排序方式: 共有73条查询结果,搜索用时 15 毫秒
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Fasinu Pius S Tekwani Babu L Nanayakkara NP Dhammika Avula Bharathi Herath HMT Bandara Wang Yan-Hong Adelli Vijender R Elsohly Mahmoud A Khan Shabana I Khan Ikhlas A Pybus Brandon S Marcsisin Sean R Reichard Gregory A McChesney James D Walker Larry A 《Malaria journal》2014,13(1):1-12
Given the threat of resistance of human malaria parasites, including to artemisinin derivatives, new agents are needed. Chloroquine (CQ) has been the most widely used anti-malarial, and new analogs (CQAns) presenting alkynes and side chain variations with high antiplasmodial activity were evaluated. Six diaminealkyne and diaminedialkyne CQAns were evaluated against CQ-resistant (CQ-R) (W2) and CQ-sensitive (CQ-S) (3D7) Plasmodium falciparum parasites in culture. Drug cytotoxicity to a human hepatoma cell line (HepG2) evaluated, allowed to calculate the drug selectivity index (SI), a ratio of drug toxicity to activity in vitro. The CQAns were re-evaluated against CQ-resistant and -sensitive P. berghei parasites in mice using the suppressive test. Docking studies with the CQAns and the human (Hss LDH) or plasmodial lactate dehydrogenase (Pf LDH) enzymes, and, a β-haematin formation assay were performed using a lipid as a catalyst to promote crystallization in vitro. All tested CQAns were highly active against CQ-R P. falciparum parasites, exhibiting half-maximal inhibitory concentration (IC50) values below 1 μΜ. CQAn33 and CQAn37 had the highest SIs. Docking studies revealed the best conformation of CQAn33 inside the binding pocket of Pf LDH; specificity between the residues involved in H-bonds of the Pf LDH with CQAn37. CQAn33 and CQAn37 were also shown to be weak inhibitors of Pf LDH. CQAn33 and CQAn37 inhibited β-haematin formation with either a similar or a 2-fold higher IC50 value, respectively, compared with CQ. CQAn37 was active in mice with P. berghei, reducing parasitaemia by 100%. CQAn33, -39 and -45 also inhibited CQ-resistant P. berghei parasites in mice, whereas high doses of CQ were inactive. The presence of an alkyne group and the size of the side chain affected anti-P. falciparum activity in vitro. Docking studies suggested a mechanism of action other than Pf LDH inhibition. The β-haematin assay suggested the presence of an additional mechanism of action of CQAn33 and CQAn37. Tests with CQAn34, CQAn37, CQAn39 and CQAn45 confirmed previous results against P. berghei malaria in mice, and CQAn33, 39 and 45 were active against CQ-resistant parasites, but CQAn28 and CQAn34 were not. The result likely reflects structure-activity relationships related to the resistant phenotype. 相似文献
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Jiang C Mithani A Gan X Belfield EJ Klingler JP Zhu JK Ragoussis J Mott R Harberd NP 《Current biology : CB》2011,21(16):1385-1390
Multicellular organisms can be regenerated from totipotent differentiated somatic cell or nuclear founders [1-3]. Organisms regenerated from clonally related isogenic founders might a priori have been expected to be phenotypically invariant. However, clonal regenerant animals display variant phenotypes caused by defective epigenetic reprogramming of gene expression [2], and clonal regenerant plants exhibit poorly understood heritable phenotypic ("somaclonal") variation [4-7]. Here we show that somaclonal variation in regenerant Arabidopsis lineages is associated with genome-wide elevation in DNA sequence mutation rate. We also show that regenerant mutations comprise?a distinctive molecular spectrum of base substitutions, insertions, and deletions that probably results from decreased DNA repair fidelity. Finally, we show that while regenerant base substitutions are a likely major genetic cause of the somaclonal variation of regenerant Arabidopsis lineages, transposon movement is unlikely to contribute substantially to that variation. We conclude that the phenotypic variation of regenerant plants, unlike that of regenerant animals, is substantially due to DNA sequence mutation. 相似文献
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Gibberellins control Arabidopsis hypocotyl growth via regulation of cellular elongation 总被引:8,自引:0,他引:8
The gibberellins (GAs) are endogenous regulators of plant growth.
Experiments are described here that test the hypothesis that GA regulates
hypocotyl growth by altering the extent of hypocotyl cell elongation. These
experiments use GA-deficient and altered GA-response mutants of
Arabidopsis thaliana (L.) Heyhn. It is shown that GA
regulates elongation, in both light- and dark-grown hypocotyls, by
influencing the rate and final extent of cellular elongation. However,
light- and dark-grown hypocotyls exhibit markedly different GA
dose-response relationships. The length of dark-grown hypocotyls is
relatively unaffected by exogenous GA, whilst light-grown hypocotyl length
is significantly increased by exogenous GA. Further analysis suggests that
GA control of hypocotyl length is close to saturation in dark-grown
hypocotyls, but not in light grown hypocotyls. The results show that a
large range of possible hypocotyl lengths is achieved via dose-dependent
GA-regulated alterations in the degree of elongation of individual
hypocotyl cells.Key words: Arabidopsis, cell
elongation, gibberellin (GA), GA mutants, hypocotyl.
相似文献
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J Daugherty TM Evans T Skillom LE Watson NP Money 《Fungal genetics and biology : FG & B》1998,24(3):354-363
Classical studies on spore release within the Saprolegniaceae (Oomycetes) led to the proposition that different mechanisms of sporangial emptying represent steps in an evolutionary transition series. We have reevaluated this idea in a phylogenetic framework using internal transcribed spacer sequences of four genera. These data were compared with the response to osmotic stress exhibited by each taxon. Saprolegnia emerges as the most basal genus, sister to Achlya, Thraustotheca, and Dictyuchus. Achlya and Thraustotheca are most closely related, while Dictyuchus appears to have evolved along a separate evolutionary lineage. The resulting phylogenetic framework is consistent with the idea that the mechanism of sporangial emptying exhibited by Saprolegnia represents the plesiomorphic condition from which the other mechanisms were derived independently. These alternative mechanisms of spore release may have resulted from a small number of mutations that inhibited axonemal development and altered the temporal and spatial expression of lytic enzymes that degrade the sporangial wall. Copyright 1998 Academic Press. 相似文献
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Harberd NP King KE Carol P Cowling RJ Peng J Richards DE 《BioEssays : news and reviews in molecular, cellular and developmental biology》1998,20(12):1001-1008
Gibberellin is an endogenous plant growth regulator. Here, we describe our present understanding of how gibberellin regulates plant growth, using recent results gained from studies of gibberellin-signalling mutants of Arabidopsis. These results show that a signalling pathway represses plant growth and that gibberellin releases this repression. In consequence, the well-known growth-promoting properties of gibberellin are due to its activity as an "inhibitor of an inhibitor" [Brian Pw. Sym Soc. Exp Bio 1957; 11:166-182 (Ref. 1)] of plant growth. 相似文献
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Identification of phytochrome B amino acid residues mutated in three new phyB mutants of Arabidopsis thaliana 总被引:1,自引:0,他引:1
Bradley J. Marie; Murphy George P.; Whitelam Garry C.; Harberd Nicholas P. 《Journal of experimental botany》1996,47(9):1449-1455
The growth and development of plants is regulated by light viathe action of photoreceptors which are responsive to the red/far-red,blue and UV regions of the spectrum. Phytochrome B (the apoproteinof which is encoded by the PHYB gene) is one of the red/far-redabsorbing photoreceptors active in this process. In this paper,the isolation and characterization of three new EMS-inducedmutations of Arabidopsis which confer phytochrome B deficiencyare described. Complementation analysis showed that these mutations(phyB-101, phyB-102 and phyB-104) were allelic with PHYB. DNAsequence analysis showed that all three mutants contain nucleotidesubstitutions in the PHYB-101 gene sequence. phyB-101 carriesa nucleotide substitution within the second exon of the PHYBgene. This G-to-A substitution is a missense mutation that convertsa glutamate residue at position 812 of the phytochrome B apoproteinto a lysine residue. phyB-102, another missense mutant, carriesa C-to-T substitution which converts a serine residue at position349 of the phytochrome B apoprotein to a phenylalanine residue.phyB-104 carries a premature stop codon as a result of a G-to-Amutation 1190 bp down-stream of the ATG start codon of the PHYBsequence. The missense mutations in phyB-101 and phyB-102 causesignificant alterations in the predicted second ary structureof their respective mutant polypeptides, and identify aminoacid residues playing crucial roles in phytochrome B function,assembly or stability. Key words: Arabidopsis thaliana, phytochromet, phyB mutants, missense mutations 相似文献