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131.
Hughes TV Emanuel SL O'Grady HR Connolly PJ Rugg C Fuentes-Pesquera AR Karnachi P Alexander R Middleton SA 《Bioorganic & medicinal chemistry letters》2008,18(18):5130-5133
A novel series of 7-[1H-indol-2-yl]-2,3-dihydro-isoindol-1-ones designed to be inhibitors of VEGF-R2 kinase was synthesized and found to potently inhibit VEGF-R2 and Aurora-A kinases. The structure-based design, synthesis, and initial SAR of the series are discussed. 相似文献
132.
Xu G Searle LL Hughes TV Beck AK Connolly PJ Abad MC Neeper MP Struble GT Springer BA Emanuel SL Gruninger RH Pandey N Adams M Moreno-Mazza S Fuentes-Pesquera AR Middleton SA Greenberger LM 《Bioorganic & medicinal chemistry letters》2008,18(12):3495-3499
We herein disclose a novel series of 4-aminopyrimidine-5-carbaldehyde oximes that are potent and selective inhibitors of both EGFR and ErbB-2 tyrosine kinases, with IC(50) values in the nanomolar range. Structure-activity relationship (SAR) studies elucidated a critical role for the 4-amino and C-6 arylamino moieties. The X-ray co-crystal structure of EGFR with 37 was determined and validated our design rationale. 相似文献
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134.
Norihito Soga John O. Connolly Meenakshi Chellaiah Juichi Kawamura Keith A. Hruska 《Cell communication & adhesion》2001,8(1):1-13
During angiogenesis endothelial cells migrate towards a chemotactic stimulus. Understanding the mechanism of endothelial cell migration is critical to the therapeutic manipulation of angiogenesis and ultimately cancer prevention. Vascular endothelial growth factor (VEGF) is a potent chemotactic stimulus of endothelial cells during angiogenesis. The endothelial cell signal transduction pathway of VEGF represents a potential target for cancer therapy, but the mechanisms of post-receptor signal transduction including the roles of rho family GTPases in regulating the cytoskeletal effects of VEGF in endothelial cells are not understood.
Here we analyze the mechanisms of cell migration in the mouse brain endothelial cell line (bEND3). Stable transfectants containing a tetracycline repressible expression vector were used to induce expression of Rac mutants. Endothelial cell haptotaxis was stimulated by constitutively active V12Rac on collagen and vitronectin coated supports, and chemotaxis was further stimulated by VEGF. Osteopontin coated supports were the most stimulatory to bEND3 haptotaxis, but VEGF was not effective in further increasing migration on osteopontin coated supports. Haptotaxis on support coated with collagen, vitronectin, and to a lesser degree osteopontin was inhibited by N17 Rac. N17 Rac expression blocked stimulation of endothelial cell chemotaxis by VEGF. As part of the chemotactic stimulation, VEGF caused a loss of actin organization at areas of cell-cell contact and increased stress fiber expression in endothelial cells which were directed towards pores in the transwell membrane. N17 Rac prevented the stimulation of cell-cell contact disruption and the stress fiber stimulation by VEGF.
These data demonstrate two pathways of regulating endothelial cell motility, one in which Rac is activated by matrix/integrin stimulation and is a crucial modulator of endothelial cell haptotaxis. The other pathway, in the presence of osteopontin, is Rac independent. VEGF stimulated chemotaxis, is critically dependent on Rac activation. Osteopontin was a potent matrix activator of motility, and perhaps one explanation for the absence of a VEGF plus osteopontin effect is that osteopontin stimulated motility was inhibitory to the Rac pathway. 相似文献
Here we analyze the mechanisms of cell migration in the mouse brain endothelial cell line (bEND3). Stable transfectants containing a tetracycline repressible expression vector were used to induce expression of Rac mutants. Endothelial cell haptotaxis was stimulated by constitutively active V12Rac on collagen and vitronectin coated supports, and chemotaxis was further stimulated by VEGF. Osteopontin coated supports were the most stimulatory to bEND3 haptotaxis, but VEGF was not effective in further increasing migration on osteopontin coated supports. Haptotaxis on support coated with collagen, vitronectin, and to a lesser degree osteopontin was inhibited by N17 Rac. N17 Rac expression blocked stimulation of endothelial cell chemotaxis by VEGF. As part of the chemotactic stimulation, VEGF caused a loss of actin organization at areas of cell-cell contact and increased stress fiber expression in endothelial cells which were directed towards pores in the transwell membrane. N17 Rac prevented the stimulation of cell-cell contact disruption and the stress fiber stimulation by VEGF.
These data demonstrate two pathways of regulating endothelial cell motility, one in which Rac is activated by matrix/integrin stimulation and is a crucial modulator of endothelial cell haptotaxis. The other pathway, in the presence of osteopontin, is Rac independent. VEGF stimulated chemotaxis, is critically dependent on Rac activation. Osteopontin was a potent matrix activator of motility, and perhaps one explanation for the absence of a VEGF plus osteopontin effect is that osteopontin stimulated motility was inhibitory to the Rac pathway. 相似文献
135.
Characteristics associated with Woolly Apple Aphid Eriosoma lanigerum, resistance of three apple rootstocks 总被引:1,自引:0,他引:1
W.R.M. Sandanayaka V.G.M. Bus P. Connolly & R. Newcomb 《Entomologia Experimentalis et Applicata》2003,109(1):63-72
The resistance characteristics of the apple resistance genes (Er1, Er2, and Er3) to the woolly apple aphid, Eriosoma lanigerum (Hausmann) (Homoptera: Aphididae) were studied according to the performance measured on apple cultivars containing these resistance genes. The resistance characteristics of Northern Spy (Er1), Robusta 5 (Er2), and Aotea (Er3) were compared to the susceptible cultivar Royal Gala, by measuring the aphid settlement, development, and survival rates correlated with electronically monitored probing behaviour. Er1 and Er2 had a higher level of resistance with a significantly shorter period of phloem feeding, suggesting that the resistance factors were present in the phloem tissue. Phenological measurements indicated that the aphids showed poor settlement, development, and survival on Er2. Er1 also showed low settlement and survival, although not as low as Er2. Aphid performance and feeding on Aotea (Er3) were similar to Royal Gala, suggesting that some woolly apple aphids in New Zealand may have recently overcome Er3 resistance. The differences in resistance mechanisms of Er1, Er2, and Er3 are discussed in relation to the strategy of pyramiding these genes to give a durable resistance to woolly apple aphid. 相似文献
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138.
Kozhiparambil K. Purushothaman Ayyappath Sarada Ariyamuthu Saraswathy Joseph D. Connolly 《Phytochemistry》1983,22(4):1042-1043
Sempervirenic acid, a new diterpene has been isolated from Solidago sempervirens and its structure determined by spectroscopic methods and chemical conversions to be 3β-acetoxy-labda-7,13-diene-15-oic acid. 相似文献
139.
Jean‐Paul A. Hobbs Geoffrey P. Jones Philip L. Munday Sean R. Connolly Maya Srinivasan 《Journal of Biogeography》2012,39(1):130-139
Aim To determine the applicability of biogeographical and ecological theory to marine species at two remote island locations. This study examines how biogeography, isolation and species geographic range size influence patterns of species richness, endemism, species composition and the abundance of coral reef fishes. Location Christmas Island and the Cocos (Keeling) Islands in the tropical eastern Indian Ocean. Methods Published species lists and underwater visual surveys were used to determine species richness, endemism, species composition and abundance of reef fishes at the islands. These data were statistically compared with patterns of species composition and abundance from the neighbouring ‘mainland’ Indonesian region. Results The two isolated reef fish communities were species‐poor and contained a distinct taxonomic composition with an overrepresentation of species with high dispersal potential. Despite low species richness, we found no evidence of density compensation, with population densities on the islands similar to those of species‐rich mainland assemblages. The mix of Indian and Pacific Ocean species and the proportional representations of the various regional faunas in the assemblages were not influenced by the relative proximity of the islands to different biogeographical provinces. Moreover, species at the edge of their range did not have a lower abundance than species at the centre of their range, and endemic species had substantially higher abundances than widespread species. At both locations, endemism was low (less than 1.2% of the community); this may be because the locations are not sufficiently isolated or old enough to promote the evolution of endemic species. Main conclusions The patterns observed generally conform to terrestrial biogeographical theory, suggesting that similar processes may be influencing species richness and community composition in reef fish communities at these remote islands. However, species abundances differed from typical terrestrial patterns, and this may be because of the life history of reef fishes and the processes maintaining isolated populations. 相似文献
140.
A power supply has been designed to improve liquid isoelectric focusing by automatically maintaining constant power applied to the column. The main advantages are (a) a reduced exposure time which is particularly important when sensitive proteins are being resolved; (b) a reduction in the loss of resolution due to diffusion or denaturation of the proteins; and (c) a considerable increase in efficiency of the use of the equipment for preparative purposes. 相似文献