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61.
Xiao SH Farrelly E Anzola J Crawford D Jiao X Liu J Ayres M Li S Huang L Sharma R Kayser F Wesche H Young SW 《Analytical biochemistry》2007,367(2):179-189
Several drugs inhibiting protein kinases have been launched successfully, demonstrating the attractiveness of protein kinases as therapeutic targets. Functional genomics research within both academia and industry has led to the identification of many more kinases as potential drug targets. Although a number of well-known formats are used for measuring protein kinase activity, some less well-characterized protein kinases identified through functional genomics present particular challenges for existing assay formats when there is limited knowledge of the endogenous substrates or activation mechanisms for these novel kinase targets. This is especially the case when a very sensitive assay is required to differentiate often highly potent inhibitors developed by late-stage medicinal chemistry programs. ACK1 is a non-receptor tyrosine kinase that has been shown to be involved in tumorigenesis and metastasis. Here we describe the development of an extremely sensitive high-throughput assay for ACK1 capable of detecting 240 fmol per well of the kinase reaction product employing a BV-tag-based electrochemiluminescence assay. This assay is universally applicable to protein tyrosine kinases using a BV-tag-labeled monoclonal antibody against phosphotyrosine. Furthermore, this assay can be extended to the evaluation of Ser/Thr kinases in those cases where an antibody recognizing the phospho-product is available. 相似文献
62.
Thiophene substituted acylguanidines as BACE1 inhibitors 总被引:1,自引:0,他引:1
Fobare WF Solvibile WR Robichaud AJ Malamas MS Manas E Turner J Hu Y Wagner E Chopra R Cowling R Jin G Bard J 《Bioorganic & medicinal chemistry letters》2007,17(19):5353-5356
A series of thiophene-substituted acylguanidines were designed from a pyrrole substituted acylguanidine HTS lead. This template allowed a greater flexibility, through differential Suzuki couplings, to explore the binding site of BACE1 and to enhance the inhibitory potencies. This exploration provided a 25-fold enhancement in potency to yield compound 10a, which was 150 nM in a BACE1 FRET assay. 相似文献
63.
64.
Kunwar A Narang H Priyadarsini KI Krishna M Pandey R Sainis KB 《Journal of cellular biochemistry》2007,102(5):1214-1224
A mononuclear 1:1 copper complex of curcumin had been found to be superior to curcumin in its anti-oxidant properties. This paper describes the radio-protective effects of the complex in splenic lymphocytes from swiss mice. The complex was found to be very effective in protecting the cells against radiation-induced suppression of glutathione peroxidase, catalase and superoxide dismutase (SOD) activities. Both curcumin and the complex protected radiation-induced protein carbonylation and lipid peroxidation in lymphocytes with the complex showing better protection than curcumin. It also showed better overall protection by decreasing the radiation-induced apoptosis. The kinetics of activation of PKCdelta and NFkappaB after irradiation in presence or absence of these compounds was looked at to identify the molecular mechanism involved. The modulation of irradiation-induced activation of PKCdelta and NFkappaB by curcumin and the complex was found different at later time periods although the initial response was similar. The early responses could be mere stress responses and the activation of crucial signaling factors at later time periods may be the determinants of the fate of the cell. In this study this delayed effect was observed in case of complex but not in case of curcumin. The delayed effect of the complex along with the fact that it is a better free radical scavenger must be the reason for its better efficacy. The complex was also found to be less cytotoxic then curcumin at similar concentration. 相似文献
65.
Pai S O'Sullivan B Abdul-Jabbar I Peng J Connoly G Khanna R Thomas R 《Immunology and cell biology》2007,85(5):370-377
Sequence variation in the Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) oncogene structure may affect antigen-presenting cell (APC) function of infected B cells and immune escape by EBV-specific T cells and thus contribute to the development of malignancy. Normal B cell-associated LMP1 (B-LMP1) upregulates B cell APC function through activation of the necrosis factor (NF)-kappaB subunit, RelB. We examined the ability of B-LMP1 and a nasopharyngeal carcinoma-associated LMP1 (NPC-LMP1) to modulate B cell APC function and T-cell responses. B lymphoma cells transfected with NPC-LMP1 stimulated resting T cells in mixed lymphocyte reaction less efficiently than B-LMP1 transfectants. Unexpectedly, antigen presentation to CD4(+) T helper cells was reduced owing to potentiation of regulatory T-cell function by NPC-LMP1 transfectants, which produce increased levels of interleukin-10, rendering CD4(+) T cells hyporesponsive. Thus, after primary EBV infection, T cells may escape activation by NPC-LMP1. These observations have important implications for the establishment of EBV-associated malignancy in the context of infection with tumour-associated EBV LMP1 variants. 相似文献
66.
Liver sinusoid on a chip: Long‐term layered co‐culture of primary rat hepatocytes and endothelial cells in microfluidic platforms
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67.
Modelling the genetic architecture of flowering time control in barley through nested association mapping 总被引:1,自引:0,他引:1
Andreas Maurer Vera Draba Yong Jiang Florian Schnaithmann Rajiv Sharma Erika Schumann Benjamin Kilian Jochen Christoph Reif Klaus Pillen 《BMC genomics》2015,16(1):290
Background
Barley, globally the fourth most important cereal, provides food and beverages for humans and feed for animal husbandry. Maximizing grain yield under varying climate conditions largely depends on the optimal timing of flowering. Therefore, regulation of flowering time is of extraordinary importance to meet future food and feed demands. We developed the first barley nested association mapping (NAM) population, HEB-25, by crossing 25 wild barleys with one elite barley cultivar, and used it to dissect the genetic architecture of flowering time.Results
Upon cultivation of 1,420 lines in multi-field trials and applying a genome-wide association study, eight major quantitative trait loci (QTL) were identified as main determinants to control flowering time in barley. These QTL accounted for 64% of the cross-validated proportion of explained genotypic variance (pG). The strongest single QTL effect corresponded to the known photoperiod response gene Ppd-H1. After sequencing the causative part of Ppd-H1, we differentiated twelve haplotypes in HEB-25, whereof the strongest exotic haplotype accelerated flowering time by 11 days compared to the elite barley haplotype. Applying a whole genome prediction model including main effects and epistatic interactions allowed predicting flowering time with an unmatched accuracy of 77% of cross-validated pG.Conclusions
The elaborated causal models represent a fundamental step to explain flowering time in barley. In addition, our study confirms that the exotic biodiversity present in HEB-25 is a valuable toolbox to dissect the genetic architecture of important agronomic traits and to replenish the elite barley breeding pool with favorable, trait-improving exotic alleles.68.
69.
Toll-like receptors (TLRs) activate a potent immunostimulatory response. There is clear evidence that overactivation of TLRs leads to infectious and inflammatory diseases. Recent biochemical studies have shown that the membrane-bound form of ST2 (ST2L), a member of the Toll-like/IL-1 receptor superfamily, negatively regulates MyD88-dependent TLR signaling pathways by sequestrating the adapters MyD88 and Mal (TIRAP). Specifically, ST2L attenuates the recruitment of Mal and MyD88 adapters to their receptors through its intracellular TIR domain. Thus, ST2L is a potent molecule that acts as a key regulator of endotoxin tolerance and modulates innate immunity. So far, the inhibitory mechanism of ST2L at the molecular level remains elusive. To develop a working hypothesis for the interactions between ST2L, TLRs (TLR1, 2, 4, and 6), and adapter molecules (MyD88 and Mal), we constructed three-dimensional models of the TIR domains of TLR4, 6, Mal, and ST2L based on homology modeling. Since the crystal structures of the TIR domains of TLR1, 2 as well as the NMR solution structure of MyD88 are known, we utilized these structures in our analysis. The TIR domains of TLR1, 2, 4, 6, MyD88, Mal and ST2L were subjected to molecular dynamics (MD) simulations in an explicit solvent environment. The refined structures obtained from the MD simulations were subsequently used in molecular docking studies to probe for potential sites of interactions. Through protein-protein docking analysis, models of the essential complexes involved in TLR2 and 4 signaling and ST2L inhibiting processes were developed. Our results suggest that ST2L may exert its inhibitory effect by blocking the molecular interface of Mal and MyD88 adapters mainly through its BB-loop region. Our predicted oligomeric signaling models may provide a basis for the understanding of the assembly process of TIR domain interactions, which has thus far proven to be difficult via in vivo studies. 相似文献
70.