer models (RAIDAR, ACC-HUMAN, OMEGA, and CKow). The goodness of fit tests showed that RAIDAR, ACC-HUMAN, OMEGA model performances were significantly improved using either of the QSARs when comparing the new model outputs to observed data. The CKow model is the only one that separates the processes in the gut and liver. This model showed the lowest residual error of all the models tested when the BioWIN model was used to represent the ruminant metabolic process in the gut and the two fish QSARs were used to represent the metabolic process in the liver. Our testing included EUSES and CalTOX which are KOW-regression models that are widely used in regulatory assessment. New regressions based on the simulated rate of the two metabolic processes are also proposed as an alternative to KOW-regression models for a screening risk assessment. The modified CKow model is more physiologically realistic, but has equivalent usability to existing KOW-regression models for estimating cattle biotransfer of organic pollutants.

Evaluation of the Plant–Craig stochastic convection scheme (v2.0) in the ensemble forecasting system MOGREPS-R (24 km) based on the Unified Model (v7.3)

The Plant–Craig stochastic convection parameterization (version 2.0) is implemented in the Met Office Regional Ensemble Prediction System (MOGREPS-R) and is assessed in comparison with the standard convection scheme with a simple stochastic scheme only, from random parameter variation. A set of 34 ensemble forecasts, each with 24 members, is considered, over the month of July 2009. Deterministic and probabilistic measures of the precipitation forecasts are assessed. The Plant–Craig parameterization is found to improve probabilistic forecast measures, particularly the results for lower precipitation thresholds. The impact on deterministic forecasts at the grid scale is neutral, although the Plant–Craig scheme does deliver improvements when forecasts are made over larger areas. The improvements found are greater in conditions of relatively weak synoptic forcing, for which convective precipitation is likely to be less predictable.