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51.
Trinidad Montero-Melendez Rachel A. E. Forfar Jennifer M. Cook Jeffrey C. Jerman Debra L. Taylor Mauro Perretti 《Cellular and molecular life sciences : CMLS》2017,74(7):1335-1345
The efficiency of drug research and development has paradoxically declined over the last decades despite major scientific and technological advances, promoting new cost-effective strategies such as drug repositioning by systematic screening for new actions of known drugs. Here, we performed a screening for positive allosteric modulators (PAMs) at melanocortin (MC) receptors. The non-steroidal anti-inflammatory drug fenoprofen, but not the similar compound ibuprofen, presented PAM activity at MC3, MC4, and MC5 receptors. In a model of inflammatory arthritis, fenoprofen afforded potent inhibition while ibuprofen was nearly inactive. Fenoprofen presented anti-arthritic actions on cartilage integrity and synovitis, effects markedly attenuated in Mc3r?/? mice. Fenoprofen displayed pro-resolving properties promoting macrophage phagocytosis and efferocytosis, independently of cyclooxygenase inhibition. In conclusion, combining repositioning with advances in G-protein coupled receptor biology (allosterism) may lead to potential new therapeutics. In addition, MC3 PAMs emerged as a viable approach to the development of innovative therapeutics for joint diseases. 相似文献
52.
<正>Dedication.This Special Issue on Parameterized Complexity of Tsinghua Science and Technology is a tribute to the influential contributions of Jianer Chen to parameterized complexity algorithmics.It is an occasion to celebrate the many important contributions to this new and prospering branch of theoretical computer science made by Jianer Chen,as he reaches the ripe young age of 60.Happy birthday,Jianer,from 相似文献
53.
Rodney G.Downey ;Judith Egan ;Michael R.Fellows ;Frances A.Rosamond ;Peter Shaw 《清华大学学报》2014,(4):329-337
The main purpose of this paper is to exposit two very different, but very general, motivational schemes in the art of parameterization and a concrete example connecting them. We introduce a dynamic version of the DOMINATING SET problem and prove that it is fixed-parameter tractable(FPT). The problem is motivated by settings where problem instances evolve. It also arises in the quest to improve a natural greedy heuristic for the DOMINATING SET problem. 相似文献
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55.
Vincent A. van der Mark Mohammed Ghiboub Casper Marsman Jing Zhao Remco van Dijk Johan K. Hiralall Kam S. Ho-Mok Zoë Castricum Wouter J. de Jonge Ronald P. J. Oude Elferink Coen C. Paulusma 《Cellular and molecular life sciences : CMLS》2017,74(4):715-730
P4-ATPases are lipid flippases that catalyze the transport of phospholipids to create membrane phospholipid asymmetry and to initiate the biogenesis of transport vesicles. Here we show, for the first time, that lipid flippases are essential to dampen the inflammatory response and to mediate the endotoxin-induced endocytic retrieval of Toll-like receptor 4 (TLR4) in human macrophages. Depletion of CDC50A, the β-subunit that is crucial for the activity of multiple P4-ATPases, resulted in endotoxin-induced hypersecretion of proinflammatory cytokines, enhanced MAP kinase signaling and constitutive NF-κB activation. In addition, CDC50A-depleted THP-1 macrophages displayed reduced tolerance to endotoxin. Moreover, endotoxin-induced internalization of TLR4 was strongly reduced and coincided with impaired endosomal MyD88-independent signaling. The phenotype of CDC50A-depleted cells was also induced by separate knockdown of two P4-ATPases, namely ATP8B1 and ATP11A. We conclude that lipid flippases are novel elements of the innate immune response that are essential to attenuate the inflammatory response, possibly by mediating endotoxin-induced internalization of TLR4. 相似文献
56.
Learning organisation literature has widely discussed the connections between “double-loop” learning and its significance to organisational performance, but paying little attention to tools and systems that can operationalise “double-loop” learning in organisations. This paper investigates the impact of applying a systems approach for service operations design, expressed as the Vanguard Method (Seddon, Freedom from command and control: a better way to make the work work, 2003), in order to activate “double-loop” learning in service organisations. Two case studies were conducted in the banking mortgage operations and adults’ social care services in the UK, using the dimensions of the learning organisation questionnaire (DLOQ), semi-structured interviews, observations, and documents. The findings of the cross-case analysis support the link of applying the Vanguard Method with operationalising “double-loop” learning through three main factors, namely systematic-operations improvement, organisational capacity development, and outside-in mode of work; that are all embedded into the seven dimensions of the DLOQ. The value of this paper is the introduction of a service operations design tool that can activate “double-loop” learning performance in the fast changing knowledge era. It also provides an impetus for service organisations to creatively influence employees’ competencies to effectively improve internal systems. 相似文献
57.
Patricia A. Burrowes María Celeste Martes Mónica Torres-Ríos Ana V. Longo 《Journal of Natural History》2017,51(11-12):643-656
Pathogen-mediated changes in host behaviour can result from hosts altering their habitat preferences. Although infection risk with pathogenic fungus Batrachochytrium dendrobatidis in amphibians is associated with environments favouring its growth, the relationship with microhabitat use has not been examined. Here, we aim to determine if microhabitats used by frogs during their nocturnal activity predict B. dendrobatidis prevalence and infection intensity. Our focal host, Eleutherodactylus coqui, is a habitat generalist that uses multiple habitats from the forest floor to the canopy. We analysed data on B. dendrobatidis occurrence in 157 adults and 122 juveniles at El Yunque National forest in Puerto Rico. We categorized each individual’s nocturnal microhabitat as forest floor, curled palm fronds in the floor, arboreal bromeliads and foliage or tree trunks 50 cm to 2.5 m above ground. We found that frogs on the forest floor had the greatest B. dendrobatidis prevalence (73%), compared with those active in vegetation above ground (55%). Overall, the probability of B. dendrobatidis infection in frogs using microhabitats on the forest floor was twice as great as for those on arboreal substrates. Differences in B. dendrobatidis prevalence and intensity in E. coqui may be explained by specific abiotic conditions of microenvironments (temperature and humidity) affecting both pathogen and host, and by the age-specific ecological requirements of hosts. Adults were found to be most active in microhabitats where individuals had lower infection burdens, suggesting pathogen-modulated habitat choice. This work has important implications for the evolutionary dynamics of enzootic diseases and provides data that may inform potential mitigation strategies against a generalist amphibian pathogen. 相似文献
58.
Miguel Bernabé-Rubio Miguel A. Alonso 《Cellular and molecular life sciences : CMLS》2017,74(22):4077-4095
Primary cilia are solitary, microtubule-based protrusions of the cell surface that play fundamental roles as photosensors, mechanosensors and biochemical sensors. Primary cilia dysfunction results in a long list of developmental and degenerative disorders that combine to give rise to a large spectrum of human diseases affecting almost any major body organ. Depending on the cell type, primary ciliogenesis is initiated intracellularly, as in fibroblasts, or at the cell surface, as in renal polarized epithelial cells. In this review, we have focused on the routes of primary ciliogenesis placing particular emphasis on the recently described pathway in renal polarized epithelial cells by which the midbody remnant resulting from a previous cell division event enables the centrosome for initiation of primary cilium assembly. The protein machinery implicated in primary cilium formation in epithelial cells, including the machinery best known for its involvement in establishing cell polarity and polarized membrane trafficking, is also discussed. 相似文献
59.
60.
Marcelo S. Perlin João F. Caldeira André A. P. Santos Martin Pontuschka 《Journal of forecasting》2017,36(4):454-467
We look into the interaction of Google's search queries and several aspects of international equity markets. Using a novel methodology for selecting words and a vector autoregressive modeling approach, we study whether the search queries of finance‐related words can have an impact on returns, volatility of returns and traded volume in four different English‐speaking countries. We identify several words whose search frequency is associated with changes in the dependent variables. In particular, we find that increases in search queries including the word stock predict increased volatility and decreased index returns over the next week. On top of that, we investigate the performance of a market‐timing strategy based on the search frequency of this word and benchmark it against random words from the Word‐Net database and a naive buy‐and‐hold strategy. The results of this empirical application are positive and particularly stronger during the global crisis of 2009. Copyright © 2016 John Wiley & Sons, Ltd. 相似文献