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Kyohei Hanaoka Mitsuo Shoji Daiki Kondo Akimasa Sato Moon Young Yang Katsumasa Kamiya 《Journal of biomolecular structure & dynamics》2013,31(11):1759-1765
The DNA religation reaction of yeast type II topoisomerase (topo II) was investigated to elucidate its metal-dependent general acid/base catalysis. Quantum mechanical/molecular mechanical calculations were performed for the topo II religation reaction, and the proton transfer pathway was examined. We found a substrate-mediated proton transfer of the topo II religation reaction, which involves the 3′ OH nucleophile, the reactive phosphate, water, Arg781, and Tyr782. Metal A stabilizes the transition states, which is consistent with a two-metal mechanism in topo II. This pathway may be required for the cleavage/religation reaction of topo IA and II and will provide a general explanation for the catalytic mechanism in the topo IA and II. 相似文献
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JiHoon Kang EunGi Kim Wanyeon Kim Ki Moon Seong HyeSook Youn Jung Woo Kim Joon Kim BuHyun Youn 《The Journal of biological chemistry》2013,288(38):27343-27357
Radioresistance is a major cause of decreasing the efficiency of radiotherapy for non-small cell lung cancer (NSCLC). To understand the radioresistance mechanisms in NSCLC, we focused on the radiation-induced Notch-1 signaling pathway involved in critical cell fate decisions by modulating cell proliferation. In this study, we investigated the use of Notch-1-regulating flavonoid compounds as novel therapeutic drugs to regulate radiosensitivity in NSCLC cells, NCI-H1299 and NCI-H460, with different levels of radioresistance. Rhamnetin and cirsiliol were selected as candidate Notch-1-regulating radiosensitizers based on the results of assay screening for activity and pharmacological properties. Treatment with rhamnetin or cirsiliol reduced the proliferation of NSCLC cells through the suppression of radiation-induced Notch-1 expression. Indeed, rhamnetin and cirsiliol increased the expression of tumor-suppressive microRNA, miR-34a, in a p53-dependent manner, leading to inhibition of Notch-1 expression. Consequently, reduced Notch-1 expression promoted apoptosis through significant down-regulation of the nuclear factor-κB pathway, resulting in a radiosensitizing effect on NSCLC cells. Irradiation-induced epithelial-mesenchymal transition was also notably attenuated in the presence of rhamnetin and cirsiliol. Moreover, an in vivo xenograft mouse model confirmed the radiosensitizing and epithelial-mesenchymal transition inhibition effects of rhamnetin and cirsiliol we observed in vitro. In these mice, tumor volume was significantly reduced by combinational treatment with irradiation and rhamnetin or cirsiliol compared with irradiation alone. Taken together, our findings provided evidence that rhamnetin and cirsiliol can act as promising radiosensitizers that enhance the radiotherapeutic efficacy by inhibiting radiation-induced Notch-1 signaling associated with radioresistance possibly via miR-34a-mediated pathways. 相似文献
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Brendan B. Larsen Lennie Chen Brandon S. Maust Moon Kim Hong Zhao Wenjie Deng Dylan Westfall Ingrid Beck Lisa M. Frenkel James I. Mullins 《PloS one》2013,8(10)
454 pyrosequencing, a massively parallel sequencing (MPS) technology, is often used to study HIV genetic variation. However, the substantial mismatch error rate of the PCR required to prepare HIV-containing samples for pyrosequencing has limited the detection of rare variants within viral populations to those present above ~1%. To improve detection of rare variants, we varied PCR enzymes and conditions to identify those that combined high sensitivity with a low error rate. Substitution errors were found to vary up to 3-fold between the different enzymes tested. The sensitivity of each enzyme, which impacts the number of templates amplified for pyrosequencing, was shown to vary, although not consistently across genes and different samples. We also describe an amplicon-based method to improve the consistency of read coverage over stretches of the HIV-1 genome. Twenty-two primers were designed to amplify 11 overlapping amplicons in the HIV-1 clade B gag-pol and env gp120 coding regions to encompass 4.7 kb of the viral genome per sample at sensitivities as low as 0.01-0.2%. 相似文献
35.
Jinyoung Y. Barnaby Moon Kim Gary Bauchan James Bunce Vangimalla Reddy Richard Charles Sicher 《PloS one》2013,8(10)
Maize (Zea mays L.) hybrids varying in drought tolerance were treated with water stress in controlled environments. Experiments were performed during vegetative growth and water was withheld for 19 days beginning 17 days after sowing. Genotypic comparisons used measured changes of leaf water potential or results were expressed by time of treatment. Total dry matter of the drought tolerant hybrid on the final harvest was 53% less than that of the intermediate and susceptible maize hybrids when plants were water sufficient. This showed that maize hybrids selected for extreme drought tolerance possessed a dwarf phenotype that affected soil water contents and leaf water potentials. Changes of shoot and root growth, leaf water potential, net photosynthesis and stomatal conductance in response to the time of water stress treatment were diminished when comparing the drought tolerant to the intermediate or susceptible maize hybrids. Genotypic differences were observed in 26 of 40 total foliar metabolites during water stress treatments. Hierarchical clustering revealed that the tolerant maize hybrid initiated the accumulation of stress related metabolites at higher leaf water potentials than either the susceptible or intermediate hybrids. Opposite results occurred when changes of metabolites in maize leaves were expressed temporally. The above results demonstrated that genotypic differences were readily observed by comparing maize hybrids differing in drought tolerance based on either time of treatment or measured leaf water potential. Current findings provided new and potentially important insights into the mechanisms of drought tolerance in maize. 相似文献
36.
Juhwan Kim Miyoung Yang Sung-Ho Kim Jong-Choon Kim Hongbing Wang Taekyun Shin Changjong Moon 《PloS one》2013,8(8)
Trimethyltin (TMT) is an organotin compound with potent neurotoxic effects characterized by neuronal destruction in selective regions, including the hippocampus. Glycogen synthase kinase-3 (GSK-3) regulates many cellular processes, and is implicated in several neurodegenerative disorders. In this study, we evaluated the therapeutic effect of lithium, a selective GSK-3 inhibitor, on the hippocampus of adult C57BL/6 mice with TMT treatment (2.6 mg/kg, intraperitoneal [i.p.]) and on cultured hippocampal neurons (12 days in vitro) with TMT treatment (5 µM). Lithium (50 mg/kg, i.p., 0 and 24 h after TMT injection) significantly attenuated TMT-induced hippocampal cell degeneration, seizure, and memory deficits in mice. In cultured hippocampal neurons, lithium treatment (0–10 mM; 1 h before TMT application) significantly reduced TMT-induced cytotoxicity in a dose-dependent manner. Additionally, the dynamic changes in GSK-3/β-catenin signaling were observed in the mouse hippocampus and cultured hippocampal neurons after TMT treatment with or without lithium. Therefore, lithium inhibited the detrimental effects of TMT on the hippocampal neurons in vivo and in vitro, suggesting involvement of the GSK-3/β-catenin signaling pathway in TMT-induced hippocampal cell degeneration and dysfunction. 相似文献
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Jung Hyun Yoon Kyung Hwa Han Eun-Kyung Kim Hee Jung Moon Min Jung Kim Young Joo Suh Ji Soo Choi Byeong-Woo Park 《PloS one》2013,8(2)