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121.
Imatinib, a protein tyrosine kinase inhibitor, may prevent the growth of glioblastoma cells. Unfortunately, its brain distribution is restricted by p-glycoprotein (p-gp or multidrug resistance protein Mdr1a), and probably by breast cancer resistance protein (Bcrp1), two efflux pumps expressed at the blood-brain barrier (BBB). We have used in situ brain perfusion to investigate the mechanisms of imatinib transport across the mouse BBB. The brain uptake of imatinib in wild-type mice was limited by saturable efflux processes. The inhibition of p-gp, by valspodar and zosuquidar, increased imatinib uptake (2.5-fold), as did the deficiency of p-gp in Mdr1a/1b(-/-) mice (5.5-fold). Perfusing imatinib with the p-gp/Bcrp1 inhibitor, elacridar, enhanced the brain uptake of imatinib in wild-type (4.1-fold) and Mdr1a/1b(-/-) mice (1.2-fold). However, the brain uptake of imatinib was similar in wild-type and Bcrp1(-/-) mice when it was perfused at a non-saturating concentration. The brain uptake of CGP74588, an active metabolite of imatinib, was low. It was increased by perfusion with elacridar (twofold), but not with valspodar and zosuquidar. CGP74588 uptake was 1.5 times greater in Bcrp1(-/-) mice than in wild-type mice. These data suggest that imatinib transport at the mouse BBB is limited by p-gp and probably by Bcrp1, and that CGP74588 transport is restricted by Bcrp1. 相似文献
122.
Vanpé C Gaillard JM Kjellander P Mysterud A Magnien P Delorme D Van Laere G Klein F Liberg O Hewison AJ 《The American naturalist》2007,169(4):481-493
Identifying factors shaping secondary sexual traits is essential in understanding how their variation may influence male fitness. Little information is available on the allocation of resources to antler growth in territorial ungulates with low sexual size dimorphism. We investigated phenotypic and environmental factors affecting both absolute and relative antler size of male roe deer in three contrasting populations in France and Sweden. In the three populations, we found marked age-specific variation in antler size, with an increase in both absolute and relative antler size between yearling and prime-age stages, followed by a decrease (senescence) for males older than 7 years. Antler size increased allometrically with body mass. This increase was particularly strong for senescent males, suggesting the evolution of two reproductive tactics: heavy old males invested particularly heavily in antler growth (potentially remaining competitive for territories), whereas light old males grew small antlers (potentially abandoning territory defense). Finally, environmental conditions had little effect on antler size: only population density negatively affected absolute antler size in one of the three populations. Antler size may therefore provide an honest signal of male phenotypic quality in roe deer. We discuss the implications of these results in terms of territory tenure and mating competition. 相似文献
123.
Holzapfel E Eisner G Alami M Barrett CM Buchanan G Lüke I Betton JM Robinson C Palmer T Moser M Müller M 《Biochemistry》2007,46(10):2892-2898
Translocation of twin-arginine precursor proteins across the cytoplasmic membrane of Escherichia coli requires the three membrane proteins TatA, TatB, and TatC. TatC and TatB were shown to be involved in precursor binding. We have analyzed in vitro a number of single alanine substitutions in tatC that were previously shown to compromise in vivo the function of the Tat translocase. All tatC mutants that were defective in precursor translocation into cytoplasmic membrane vesicles concomitantly interfered with precursor binding not only to TatC but also to TatB. Hence structural changes of TatC that affect precursor targeting simultaneously abolish engagement of the twin-arginine signal sequence with TatB and block the formation of a functional Tat translocase. Since these phenotypes were observed for tatC mutations spread over the first half of TatC, this entire part of the molecule must globally be involved in precursor binding. 相似文献
124.
The crystal structure of Rv0813c from Mycobacterium tuberculosis reveals a new family of fatty acid-binding protein-like proteins in bacteria 下载免费PDF全文
Shepard W Haouz A Graña M Buschiazzo A Betton JM Cole ST Alzari PM 《Journal of bacteriology》2007,189(5):1899-1904
The gene Rv0813c from Mycobacterium tuberculosis, which codes for a hypothetical protein of unknown function, is conserved within the order Actinomycetales but absent elsewhere. The crystal structure of Rv0813c reveals a new family of proteins that resemble the fatty acid-binding proteins (FABPs) found in eukaryotes. Rv0813c adopts the 10-stranded beta-barrel fold typical of FABPs but lacks the double-helix insert that covers the entry to the binding site in the eukaryotic proteins. The barrel encloses a deep cavity, at the bottom of which a small cyclic ligand was found to bind to the hydroxyl group of Tyr192. This residue is part of a conserved Arg-X-Tyr motif much like the triad that binds the carboxylate group of fatty acids in FABPs. Most of the residues forming the internal surface of the cavity are conserved in homologous protein sequences found in CG-rich prokaryotes, strongly suggesting that Rv0813c is a member of a new family of bacterial FABP-like proteins that may have roles in the recognition, transport, and/or storage of small molecules in the bacterial cytosol. 相似文献
125.
Winum JY Thiry A Cheikh KE Dogné JM Montero JL Vullo D Scozzafava A Masereel B Supuran CT 《Bioorganic & medicinal chemistry letters》2007,17(10):2685-2691
A series of aromatic/heterocyclic sulfonamides incorporating 2,3:4,5-bis-O-(isopropylidene)-beta-d-fructopyranosyl-thioureido moieties has been synthesized and assayed for the inhibition of seven human isoforms of the zinc enzyme carbonic anhydrase (hCA, EC 4.2.1.1). The new derivatives behaved as weak hCA I inhibitors (K(I)s of 9.4 -13.3microM), were efficient hCA II inhibitors (K(I)s of 6-750nM), and slightly inhibited isoforms hCA IV and hCA VA. Only the sulfanilamide derivative showed efficient and selective inhibition of hCA IV (K(I) of 10nM). These derivatives also showed excellent hCA VII inhibitory activity (K(I)s of 10-79nM), being less efficient as inhibitors of the transmembrane isoforms hCA IX (K(I)s of 10-4500nM) and hCA XIV (K(I)s of 21-3500nM). Two of the new compounds showed anticonvulsant action in a maximal electroshock seizure test in mice, with the fluorosulfanilamide derivative being a more efficient anticonvulsant than the antiepileptic drug topiramate. 相似文献
126.
127.
Soulat D Jault JM Geourjon C Gouet P Cozzone AJ Grangeasse C 《FEMS microbiology letters》2007,274(2):252-259
The catalytic mechanism of bacterial tyrosine-kinases (PTK) is poorly understood. These enzymes possess Walker A and B ATP-binding motifs, which are effectively required for their autophosphorylation whereas these motifs are usually found in ATP-binding proteins but not in eukaryotic protein-kinases. It was previously shown that the PTK Wzc in Escherichia coli undergoes intra- and interphosphorylation. In this work, it is shown that, in addition to its kinase activity, Wzc produces free inorganic phosphate. It is demonstrated that this ATPase activity is increased significantly by intraphosphorylation of Wzc. The fact that intraphosphorylation of Wzc does not affect Wzc affinity for ATP was also demonstrated and it was suggested that it could rather modify the local environment of the ATP molecule in the catalytic site so as to render Wzc more liable to catalyze ATP hydrolysis and interphosphorylation. These results should contribute to better understanding of the catalytic mechanism of this particular class of tyrosine-kinases, which seems, so far, restricted to bacteria. 相似文献
128.
Tony Robinet Eric Feunteun Philippe Keith Gérard Marquet Jean-Michel Olivier Elodie Réveillac Pierre Valade 《Environmental Biology of Fishes》2007,78(2):93-105
Anguillid eels were sampled from permanent rivers in the Réunion and Mauritius islands, western Indian Ocean, with a standardized
electrofishing method. A. marmorata was very dominant, corresponding to 91.7 and 90.7% of all the eels collected in Réunion and Mauritius, respectively. Three
other species (A. mossambica, A. bicolor bicolor and A. nebulosa labiata) were also present in both islands. A. marmorata showed a strong altitudinal gradient of densities from the lower to upper zones, especially in the younger stages (TL <250 mm),
while A. mossambica was only found in the upper zones and A. bicolor bicolor occurred only in the lower zones (A. nebulosa labiata was rare). The eel species composition in freshwaters of both islands is very similar because these two adjoining islands
are located in the same trail of drifting marine larvae. Mean estimated eel biomasses were noticeably low (11.1 and 22.2 kg ha−1 in Réunion and Mauritius islands, respectively), especially when compared to those of other tropical insular systems without
any eel fishery (Comoros or Polynesia, more than 100 kg ha−1). Nevertheless, the fluvial recruitment of A. marmorata seemed to be regular during the surveyed period, staggering from October to April. The obvious lack of large eels in Mauritius
but more significantly in Réunion suggests a high pressure from traditional fishery, and the local reproductive turnover is
uncertain. Because sexual maturation seems to occur at a large body size for A. marmorata, as for temperate species, the Réunion and Mauritius rivers may only have a weak contribution to the regional production
of spawners. However, the giant mottled eel population in the western Indian Ocean is believed to be panmictic at the regional
scale, and may not rely exclusively on these islands’ contribution. A comparison is made with those of freshwater systems
in other tropical islands. 相似文献
129.
130.
Jongho Sun J. Benjamin Miller Emma Granqvist Audrey Wiley-Kalil Enrico Gobbato Fabienne Maillet Sylvain Cottaz Eric Samain Muthusubramanian Venkateshwaran Sébastien Fort Richard J. Morris Jean-Michel Ané Jean Dénarié Giles E.D. Oldroyd 《The Plant cell》2015,27(3):823-838
Establishment of arbuscular mycorrhizal interactions involves plant recognition of diffusible signals from the fungus, including lipochitooligosaccharides (LCOs) and chitooligosaccharides (COs). Nitrogen-fixing rhizobial bacteria that associate with leguminous plants also signal to their hosts via LCOs, the so-called Nod factors. Here, we have assessed the induction of symbiotic signaling by the arbuscular mycorrhizal (Myc) fungal-produced LCOs and COs in legumes and rice (Oryza sativa). We show that Myc-LCOs and tetra-acetyl chitotetraose (CO4) activate the common symbiosis signaling pathway, with resultant calcium oscillations in root epidermal cells of Medicago truncatula and Lotus japonicus. The nature of the calcium oscillations is similar for LCOs produced by rhizobial bacteria and by mycorrhizal fungi; however, Myc-LCOs activate distinct gene expression. Calcium oscillations were activated in rice atrichoblasts by CO4, but not the Myc-LCOs, whereas a mix of CO4 and Myc-LCOs activated calcium oscillations in rice trichoblasts. In contrast, stimulation of lateral root emergence occurred following treatment with Myc-LCOs, but not CO4, in M. truncatula, whereas both Myc-LCOs and CO4 were active in rice. Our work indicates that legumes and non-legumes differ in their perception of Myc-LCO and CO signals, suggesting that different plant species respond to different components in the mix of signals produced by arbuscular mycorrhizal fungi. 相似文献