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51.
AG Dossetter J Bowyer CR Cook JJ Crawford JE Finlayson NM Heron C Heyes AJ Highton JA Hudson A Jestel S Krapp PA Macfaul TM McGuire AD Morley JJ Morris KM Page LR Ribeiro H Sawney S Steinbacher C Smith 《Bioorganic & medicinal chemistry letters》2012,22(17):5563-5568
The discovery of nitrile compound 4, a potent inhibitor of Cathepsin K (Cat K) with good bioavailability in dog is described. The compound was used to demonstrate target engagement and inhibition of Cat K in an in vivo dog PD model. The margin to hERG ion channel inhibition was deemed too low for a clinical candidate and an optimisation program to find isosteres or substitutions on benzothiazole group led to the discovery of 20, 24 and 27; all three free from hERG inhibition. 相似文献
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Invasion through the extracellular matrix (ECM) is important for wound healing, immunological responses and metastasis. We established an invasion-based cell motility screen using Boyden chambers overlaid with Matrigel to select for pro-invasive genes. By this method we identified antisense to MARCKS related protein (MRP), whose family member MARCKS is a target of miR-21, a microRNA involved in tumor growth, invasion and metastasis in multiple human cancers. We confirmed that targeted knockdown of MRP, in both EpRas mammary epithelial cells and PC3 prostate cancer cells, promoted in vitro cell migration that was blocked by trifluoperazine. Additionally, we observed increased immunofluoresence of E-cadherin, β-catenin and APC at sites of cell-cell contact in EpRas cells with MRP knockdown suggesting formation of adherens junctions. By wound healing assay we observed that reduced MRP supported collective cell migration, a type of cell movement where adherens junctions are maintained. However, destabilized adherens junctions, like those seen in EpRas cells, are frequently important for oncogenic signaling. Consequently, knockdown of MRP in EpRas caused loss of tumorigenesis in vivo, and reduced Wnt3a induced TCF reporter signaling in vitro. Together our data suggest that reducing MRP expression promotes formation of adherens junctions in EpRas cells, allowing collective cell migration, but interferes with oncogenic β-catenin signaling and tumorigenesis. 相似文献
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Selim Terhzaz Andrew J. Finlayson Laura Stirrat JingLi Yang Herve Tricoire Debra J. Woods Julian A.T. Dow Shireen-A. Davies 《Cellular signalling》2010,22(5):737-748
Organismal stress responses to oxidative stress are relevant to ageing and disease and involve key cell-/tissue-specific signal transduction mechanisms. Using Drosophila, an established in vivo model for stress studies, we show that cell-specific inositol phosphate signalling specifically via inositol 1,4,5 trisphosphate 3-kinase (InsP3 3-K, IP3K), negatively regulates organismal responses to oxidative stress. We demonstrate that the Drosophila Malpighian tubule (equivalent to vertebrate kidney and liver) is a key epithelial sensor for organismal oxidative stress responses: precise targeting of either gain-of-function constructs of Drosophila IP3Ks (IP3K-1 and IP3K-2), or loss-of-function (RNAi) constructs to only one cell type in tubule reversibly modulates survival of stress-challenged adult flies. In vivo, targeted IP3K-1 directly increases H2O2 production, pro-apoptotic caspase-9 activity and mitochondrial membrane potential. The mitochondrial calcium load in tubule principal cells–assessed by luminescent and fluorescent genetically-encoded mitochondrial calcium reporters–is significantly increased by IP3K-1 under oxidative stress conditions, leading to apoptosis.The Drosophila orthologues of human apoptotic bcl-2 genes include debcl and buffy. Oxidative stress challenge does not modulate gene expression of either debcl or buffy in tubules; and altered debcl expression does not influence survival rates under oxidative stress challenge. Finally, targeted over-expression of either debcl or buffy to tubule principal cells does not impact on tubule caspase-9 activity. Thus, IP3K-1 modulates epithelial cell apoptosis without involvement of bcl-2-type proteins. 相似文献
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KASSO DAÏNOU JEAN‐PHILIPPE BIZOUX JEAN‐LOUIS DOUCET GRÉGORY MAHY OLIVIER J. HARDY MYRIAM HEUERTZ 《Molecular ecology》2010,19(20):4462-4477
The impact of the Pleistocene climate oscillations on the structure of biodiversity in tropical regions remains poorly understood. In this study, the forest refuge theory is examined at the molecular level in Milicia excelsa, a dioecious tree with a continuous range throughout tropical Africa. Eight nuclear microsatellites (nSSRs) and two sequences and one microsatellite from chloroplast DNA (cpDNA) showed a deep divide between samples from Benin and those from Lower Guinea. This suggests that these populations were isolated in separate geographical regions, probably for several glacial cycles of the Pleistocene, and that the nuclear gene pools were not homogenized despite M. excelsa’s wind‐pollination syndrome. The divide could also be related to seed dispersal patterns, which should be largely determined by the migration behaviour of M. excelsa’s main seed disperser, the frugivorous bat Eidolon helvum. Within Lower Guinea, a north–south divide, observed with both marker types despite weak genetic structure (nSSRs: FST = 0.035, cpDNA: GST = 0.506), suggested the existence of separate Pleistocene refugia in Cameroon and the Gabon/Congo region. We inferred a pollen‐to‐seed dispersal distance ratio of c. 1.8, consistent with wide‐ranging gene dispersal by both wind and bats. Simulations in an Approximate Bayesian Computation framework suggested low nSSR and cpDNA mutation rates, but imprecise estimates of other demographic parameters, probably due to a substantial gene flow between the Lower Guinean gene pools. The decline of genetic diversity detected in some Gabonese populations could be a consequence of the relatively recent establishment of a closed canopy forest, which could negatively affect M. excelsa’s reproductive system. 相似文献
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A rapid and sensitive solid-phase radioimmunoassay for serum hLH has been developed which requires only 1 day to complete. Assay of sera from normal women provided values which agree with those obtained by other methods. At ovulation the mean of the hLH peaks for eight cycles was 27.1 mIU hLH/ml of serum. The minimum was 1.7 mIU/ml in the luteal phase. 相似文献
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Mapping of quantitative trait loci on porcine chromosome 4 总被引:6,自引:0,他引:6
G. A. Walling A. L. Archibald J. A. Cattermole A. C. Downing H. A. Finlayson D. Nicholson C. A. Walker C. S. Haley & P. M. Visscher 《Animal genetics》1998,29(6):415-424
A F2 population derived from a cross between European Large White and Chinese Meishan pigs was established in order to study the genetic basis of breed differences for growth and fat traits. Chromosome 4 was chosen for initial study as previous work had revealed quantitative trait loci (QTLs) on this chromosome affected growth and fat traits in a Wild Boar × Large White cross. Individuals in the F2 population were typed for nine markers spanning a region of approximately 124 c m . We found evidence for QTLs affecting growth between weaning and the end of test (additive effect: 43·4 g/day) and fat depth measured in the mid-back position (additive effect: 1·82 mm). There was no evidence of interactions between the QTLs and sex, grandparents or F1 sires, suggesting that the detected QTLs were fixed for alternative alleles in the Meishan and Large White breeds. Comparison of locations suggests that these QTLs could be the same as those found in the Wild Boar × Large White cross. 相似文献
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Litterfall from a Melaleuca forest was investigated as part of chemical cycling studies on the Magela Creek floodplain in tropical, northern Australia. The forest contained two species of tree, Melaleuca cajaputi and Melaleuca viridiflora, with a combined average density of 294 trees ha–1. The M. viridiflora trees had diameter breast height measurements ranging from 11.8 to 62.0 cm, median class 25.1–30.0cm and a mean value of 29.2±1.0 cm, compared to 13.0 to 66.3 cm, 30.1–35.0cm and 33.5±1.0cm for M. cajaputi trees. A regression model between tree height, diameter breast height and fresh weight was determined and used to calculate average tree weights of 775±1.6kg for M. viridiflora and 1009±1.6kg for M. cajaputi, and a total above-ground fresh weight of 263±0.3t ha–1. The weight of litter recorded each month on the ground beneath the tree canopy ranged from 582±103 to 2176±376 g m–2 with a monthly mean value of 1105±51 g m–2. The coefficient of variation of 52% on this mean indicates the large spatial and temporal variability in litter distribution over the study site. This variability was greatly affected by the pattern of water flow and litter transport during the Wet season. Litterfall from the trees was evaluated using two techniques - nets and trays. The results from these techniques were not significantly different with annual litterfall collected in the nets being 705 ± 25 g m–2 and in the trays 716±49 g m–2. The maximum monthly amount of litterfall, 108 ±55g m–2, occurred during the Dry season months of June–July. Leaf material comprised 70% of the total annual weight of litter, 480±29 g m–2 in the nets and 495 ± 21 g m–2 in the trays. The tree density and weight of litter suggest that the Melaleuca forests are highly productive and contribute a large amount of material to the detrital/debris turnover cycle on the floodplain. 相似文献