²¹⁰Pb- ²²⁶Ra chronology reveals rapid growth rate of Madrepora oculata and Lophelia pertusa on world's largest cold-water coral reef

Here we show the use of the 210Pb- 226Ra excess method to determine the growth rate of two corals from the world's largest known cold-water coral reef, Røst Reef, north of the Arctic circle off Norway. Colonies of each of the two species that build the reef, Lophelia pertusa and Madrepora oculata, were collected alive at 350 m depth using a submersible. Pb and Ra isotopes were measured along the major growth axis of both specimens using low level alpha and gamma spectrometry and trace element compositions were studied. 210Pb and 226Ra differ in the way they are incorporated into coral skeletons. Hence, to assess growth rates, we considered the exponential decrease of initially incorporated 210Pb, as well as the increase in 210Pb from the decay of 226Ra and contamination with 210Pb associated with Mn-Fe coatings that we were unable to remove completely from the oldest parts of the skeletons. 226Ra activity was similar in both coral species, so, assuming constant uptake of 210Pb through time, we used the 210Pb- 226Ra chronology to calculate growth rates. The 45.5 cm long branch of M. oculata was 31 yr with an average linear growth rate of 14.4 ± 1.1 mm yr -1 (2.6 polyps per year). Despite cleaning, a correction for Mn-Fe oxide contamination was required for the oldest part of the colony; this correction corroborated our radiocarbon date of 40 yr and a mean growth rate of 2 polyps yr -1. This rate is similar to the one obtained in aquarium experiments under optimal growth conditions. For the 80 cm-long L. pertusa colony, metal-oxide contamination remained in both the middle and basal part of the coral skeleton despite cleaning, inhibiting similar age and growth rate estimates. The youngest part of the colony was free of metal oxides and this 15 cm section had an estimated a growth rate of 8 mm yr -1, with high uncertainty (∼1 polyp every two to three years). We are less certain of this 210Pb growth rate estimate which is within the lowermost ranges of previous growth rate estimates. We show that 210Pb- 226Ra dating can be successfully applied to determine the age and growth rate of framework-forming cold-water corals if Mn-Fe oxide deposits can be removed. Where metal oxides can be removed, large M. oculata and L. pertusa skeletons provide archives for studies of intermediate water masses with an up to annual time resolution and spanning over many decades. © 2012 Author(s)

Role of endolysosomes in HIV-1 Tat-induced neurotoxicity

Combined anti-retroviral therapeutic drugs effectively increase the lifespan of HIV-1-infected individuals who then have a higher prevalence of HAND (HIV-1 associated neurocognitive disorder). Soluble factors including HIV-1 proteins released from HIV-1-infected cells have been implicated in the pathogenesis of HAND, and particular attention has been paid to the HIV-1 Tat (transactivator of transcription) protein because of its ability to directly excite neurons and cause neuronal cell death. Since HIV-1 Tat enters cells by receptor-mediated endocytosis and since endolysosomes play an important role in neuronal cell life and death, we tested here the hypothesis that HIV-1 Tat neurotoxicity is associated with changes in the endolysosome structure and function and also autophagy. Following the treatment of primary cultured rat hippocampal neurons with HIV-1 Tat or as controls mutant-Tat or PBS, neuronal viability was determined using a triple staining method. Preceding observations of HIV-1 Tat-induced neuronal cell death, we observed statistically significant changes in the structure and membrane integrity of endolysosomes, endolysosome pH and autophagy. As early as 24 h after HIV-1 Tat was applied to neurons, HIV-1 Tat accumulated in endolysosomes, endolysosome morphology was affected and their size increased, endolysosome membrane integrity was disrupted, endolysosome pH increased, specific activities of endolysosome enzymes decreased and autophagy was inhibited, as indicated by the significant changes in three markers for autophagy. In contrast, statistically significant levels of HIV-1 Tat-induced neuronal cell death were observed only after 48 h of HIV-1 Tat treatment. Our findings suggest that endolysosomes are involved in HIV-1 Tat-induced neurotoxicity and may represent a target for therapeutic intervention against HAND

Polarization of coalitions in an agent-based model of political discourse

Political discourse is the verbal interaction between political actors in a policy domain. This article explains the formation of polarized advocacy or discourse coalitions in this complex phenomenon by presenting a dynamic, stochastic, and discrete agent-based model based on graph theory and local optimization. In a series of thought experiments, actors compute their utility of contributing a specific statement to the discourse by following ideological criteria, preferential attachment, agenda-setting strategies, governmental coherence, or other mechanisms. The evolving macro-level discourse is represented as a dynamic network and evaluated against arguments from the literature on the policy process. A simple combination of four theoretical mechanisms is already able to produce artificial policy debates with theoretically plausible properties. Any sufficiently realistic configuration must entail innovative and path-dependent elements as well as a blend of exogenous preferences and endogenous opinion formation mechanisms

The impact of Cochrane Systematic Reviews : a mixed method evaluation of outputs from Cochrane Review Groups supported by the UK National Institute for Health Research

© 2014 Bunn et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background: There has been a growing emphasis on evidence-informed decision making in health care. Systematic reviews, such as those produced by the Cochrane Collaboration, have been a key component of this movement. The UK National Institute for Health Research (NIHR) Systematic Review Programme currently supports 20 Cochrane Review Groups (CRGs). The aim of this study was to identify the impacts of Cochrane reviews published by NIHR funded CRGs during the years 2007-11. Methods: We sent questionnaires to CRGs and review authors, interviewed guideline developers and used bibliometrics and documentary review to get an overview of CRG impact and to evaluate the impact of a sample of 60 Cochrane reviews. We used a framework with four categories (knowledge production, research targeting, informing policy development, and impact on practice/services). Results: A total of 1502 new and updated reviews were produced by the 20 NIHR funded CRGs between 2007-11. The clearest impacts were on policy with a total of 483 systematic reviews cited in 247 sets of guidance; 62 were international, 175 national (87 from the UK) and 10 local. Review authors and CRGs provided some examples of impact on practice or services, for example safer use of medication, the identification of new effective drugs or treatments and potential economic benefits through the reduction in the use of unproven or unnecessary procedures. However, such impacts are difficult to objectively document and the majority of reviewers were unsure if their review had produced specific impacts. Qualitative data suggested that Cochrane reviews often play an instrumental role in informing guidance although a poor fit with guideline scope or methods, reviews being out of date and a lack of communication between CRGs and guideline developers were barriers to their use. Conclusions: Health and economic impacts of research are generally difficult to measure. We found that to be the case with this evaluation. Impacts on knowledge production and clinical guidance were easier to identify and substantiate than those on clinical practice. Questions remain about how we define and measure impact and more work is needed to develop suitable methods for impact analysis.Peer reviewe

Evaluating the successful implementation of evidence into practice using the PARiHS framework : theoretical and practical challenges

Background The PARiHS framework (Promoting Action on Research Implementation in Health Services) has proved to be a useful practical and conceptual heuristic for many researchers and practitioners in framing their research or knowledge translation endeavours. However, as a conceptual framework it still remains untested and therefore its contribution to the overall development and testing of theory in the field of implementation science is largely unquantified. Discussion This being the case, the paper provides an integrated summary of our conceptual and theoretical thinking so far and introduces a typology (derived from social policy analysis) used to distinguish between the terms conceptual framework, theory and model – important definitional and conceptual issues in trying to refine theoretical and methodological approaches to knowledge translation. Secondly, the paper describes the next phase of our work, in particular concentrating on the conceptual thinking and mapping that has led to the generation of the hypothesis that the PARiHS framework is best utilised as a two-stage process: as a preliminary (diagnostic and evaluative) measure of the elements and sub-elements of evidence (E) and context (C), and then using the aggregated data from these measures to determine the most appropriate facilitation method. The exact nature of the intervention is thus determined by the specific actors in the specific context at a specific time and place. In the process of refining this next phase of our work, we have had to consider the wider issues around the use of theories to inform and shape our research activity; the ongoing challenges of developing robust and sensitive measures; facilitation as an intervention for getting research into practice; and finally to note how the current debates around evidence into practice are adopting wider notions that fit innovations more generally. Summary The paper concludes by suggesting that the future direction of the work on the PARiHS framework is to develop a two-stage diagnostic and evaluative approach, where the intervention is shaped and moulded by the information gathered about the specific situation and from participating stakeholders. In order to expedite the generation of new evidence and testing of emerging theories, we suggest the formation of an international research implementation science collaborative that can systematically collect and analyse experiences of using and testing the PARiHS framework and similar conceptual and theoretical approaches. We also recommend further refinement of the definitions around conceptual framework, theory, and model, suggesting a wider discussion that embraces multiple epistemological and ontological perspectives

Hydrogenation of alkylaromatics over Rh/silica

The hydrogenation, and competitive hydrogenation, of toluene, ethylbenzene, propylbenzene and the xylenes has been studied over a rhodium catalyst in the liquid phase at 323 K and 3 bar(g). The reactivity of the aromatics gave an order of para-xylene > ortho-xylene > meta-xylene > toluene > ethylbenzene ≫ propylbenzene. Kinetic analysis revealed that the order of reaction in hydrogen was typically first order while the reaction order in toluene was zero order and negative half order for ethylbenzene. The reaction order for propylbenzene and the xylenes was negative first order. Apparent activation energies were calculated and all were in the range 26–46 kJ mol−1. Competitive hydrogenation between toluene, ethylbenzene and propylbenzene revealed that the propylbenzene was the most strongly adsorbed aromatic in agreement with the strongly negative reaction order. The xylenes gave an order of reactivity of para > ortho > meta following the increasing negative reaction order. Reactions with deuterium revealed an inverse kinetic isotope effect, most likely related to the change in hybridization of the carbon from sp2 to sp3, for all reactions, except that of ortho-xylene. Rapid exchange of the methyl group hydrogens was observed with all the xylenes, whereas total exchange was noted with toluene. The generation of trans-1,2-dimethylcyclohexane was explained by the formation of two intermediates, 1,2-dimethylcyclohexene and 1,6-dimethylcyclohexene, which give the cis-1,2-dimethylcyclohexane and trans-1,2-dimethylcyclohexane, respectively

Fangchinoline Inhibits Human Immunodeficiency Virus Type 1 Replication by Interfering with gp160 Proteolytic Processing

The introduction of highly active antiretroviral therapy has led to a significant reduction in the morbidity and mortality of acquired immunodeficiency syndrome patients. However, the emergence of drug resistance has resulted in the failure of treatments in large numbers of patients and thus necessitates the development of new classes of anti-HIV drugs. In this study, more than 200 plant-derived small-molecule compounds were evaluated in a cell-based HIV-1 antiviral screen, resulting in the identification of a novel HIV-1 inhibitor (fangchinoline). Fangchinoline, a bisbenzylisoquinoline alkaloid isolated from Radix Stephaniae tetrandrae, exhibited antiviral activity against HIV-1 laboratory strains NL4-3, LAI and BaL in MT-4 and PM1 cells with a 50% effective concentration ranging from 0.8 to 1.7 µM. Mechanism-of-action studies showed that fangchinoline did not exhibit measurable antiviral activity in TZM-b1 cells but did inhibit the production of infectious virions in HIV-1 cDNA transfected 293T cells, which suggests that the compound targets a late event in infection cycle. Furthermore, the antiviral effect of fangchinoline seems to be HIV-1 enve1ope-dependent, as the production of infectious HIV-1 particles packaged with a heterologous envelope, the vesicular stomatitis virus G glycoprotein, was unaffected by fangchinoline. Western blot analysis of HIV envelope proteins expressed in transfected 293T cells and in isolated virions showed that fangchinoline inhibited HIV-1 gp160 processing, resulting in reduced envelope glycoprotein incorporation into nascent virions. Collectively, our results demonstrate that fangchinoline inhibits HIV-1 replication by interfering with gp160 proteolytic processing. Fangchinoline may serve as a starting point for developing a new HIV-1 therapeutic approach

Circulating CD62E+ Microparticles and Cardiovascular Outcomes

BACKGROUND: Activated endothelial cells release plasma membrane submicron vesicles expressing CD62E (E-selectin) into blood, known as endothelial microparticles (EMPs). We studied whether the levels of endothelial microparticles expressing CD62E(+), CD31(+)/Annexin-V(+), or CD31(+)/CD42(-) predict cardiovascular outcomes in patients with stroke history. METHODS/PRINCIPAL FINDINGS: Patients with stroke history at least 3 months prior to enrolment were recruited. Peripheral blood EMP levels were measured by flow cytometry. Major cardiovascular events and death were monitored for 36 months. Three hundred patients were enrolled, of which 298 completed the study according to protocol. Major cardiovascular events occurred in 29 patients (9.7%). Nine patients died, five from cardiovascular causes. Cumulative event-free survival rates were lower in patients with high levels of CD62E(+) microparticles. Multivariate Cox regression analysis adjusted for cardiovascular risk factors, medications and stroke etiologic groups showed an association between a high CD62E(+) microparticle level and a risk of major cardiovascular events and hospitalization. Levels of other kinds of EMPs expressing CD31(+)/Annexin-V(+) or CD31(+)/CD42(-) markers were not predictive of cardiovascular outcomes. CONCLUSION: A high level of CD62E(+) microparticles is associated with cardiovascular events in patients with stroke history, suggesting that the systemic endothelial activation increases the risk for cardiovascular morbidities

Resveratrol increases BRCA1 and BRCA2 mRNA expression in breast tumour cell lines

International audienceThe phytochemical resveratrol, found in grapes, berries and peanuts, has been found to possess cancer chemopreventive effects by inhibiting diverse cellular events associated with tumour initiation, promotion and progression. Resveratrol is also a phyto-oestrogen, binds to and activates oestrogen receptors that regulate the transcription of oestrogen-responsive target genes such as the breast cancer susceptibility genes BRCA1 and BRCA2. We investigated the effects of resveratrol on BRCA1 and BRCA2 expression in human breast cancer cell lines (MCF7, HBL 100 and MDA-MB 231) using quantitative real-time RT-PCR, and by perfusion chromatography of the proteins. All cell lines were treated with 30 microM resveratrol. The expressions of BRCA1 and BRCA2 mRNAs were increased although no change in the expression of the proteins were found. These data indicate that resveratrol at 30 micro M can increase expression of genes involved in the aggressiveness of human breast tumour cell lines