A computationally designed binding mode flip leads to a novel class of potent tri-vector cyclophilin inhibitors.

Cyclophilins (Cyps) are a major family of drug targets that are challenging to prosecute with small molecules because the shallow nature and high degree of conservation of the active site across human isoforms offers limited opportunities for potent and selective inhibition. Herein a computational approach based on molecular dynamics simulations and free energy calculations was combined with biophysical assays and X-ray crystallography to explore a flip in the binding mode of a reported urea-based Cyp inhibitor. This approach enabled access to a distal pocket that is poorly conserved among key Cyp isoforms, and led to the discovery of a new family of sub-micromolar cell-active inhibitors that offer unprecedented opportunities for the development of next-generation drug therapies based on Cyp inhibition. The computational approach is applicable to a broad range of organic functional groups and could prove widely enabling in molecular design.

Bioaccessibility of metals in soils and dusts contaminated by marine antifouling paint particles.

Fragments of antifouling paint and environmental geosolids have been sampled from the island of Malta and analysed for total and bioaccessible metals. Total concentrations of Ba, Cd, Cu, Pb, Sn and Zn were two to three orders of magnitude higher in spent antifouling composites relative to respective values in background soils and road dusts. Paint fragments were visible in geosolids taken from the immediate vicinity of boat maintenance facilities and mass balance calculations, based on Ba as a paint tracer, suggested that the most contaminated soils, road dusts and boatyard dusts contained about 1%, 7% and 9%, respectively, of antifouling particles. Human bioaccessibilities of metals were evaluated in selected samples using a physiologically based extraction technique. Accessibilities of Cd, Cu, Pb and Zn in the most contaminated solids were sufficient to be cause for concern for individuals working in the boat repair industry and to the wider, local community.

Chemicals in household products: problems with solutions.

The success of a regulatory regime in decreasing point-source emissions of some harmful chemicals has highlighted the significance of other sources. A growing number of potentially harmful chemicals have been incorporated into an expanding range of domestic household products and are sold worldwide. Tighter regulation has been proposed, and the European Commission has introduced the Regulation on the Registration, Evaluation, and Authorisation of Chemicals to address this concern. However, it is clear that in addition to the regulation, there is a potential to effect change through retailer and consumer attitudes and behaviours. Interviews were conducted with 7 key stakeholder groups to identify critical issues, which were then explored using a public survey questionnaire (1,008 respondents) and 8 subsequent focus groups. The findings demonstrated that the issue of chemicals in products is of concern to consumers for reasons of personal health rather than environmental protection. Key obstacles to the wider purchase of "green-alternative" products included perceived high cost and poor performance, lack of availability of products, and poor information concerning such products. Although improved regulation was seen as part of the solution, consumers must also play a role. It was clear from this study that consumers are not currently able to make informed choices about the chemicals they use but that they would be receptive to moving toward a more sustainable use of chemicals in the future if empowered to do so.

Recurrent brief depression and personality traits in allergy, anxiety and premenstrual syndrome patients: a general practice survey.

BACKGROUND: Recurrent brief depression (RBD) is a common disorder, poorly characterised in clinical studies. Some problems associated with the diagnosis and treatment of RBD may be improved if patients are easier to identify. This study investigates the distribution of RBD and personality types within three common syndromes. MATERIAL/METHODS: A survey of adult patients in one general practice. Patients with anxiety, PMS or an allergy condition (n=1094) were screened for exclusion criteria, including depression. Of the study sample (n=384) 159 patients were interviewed. RBD patients were identified by DSM-IV criteria. The Hospital Anxiety and Depression Scale was used to categorise RBD (symptom scores of at least moderate severity) and RBD-res (milder symptoms) patients. Trait anxiety and personality dimensions were measured with the State-Trait Anxiety Inventory (STAI) and Eysencks' Personality Questionnaire (EPQ-R). RESULTS: In the syndrome groups, 40% of anxiety or PMS patients and 21% of allergy patients had a recurrent problem with brief depression, with half reporting symptoms of at least moderate severity. Patients with brief depression showed syndrome specific symptom and impairment differences for sleep, cognition, medication and suicide ideation. There were significant differences in the distribution of STAI, neuroticism (N) and extraversion (E) scores between patients in the RBD and no depression categories. In the anxiety group, high STAI or N scores, and low E scores identified all patients with RBD. CONCLUSIONS: This study reveals a substantial burden of RBD in a practice population who were not receiving treatment nor consulting for depression. Trait scores were useful markers of RBD in patients with an anxiety condition.

The impact of legislation on the usage and environmental concentrations of Irgarol 1051 in UK coastal waters.

In 2001, legislative measures were introduced in the UK to restrict usage of antifouling agents in small (<25 m) vessel paints to dichlofluanid, zinc pyrithione and zineb. This removed the previously popular booster biocides diuron and Irgarol 1051 from the market. To investigate the impact of this legislation, water samples were taken from locations where previous biocide levels were well documented. Results from analyses demonstrate a clear reduction in water concentrations of Irgarol 1051 (between 10% and 55% of that found during pre-restriction studies), indicating that legislation appears to have been effective. Although other booster biocides were screened for (chlorothalonil, dichlofluanid and Sea-Nine 211), they were below the limits of detection (<1 ng/l) in all samples. A survey of chandlers and discussions with legislative authorities supports these results and concurs the removal of Irgarol 1051 based paints from the market using simple regulations at a manufacturer level with little regulation at a retailer level.