Allen T.E.H.,University of Cambridge |
Goodman J.M.,University of Cambridge |
Gutsell S.,Colworth Science Park |
Russell P.J.,Colworth Science Park
Chemical Research in Toxicology | Year: 2014
Consumer and environmental safety decisions are based on exposure and hazard data, interpreted using risk assessment approaches. The adverse outcome pathway (AOP) conceptual framework has been presented as a logical sequence of events or processes within biological systems which can be used to understand adverse effects and refine current risk assessment practices in ecotoxicology. This framework can also be applied to human toxicology and is explored on the basis of investigating the molecular initiating events (MIEs) of compounds. The precise definition of the MIE has yet to reach general acceptance. In this work we present a unified MIE definition: an MIE is the initial interaction between a molecule and a biomolecule or biosystem that can be causally linked to an outcome via a pathway. Case studies are presented, and issues with current definitions are addressed. With the development of a unified MIE definition, the field can look toward defining, classifying, and characterizing more MIEs and using knowledge of the chemistry of these processes to aid AOP research and toxicity risk assessment. We also present the role of MIE research in the development of in vitro and in silico toxicology and suggest how, by using a combination of biological and chemical approaches, MIEs can be identified and characterized despite a lack of detailed reports, even for some of the most studied molecules in toxicology. (Figure Presented). © 2014 American Chemical Society.
McGlone F.,University of Liverpool |
Reilly D.,Colworth Science Park
Neuroscience and Biobehavioral Reviews | Year: 2010
The cutaneous senses are traditionally thought to comprise four recognized submodalities that relay tactile, thermal, painful and pruritic (itch) information to the central nervous system, but there is growing evidence for the presence of a fifth modality that conveys positive affective (pleasant) properties of touch. Cutaneous sensory channels can be further classified as serving predominantly either discriminative or affective functions. The former provides information about the spatial and temporal localisation of events on the body surface, e.g., the presence of an insect or the temperature of a cold wind; and the latter, although widely recognised as providing the afferent neural input driving the negative emotional experience of pain, is here posited to provide the afferent neural input driving the positive emotional experience of affiliative touch as well. A distinction is made between the properties of fast conducting myelinated afferents and those of slowly conducting unmyelinated afferents, with the former subserving a sensory-discriminative role, and the latter an affective-motivational one. Here we review the basic elements of the somatosensory system and outline evidence for the inclusion of the 'fifth' sub-modality, conveyed by low-threshold C-fiber mechanoreceptors as the counterpart of high-threshold C-fiber nociceptors with both C-fiber systems serving opposing aspects of affective touch, yet underpining a common mechanism for the preservation of self and species. © 2009.
Brandao M.,European Commission - Joint Research Center Ispra |
I Canals L.M.,Colworth Science Park
International Journal of Life Cycle Assessment | Year: 2013
Purpose: The inclusion of land-use activities in life cycle assessment (LCA) has been subject to much debate in the LCA community. Despite the recent methodological developments in this area, the impacts of land occupation and transformation on its long-term ability to produce biomass (referred to here as biotic production potential [BPP]) - an important endpoint for the Area of Protection (AoP) Natural Resources - have been largely excluded from LCAs partly due to the lack of life cycle impact assessment methods. Materials and methods: Several possible methods/indicators for BPP associated with biomass, carbon balance, soil erosion, salinisation, energy, soil biota and soil organic matter (SOM) were evaluated. The latter indicator was considered the most appropriate for LCA, and characterisation factors for eight land use types at the climate region level were developed. Results and discussion: Most of the indicators assessed address land-use impacts satisfactorily for land uses that include biotic production of some kind (agriculture or silviculture). However, some fail to address potentially important land use impacts from other life cycle stages, such as those arising from transport. It is shown that the change in soil organic carbon (SOC) can be used as an indicator for impacts on BPP, because SOC relates to a range of soil properties responsible for soil resilience and fertility. Conclusions: The characterisation factors developed suggest that the proposed approach to characterize land use impacts on BBP, despite its limitations, is both possible and robust. The availability of land-use-specific and biogeographically differentiated data on SOC makes BPP impact assessments operational. The characterisation factors provided allow for the assessment of land-use impacts on BPP, regardless of where they occur thus enabling more complete LCAs of products and services. Existing databases on every country's terrestrial carbon stocks and land use enable the operability of this method. Furthermore, BPP impacts will be better assessed by this approach as increasingly spatially specific data are available for all geographical regions of the world at a large scale. The characterisation factors developed are applied to the case studies (Part D of this special issue), which show the practical issues related to their implementation. © 2012 Springer-Verlag.
Blake K.L.,University of Leeds |
Blake K.L.,Colworth Science Park |
O'Neill A.J.,University of Leeds
Journal of Antimicrobial Chemotherapy | Year: 2013
Objectives: To establish an experimental platform in Staphylococcus aureus for identifying genetic loci that determine intrinsic antibiotic susceptibility and/or that have the potential to contribute to acquired antibiotic resistance. A near-saturation S. aureus transposon (Tn) library was screened for mutants exhibiting altered susceptibility to the antistaphylococcal agents daptomycin, vancomycin and nisin. Methods: S. aureus SH1000 was mutagenized with Tn InsTetG+2Cm by electroporation of transposomes. Approximately 20500 transposants were screened for increased or reduced susceptibility to the three antistaphylococcal agents and Tn insertion sites were mapped by DNA sequencing in mutants of interest. Results: Transposants exhibiting hypersusceptibility or reduced susceptibility were identified for all three antibacterial agents; mapping of Tn insertion sites in these mutants identified genetic determinants of intrinsic susceptibility and potential contributors to acquired resistance, respectively. Tn insertions in the dlt operon caused cross-hypersusceptibility to vancomycin, daptomycin and nisin. Daptomycin hypersusceptibility was also associated with disruption of genes directing lipoteichoic acid and riboflavin biosynthesis, apparent inactivation of a putative membrane protein encoded by SAOUHSC_00957 and truncation of the cell-division gene ezrA. Tn-mediated disruption of the vraDE- and SAOUHSC_02953/4-encoded ABC transporters conferred hypersusceptibility to nisin. Reduced susceptibility to both daptomycin and vancomycin was associated with Tn insertions in rpsU and upstream of yycFG. Several loci were associated with reduced susceptibility to nisin, including two genes encoding putative glycosyltransferases. Conclusions: Tn library screening identified both known and novel modulators of antibacterial susceptibility in S. aureus and therefore represents a useful approach towards delineating the staphylococcal resistome. © The Author 2012. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.
Soureti A.,Colworth Science Park
Journal of medical Internet research | Year: 2011
A healthy diet, low in saturated fat and high in fiber, is a popular medical recommendation in preventing cardiovascular disease (CVD). One approach to motivating healthier eating is to raise individuals' awareness of their CVD risk and then help them form specific plans to change. The aim was to explore the combined impact of a Web-based CVD risk message and a fully automated planning tool on risk perceptions, intentions, and saturated fat intake changes over 4 weeks. Of the 1187 men and women recruited online, 781 were randomly allocated to one of four conditions: a CVD risk message, the same CVD risk message paired with planning, planning on its own, and a control group. All outcome measures were assessed by online self-reports. Generalized linear modeling was used to analyze the data. Self-perceived consumption of low saturated fat foods (odds ratio 11.40, 95% CI 1.86-69.68) and intentions to change diet (odds ratio 21.20, 95% CI 2.6-172.4) increased more in participants allocated to the planning than the control group. No difference was observed between the four conditions with regard to percentage saturated fat intake changes. Contrary to our expectations, there was no difference in perceived and percentage saturated fat intake change between the CVD risk message plus planning group and the control group. Risk perceptions among those receiving the CVD risk message changed to be more in line with their age (change in slope(individual) = 0.075, P = .01; change in slope(comparative) = 0.100, P = .001), whereas there was no change among those who did not receive the CVD risk message. There was no evidence that combining a CVD risk message with a planning tool reduces saturated fat intake more than either alone. Further research is required to identify ways in which matching motivational and volitional strategies can lead to greater behavior changes.
Franco A.,Colworth Science Park
Integrated environmental assessment and management | Year: 2013
SimpleTreat 3.1 is the sewage treatment plant (STP) model implemented in the European Union (EU) framework for the environmental risk assessment of chemicals. The model was originally designed for neutral hydrophobic chemicals, whereas many substances currently under regulatory scrutiny, are ionizable at environmental pH. Although the model has been adapted to describe ionization (SimpleTreat 3.1), the fate of organic ions is limited to the unbound aqueous phase, which seriously restricts the applicability domain. New regressions were implemented to estimate the sludge-water partition coefficient normalized to organic carbon (KOC ) of monovalent acids and bases from the octanol-water partition coefficient (KOW ), the dissociation constant (pKa) and the pH. We evaluated the updated model (SimpleTreat 3.2) with 10 test chemicals by comparing predictions with monitoring data collected from the literature. Test chemicals were specifically selected to challenge the applicability domain and to cover a wide range of functionality and physical-chemical properties. Although predicted effluent concentrations are generally conservative, SimpleTreat 3.2 provides reasonable estimates for use in lower-tier risk assessment for neutral and monovalent ionizable chemicals. The accuracy of the new KOC regressions is acceptable for monovalent acid but is lower for bases, for which measured sludge KOC is highly recommended. Measured KOC are also recommended for ionic surfactants and necessary for organic ligands, which may limit the applicability of SimpleTreat using a basic input data set. The conservative nature of model estimates reflects the default worst case, non-numerical parameterization of biodegradation rates and the assumption that biodegradation is limited to the unbound aqueous phase. The potential of refining the description of biodegradation using higher tier simulation tests is explored in a parallel article (Franco et al. this issue). © 2013 SETAC.
Franco A.,Colworth Science Park
Integrated environmental assessment and management | Year: 2013
Given the large number of chemicals under regulatory scrutiny, models play a crucial role in the screening phase of the environmental risk assessment. The sewage treatment plant (STP) model SimpleTreat 3.1 is routinely applied as part of the European Union System for the Evaluation of Substances to estimate the fate and elimination of organic chemicals discharged via sewage. SimpleTreat estimates tend to be conservative and therefore only useful for lower-tier assessments. A probabilistic version of SimpleTreat was built on the updated version of the model (SimpleTreat 3.2, presented in a parallel article in this issue), embracing likeliest as well as worst-case conditions in a statistically robust way. Probabilistic parameters representing the variability of sewage characteristics, STP design, and operational parameters were based on actual STP conditions for activated sludge plants in Europe. An evaluation study was carried out for 4 chemicals with distinct sorption and biodegradability profiles: tonalide, triclosan, trimethoprim, and linear alkylbenzene sulfonate. Simulations incorporated information on biodegradability simulation studies with activated sludge (OECD 314B and OECD 303A tests). Good agreement for both median values and variability ranges was observed between model estimates and monitoring data. The uncertainty analysis highlighted the importance of refined data on partitioning and biodegradability in activated sludge to achieve realistic estimates. The study indicates that the best strategy to refine the exposure assessment of down-the-drain chemicals is by integrating higher-tier laboratory data with probabilistic STP simulations and, if possible, by comparing them with monitoring data for validation. © 2013 SETAC.
Martin J.E.,University of Bristol |
Patil A.J.,University of Bristol |
Butler M.F.,Colworth Science Park |
Mann S.,University of Bristol
Advanced Functional Materials | Year: 2011
Given the urgent need for soft materials with high functional value, hydrogels based on the integrative assembly of organic polymers and nanoscale inorganic building blocksa-so-called nanocomposite polymer hydrogelsa-offer a generic approach to swollen hybrid networks with tuneable and synergistic properties. Here, we report a new approach to assembling nanocomposite polymer hydrogels with multiple levels of structural complexity and enhanced functionality by using nanoscale integration of mesostructured inorganic building blocks capable of sequestering and releasing drugs (ibuprofen, aspirin, naproxen) and enzymes (glucose oxidase). The viscoelastic materials are produced by noncovalent crosslinking of poly(vinylpyrrolidone) in the presence of low amounts (1-5 wt%) of an exfoliated synthetic organoclay that undergoes in situ guest-molecule-directed self-assembly. The hydrogels can be moulded into shape-persistent, free-standing objects that are stable between pH values of 4 to 11 and self-heal when damaged. Significantly, the mesostructured nanocomposite polymer hydrogels, which can be reversibly dried and reconstituted in the form of highly swollen materials, exhibit sustained drug release and can be recharged and reused. The results provide important guidelines for developing new multifunctional nanocomposite polymer hydrogels based on the concerted self-assembly of inorganic building blocks with mesostructured interiors. New multifunctional nanocomposite polymer hydrogels with mesostructured crosslinking units are prepared by in situ self-assembly of organoclay sheets and guest-drug or protein molecules within a poly(vinylpyrrolidone) matrix. The mesostructured hydrogels are mouldable, swellable, and self-adhesive, and exhibit sustained drug release compared with their exfoliated counterparts. © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Frith W.J.,Colworth Science Park
Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences | Year: 2016
In this opinion piece, some specific challenges in the field of peptide self-assembly and gel formation are discussed. One major hurdle to finding functional small peptides is that there are a huge number of compounds to explore, which increases exponentially with the peptide size. This in itself creates a barrier to the discovery and application of materials, both through the difficulty of finding the peptides, and because protecting inventions also becomes more difficult. Recent work has shown that computer simulations may provide us a route to explore such a huge compound space; this is discussed along with the prospect for future developments. At the microscopic scale, many fibril-forming peptides form gels, apparently through a process of lateral association of primary self-assembled filaments, which leads to a relatively coarse-grained structure of rigid interconnects. However, recent data obtained on Fmoc-tyrosine gels appear to indicate that the gel microstructure is both more flexible and finer grained than previously believed. As such, it is clear that there is a considerable amount that is still not understood regarding this class of gel. This article is part of the themed issue 'Soft interfacial materials: from fundamentals to formulation'. © 2016 The Author(s) Published by the Royal Society. All rights reserved.
Gouin T.,Colworth Science Park
Environmental Science and Policy | Year: 2010
There is continuing activity among regulatory bodies to assess and prioritize chemicals used in commerce based on their potential to be persistent, bioaccumulative, and toxic (PBT). Reliable data needed to perform a PBT hazard or risk assessment, however, may not always be readily available. Consequently concern may arise regarding the potential for false positives and false negatives to be wrongly classified. In order to more effectively classify substances, adequate time is needed to acquire the necessary data to support the overall PBT assessment. Of particular interest is the question of whether or not restrictions on the use and manufacture of a substance can be delayed to allow time to conduct the necessary field and laboratory studies of a particular substance? To address this question it is demonstrated that chemical partitioning property and environmental persistence information can be effectively combined to provide guidance for regulatory priority setting. Specifically, it is argued that substances that have media specific half-life values that exceed the regulatory threshold value for persistence under the EU chemicals REACH program, for example, are more likely to have a 'legacy' associated with their use when the logKOA>8, and when they are emitted to air or soil. Thus, precautionary actions limiting the use and manufacture of the substance may be warranted. Whereas substances emitted to air with logKOA<6 and logKAW>-2 are less likely to have a 'legacy' associated with their use. Thus precautionary actions in the absence of data may not be warranted. © 2010 Elsevier Ltd.