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Jo Ishizawa Kensuke Kojima Teresa McQueen Vivian Ruvolo Dhruv Chachad Graciela M. Nogueras-Gonzalez Xuelin Huang William E. Pierceall E. J. Dettman Michael H. Cardone Sharon Shacham Marina Konopleva Michael Andreeff 《PloS one》2015,10(9)
BH3 profiling measures the propensity of transformed cells to undergo intrinsic apoptosis and is determined by exposing cells to BH3-mimicking peptides. We hypothesized that basal levels of prosurvival BCL-2 family proteins may modulate the predictive power of BH3 profiling and termed it mitochondrial profiling. We investigated the correlation between cell sensitivity to apoptogenic agents and mitochondrial profiling, using a panel of acute myeloid leukemias induced to undergo apoptosis by exposure to cytarabine, the BH3 mimetic ABT-199, the MDM2 inhibitor Nutlin-3a, or the CRM1 inhibitor KPT-330. We found that the apoptogenic efficacies of ABT-199 and cytarabine correlated well with BH3 profiling reflecting BCL2, but not BCL-XL or MCL-1 dependence. Baseline BCL-2 protein expression analysis increased the ability of BH3 profiling to predict resistance mediated by MCL-1. By utilizing engineered cells with overexpression or knockdown of BCL-2 family proteins, Ara-C was found to be independent, while ABT-199 was dependent on BCL-XL. BCL-2 and BCL-XL overexpression mediated resistance to KPT-330 which was not reflected in the BH3 profiling assay, or in baseline BCL-2 protein levels. In conclusion, mitochondrial profiling, the combination of BH3 profiling and prosurvival BCL-2 family protein analysis, represents an improved approach to predict efficacy of diverse agents in AML and may have utility in the design of more effective drug combinations. 相似文献
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This study used data from a nationwide survey in Japan to model the developmental course of social skills during early childhood. The goals of this study were to identify longitudinal profiles of social skills between 2 and 5 years of age using a group-based trajectory approach, and to investigate whether and to what extent parenting practices at 2 years of age predicted developmental trajectories of social skills during the preschool period. A relatively large sample of boys and girls (N > 1,000) was assessed on three social skill dimensions (Cooperation, Self-control, and Assertion) at four time points (ages 2, 3, 4, and 5), and on four parenting practices (cognitive and emotional involvement, avoidance of restriction and punishment, social stimulation, and social support for parenting) at age 2. The results indicated that for each social skill dimension, group-based trajectory models identified three distinct trajectories: low, moderate, and high. Multinomial regression analysis revealed that parenting practice variables showed differential contributions to development of child social skills. Specifically, Cooperation and Assertion were promoted by cognitive and emotional involvement, Self-control by social stimulation, and Assertion by avoidance of restriction and punishment. Abundant social support for parenting was not associated with higher child social skills trajectories. We found heterogeneity in developmental profiles of social skills during the preschool ages, and we identified parenting practices that contributed to different patterns of social skills development. We discussed the implications of higher-quality parenting practices on the improvement of child social skills across early childhood. 相似文献
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Masatomo So Yuto Kimura Keiichi Yamaguchi Toshihiko Sugiki Toshimichi Fujiwara Cesar Aguirre Kensuke Ikenaka Hideki Mochizuki Yasushi Kawata Yuji Goto 《Protein science : a publication of the Protein Society》2021,30(8):1701
Amyloid fibril formation is associated with various amyloidoses, including neurodegenerative diseases such as Alzheimer''s and Parkinson''s diseases. Amyloid fibrils form above the solubility of amyloidogenic proteins or peptides upon breaking supersaturation, followed by a nucleation and elongation mechanism, which is similar to the crystallization of solutes. Many additives, including salts, detergents, and natural compounds, promote or inhibit amyloid formation. However, the underlying mechanisms of the opposing effects are unclear. We examined the effects of two polyphenols, that is, epigallocatechin gallate (EGCG) and kaempferol‐7─O─glycoside (KG), with high and low solubilities, respectively, on the amyloid formation of α‐synuclein (αSN). EGCG and KG inhibited and promoted amyloid formation of αSN, respectively, when monitored by thioflavin T (ThT) fluorescence or transmission electron microscopy (TEM). Nuclear magnetic resonance (NMR) analysis revealed that, although interactions of αSN with soluble EGCG increased the solubility of αSN, thus inhibiting amyloid formation, interactions of αSN with insoluble KG reduced the solubility of αSN, thereby promoting amyloid formation. Our study suggests that opposing effects of polyphenols on amyloid formation of proteins and peptides can be interpreted based on the solubility of polyphenols. 相似文献
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Kensuke Miyamoto Toshihisa Kotake Makiko Sasamoto Marian Saniewski Junichi Ueda 《Journal of plant research》2010,123(3):363-370
The purpose of this study was to investigate the hormonal regulation of gummosis in grape hyacinth (Muscari armeniacum) bulbs, focusing especially on the chemical composition of the gums. The application of ethephon (2-chloroethylphosphonic
acid), an ethylene-releasing compound, at 1% and 2% (w/w) in lanolin as well as ethylene induced gummosis in the bulbs within
several days. Methyl jasmonate (JA-Me, 0.1–2% in lanolin) alone had no effect on gummosis. However, simultaneous application
of JA-Me and ethephon led to extreme stimulation of ethephon-induced gummosis. Ethephon-induced gummosis in the bulbs depended
on the maturation stage of the bulbs, increasing from April to July, but decreasing from August to September. Regardless of
the presence of JA-Me, the application of ethephon to the inflorescence axis of grape hyacinths did not induce gummosis. Gel
permeation chromatography analysis revealed that gums were homogenous polysaccharides with an average molecular mass of ca.
8.3 kDa. Analysis of the sugar composition of the gums after hydrolysis revealed that the molar ratio of Rha:Ara:Gal:GalA:GlcA
was 25:10:40:7:15. These results suggest that principal factors of gummosis as well as the chemical composition of gums differ
between species of bulbous plants. 相似文献
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Akashi Ohtaki Kensuke Murata Yuichi Sato Keiichi Noguchi Hideyuki Miyatake Naoshi Dohmae Kazuhiro Yamada Masafumi Yohda Masfumi Odaka 《Biochimica et Biophysica Acta - Proteins and Proteomics》2010,1804(1):184-192
In this study, we have structurally characterized the amidase of a nitrile-degrading bacterium, Rhodococcus sp. N-771 (RhAmidase). RhAmidase belongs to amidase signature (AS) family, a group of amidase families, and is responsible for the degradation of amides produced from nitriles by nitrile hydratase. Recombinant RhAmidase exists as a dimer of about 107 kDa. RhAmidase can hydrolyze acetamide, propionamide, acrylamide and benzamide with kcat/Km values of 1.14 ± 0.23 mM− 1s− 1, 4.54 ± 0.09 mM− 1s− 1, 0.087 ± 0.02 mM− 1s− 1 and 153.5 ± 7.1 mM− 1s− 1, respectively. The crystal structures of RhAmidase and its inactive mutant complex with benzamide (S195A/benzamide) were determined at resolutions of 2.17 Å and 2.32 Å, respectively. RhAmidase has three domains: an N-terminal α-helical domain, a small domain and a large domain. The N-terminal α-helical domain is not found in other AS family enzymes. This domain is involved in the formation of the dimer structure and, together with the small domain, forms a narrow substrate-binding tunnel. The large domain showed high structural similarities to those of other AS family enzymes. The Ser-cis Ser-Lys catalytic triad is located in the large domain. But the substrate-binding pocket of RhAmidase is relatively narrow, due to the presence of the helix α13 in the small domain. The hydrophobic residues from the small domain are involved in recognizing the substrate. The small domain likely participates in substrate recognition and is related to the difference of substrate specificities among the AS family amidases. 相似文献
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