Antiplasmodial Activity of Nitroaromatic Compounds : Correlation with Their Reduction Potential and Inhibitory Action on Plasmodium falciparum Glutathione Reductase

With the aim to clarify the mechanism(s) of action of nitroaromatic compounds against the malaria parasite Plasmodium falciparum, we examined the single-electron reduction by P. falciparum ferredoxin:NADP+ oxidoreductase (PfFNR) of a series of nitrofurans and nitrobenzenes (n = 23), and their ability to inhibit P. falciparum glutathione reductase (PfGR). The reactivity of nitroaromatics in PfFNR-catalyzed reactions increased with their single-electron reduction midpoint potential (E17). Nitroaromatic compounds acted as non- or uncompetitive inhibitors towards PfGR with respect to NADPH and glutathione substrates. Using multiparameter regression analysis, we found that the in vitro activity of these compounds against P. falciparum strain FcB1 increased with their E17 values, octanol/water distribution coefficients at pH 7.0 (log D), and their activity as PfGR inhibitors. Our data demonstrate that both factors, the ease of reductive activation and the inhibition of PfGR, are important in the antiplasmodial in vitro activity of nitroaromatics. To the best of our knowledge, this is the first quantitative demonstration of this kind of relationship. No correlation between antiplasmodial activity and ability to inhibit human erythrocyte GR was detected in tested nitroaromatics. Our data suggest that the efficacy of prooxidant antiparasitic agents may be achieved through their combined action, namely inhibition of antioxidant NADPH:disulfide reductases, and the rapid reduction by single-electron transferring dehydrogenases-electrontransferases

Responses of two marine top predators to an offshore wind farm

Quantifying the likely effects of offshore wind farms on wildlife is fundamental before permission for development can be granted by any Determining Authority. The effects on marine top predators from displacement from important habitat are key concerns during offshore wind farm construction and operation. In this respect, we present evidence for no significant displacement from a UK offshore wind farm for two broadly distributed species of conservation concern: common guillemot (Uria aalge) and harbor porpoise (Phocoena phocoena). Data were collected during boat-based line transect surveys across a 360 km2 study area that included the Robin Rigg offshore wind farm. Surveys were conducted over 10 years across the preconstruction, construction, and operational phases of the development. Changes in guillemot and harbor porpoise abundance and distribution in response to offshore wind farm construction and operation were estimated using generalized mixed models to test for evidence of displacement. Both common guillemot and harbor porpoise were present across the Robin Rigg study area throughout all three development phases. There was a significant reduction in relative harbor porpoise abundance both within and surrounding the Robin Rigg offshore wind farm during construction, but no significant difference was detected between the preconstruction and operational phases. Relative common guillemot abundance remained similar within the Robin Rigg offshore wind farm across all development phases. Offshore wind farms have the potential to negatively affect wildlife, but further evidence regarding the magnitude of effect is needed. The empirical data presented here for two marine top predators provide a valuable addition to the evidence base, allowing future decision making to be improved by reducing the uncertainty of displacement effects and increasing the accuracy of impact assessments

Optical microbubble resonator

We develop a method for fabricating very small silica microbubbles having a micrometer-order wall thickness and demonstrate the first optical microbubble resonator. Our method is based on blowing a microbubble using stable radiative CO2 laser heating rather than unstable convective heating in a flame or furnace. Microbubbles are created along a microcapillary and are naturally opened to the input and output microfluidic or gas channels. The demonstrated microbubble resonator has 370 µm diameter, 2 µm wall thickness, and a Q factor exceeding 10

BlueHealth: a study programme protocol for mapping and quantifying the potential benefits to public health and well-being from Europe's blue spaces

This is the final version of the article. Available from BMJ Publishing Group via the DOI in this record.INTRODUCTION: Proximity and access to water have long been central to human culture and accordingly deliver countless societal benefits. Over 200 million people live on Europe's coastline, and aquatic environments are the top recreational destination in the region. In terms of public health, interactions with 'blue space' (eg, coasts, rivers, lakes) are often considered solely in terms of risk (eg, drowning, microbial pollution). Exposure to blue space can, however, promote health and well-being and prevent disease, although underlying mechanisms are poorly understood. AIMS AND METHODS: The BlueHealth project aims to understand the relationships between exposure to blue space and health and well-being, to map and quantify the public health impacts of changes to both natural blue spaces and associated urban infrastructure in Europe, and to provide evidence-based information to policymakers on how to maximise health benefits associated with interventions in and around aquatic environments. To achieve these aims, an evidence base will be created through systematic reviews, analyses of secondary data sets and analyses of new data collected through a bespoke international survey and a wide range of community-level interventions. We will also explore how to deliver the benefits associated with blue spaces to those without direct access through the use of virtual reality. Scenarios will be developed that allow the evaluation of health impacts in plausible future societal contexts and changing environments. BlueHealth will develop key inputs into policymaking and land/water-use planning towards more salutogenic and sustainable uses of blue space, particularly in urban areas. ETHICS AND DISSEMINATION: Throughout the BlueHealth project, ethics review and approval are obtained for all relevant aspects of the study by the local ethics committees prior to any work being initiated and an ethics expert has been appointed to the project advisory board. So far, ethical approval has been obtained for the BlueHealth International Survey and for community-level interventions taking place in Spain, Italy and the UK. Engagement of stakeholders, including the public, involves citizens in many aspects of the project. Results of all individual studies within the BlueHealth project will be published with open access. After full anonymisation and application of any measures necessary to prevent disclosure, data generated in the project will be deposited into open data repositories of the partner institutions, in line with a formal data management plan. Other knowledge and tools developed in the project will be made available via the project website (www.bluehealth2020.eu). Project results will ultimately provide key inputs to planning and policy relating to blue space, further stimulating the integration of environmental and health considerations into decision-making, such that blue infrastructure is developed across Europe with both public health and the environment in mind.This work was supported by funding received from the European Union’s Horizon 2020 research and innovation programme under grant agreement no. 666773

A Plasmodium falciparum FcB1-schizont-EST collection providing clues to schizont specific gene structure and polymorphism

<p>Abstract</p> <p>Background</p> <p>The <it>Plasmodium falciparum </it>genome (3D7 strain) published in 2002, revealed ~5,400 genes, mostly based on <it>in silico </it>predictions. Experimental data is therefore required for structural and functional assessments of <it>P. falciparum </it>genes and expression, and polymorphic data are further necessary to exploit genomic information to further qualify therapeutic target candidates. Here, we undertook a large scale analysis of a <it>P. falciparum </it>FcB1-schizont-EST library previously constructed by suppression subtractive hybridization (SSH) to study genes expressed during merozoite morphogenesis, with the aim of: 1) obtaining an exhaustive collection of schizont specific ESTs, 2) experimentally validating or correcting <it>P. falciparum </it>gene models and 3) pinpointing genes displaying protein polymorphism between the FcB1 and 3D7 strains.</p> <p>Results</p> <p>A total of 22,125 clones randomly picked from the SSH library were sequenced, yielding 21,805 usable ESTs that were then clustered on the <it>P. falciparum </it>genome. This allowed identification of 243 protein coding genes, including 121 previously annotated as hypothetical. Statistical analysis of GO terms, when available, indicated significant enrichment in genes involved in "entry into host-cells" and "actin cytoskeleton". Although most ESTs do not span full-length gene reading frames, detailed sequence comparison of FcB1-ESTs versus 3D7 genomic sequences allowed the confirmation of exon/intron boundaries in 29 genes, the detection of new boundaries in 14 genes and identification of protein polymorphism for 21 genes. In addition, a large number of non-protein coding ESTs were identified, mainly matching with the two A-type rRNA units (on chromosomes 5 and 7) and to a lower extent, two atypical rRNA loci (on chromosomes 1 and 8), TARE subtelomeric regions (several chromosomes) and the recently described telomerase RNA gene (chromosome 9).</p> <p>Conclusion</p> <p>This FcB1-schizont-EST analysis confirmed the actual expression of 243 protein coding genes, allowing the correction of structural annotations for a quarter of these sequences. In addition, this analysis demonstrated the actual transcription of several remarkable non-protein coding loci: 2 atypical rRNA, TARE region and telomerase RNA gene. Together with other collections of <it>P. falciparum </it>ESTs, usually generated from mixed parasite stages, this collection of FcB1-schizont-ESTs provides valuable data to gain further insight into the <it>P. falciparum </it>gene structure, polymorphism and expression.</p

Associations between green/blue spaces and mental health across 18 countries

Living near, recreating in, and feeling psychologically connected to, the natural world are all associated with better mental health, but many exposure-related questions remain. Using data from an 18-country survey (n= 16,307) we explored associations between multiple measures of mental health (positive well-being, mental distress, depression/anxiety medication use) and: (a) exposures (residential/recreational visits) to diferent natural settings (green/inland-blue/coastalblue spaces); and (b) nature connectedness, across season and country. People who lived in greener/ coastal neighbourhoods reported higher positive well-being, but this association largely disappeared when recreational visits were controlled for. Frequency of recreational visits to green, inland-blue, and coastal-blue spaces in the last 4 weeks were all positively associated with positive well-being and negatively associated with mental distress. Associations with green space visits were relatively consistent across seasons and countries but associations with blue space visits showed greater heterogeneity. Nature connectedness was also positively associated with positive well-being and negatively associated with mental distress and was, along with green space visits, associated with a lower likelihood of using medication for depression. By contrast inland-blue space visits were associated with a greater likelihood of using anxiety medication. Results highlight the benefts of multi-exposure, multi-response, multi-country studies in exploring complexity in nature-health associations.info:eu-repo/semantics/publishedVersio

Mapping Out the Role of σ-Silane Complexes in the Ruthenium-Catalyzed Hydrosilylation of Nitriles

A combined synthetic, mechanistic, and computational study is reported, which provides unique insight into the role of σ-silane complexes in the catalytic hydrosilylation of nitriles. A novel, highly efficient, highly active, and regioselective catalytic monohydrosilylation of aromatic nitriles with secondary silanes using a ruthenium dihydrogen catalyst is reported along with a novel mechanism for hydrosilylation of nitriles. Investigations into the mechanism of this transformation have revealed the influence of σ-Si-H complexes in fine-tuning the selectivity of this hydrosilylation reaction. Displacement of the dihydrogen ligand on the ruthenium precatalyst, ruthenium bis-(dihydrogen) complex [RuH2(η2-H2)2(PCy3)2], 1, by diphenylsilane leads to the formation of new ruthenium σ-Si-H complexes, [RuH2(η2-H2)(η2-HSiHPh2)(PCy3)2], 2, and [RuH2(η3-H2SiPh2)(PCy3)2], 3. Complex 3 reacts readily with benzonitrile leading to hydrosilylation of the nitrile and coordination of the silylimine formed to the ruthenium as a σ-H-Si-N-silylimine complex, [RuH2(η2-HSiPh2NCHPh)(PCy3)2] (4). This systematic investigation of this reactivity led to the discovery of the first direct evidence of an N-silylimine-coordinated ruthenium complex and its involvement in a catalytic hydrosilylation reaction. This led to the discovery of a catalytic protocol for the efficient and selective coupling of secondary silanes with a range of nitriles using 1 as the catalyst. It is proposed that complexes 3 and 4 are key intermediates on the catalytic reaction coordinate, which leads to hydrosilylation of the nitrile. This is supported by DFT calculations along with the observation that 3 and 4 are catalytically active. The Si-N bond formation was found to proceed via direct attack of the nitrile at the silicon atom in 3. Through carefully chosen structural studies and tests of the new ruthenium complexes, along with DFT calculations, the mechanism of the catalytic hydrosilylation of nitriles has been successfully explained

Research note: residential distance and recreational visits to coastal and inland blue spaces in eighteen countries

Varied categorisations of residential distance to bluespace in population health studies make comparisons difficult. Using survey data from eighteen countries, we modelled relationships between residential distance to blue spaces (coasts, lakes, and rivers), and self-reported recreational visits to these environments at least weekly, with penalised regression splines. We observed exponential declines in visit probability with increasing distance to all three environments and demonstrated the utility of derived categorisations. These categories may be broadly applicable in future research where the assumed underlying mechanism between residential distance to a blue space and a health outcome is direct recreational contact.info:eu-repo/semantics/publishedVersio

Molecular, functional and structural properties of the prolyl oligopeptidase of Trypanosoma cruzi (POP Tc80), which is required for parasite entry into mammalian cells.

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