2,038 research outputs found

    Exploration of a potent PI3 kinase/mTOR inhibitor as a novel anti-fibrotic agent in IPF

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    © 2016 BMJ Publishing Group Ltd & British Thoracic Society.Rationale Idiopathic pulmonary fibrosis (IPF) is the most rapidly progressive and fatal of all fibrotic conditions with no curative therapies. Common pathomechanisms between IPF and cancer are increasingly recognised, including dysfunctional pan-PI3 kinase (PI3K) signalling as a driver of aberrant proliferative responses. GSK2126458 is a novel, potent, PI3K/mammalian target of rapamycin (mTOR) inhibitor which has recently completed phase I trials in the oncology setting. Our aim was to establish a scientific and dosing framework for PI3K inhibition with this agent in IPF at a clinically developable dose. Methods We explored evidence for pathway signalling in IPF lung tissue and examined the potency of GSK2126458 in fibroblast functional assays and precision-cut IPF lung tissue. We further explored the potential of IPF patient-derived bronchoalveolar lavage (BAL) cells to serve as pharmacodynamic biosensors to monitor GSK2126458 target engagement within the lung. Results We provide evidence for PI3K pathway activation in fibrotic foci, the cardinal lesions in IPF. GSK2126458 inhibited PI3K signalling and functional responses in IPF-derived lung fibroblasts, inhibiting Akt phosphorylation in IPF lung tissue and BAL derived cells with comparable potency. Integration of these data with GSK2126458 pharmacokinetic data from clinical trials in cancer enabled modelling of an optimal dosing regimen for patients with IPF. Conclusions Our data define PI3K as a promising therapeutic target in IPF and provide a scientific and dosing framework for progressing GSK2126458 to clinical testing in this disease setting. A proof-ofmechanism trial of this agent is currently underway. Trial registration number NCT01725139, pre-clinical

    A systematic review of adaptive wildlife management for the control of invasive, non-native mammals, and other human–wildlife conflicts

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    1.We are entering an era where species declines are occurring at their fastest ever rate, and the increased spread of non-native species is among the top causes. High uncertainty in biological processes makes the accurate prediction of the outcomes of management interventions very challenging. Adaptive management (AM) offers solutions to reduce uncertainty and improve predictability so that the outcomes of interventions can continuously improve. 2.We quantitatively assess the extent to which AM is used for managing vertebrates, with a focus on invasive non-native species (INNS). Using the Web of Science, we evaluated 3992 articles returned by the search terms ‘adaptive management’ or ‘adaptive harvest management’ against seven recommended elements of AM (engagement with stakeholders, defining objectives, forecasting and estimating uncertainty, implementing management, monitoring populations, adjusting management in response to monitoring, and improving forecasting and reducing uncertainty in response to monitoring populations). 3.The use of AM for vertebrates was reported in 56 (1%) of the evaluated studies; including four for managing INNS. Of these, ten studies excluding INNS and no studies of INNS management implemented all seven recommended elements of AM. Those elements infrequently implemented were: the use of analysis or models to forecast and represent uncertainty (44%) and the feedback of monitoring data to improve forecasting and reduce uncertainty (25%). 4.Complete active AM has rarely been implemented and reported for managing INNS, despite the significant advantages it offers. Among studies purporting to have implemented AM, most did not use analyses or models to forecast and represent uncertainty, while most defined objectives, implemented management, and monitored populations.5.Improvements to ongoing control programmes and much broader adoption of the AM approach are required to increase the efficiency and success of INNS management campaigns and reduce their negative impacts on native species

    Properties of Light Flavour Baryons in Hypercentral quark model

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    The light flavour baryons are studied within the quark model using the hyper central description of the three-body system. The confinement potential is assumed as hypercentral coulomb plus power potential (hCPPνhCPP_\nu) with power index ν\nu. The masses and magnetic moments of light flavour baryons are computed for different power index, ν\nu starting from 0.5 to 1.5. The predicted masses and magnetic moments are found to attain a saturated value with respect to variation in ν\nu beyond the power index ν>\nu> 1.0. Further we computed transition magnetic moments and radiative decay width of light flavour baryons. The results are in good agreement with known experimental as well as other theoretical models.Comment: Accepted in Pramana J. of Physic

    Spatial ecology of jaguars, pumas, and ocelots: a review of the state of knowledge

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    Knowledge of the spatial ecology of mammalian carnivores is critical for understanding species’ biology and designing effective conservation and management interventions. We reviewed the available information about the spatial ecology of jaguars Panthera onca, pumas Puma concolor, and ocelots Leopardus pardalis, and we examined how sex and extrinsic variables affect their spatial behaviour. Sixty-one articles addressing home range, home range overlap, daily net displacement (straight-line distance between two locations on consecutive days), and/or distance of dispersal of the three species were included. Meta-analysis, ANOVA, ANCOVA, and beta regression tests were run to analyse differences among species and sexes and to elucidate the influence of other variables, such as latitude and ecoregion, on spatial behaviour. Pumas had on average larger home ranges (mean ± SE: 281.87 ± 35.76 km) than jaguars (128.61 ± 49.5 km) and ocelots (12.46 ± 3.39 km). Intersexual range overlap was higher than intrasexual range overlap in jaguars and pumas. Sex affected the home range size of all three species, but only influenced daily net displacement in ocelots. Ecoregion affected the home range size of all three species but did not significantly affect either the daily net displacement or the dispersal distance of pumas. Latitude affected the home range size of jaguars and pumas. It did not affect daily net displacement or dispersal distance in jaguars and pumas, but did affect daily net displacement in ocelots. Although there was a lack of studies in most countries for the three species, information was particularly lacking in the Neotropics for jaguars and pumas and in North America for ocelots. Researchers usually presented low sample sizes and used different methods to examine the ecological issues considered here. Homogenisation of methods is needed to clarify the ecology of these species and to allow a better understanding of the threats to their populations.Peer Reviewe

    Mosquito Abundance, Bed net Coverage and Other Factors Associated with Variations in Sporozoite Infectivity Rates in Four Villages of Rural Tanzania.

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    Entomological surveys are of great importance in decision-making processes regarding malaria control strategies because they help to identify associations between vector abundance both species-specific ecology and disease intervention factors associated with malaria transmission. Sporozoite infectivity rates, mosquito host blood meal source, bed net coverage and mosquito abundance were assessed in this study. A longitudinal survey was conducted in four villages in two regions of Tanzania. Malaria vectors were sampled using the CDC light trap and pyrethrum spray catch methods. In each village, ten paired houses were selected for mosquitoes sampling. Sampling was done in fortnight case and study was undertaken for six months in both Kilimanjaro (Northern Tanzania) and Dodoma (Central Tanzania) regions. A total of 6,883 mosquitoes were collected including: 5,628 (81.8%) Anopheles arabiensis, 1,100 (15.9%) Culex quinquefasciatus, 89 (1.4%) Anopheles funestus, and 66 (0.9%) Anopheles gambiae s.s. Of the total mosquitoes collected 3,861 were captured by CDC light trap and 3,022 by the pyrethrum spray catch method. The overall light trap: spray catch ratio was 1.3:1. Mosquito densities per room were 96.5 and 75.5 for light trap and pyrethrum spray catch respectively. Mosquito infectivity rates between villages that have high proportion of bed net owners and those without bed nets was significant (P < 0.001) and there was a significant difference in sporozoite rates between households with and without bed nets in these four villages (P < 0.001). Malaria remains a major problem in the study areas characterized as low transmission sites. Further studies are required to establish the annual entomological inoculation rates and to observe the annual parasitaemia dynamics in these communities. Outdoor mosquitoes collection should also be considered

    The extraordinary evolutionary history of the reticuloendotheliosis viruses

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    The reticuloendotheliosis viruses (REVs) comprise several closely related amphotropic retroviruses isolated from birds. These viruses exhibit several highly unusual characteristics that have not so far been adequately explained, including their extremely close relationship to mammalian retroviruses, and their presence as endogenous sequences within the genomes of certain large DNA viruses. We present evidence for an iatrogenic origin of REVs that accounts for these phenomena. Firstly, we identify endogenous retroviral fossils in mammalian genomes that share a unique recombinant structure with REVs—unequivocally demonstrating that REVs derive directly from mammalian retroviruses. Secondly, through sequencing of archived REV isolates, we confirm that contaminated Plasmodium lophurae stocks have been the source of multiple REV outbreaks in experimentally infected birds. Finally, we show that both phylogenetic and historical evidence support a scenario wherein REVs originated as mammalian retroviruses that were accidentally introduced into avian hosts in the late 1930s, during experimental studies of P. lophurae, and subsequently integrated into the fowlpox virus (FWPV) and gallid herpesvirus type 2 (GHV-2) genomes, generating recombinant DNA viruses that now circulate in wild birds and poultry. Our findings provide a novel perspective on the origin and evolution of REV, and indicate that horizontal gene transfer between virus families can expand the impact of iatrogenic transmission events

    Ultraviolet radiation shapes seaweed communities

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    Reciprocity as a foundation of financial economics

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    This paper argues that the subsistence of the fundamental theorem of contemporary financial mathematics is the ethical concept ‘reciprocity’. The argument is based on identifying an equivalence between the contemporary, and ostensibly ‘value neutral’, Fundamental Theory of Asset Pricing with theories of mathematical probability that emerged in the seventeenth century in the context of the ethical assessment of commercial contracts in a framework of Aristotelian ethics. This observation, the main claim of the paper, is justified on the basis of results from the Ultimatum Game and is analysed within a framework of Pragmatic philosophy. The analysis leads to the explanatory hypothesis that markets are centres of communicative action with reciprocity as a rule of discourse. The purpose of the paper is to reorientate financial economics to emphasise the objectives of cooperation and social cohesion and to this end, we offer specific policy advice
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