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61.
Angell RM Atkinson FL Brown MJ Chuang TT Christopher JA Cichy-Knight M Dunn AK Hightower KE Malkakorpi S Musgrave JR Neu M Rowland P Shea RL Smith JL Somers DO Thomas SA Thompson G Wang R 《Bioorganic & medicinal chemistry letters》2007,17(5):1296-1301
The identification and exploration of a novel, potent and selective series of N-(3-cyano-4,5,6,7-tetrahydro-1-benzothien-2-yl)amide inhibitors of JNK2 and JNK3 kinases is described. Compounds 5a and 11a were identified as potent inhibitors of JNK3 (pIC50 6.7 and 6.6, respectively), with essentially equal potency against JNK2 (pIC50 6.5). Selectivity within the mitogen-activated protein kinase (MAPK) family, against JNK1, p38alpha and ERK2, was observed for the series. X-ray crystallography of 5e and 8a in JNK3 revealed a unique binding mode, with the 3-cyano substituent forming an H-bond acceptor interaction with the hinge region of the ATP-binding site. 相似文献
62.
C. A. McCartney D. J. Somers G. Fedak R. M. DePauw J. Thomas S. L. Fox D. G. Humphreys O. Lukow M. E. Savard B. D. McCallum J. Gilbert W. Cao 《Molecular breeding : new strategies in plant improvement》2007,20(3):209-221
FHB resistance QTL alleles from Nyuubai, Sumai-3, and Wuhan-1 were evaluated for their effect on Fusarium head blight (FHB)
index, Fusarium damaged kernels (FDK), deoxynivalenol (DON) accumulation, plant height, anthesis date, and numerous grain
quality traits in three elite Canadian spring wheat backgrounds. The three FHB resistance parameters were negatively correlated
with plant height in the three populations. The Wuhan-1 4B resistance allele was the most effective resistance allele but
was associated with a 9.3 cm increase in plant height. The Wuhan-1 2D, Nyuubai 3BSc, Sumai-3 3BSc, Nyuubai 5AS, and Sumai-3
5AS alleles were also effective FHB resistance alleles in these populations. The Nyuubai and Sumai-3 3BS alleles were the
least effective of the FHB resistance alleles in the FHB nursery tests. The Sumai-3 5AS resistance allele was significantly
associated with reduced grain protein content, while the same trend was observed for the Nyuubai 5AS resistance allele but
was not significant. FHB resistance tended to increase with more FHB resistance alleles introgressed into the elite genetic
background, which suggested that marker-assisted selection (MAS) will prove useful for improving FHB resistance in Canadian
germplasm. 相似文献
63.
64.
Somers SJ Lacerda L Opie L Lecour S 《Physiological research / Academia Scientiarum Bohemoslovaca》2011,60(6):971-974
Postconditioning (PostC) is a recently discovered phenomenon whereby brief repetitive cycles of ischaemia with intermittent reperfusion following prolonged ischaemia elicit cardioprotection. This study investigated whether the age, genetic characteristics or number of repetitive cycles influenced the protective effect of PostC in mice. C57BL/6 floxed or non-floxed STAT-3 mice aged between 14-16 weeks (young) or 18-20 weeks (older) were perfused on a Langendorff apparatus and subjected to 35 min global ischaemia and 45 min reperfusion. PostC was elicited by either 3 (PostC-3) or 6 cycles (PostC-6) of 10 s ischaemia and 10 s reperfusion. PostC-3 and PostC-6 in both young and older non-floxed mice reduced the myocardial infarct size. In contrast, only PostC-3 reduced myocardial infarct size in young floxed mice. Neither PostC-3 nor PostC-6 reduced the infarct in older floxed mice. Our data reveal that genetic characteristics, a minute difference in age or the number of postconditioning cycles are critical factors to be considered for the successful effect of ischaemic postconditioning in a murine model. Moreover, these factors should be taken into consideration for future experimental research or clinical applications of this protective phenomenon. 相似文献
65.
Brooke R Snyder Pei-Hsun Cheng Jinjing Yang Shang-Hsun Yang Anderson HC Huang Anthony WS Chan 《BMC cell biology》2011,12(1):1-8
Background
Activation by extracellular ligands of G protein-coupled (GPCRs) and tyrosine kinase receptors (RTKs), results in the generation of second messengers that in turn control specific cell functions. Further, modulation/amplification or inhibition of the initial signalling events, depend on the recruitment onto the plasma membrane of soluble protein effectors. High throughput methodologies to monitor quantitatively second messenger production, have been developed over the last years and are largely used to screen chemical libraries for drug development. On the contrary, no such high throughput methods are yet available for the other aspect of GPCRs regulation, i.e. protein translocation to the plasma membrane, despite the enormous interest of this phenomenon for the modulation of receptor downstream functions. Indeed, to date, the experimental procedures available are either inadequate or complex and expensive.Results
Here we describe the development of a novel conceptual approach to the study of cytosolic proteins translocation to the inner surface of the plasma membrane. The basis of the technique consists in: i) generating chimeras between the protein of interests and the calcium (Ca2+)-sensitive, luminescent photo-protein, aequorin and ii) taking advantage of the large Ca2+ concentration [Ca2+] difference between bulk cytosolic and the sub-plasma membrane rim.Conclusion
This approach, that keeps unaffected the translocation properties of the signalling protein, can in principle be applied to any protein that, upon activation, moves from the cytosol to the plasma membrane. Thus, not only the modulation of GPCRs and RTKs can be investigated in this way, but that of all other proteins that can be recruited to the plasma membrane also independently of receptor activation. Moreover, its automated version, which can provide information about the kinetics and concentration-dependence of the process, is also applicable to high throughput screening of drugs affecting the translocation process. 相似文献66.
In most animals, multiple genes encode protein kinase C (PKC) proteins. Pharmacological studies have revealed numerous roles for this protein family, yet the in vivo roles of specific PKC proteins and the functional targets of PKC activation are poorly understood. We find that in Caenorhabditis elegans, two PKC genes, pkc-1 and tpa-1, are required for mechanosensory response; the role of the nPKCε/η ortholog, pkc-1, was examined in detail. pkc-1 function is required for response to nose touch in adult C. elegans and pkc-1 likely acts in the interneurons that regulate locomotion which are direct synaptic targets of mechanosensory neurons. Previous studies have suggested numerous possible targets of pkc-1; our analysis indicates that pkc-1 may act via the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) pathway. We find that ERK/MAPK pathway function is required for mechanosensory response in C. elegans and that at least one component of this pathway, lin-45 Raf, acts in interneurons of the mechanosensory circuit. Genetic analysis indicates that lin-45 and pkc-1 act together to regulate nose touch response. Thus, these results functionally link two conserved signaling pathways in adult C. elegans neurons and define distinct roles for PKC genes in vivo. 相似文献
67.
Phage display is a high-throughput technology used to identify ligands for a given target. A drawback of the approach is the absence of PTMs in phage-displayed peptides. The applicability of phage display could be broadened considerably by the implementation of PTMs in this system. The aim of this study was to investigate the possible application of citrullination, a PTM of an arginine into a citrulline amino acid, in filamentous (M13) and lytic (T7) phage display. After in vitro citrullination of T7 and M13 phages, citrullination was confirmed and the infectivity of both citrullinated and non-citrullinated phage was compared by titer determination. We demonstrated the successful in vitro citrullination of T7 and M13 phage-displayed peptides. This in vitro modification did not affect the viability or infectivity of the T7 virions, a necessary prerequisite for the implementation of this approach in T7 phage display. For M13 phage, however, the infecting phage titer decreased five-fold upon citrullination, limiting the use of this modification in M13 phage display. In conclusion, in vitro citrullination can be applied in T7 phage display giving rise to a high-throughput and sensitive approach to identify citrulline-containing ligands by the use of the strengths of phage display technology. 相似文献
68.
Corveleyn A Janssen H Martini A Somers R Cools J Marynen P 《Journal of cellular biochemistry》2005,94(6):1112-1125
69.
Three current papers in Cell and in this issue of Developmental Cell highlight the role of the exocyst in recycling of membrane proteins from endosomes to the plasma membrane in asymmetric cell division and polarized epithelial cells. 相似文献
70.