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61.
Brian A. Davies Leslie O. Morton John R. Jefferson Cody N. Rozeveld Luke C. Doskey Nicholas F. LaRusso David J. Katzmann 《Molecular biology of the cell》2020,31(22):2463
Intercellular communication is critical for organismal homeostasis, and defects can contribute to human disease states. Polarized epithelial cells execute distinct signaling agendas via apical and basolateral surfaces to communicate with different cell types. Small extracellular vesicles (sEVs), including exosomes and small microvesicles, represent an understudied form of intercellular communication in polarized cells. Human cholangiocytes, epithelial cells lining bile ducts, were cultured as polarized epithelia in a Transwell system as a model with which to study polarized sEV communication. Characterization of isolated apically and basolaterally released EVs revealed enrichment in sEVs. However, differences in apical and basolateral sEV composition and numbers were observed. Genetic or pharmacological perturbation of cellular machinery involved in the biogenesis of intralumenal vesicles at endosomes (the source of exosomes) revealed general and domain-specific effects on sEV biogenesis/release. Additionally, analyses of signaling revealed distinct profiles of activation depending on sEV population, target cell, and the function of the endosomal sorting complex required for transport (ESCRT)-associated factor ALG-2–interacting protein X (ALIX) within the donor cells. These results support the conclusion that polarized cholangiocytes release distinct sEV pools to mediate communication via their apical and basolateral domains and suggest that defective ESCRT function may contribute to disease states through altered sEV signaling. 相似文献
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63.
David A. Sandham Claire Adcock Kamlesh Bala Lucy Barker Zarin Brown Gerald Dubois David Budd Brian Cox Robin A. Fairhurst Markus Furegati Catherine Leblanc Jodie Manini Rachael Profit John Reilly Rowan Stringer Alfred Schmidt Katharine L. Turner Simon J. Watson Jennifer Willis Gareth Williams Caroline Wilson 《Bioorganic & medicinal chemistry letters》2009,19(16):4794-4798
High throughput screening identified a 7-azaindole-3-acetic acid scaffold as a novel CRTh2 receptor antagonist chemotype, which could be optimised to furnish a highly selective compound with good functional potency for inhibition of human eosinophil shape change in whole blood and oral bioavailability in the rat. 相似文献
64.
Anita H. Lewin Hernán A. Navarro Brian P. Gilmour 《Bioorganic & medicinal chemistry letters》2009,19(20):5913-5914
The ability of amiodarone and its putative metabolites to activate unmodified human trace amine associated receptor 1 (hTAAR1) stably expressed in CHO cell lines was evaluated. Receptor activation was monitored by measuring the accumulation of cAMP, the putative hTAAR1 native second messenger, or calcium mobilization in cells where the receptor was coupled to the promiscuous Gq, Gα16. Despite literature reports of activation of rodent TAAR1 by these agents, no response was seen in either cell line although robust activation was obtained with the endogenous ligand β-phenethylamine. These results indicate that TAAR1 activation by amiodarone and its analogs is species specific. 相似文献
65.
Angelica Mendoza Beltran Brian Cox Chris Mutel Detlef P. van Vuuren David Font Vivanco Sebastiaan Deetman Oreane Y. Edelenbosch Jeroen Guinée Arnold Tukker 《Journal of Industrial Ecology》2020,24(1):64-79
Prospective life cycle assessment (LCA) needs to deal with the large epistemological uncertainty about the future to support more robust future environmental impact assessments of technologies. This study proposes a novel approach that systematically changes the background processes in a prospective LCA based on scenarios of an integrated assessment model (IAM), the IMAGE model. Consistent worldwide scenarios from IMAGE are evaluated in the life cycle inventory using ecoinvent v3.3. To test the approach, only the electricity sector was changed in a prospective LCA of an internal combustion engine vehicle (ICEV) and an electric vehicle (EV) using six baseline and mitigation climate scenarios until 2050. This case study shows that changes in the electricity background can be very important for the environmental impacts of EV. Also, the approach demonstrates that the relative environmental performance of EV and ICEV over time is more complex and multifaceted than previously assumed. Uncertainty due to future developments manifests in different impacts depending on the product (EV or ICEV), the impact category, and the scenario and year considered. More robust prospective LCAs can be achieved, particularly for emerging technologies, by expanding this approach to other economic sectors beyond electricity background changes and mobility applications as well as by including uncertainty and changes in foreground parameters. A more systematic and structured composition of future inventory databases driven by IAM scenarios helps to acknowledge epistemological uncertainty and to increase the temporal consistency of foreground and background systems in LCAs of emerging technologies. 相似文献
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67.
Brian P. Chadwick 《Chromosoma》2009,118(6):675-681
Almost half of the human genome consists of repetitive DNA. Understanding what role these elements have in setting up chromatin
states that underlie gene and chromosome function in complex genomes is paramount. The function of some types of repetitive
DNA is obvious by virtue of their location, such as the alphoid arrays that define active centromeres. However, there are
many other types of repetitive DNA whose evolutionary origins and current roles in genome biology remain unknown. One type
of repetitive DNA that falls into this class is the macrosatellites. The relevance of these sequences to disease is clearly
demonstrated by the 4q macrosatellite (D4Z4), whereupon contraction in the size of the array is associated with the onset
of facioscapulohumeral muscular dystrophy. Here, I describe recent findings relating to the chromatin organization of D4Z4
and that of the X-linked macrosatellite DXZ4, highlighting the fact that these enigmatic sequences share more than a similar
name. 相似文献
68.
An increased cytoplasmic Ca2+ concentration ([Ca2+]i) has been implicated in the pathogenesis of cystic fibrosis. We compared the [Ca2+]i levels of normal and cystic fibrosis peripheral blood lymphocytes and Epstein-Barr virus-transformed lymphoblasts using quin 2, an internally trapped indicator. The [Ca2+]i levels of normal and cystic fibrosis cells were not significantly different. The ionophore-releasable intracellular Ca2+ stores were also comparable in both types of individual. 相似文献
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