Insights into the effects on metal binding of the systematic substitution of five key glutamate ligands in the ferritin of Escherichia coli

Ferritins are nearly ubiquitous iron storage proteins playing a fundamental role in iron metabolism. They are composed of 24 subunits forming a spherical protein shell encompassing a central iron storage cavity. The iron storage mechanism involves the initial binding and subsequent O-2-dependent oxidation of two Fe2+ ions located at sites A and B within the highly conserved dinuclear "ferroxidase center" in individual subunits. Unlike animal ferritins and the heme-containing bacterioferritins, the Escherichia coli ferritin possesses an additional iron-binding site (site C) located on the inner surface of the protein shell close to the ferroxidase center. We report the structures of five E. coli ferritin variants and their Fe3+ and Zn2+ (a redox-stable alternative for Fe2+) derivatives. Single carboxyl ligand replacements in sites A, B, and C gave unique effects on metal binding, which explain the observed changes in Fe2+ oxidation rates. Binding of Fe2+ at both A and B sites is clearly essential for rapid Fe2+ oxidation, and the linking of Fe-B(2+) to Fe-C(2+) enables the oxidation of three Fe2+ ions. The transient binding of Fe2+ at one of three newly observed Zn2+ sites may allow the oxidation of four Fe2+ by one dioxygen molecule.

Mapping antimalarial pharmacophores as a useful tool for the rapid discovery of drugs effective in vivo: design, construction, characterization, and pharmacology of metaquine

Resistant strains of Plasmodium falciparum and the unavailability of useful antimalarial vaccines reinforce the need to develop new efficacious antimalarials. This study details a pharmacophore model that has been used to identify a potent, soluble, orally bioavailable antimalarial bisquinoline, metaquine (N,N'-bis(7-chloroquinolin-4-yl)benzene-1,3-diamine) (dihydrochloride), which is active against Plasmodium berghei in vivo (oral ID50 of 25 mu mol/kg) and multidrug-resistant Plasmodium falciparum K1 in vitro (0.17 mu M). Metaquine shows strong affinity for the putative antimalarial receptor, heme at pH 7.4 in aqueous DMSO. Both crystallographic analyses and quantum mechanical calculations (HF/6-31+G*) reveal important regions of protonation and bonding thought to persist at parasitic vacuolar pH concordant with our receptor model. Formation of drug-heme adduct in solution was confirmed using high-resolution positive ion electrospray mass spectrometry. Metaquine showed strong binding with the receptor in a 1: 1 ratio (log K = 5.7 +/- 0.1) that was predicted by molecular mechanics calculations. This study illustrates a rational multidisciplinary approach for the development of new 4-aminoquinoline antimalarials, with efficacy superior to chloroquine, based on the use of a pharmacophore model.

Evidence of systematic approaches to innovation in facilities management

Purpose – This paper seeks to examine the nature of “service innovation” in the facilities management (FM) context. It reviews recent thinking on “service innovation” as distinct from “product innovation”. Applying these contemporary perspectives it describes UK case studies of 11 innovations in different FM organisations. These include both in-house client-based innovations and third-party innovations. Design/methodology/approach – The study described in the paper encompasses 11 different innovations that constitute a mix of process, product and practice innovations. All of the innovations stem from UK-based organisations that were subject to in-depth interviews regarding the identification, screening, commitment of resources and implementation of the selected innovations. Findings – The research suggested that service innovation is highly active in the UK FM sector. However, the process of innovation rarely followed a common formalized path. Generally, the innovations were one-shot commitments at the early stage. None of the innovations studied failed to proceed to full adoption stage. This was either due to the reluctance of participating organisations to volunteer “tested but unsuccessful” innovations or the absence of any trial methods that might have exposed an innovations shortcomings. Research limitations/implications – The selection of innovations was restricted to the UK context. Moreover, the choice of innovations was partly determined by the innovating organisation. This selection process appeared to emphasise “one-shot” high profile technological innovations, typically associated with software. This may have been at the expense of less resource intensive, bottom-up innovations. Practical implications – This paper suggests that there is a role for “research and innovation” teams within larger FM organisations, whether they are client-based or third-party. Central to this philosophy is an approach that is open to the possibility of failure. The innovations studied were risk averse with a firm commitment to proceed at the early stage. Originality/value – This paper introduces new thinking on the subject of “service innovation” to the context of FM. It presents research and development as a planned solution to innovation. This approach will enable service organisations to fully test and exploit service innovations.

Childhood obesity: should primary school children be routinely screened? A systematic review and discussion of the evidence

Background: Population monitoring has been introduced in UK primary schools in an effort to track the growing obesity epidemic. It has been argued that parents should be informed of their child's results, but is there evidence that moving from monitoring to screening would be effective? We describe what is known about the effectiveness of monitoring and screening for overweight and obesity in primary school children and highlight areas where evidence is lacking and research should be prioritised. Design: Systematic review with discussion of evidence gaps and future research. Data sources: Published and unpublished studies ( any language) from electronic databases ( inception to July 2005), clinical experts, Primary Care Trusts and Strategic Health Authorities, and reference lists of retrieved studies. Review methods: We included any study that evaluated measures of overweight and obesity as part of a population-level assessment and excluded studies whose primary outcome measure was prevalence. Results: There were no trials assessing the effectiveness of monitoring or screening for overweight and obesity. Studies focussed on the diagnostic accuracy of measurements. Information on the attitudes of children, parents and health professionals to monitoring was extremely sparse. Conclusions: Our review found a lack of data on the potential impact of population monitoring or screening for obesity and more research is indicated. Identification of effective weight reduction strategies for children and clarification of the role of preventative measures are priorities. It is difficult to see how screening to identify individual children can be justified without effective interventions.

Systematic distortions of perceptual stability investigated using immersive virtual reality

Using an immersive virtual reality system, we measured the ability of observers to detect the rotation of an object when its movement was yoked to the observer's own translation. Most subjects had a large bias such that a static object appeared to rotate away from them as they moved. Thresholds for detecting target rotation were similar to those for an equivalent speed discrimination task carried out by static observers, suggesting that visual discrimination is the predominant limiting factor in detecting target rotation. Adding a stable visual reference frame almost eliminated the bias. Varying the viewing distance of the target had little effect, consistent with observers underestimating distance walked. However, accuracy of walking to a briefly presented visual target was high and not consistent with an underestimation of distance walked. We discuss implications for theories of a task-independent representation of visual space. © 2005 Elsevier Ltd. All rights reserved.

A systematic review of the routine monitoring of growth in children of primary school age to identify growth-related conditions

Objectives: To clarify the role of growth monitoring in primary school children, including obesity, and to examine issues that might impact on the effectiveness and cost-effectiveness of such programmes. Data sources: Electronic databases were searched up to July 2005. Experts in the field were also consulted. Review methods: Data extraction and quality assessment were performed on studies meeting the review's inclusion criteria. The performance of growth monitoring to detect disorders of stature and obesity was evaluated against National Screening Committee (NSC) criteria. Results: In the 31 studies that were included in the review, there were no controlled trials of the impact of growth monitoring and no studies of the diagnostic accuracy of different methods for growth monitoring. Analysis of the studies that presented a 'diagnostic yield' of growth monitoring suggested that one-off screening might identify between 1: 545 and 1: 1793 new cases of potentially treatable conditions. Economic modelling suggested that growth monitoring is associated with health improvements [ incremental cost per quality-adjusted life-year (QALY) of pound 9500] and indicated that monitoring was cost-effective 100% of the time over the given probability distributions for a willingness to pay threshold of pound 30,000 per QALY. Studies of obesity focused on the performance of body mass index against measures of body fat. A number of issues relating to human resources required for growth monitoring were identified, but data on attitudes to growth monitoring were extremely sparse. Preliminary findings from economic modelling suggested that primary prevention may be the most cost-effective approach to obesity management, but the model incorporated a great deal of uncertainty. Conclusions: This review has indicated the potential utility and cost-effectiveness of growth monitoring in terms of increased detection of stature-related disorders. It has also pointed strongly to the need for further research. Growth monitoring does not currently meet all NSC criteria. However, it is questionable whether some of these criteria can be meaningfully applied to growth monitoring given that short stature is not a disease in itself, but is used as a marker for a range of pathologies and as an indicator of general health status. Identification of effective interventions for the treatment of obesity is likely to be considered a prerequisite to any move from monitoring to a screening programme designed to identify individual overweight and obese children. Similarly, further long-term studies of the predictors of obesity-related co-morbidities in adulthood are warranted. A cluster randomised trial comparing growth monitoring strategies with no growth monitoring in the general population would most reliably determine the clinical effectiveness of growth monitoring. Studies of diagnostic accuracy, alongside evidence of effective treatment strategies, could provide an alternative approach. In this context, careful consideration would need to be given to target conditions and intervention thresholds. Diagnostic accuracy studies would require long-term follow-up of both short and normal children to determine sensitivity and specificity of growth monitoring.

A systematic review of controlled trials of interventions to prevent childhood obesity and overweight: realistic synthesis of the evidence

Background: Preventing childhood overweight and obesity has become a major public health issue in developed and developing countries. Systematic reviews of this topic have not provided practice-relevant guidance because of the generally low quality of research and the heterogeneity of reported effectiveness. Aim: To present practice-relevant guidance on interventions to reduce at least one measure of adiposity in child populations that do or do not contain overweight or obese children. Design: Systematic review of eligible randomized, controlled trials or controlled trials using a novel approach to synthesizing the trial results through application of descriptive epidemiological and realistic evaluation concepts. Eligible trials involved at least 30 participants, lasted at least 12 weeks and involved non-clinical child populations. Results: Twenty-eight eligible trials were identified to 30 April 2006. Eleven trials were effective and 17 were ineffective in reducing adiposity. Blind to outcome, the main factor distinguishing effective from ineffective trials was the provision of moderate to vigorous aerobic physical activity in the former on a relatively 'compulsory' rather than 'voluntary' basis. Conclusions: By using a novel approach to synthesizing trials, a decisive role for the 'compulsory' provision of aerobic physical activity has been demonstrated. Further research is required to identify how such activity can be sustained and transformed into a personally chosen behaviour by children and over the life course. (C) 2007 The Royal Institute of Public Health. Published by Elsevier Ltd. All rights reserved.

Teaching assistants and pupils' academic and social engagement in mainstream schools: insights from systematic literature reviews

The last 20 years have seen a huge expansion in the additional adults working in classrooms in the UK, USA, and other countries. This paper presents the findings of a series of systematic literature reviews about teaching assistants. The first two reviews focused on stakeholder perceptions of teaching assistant contributions to academic and social engagement. Stakeholders were pupils, teachers, TAs, headteachers and parents. Perceptions focused on four principal contributions that teaching assistants contribute to: pupils’ academic and socio-academic engagement; inclusion; maintenance of stakeholder relations; and support for the teacher. The third review explored training. Against a background of patchy training provision both in the UK and the USA, strong claims are made for the benefits to TAs of training provided, particularly in building confidence and skills. The conclusions include implications for further training and the need for further research to gain an in-depth understanding as to precisely the manner in which TAs engage with children.

FACSGen: a tool to synthesize emotional facial expressions through systematic manipulation of facial action units

To investigate the perception of emotional facial expressions, researchers rely on shared sets of photos or videos, most often generated by actor portrayals. The drawback of such standardized material is a lack of flexibility and controllability, as it does not allow the systematic parametric manipulation of specific features of facial expressions on the one hand, and of more general properties of the facial identity (age, ethnicity, gender) on the other. To remedy this problem, we developed FACSGen: a novel tool that allows the creation of realistic synthetic 3D facial stimuli, both static and dynamic, based on the Facial Action Coding System. FACSGen provides researchers with total control over facial action units, and corresponding informational cues in 3D synthetic faces. We present four studies validating both the software and the general methodology of systematically generating controlled facial expression patterns for stimulus presentation.