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541.
Xue CB He X Roderick J Corbett RL Duan JJ Liu RQ Covington MB Newton RC Trzaskos JM Magolda RL Wexler RR Decicco CP 《Bioorganic & medicinal chemistry letters》2003,13(24):4293-4297
Rational design based on the broad spectrum MMP inhibitor CGS 27023A led to the identification of a novel series of cyclic succinate TACE inhibitors. As a mixture of two enantiomers, the lead compound 17b exhibited potent enzyme activity (IC(50)=8 nM) in the inhibition of porcine TNF-alpha converting enzyme (pTACE) and excellent selectivity over aggrecanase and MMP-1, -2 and -9. 相似文献
542.
The yeast nucleoporin Nup2p is associated primarily with the nuclear basket of nuclear pore complexes and is required for efficient importin-alpha:beta-mediated nuclear protein import as well as efficient nuclear export of Kap60p/importin-alpha. Residues 1-51 of Nup2p bind tightly to Kap60p and are required for Nup2p function in vivo. We have determined the 2.6 A resolution crystal structure of a complex between this region of Nup2p and the armadillo repeat domain of Kap60p. Nup2p binds along the inner concave groove of Kap60p, but its interaction interface is different from that employed for nuclear localization signal (NLS) recognition although there is some overlap between them. Nup2p binds Kap60p more strongly than NLSs and accelerates release of NLSs from Kap60p. Nup2p itself is released from Kap60p by Cse1p:RanGTP only in the presence of the importin-beta binding (IBB) domain of Kap60p. These data indicate that Nup2p increases the overall rate of nuclear trafficking by coordinating nuclear import termination and importin recycling as a concerted process. 相似文献
543.
The regulation of virulence in phytopathogenic Erwinia species: quorum sensing,antibiotics and ecological considerations 总被引:5,自引:0,他引:5
544.
Restriction digestion is routinely performed in a buffer compatible with the restriction enzyme used. To load the samples
on agarose gels for electrophoresis it is then necessary to add a loading buffer. A 10X loading buffer is often used, and
consists of a dye to track the electrophoresis and a dense solution so that the digestion mixture sinks into the well. We
describe a new buffer, which acts as a universal digestion buffer as well as a loading buffer. This avoids double handling
of samples, which wastes both time and consumables. Importantly, the efficiency of digestion was found not to be significantly
decreased in this new buffer. 相似文献
545.
546.
Colazo MG Kastelic JP Martínez MF Whittaker PR Wilde R Ambrose JD Corbett R Mapletoft RJ 《Theriogenology》2004,61(6):1115-1124
The objectives were to determine pregnancy rates following fixed-time AI (FTAI) in heifers: (1). given GnRH or estradiol cypionate (ECP) to synchronize follicular wave emergence and ovulation in a CIDR-based protocol; and (2). fed diets supplemented with flax or sunflower seeds. At two locations, Angus and crossbred Angus heifers (n=983) were examined ultrasonically to confirm reproductive maturity and randomly allocated to six synchronization groups in a 2 x 3 factorial design. On Day 0 (start of synchronization treatments), heifers received a CIDR and either 100 microg GnRH i.m. (n=492) or 1mg ECP plus 50 mg progesterone i.m. (n=491); in these groups, CIDR removal and PGF treatment were done concurrently on Days 7 and 8.5, respectively. Heifers were re-randomized to receive 0.5 mg ECP i.m. at CIDR removal or 24 h later (with FTAI 58-60 h after CIDR removal in both groups), or 100 microg GnRH i.m. concurrent with FTAI (52-54 h after CIDR removal). The heifers were fed a barley silage-based diet for 50 days (from Day -25 to 25) supplemented with 1kg/heifer per day of flax seed (n=321), sunflower seed (n=324), or no oilseed (n=338). Pregnancy rate to FTAI (overall, 56.2%) was not affected by treatment at CIDR insertion (P = 0.96) but was higher (P < 0.05) in heifers given ECP 24h after CIDR removal (216/330, 65.4%) than in those given either ECP at CIDR removal (168/322, 52.1%) or GnRH at AI (169/331, 51.1%). Overall, there was no effect of diet on pregnancy rates (P = 0.46). In summary, pregnancy rate to FTAI was not significantly affected by treatment at CIDR insertion to synchronize follicular wave emergence, but 0.5mg ECP 24h after CIDR removal (to synchronize ovulation) resulted in the highest pregnancy rate. 相似文献
547.
548.
549.
The regulated process of protein import into the nucleus of a eukaryotic cell is mediated by specific nuclear localization signals (NLSs) that are recognized by protein import receptors. This study seeks to decipher the energetic details of NLS recognition by the receptor importin alpha through quantitative analysis of variant NLSs. The relative importance of each residue in two monopartite NLS sequences was determined using an alanine scanning approach. These measurements yield an energetic definition of a monopartite NLS sequence where a required lysine residue is followed by two other basic residues in the sequence K(K/R)X(K/R). In addition, the energetic contributions of the second basic cluster in a bipartite NLS ( approximately 3 kcal/mol) as well as the energy of inhibition of the importin alpha importin beta-binding domain ( approximately 3 kcal/mol) were also measured. These data allow the generation of an energetic scale of nuclear localization sequences based on a peptide's affinity for the importin alpha-importin beta complex. On this scale, a functional NLS has a binding constant of approximately 10 nm, whereas a nonfunctional NLS has a 100-fold weaker affinity of 1 microm. Further correlation between the current in vitro data and in vivo function will provide the foundation for a comprehensive quantitative model of protein import. 相似文献
550.
Differential alterations in tachykinin NK2 receptors in isolated colonic circular smooth muscle in inflammatory bowel disease and idiopathic chronic constipation 总被引:12,自引:0,他引:12
Inflammatory bowel disease (IBD) and idiopathic chronic constipation (ICC) are intestinal disorders which disrupt normal colonic motility. Enteric tachykinins are well-recognised to play a role in the motor control of the gut, and increased colonic levels of substance P are seen in IBD, whereas decreased levels have been reported in ICC. In this investigation, we have characterised the tachykinin receptor population of normal human colonic circular smooth muscle and examined any changes that occur in IBD and ICC. The selective tachykinin NK2 receptor agonist, [beta-Ala8]neurokinin A(4-10), caused concentration-dependent contractions in healthy tissues; neither NK1 receptor-selective nor NK3 receptor-selective agonists were contractile. In diseased preparations also, only [beta-Ala8]neurokinin A(4-10) caused contractions with EC50 values similar to health. The maximum contractile responses (Emax), however, were significantly decreased in both forms of IBD but significantly increased in ICC. The muscarinic acetylcholine receptor agonist, carbachol, also caused contractions in diseased tissues, but EC50 and Emax values were not significantly different from health. The differential changes in contractility found in IBD and ICC are specific to NK2 receptors, and may reflect the altered levels of substance P or other tachykinins found in these intestinal disorders. 相似文献