29,804 research outputs found

    Confluence Competition 2015

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    Effect of oleic acid supplementation on prostaglandin production in maternal endometrial and fetal allantochorion cells isolated from late gestation ewes

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    Elevated circulating non-esterified fatty acids including oleic acid (OA) are associated with many pregnancy related complications. Prostaglandins (PGs) play crucial roles during parturition. We investigated the effect of OA supplementation on PG production using an in vitro model of ovine placenta

    Bitopic binding mode of an M1 muscarinic acetylcholine receptor agonist associated with adverse clinical trial outcomes

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    The realisation of the therapeutic potential of targeting the M1 muscarinic acetylcholine receptor (M1 mAChR) for the treatment of cognitive decline in Alzheimer's disease has prompted the discovery of M1 mAChR ligands showing efficacy in alleviating cognitive dysfunction in both rodents and humans. Among these is GSK1034702, described previously as a potent M1 receptor allosteric agonist, which showed pro-cognitive effects in rodents and improved immediate memory in a clinical nicotine withdrawal test but induced significant side-effects. Here we provide evidence using ligand binding, chemical biology and functional assays to establish that rather than the allosteric mechanism claimed, GSK1034702 interacts in a bitopic manner at the M1 mAChR such that it can concomitantly span both the orthosteric and an allosteric binding site. The bitopic nature of GSK1034702 together with the intrinsic agonist activity and a lack of muscarinic receptor subtype selectivity reported here, all likely contribute to the adverse effects of this molecule in clinical trials. We conclude that these properties, whilst imparting beneficial effects on learning and memory, are undesirable in a clinical candidate due to the likelihood of adverse side effects. Rather, our data supports the notion that "pure" positive allosteric modulators showing selectivity for the M1 mAChR with low levels of intrinsic activity would be preferable to provide clinical efficacy with low adverse responses

    Effects of cell elasticity on the migration behavior of a monolayer of motile cells: Sharp Interface Model

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    In order to study the effect of cell elastic properties on the behavior of assemblies of motile cells, this paper describes an alternative to the cell phase field (CPF) \cite{Palmieri2015} we have previously proposed. The CPF is a multi-scale approach to simulating many cells which tracked individual cells and allowed for large deformations. Though results were largely in agreement with experiment that focus on the migration of a soft cancer cell in a confluent layer of normal cells \cite{Lee2012}, simulations required large computing resources, making more detailed study unfeasible. In this work we derive a sharp interface limit of CPF, including all interactions and parameters. This new model offers over 200200 fold speedup when compared to our original CPF implementation. We demonstrate that this model captures similar behavior and allows us to obtain new results that were previously intractable. We obtain the full velocity distribution for a large range of degrees of confluence, ρ\rho, and show regimes where its tail is heavier and lighter than a normal distribution. Furthermore, we fully characterize the velocity distribution with a single parameter, and its dependence on ρ\rho is fully determined. Finally, cell motility is shown to linearly decrease with increasing ρ\rho, consistent with previous theoretical results

    Water Planning In Alcobaça Cistercian Lands / O Ordenamento Hidråulico no Território Cisterciense de Alcobaça

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    This paper concerns the main domain (coutos) of the Cistercian Abbey of Alcobaça (central Portugal), founded in 1153. It shows the involvement of the monks in shaping hydraulic landscapes along time. This monastic territory is limited westwards by the Atlantic ocean with a cliff coast indented by two large gulfs, the former Pederneira and Alfeizerão lagoons, sanded up presently. These landscapes have been consolidated along with the monks’ intervention in the hydrographic plan, particularly through a network of canals, the types of which can be summarized as follows: canals for water conveyance and evacuation, to and from the abbey buildings; canals related with water-powered engines as grain-, oil-, saw- and fulling-mills, forges and other industrial devices; canals consequent to the diversion of rivers and streams with two main purposes: to drain the fields in order to improve the marshes for agricultural use, and to irrigate cultures

    Heritage entrepreneurship. Agency-driven promotion of the Mediterranean diet in Spain.

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    This article explores the role of the agency in the social process that constitutes cultural heritage. By introducing the concept of heritage entrepreneurship to explain the conversion of cultural elements into heritage, we discuss the case of the Mediterranean diet (MD) in Spain. We explore the role of an expert NGO in the recent inclusion of the MD in the UNESCO Representative List of the intangible cultural heritage of Humanity. Empirical evidence is presented for two basic patterns of heritage entrepreneurship, namely the construction and promotion of cultural heritage. First, we show how the community-heritage narrative is constructed in the official nomination file of the MD. Second, we analyse how businesses, governments and researchers constitute a specific heritage entrepreneur. We argue that the promotion of the MD as cultural heritage makes ordinary food different, both qualitatively (healthy and sustainable) and culturally (Mediterranean and traditional). We then look at the specific political, economic and scientific value of such a difference and its uses in Spain
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