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Cui YM Yasutomi E Otani Y Yoshinaga T Ido K Sawada K Kawahata M Yamaguchi K Ohwada T 《Bioorganic & medicinal chemistry letters》2008,18(24):6386-6389
Oxime ether derivatives of the benzylic ketone of 12,14-dichlorodehydroabietic acid (diCl-DHAA, 4b) were synthesised, and their BK channel-opening activity was evaluated in an assay system of CHO-K1 cells expressing hBKalpha channels. Oxime ether structure on the B ring of diCl-DHAA significantly increased the BK channel-opening activity. 相似文献
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Ubiquitin (Ub) is a small protein (8 kDa) found in all eukaryotic cells, which is conjugated covalently to numerous proteins, tagging them for recognition by a downstream effector. One of the best characterized functions of Ub is targeting proteins for either selective degradation by the proteasome, or for bulk degradation by the autophagy-lysosome system. The executing arm of the UPS is the 26S proteasome, a large multicatalytic complex. While much is known about the synthesis and assembly of the proteasome's subunits, the mechanism(s) underlying its removal has remained obscure, similar to that of many other components of the ubiquitin-proteasome system. Our recent study identified autophagy as the degrading mechanism for the mammalian proteasome, mostly under stress conditions. Amino acid starvation induces specific ubiquitination of certain 19S proteasomal subunits that is essential for its binding to SQSTM1/p62, the protein that shuttles the ubiquitinated proteasome to the autophagic machinery. SQSTM1 delivers ubiquitinated substrates for proteasomal degradation via interaction of its PB1 domain with the 19S proteasomal subunit PSMD4/Rpn10, in situations where the proteasome serves as a “predator." In contrast, we found that the UBA domain of SQSTM1 is essential for its interaction with the ubiquitinated proteasome and its delivery to the autophagosome, rendering the proteasome a “prey.” 相似文献
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The perception of pictorial gaze cues was examined in long-tailed macaques (Macaca fascicularis). A computerised object-location task was used to explore whether the monkeys would show faster response time to locate a target when its appearance was preceded with congruent as opposed to incongruent gaze cues. Despite existing evidence that macaques preferentially attend to the eyes in facial images and also visually orient with depicted gaze cues, the monkeys did not show faster response times on congruent trials either in response to schematic or photographic stimuli. These findings coincide with those reported for baboons testing with a similar paradigm in which gaze cues preceded a target identification task [Fagot, J., Deruelle, C., 2002. Perception of pictorial gaze by baboons (Papio papio). J. Exp. Psychol. 28, 298-308]. When tested with either pictorial stimuli or interactants, nonhuman primates readily follow gaze but do not seem to use this mechanism to identify a target object; there seems to be some mismatch in performance between attentional changes and manual responses to gaze cues on ostensibly similar tasks. 相似文献
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Matteo M. Trucco Ola Awad Breelyn A. Wilky Seth D. Goldstein Ruili Huang Robert L. Walker Preeti Shah Varalakshmi Katuri Naheed Gul Yuelin J. Zhu Edward F. McCarthy Ido Paz-Priel Paul S. Meltzer Christopher P. Austin Menghang Xia David M. Loeb 《PloS one》2013,8(11)
Chordoma is a rare primary bone malignancy that arises in the skull base, spine and sacrum and originates from remnants of the notochord. These tumors are typically resistant to conventional chemotherapy, and to date there are no FDA-approved agents to treat chordoma. The lack of in vivo models of chordoma has impeded the development of new therapies for this tumor. Primary tumor from a sacral chordoma was xenografted into NOD/SCID/IL-2R γ-null mice. The xenograft is serially transplantable and was characterized by both gene expression analysis and whole genome SNP genotyping. The NIH Chemical Genomics Center performed high-throughput screening of 2,816 compounds using two established chordoma cell lines, U-CH1 and U-CH2B. The screen yielded several compounds that showed activity and two, sunitinib and bortezomib, were tested in the xenograft. Both agents slowed the growth of the xenograft tumor. Sensitivity to an inhibitor of IκB, as well as inhibition of an NF-κB gene expression signature demonstrated the importance of NF-κB signaling for chordoma growth. This serially transplantable chordoma xenograft is thus a practical model to study chordomas and perform in vivo preclinical drug testing. 相似文献
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