MEASUREMENT AND MODELING OF THE TOXICITY OF BINARY MIXTURES IN THE NEMATODE CAENORHABDITIS ELEGANS-A TEST OF INDEPENDENT ACTION

Ecological risk assessments must increasingly consider the effects of chemical mixtures on the environment as anthropogenic pollution continues to grow in complexity. Yet testing every possible mixture combination is impractical and unfeasible; thus, there is an urgent need for models that can accurately predict mixture toxicity from single-compound data. Currently, two models are frequently used to predict mixture toxicity from single-compound data: Concentration addition and independent action (IA). The accuracy of the predictions generated by these models is currently debated and needs to be resolved before their use in risk assessments can be fully justified. The present study addresses this issue by determining whether the IA model adequately described the toxicity of binary mixtures of five pesticides and other environmental contaminants (cadmium, chlorpyrifos, diuron, nickel, and prochloraz) each with dissimilar modes of action on the reproduction of the nematode Caenorhabditis elegans. In three out of 10 cases, the IA model failed to describe mixture toxicity adequately with significant or antagonism being observed. In a further three cases, there was an indication of synergy, antagonism, and effect-level-dependent deviations, respectively, but these were not statistically significant. The extent of the significant deviations that were found varied, but all were such that the predicted percentage effect seen on reproductive output would have been wrong by 18 to 35% (i.e., the effect concentration expected to cause a 50% effect led to an 85% effect). The presence of such a high number and variety of deviations has important implications for the use of existing mixture toxicity models for risk assessments, especially where all or part of the deviation is synergistic.

Observed trends and teleconnections of the Siberian high: A recently declining center of action

This study investigates variability in the intensity of the wintertime Siberian high (SH) by defining a robust SH index (SHI) and correlating it with selected meteorological fields and teleconnection indices. A dramatic trend of -2.5 hPa decade(-1) has been found in the SHI between 1978 and 2001 with unprecedented (since 1871) low values of the SHI. The weakening of the SH has been confirmed by analyzing different historical gridded analyses and individual station observations of sea level pressure (SLP) and excluding possible effects from the conversion of surface pressure to SLP. SHI correlation maps with various meteorological fields show that SH impacts on circulation and temperature patterns extend far outside the SH source area extending from the Arctic to the tropical Pacific. Advection of warm air from eastern Europe has been identified as the main mechanism causing milder than normal conditions over the Kara and Laptev Seas in association with a strong SH. Despite the strong impacts of the variability in the SH on climatic variability across the Northern Hemisphere, correlations between the SHI and the main teleconnection indices of the Northern Hemisphere are weak. Regression analysis has shown that teleconnection indices are not able to reproduce the interannual variability and trends in the SH. The inclusion of regional surface temperature in the regression model provides closer agreement between the original and reconstructed SHI.

CAFS in action

For those few readers who do not know, CAFS is a system developed by ICL to search through data at speeds of several million characters per second. Its full name is Content Addressable File Store Information Search Processor, CAFS-ISP or CAFS for short. It is an intelligent hardware-based searching engine, currently available with both ICL's 2966 family of computers and the recently announced Series 39, operating within the VME environment. It uses content addressing techniques to perform fast searches of data or text stored on discs: almost all fields are equally accessible as search keys. Software in the mainframe generates a search task; the CAFS hardware performs the search, and returns the hit records to the mainframe. Because special hardware is used, the searching process is very much more efficient than searching performed by any software method. Various software interfaces are available which allow CAFS to be used in many different situations. CAFS can be used with existing systems without significant change. It can be used to make online enquiries of mainframe files or databases or directly from user written high level language programs. These interfaces are outlined in the body of the report.

Reactions of artemisinin and arteether with acid: Implications for stability and mode of antimalarial action

The currently accepted mechanism of trioxane antimalarial action involves generation of free radicals within or near susceptible sites probably arising from the production of distonic radical anions. An alternative mechanistic proposal involving the ionic scission of the peroxide group and consequent generation of a carbocation at C-4 has been suggested to account for antimalarial activity. We have investigated this latter mechanism using DFT (B3LYP/6-31+G* level) and established the preferred Lewis acid protonation sites (artemisinin O5a >> O4a approximate to O3a > O2a > O1a; arteether O4a >= O3a > O5b >> O2a > O1a; Figure 3) and the consequent decomposition pathways and hydrolysis sites. In neither molecule is protonation likely to occur on the peroxide bond O1-O2 and therefore lead to scission. Therefore, the alternative radical pathway remains the likeliest explanation for antimalarial action.

Identification of hepatic molecular mechanisms of action of alpha-tocopherol using global gene expression profile analysis in rats

The recent discovery that vitamin E (VE) regulates gene activity at the transcriptional level indicates that VE may exert part of its biological effects by mechanisms which may be independent of its well-recognised antioxidant function. The objective of this study was the identification of hepatic vitamin E-sensitive genes and examination of the effects of VE on their corresponding biological endpoints. Two groups of male rats were randomly assigned to either a VE-sufficient diet or to a control diet deficient in VE for 290 days. High-density oligonucleotide microarrays comprising over 7000 genes were used to assess the transcriptional response of the liver. Differential gene expression was monitored over a period of 9 months, at four different time-points, and rats were individually profiled. This experimental strategy identified several VE-sensitive genes, which were chronically altered by dietary VE. VE supplementation down-regulated scavenger receptor CD36, coagulation factor IX and 5-alpha-steroid reductase type 1 mRNA levels while hepatic gamma glutamyl-cysteinyl synthetase was significantly up-regulated. Measurement of the corresponding biological endpoints such as activated partial thromboplastin time, plasma dihydrotestosterone and hepatic glutathione substantiated the gene chip data which indicated that dietary VE plays an important role in a range of metabolic processes within the liver. (C) 2004 Elsevier B.V. All rights reserved.

Antipsychotic drug action: antagonism, inverse agonism or partial agonism

The positive, psychotic symptoms of schizophrenia can be treated by antipsychotic drugs and it has been assumed that these are antagonists at the D-2 and D-3 dopamine receptors in the brain. Recently, the D-2/D-3 partial agonist aripiprazole has been introduced as an antipsychotic drug. It has also been realized that, using in vitro assays, the other antipsychotic drugs are in fact inverse agonists at D-2/D-3 dopamine receptors. This raises questions about how these disparate drugs can achieve a similar clinical outcome. In this review, I shall consider the efficacies of these drugs in signalling assays and how these efficacies might affect treatment outcomes. It seems that the treatment outcome might depend on the overall level of cell stimulation, which is in turn dependent on the level of residual dopamine and the efficacy of the drug in signalling assays.

Return of the 'Angry Woman': authenticating female physical action in contemporary cinema

In 1999, Elizabeth Hills pointed up the challenges that physically active women on film still posed, in cultural terms, and in relation to certain branches of feminist theory . Since then, a remarkable number of emphatically active female heroes have appeared on screen, from 'Charlie’s Angels' to 'Resident Evil', 'Aeon Flux', and the 'Matrix' and 'X-Men' trilogies. Nevertheless, in a contemporary Western culture frequently characterised as postfeminist, these seem to be the ‘acceptable face’ – and body – of female empowerment: predominantly white, heterosexual, often scantily clad, with the traditional hero’s toughness and resolve re-imagined in terms of gender-biased notions of decorum: grace and dignity alongside perfect hair and make-up, and a body that does not display unsightly markers of physical exertion. The homogeneity of these representations is worth investigating in relation to critical claims that valorise such air-brushed, high-kicking 'action babes' for their combination of sexiness and strength, and the feminist and postfeminist discourses that are refracted through such readings. Indeed, this arguably ‘safe’ set of depictions, dovetailing so neatly with certain postfeminist notions of ‘having it all’, suppresses particular kinds of spectacles in relation to the active female body: images of physical stress and extension, biological consequences of violence and dangerous motivations are all absent. I argue that the untidy female exertions refused in popular “action babe” representations are now erupting into view in a number of other contemporaneous movies – 'Kill Bill' Vols 1 & 2, 'Monster', and 'Hard Candy' – that mark the return of that which is repressed in the mainstream vision of female power – that is, a more viscerally realistic physicality, rage and aggression. As such, these films engage directly with the issue of how to represent violent female agency. This chapter explores what is at stake at a representational level and in terms of spectatorial processes of identification in the return of this particularly visceral rendering of the female avenger.

Modeling data with structural and temporal correlation using lower level and higher level multilevel models

Novel imaging techniques are playing an increasingly important role in drug development, providing insight into the mechanism of action of new chemical entities. The data sets obtained by these methods can be large with complex inter-relationships, but the most appropriate statistical analysis for handling this data is often uncertain - precisely because of the exploratory nature of the way the data are collected. We present an example from a clinical trial using magnetic resonance imaging to assess changes in atherosclerotic plaques following treatment with a tool compound with established clinical benefit. We compared two specific approaches to handle the correlations due to physical location and repeated measurements: two-level and four-level multilevel models. The two methods identified similar structural variables, but higher level multilevel models had the advantage of explaining a greater proportion of variation, and the modeling assumptions appeared to be better satisfied.

Mobilising community action towards a low-carbon future: Opportunities and challenges for local government in the UK

Over the last decade the important role that local authorities can play in catalyzing communityaction on climate change has been repeatedly emphasised by the UK Government. The paper examines this policy context and explores the options available to local authorities in terms of reaching and engaging their communities. The type of progressive response shown by some UKlocal authorities is illustrated with empirical evidence gathered through a study conducted in the London Borough of Islington focusing on their recently established ‘Green Living Centre’. The results confirm interest in this major council-led community initiative, with positive attitudes expressed by the majority of those questioned in terms of the advice and information available. However, it is also clear that many participants had preexisting pro-environmental attitudes and behavioural routines. Results from a broader sample of Islington residents indicate a substantial challenge in reaching the wider community, where enthusiasm for sustainability change and interest in this type of scheme were more mixed. The prospect for local government in addressing this challenge – and their ability to trigger and capitalize upon concepts of social change at the community level towardsalowercarbon future – is discussed in the final part of the paper.

A mesoscopic modelling approach to anaesthetic action on brain electrical activity

Relating the measurable, large scale, effects of anaesthetic agents to their molecular and cellular targets of action is necessary to better understand the principles by which they affect behavior, as well as enabling the design and evaluation of more effective agents and the better clinical monitoring of existing and future drugs. Volatile and intravenous general anaesthetic agents (GAs) are now known to exert their effects on a variety of protein targets, the most important of which seem to be the neuronal ion channels. It is hence unlikely that anaesthetic effect is the result of a unitary mechanism at the single cell level. However, by altering the behavior of ion channels GAs are believed to change the overall dynamics of distributed networks of neurons. This disruption of regular network activity can be hypothesized to cause the hypnotic and analgesic effects of GAs and may well present more stereotypical characteristics than its underlying microscopic causes. Nevertheless, there have been surprisingly few theories that have attempted to integrate, in a quantitative manner, the empirically well documented alterations in neuronal ion channel behavior with the corresponding macroscopic effects. Here we outline one such approach, and show that a range of well documented effects of anaesthetics on the electroencephalogram (EEG) may be putatively accounted for. In particular we parameterize, on the basis of detailed empirical data, the effects of halogenated volatile ethers (a clinically widely used class of general anaesthetic agent). The resulting model is able to provisionally account for a range of anaesthetically induced EEG phenomena that include EEG slowing, biphasic changes in EEG power, and the dose dependent appearance of anomalous ictal activity, as well as providing a basis for novel approaches to monitoring brain function in both health and disease.

Processing reflexives in a second language: the timing of structural and discourse-level information

We report the results from two eye-movement monitoring experiments examining the processing of reflexive pronouns by proficient German-speaking learners of second language (L2) English. Our results show that the nonnative speakers initially tried to link English argument reflexives to a discourse-prominent but structurally inaccessible antecedent, thereby violating binding condition A. Our native speaker controls, in contrast, showed evidence of applying condition A immediately during processing. Together, our findings show that L2 learners’ initial focusing on a structurally inaccessible antecedent cannot be due to first language influence and is also independent of whether the inaccessible antecedent c-commands the reflexive. This suggests that unlike native speakers, nonnative speakers of English initially attempt to interpret reflexives through discourse-based coreference assignment rather than syntactic binding.

Building collaborative partnerships for climate change action in Maputo, Mozambique

The authors examine partnerships as a policy strategy for climate change governance in cities in the Global South. Partnerships offer the opportunity to link the actions of diverse actors operating at different scales and, thus, they may be flexible enough to deal with uncertain futures and changing development demands. However, simultaneously, partnerships may lack effectiveness in delivering action at the local level, and may constitute a strategy for some actors to legitimate their objectives in spite of the interests of other partners. Engaging with the specific example of urban governance in Maputo, Mozambique, the authors present an analysis of potential partnerships in this context, in relation to the actors that are willing and able to intervene to deliver climate change action. What, they ask, are the challenges to achieving common objectives in partnerships from the perspective of local residents in informal settlements? The analysis describes a changing context of climate change governance in the city, in which the prospects of access to international finance for climate change adaptation are moving institutional actors towards engaging with participatory processes at the local level. However, the analysis suggests a question about the extent to which local communities are actually perceived as actors with legitimate interests who can intervene in partnerships, and whether their interests are recognised.