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1.
Davide Danovi Amos Folarin Sabine Gogolok Christine Ender Ahmed M. O. Elbatsh P?r G. Engstr?m Stefan H. Stricker Sladjana Gagrica Ana Georgian Ding Yu Kin Pong U Kevin J. Harvey Patrizia Ferretti Patrick J. Paddison Jane E. Preston N. Joan Abbott Paul Bertone Austin Smith Steven M. Pollard 《PloS one》2013,8(10)
Glioblastoma multiforme (GBM) is the most common primary brain cancer in adults and there are few effective treatments. GBMs contain cells with molecular and cellular characteristics of neural stem cells that drive tumour growth. Here we compare responses of human glioblastoma-derived neural stem (GNS) cells and genetically normal neural stem (NS) cells to a panel of 160 small molecule kinase inhibitors. We used live-cell imaging and high content image analysis tools and identified JNJ-10198409 (J101) as an agent that induces mitotic arrest at prometaphase in GNS cells but not NS cells. Antibody microarrays and kinase profiling suggested that J101 responses are triggered by suppression of the active phosphorylated form of polo-like kinase 1 (Plk1) (phospho T210), with resultant spindle defects and arrest at prometaphase. We found that potent and specific Plk1 inhibitors already in clinical development (BI 2536, BI 6727 and GSK 461364) phenocopied J101 and were selective against GNS cells. Using a porcine brain endothelial cell blood-brain barrier model we also observed that these compounds exhibited greater blood-brain barrier permeability in vitro than J101. Our analysis of mouse mutant NS cells (INK4a/ARF−/−, or p53−/−), as well as the acute genetic deletion of p53 from a conditional p53 floxed NS cell line, suggests that the sensitivity of GNS cells to BI 2536 or J101 may be explained by the lack of a p53-mediated compensatory pathway. Together these data indicate that GBM stem cells are acutely susceptible to proliferative disruption by Plk1 inhibitors and that such agents may have immediate therapeutic value. 相似文献
2.
R. D. Preston 《Planta》1988,174(1):67-74
A brief review is given of the changing views over the years, as knowledge of wall structure has developed, concerning the mechanism whereby cellulose chains may be oriented. This leads to an examination of current concepts, particularly those concerning microtubules. It is shown that none of the mechanisms suggested whereby microtubules might cause orientation of cellulose microfibrils is consistent with the known range of molecular architectures found in plant cell walls. It is further concluded that any mechanism which necessitates an indissoluble link between the plasmalemma and the cellulose-synthesising complex at the tip of a microfibril is unacceptable. A new proposal is presented in which it is speculated that both microtubules and microfibrils are oriented by a mechanism separate from both. It is shown that if two vectors are contemplated, one parallel to cell length and one at right angles, and a sensor exists on the plasmalemma surface which responds to changes in the vectors, then all known wall structures may be explained. The possible nature of the vectors and the sensor are considered. 相似文献
3.
R Smith R R Preston S Schulz M L Gagnon J Van Houten 《Biochimica et biophysica acta》1987,928(2):171-178
Paramecium tetraurelia is attracted to cyclic AMP, which probably, as other attractants, signifies the presence of food. Attraction to cyclic AMP was specific, saturable, and, therefore, likely to be receptor-mediated. In these studies, we measured the binding of cyclic [3H]AMP to whole cells and found it to be saturable, reversible, and displaying specificity similar to that of attraction. An HPLC method of separating nucleotides was devised and used to determine that external cyclic AMP was degraded in the absence of IBMX, a phosphodiesterase inhibitor, and that cyclic AMP was taken into the cells in small amounts. Since binding and attraction were subsequently measured in the presence of IMBX, it was cyclic AMP and not a degradation product that served as the attractant stimulus for Paramecium. 相似文献
4.
Andrew A. Lackner Morten Schidt Gary C. Armitage Peter F. Moore Robert J. Munn Preston A. Marx Murray B. Gardner Linda J. Lowenstine 《Journal of medical primatology》1989,18(3-4):195-207
Simian acquired immune deficiency syndrome (SAIDS) caused by the type D retrovirus SRV-1 results in opportunistic infections and a spectrum of oral lesions similar to those seen in humans with AIDS. To better understand the pathogenesis of these oral lesions we have retrospectively examined the oral mucosa from ten rhesus monkeys that died with SAIDS and prospectively examined the oral mucosa of ten additional animals inoculated with SRV-1 to determine at what time, and in what cells SRV-1 infection of the oral mucosa occurs. Using single and double label immunohistologic techniques, and electron microscopy we detected SRV-1 in clusters of oral epithelial cells and rare Langerhans cells as early as 1 month postinoculation. 相似文献
5.
Ratio imaging in fluorescence microscopy is used in measuring parameters such as pH, pCa, cytoplasmic porosity, and the relative concentration of fluorescent analogs within single cells. The fastest method for ratio imaging is to use lookup tables on special-purpose image processors. Since lookup tables store integers in integer addresses, using a lookup table will generate rounding errors. The magnitude of the error will depend on the transformation performed and on the number of levels used in the lookup table. We examined ratio imaging by lookup table and computed the errors generated by both inversion and log subtraction methods. Both uniformly fluorescing fields and fluorescing cell images were employed to provide data for use in confirming our calculations and illustrating both the magnitude and spatial incidence of errors. It is shown that, through proper design of lookup tables, a significant reduction can be made in the errors generated in comparison with common methods available in most image processors. 相似文献
6.
Richard R. Keen Lisa A. Stella D. Preston Flanigan William E. M. Lands 《Free radical biology & medicine》1990,9(6):485-494
Fatty acid hydroperoxides in the plasma of 18 patients who were undergoing normal postoperative periods following major thoracic or abdominal operations were measured by using a sensitive assay based upon the activation of the cyclooxygenase activity of prostaglandin H synthase. Following major thoracic operations of nine patients, the mean difference between the arterial (0.49 ± 0.13 μM, mean ± S.E.M.) and mixed venous (−0.09 ± 0.12 μM) level of hydroperoxide was 0.58 ± 0.13 μM (p < 0.01). In marked contrast to this result, major abdominal operations of nine patients led to a mean difference between the arterial (−0.19 ± 0.16 μM) and mixed venous (0.46 ± 0.08 μM) hydroperoxide levels of −0.65 ± 0.17 μM (p < 0.01). Both pulmonary and intraabdominal tissues appear capable of generating significant amounts of fatty acid hydroperoxide in response to standard surgical procedures. The A-MV differences suggest that the blood-borne hydroperoxides were rapidly cleared from the circulation by tissue capillary beds. 相似文献
7.
The Escherichia coli supF gene encoding the suppressor tyrosine tRNA in a human shuttle plasmid, pZ189, was used as a target for molecular analysis of X-ray-induced mutations in human lymphoblastoid cells. Following replication of the in vitro-irradiated plasmid in human cells, the mutant supF-containing molecules were cloned by phenotypic screening in E. coli and the nature of the mutations was determined by direct sequencing of the tRNA gene. At 160 Gy the mutant frequency was 13 times (0.39%) that observed in unirradiated controls (0.031%). When control plasmid was replicated directly in E. coli, the mutant frequency was 16 times less than that of the plasmid passaged through the human cells. The distribution of mutations was highly nonrandom and remarkably similar in both irradiated and control DNAs. The majority of the mutations were transitions involving G.C pairs and occurred selectively at most 5'-TC (3'-AG) sequences. These mutations at C's were preferentially distributed in the nontranscribed strand. We propose that mutations in the control plasmid result from oxidative damages that occur during and/or after its incorporation into human cells and that these damages are similar to those induced by ionizing radiation. The hot spots for mutations suggest that the proximate nucleotide sequence and the overall conformation of the target DNA are important in the production and/or processing of these damages during repair and replication. 相似文献
8.
The mutual diffusion coefficient of the bovine nasal cartilage proteoglycan subunit is found to increase rapidly with increasing concentration and decreasing ionic strength. These results have been obtained by analysis of the boundary relaxation of concentration gradients in the analytical ultracentrifuge by schlieren optics. The diffusion behavior can be understood in terms of the nonideality of the proteoglycan. The magnitude of the nonideality is dominated by charge interactions, whereas the influence of molecular size and associated excluded-volume interactions is small. The concentration dependence of the apparent diffusion coefficient of the proteoglycan subunit from dynamic light scattering was found, in contrast, to decrease with increasing concentration. Computer simulation of the dynamic light scattering suggests that the presence of a small population of aggregates may account for the difference in the two types of diffusion measurement due to their marked influence on the scattering. 相似文献
9.
A combined single-turnover flash and 35Cl NMR technique has been used to monitor S-state dependence of Cl− binding to PS-II particles derived from mangrove (Avicennia marina). No detectable high-affinity binding was found to particles in the S0 and S1 states, but binding with an affinity comparable to that which activates O2 evolution was found in the S2 and S3 states. 相似文献
10.
Amoeboid locomotion of Acanthamoeba castellanii with special reference to cell-substratum interactions 总被引:1,自引:0,他引:1
The amoeboid locomotion of Acanthamoeba castellanii has been studied by observation of individual cells moving on a planar glass substratum. Cell-substratum interactions involved in traction have been observed by reflexion interference microscopy. A variable part of the ventral surface of A. castellanii formed a protean platform, the 'associated contact', from which filopodia were subtended; these established stable, focal adhesions (approximately 0.4 micron diameter) on the substratum beneath. Surprisingly, acanthopodia, a prominent feature of this protozoon, did not play an obvious role in traction. The dimensions of the cell-substratum gap in the associated contact could be modulated by the concentration of ambient electrolyte. Dilution of electrolyte from 50 mM-KC1 to 2mM resulted in (i) an increase in the cell-substratum gap, (ii) a marked decrease in cell motility, (iii) reduced cell adhesion to glass. 相似文献