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the 14th letter of the Roman alphabet (同)n

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nitrogenの化学記号
neodymiumの化学記号

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1. 急性偽性腸閉塞（オギルビー症候群） acute colonic pseudo obstruction ogilvies syndrome
2. 慢性偽性腸閉塞 chronic intestinal pseudo obstruction
3. 世界各地における蛇咬傷：臨床症状および診断 snakebites worldwide clinical manifestations and diagnosis
4. 世界中でのヘビ咬傷：マネージメント snakebites worldwide management
5. 新生児および幼児における神経筋接合部障害 neuromuscular junction disorders in newborns and infants

English Journal

Long-term activation upon brief exposure to xanomleline is unique to M1 and M4 subtypes of muscarinic acetylcholine receptors.

Šantrůčková E1, Doležal V2, El-Fakahany EE1, Jakubík J2.Author information 1Department of Experimental and Clinical Pharmacology, University of Minnesota College of Pharmacy, Minneapolis, United States of America.2Institute of Physiology Academy of Sciences of the Czech Republic, Prague, Czech Republic.AbstractXanomeline is an agonist endowed with functional preference for M1/M4 muscarinic acetylcholine receptors. It also exhibits both reversible and wash-resistant binding to and activation of these receptors. So far the mechanisms of xanomeline selectivity remain unknown. To address this question we employed microfluorometric measurements of intracellular calcium levels and radioligand binding to investigate differences in the short- and long-term effects of xanomeline among muscarinic receptors expressed individually in Chinese hamster ovary cells. 1/One-min exposure of cells to xanomeline markedly increased intracellular calcium at hM1 and hM4, and to a lesser extent at hM2 and hM3 muscarinic receptors for more than 1 hour. 2/Unlike the classic agonists carbachol, oxotremorine, and pilocarpine 10-min exposure to xanomeline did not cause internalization of any receptor subtype. 3/Wash-resistant xanomeline selectively prevented further increase in intracellular calcium by carbachol at hM1 and hM4 receptors. 4/After transient activation xanomeline behaved as a long-term antagonist at hM5 receptors. 5/The antagonist N-methylscopolamine (NMS) reversibly blocked activation of hM1 through hM4 receptors by xanomeline. 6/NMS prevented formation of xanomeline wash-resistant binding and activation at hM2 and hM4 receptors and slowed them at hM1, hM3 and hM5 receptors. Our results show commonalities of xanomeline reversible and wash-resistant binding and short-time activation among the five muscarinic receptor subtypes. However long-term receptor activation takes place in full only at hM1 and hM4 receptors. Moreover xanomeline displays higher efficacy at hM1 and hM4 receptors in primary phasic intracellular calcium release. These findings suggest the existence of particular activation mechanisms specific to these two receptors.
PloS one.PLoS One.2014 Feb 18;9(2):e88910. doi: 10.1371/journal.pone.0088910. eCollection 2014.
Xanomeline is an agonist endowed with functional preference for M1/M4 muscarinic acetylcholine receptors. It also exhibits both reversible and wash-resistant binding to and activation of these receptors. So far the mechanisms of xanomeline selectivity remain unknown. To address this question we empl
PMID 24558448

New α-adrenergic property for synthetic MTβ and CM-3 three-finger fold toxins from black mamba.

Blanchet G1, Upert G, Mourier G, Gilquin B, Gilles N, Servent D.Author information 1CEA, iBiTec-S, Service d'Ingénierie Moléculaire des Protéines (SIMOPRO), F-91191 Gif sur Yvette, France; UFR Sciences de la Vie, Université Pierre et Marie Curie (UPMC), 4 place Jussieu, Paris, France.AbstractDespite their isolation more than fifteen years ago from the venom of the African mamba Dendroaspis polylepis, very few data are known on the functional activity of MTβ and CM-3 toxins. MTβ was initially classified as a muscarinic toxin interacting non-selectively and with low affinity with the five muscarinic receptor subtypes while no biological function was determined for CM-3. Recent results highlight the multifunctional activity of three-finger fold toxins for muscarinic and adrenergic receptors and reveal some discrepancies in the pharmacological profiles of their venom-purified and synthetic forms. Here, we report the pharmacological characterization of chemically-synthesized MTβ and CM-3 toxins on nine subtypes of muscarinic and adrenergic receptors and demonstrate their high potency for α-adrenoceptors and in particular a sub-nanomolar affinity for the α1A-subtype. Strikingly, no or very weak affinity were found for muscarinic receptors, highlighting that pharmacological characterizations of venom-purified peptides may be risky due to possible contaminations. The biological profile of these two homologous toxins looks like that one previously reported for the Dendroaspis angusticeps ρ-Da1a toxin. Nevertheless, MTβ and CM-3 interact more potently than ρ-Da1a with α1B- and α1D-AR subtypes. A computational analysis of the stability of the MTβ structure suggests that mutation S38I, could be involved in this gain in function.
Toxicon : official journal of the International Society on Toxinology.Toxicon.2013 Dec 1;75:160-7. doi: 10.1016/j.toxicon.2013.04.017. Epub 2013 May 3.
Despite their isolation more than fifteen years ago from the venom of the African mamba Dendroaspis polylepis, very few data are known on the functional activity of MTβ and CM-3 toxins. MTβ was initially classified as a muscarinic toxin interacting non-selectively and with low affinity with the fi
PMID 23648423

Efficacy as an intrinsic property of the M(2) muscarinic receptor in its tetrameric state.

Redka DS1, Heerklotz H, Wells JW.Author information 1Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto , Toronto, Ontario, Canada M5S 3M2.AbstractMuscarinic and other G protein-coupled receptors exhibit an agonist-specific heterogeneity that tracks efficacy and commonly is attributed to an effect of the G protein on an otherwise homogeneous population of sites. To examine this notion, M2 muscarinic receptors were purified from Sf9 cells as monomers devoid of G protein and reconstituted as tetramers in phospholipid vesicles. In assays with N-[(3)H]methylscopolamine, seven agonists revealed a dispersion of affinities indicative of two or more classes of sites. Unlabeled N-methylscopolamine and the antagonist quinuclidinylbenzilate recognized one class of sites; atropine recognized two classes with a preference that was the opposite of that of agonists, as indicated by the effects of N-ethylmaleimide. The data were inconsistent with an explicit model of constitutive asymmetry within a tetramer, and the fit improved markedly upon the introduction of cooperative interactions (P < 0.00001). Purified monomers appeared to be homogeneous or nearly so to all ligands except the partial agonists pilocarpine and McN-A-343, where heterogeneity emerged from intramolecular cooperativity between the orthosteric site and an allosteric site. The breadth of each dispersion was quantified empirically as the area between the fitted curve for two classes of sites and the theoretical curve for a single class of lower affinity, which approximates the expected effect of GTP if a G protein were present. The areas measured for 10 ligands at reconstituted tetramers correlated with similar measures of heterogeneity and with intrinsic activities reported previously for binding and response in natural membranes (P ≤ 0.00002). The data suggest that the GTP-sensitive heterogeneity typically revealed by agonists at M2 receptors is intrinsic to the receptor in its tetrameric state. It exists independently of the G protein, and it appears to arise at least in part from cooperativity between linked orthosteric sites.
Biochemistry.Biochemistry.2013 Oct 22;52(42):7405-27. doi: 10.1021/bi4003869. Epub 2013 Oct 11.
Muscarinic and other G protein-coupled receptors exhibit an agonist-specific heterogeneity that tracks efficacy and commonly is attributed to an effect of the G protein on an otherwise homogeneous population of sites. To examine this notion, M2 muscarinic receptors were purified from Sf9 cells as mo
PMID 24047497