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p62 Promotes Amino Acid Sensitivity of mTOR Pathway and Hepatic Differentiation in Adult Liver Stem/Progenitor Cells 下载免费PDF全文
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Tsuyoshi Shinozuka Tomoharu Tsukada Kunihiko Fujii Eri Tokumaru Kousei Shimada Yoshiyuki Onishi Yumi Matsui Satoko Wakimoto Masanori Kuroha Tsuneaki Ogata Kazushi Araki Jun Ohsumi Ryoko Sawamura Nobuaki Watanabe Hideki Yamamoto Kazunori Fujimoto Yoshiro Tani Makoto Mori Jun Tanaka 《Bioorganic & medicinal chemistry》2018,26(18):5099-5117
Attempts were made to reduce the lipophilicity of previously synthesized compound (II) for the avoidance of hepatotoxicity. The replacement of the left-hand side benzene with 2-pyridine resulted in the substantial loss of potency. Because poor membrane permeability was responsible for poor potency in vitro, the adjustment of lipophilicity was examined, which resulted in the discovery of dimethyl pyridine derivative (I, DS-6930). In preclinical studies, DS-6930 demonstrated high PPARγ agonist potency with robust plasma glucose reduction. DS-6930 maintained diminished PPARγ-related adverse effects upon toxicological evaluation in vivo, and demonstrated no hepatotoxicity. Cofactor recruitment assay showed that several cofactors, such as RIP140 and PGC1, were significantly recruited, whereas several canonical factors was not affected. This selective cofactor recruitment was caused due to the distinct binding mode of DS-6930. The calcium salt, DS-6930b, which is expected to be an effective inducer of insulin sensitization without edema, could be evaluated clinically in T2DM patients. 相似文献
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Modification of lipid A structure and activity by the introduction of palmitoyltransferase gene to the acyltransferase‐knockout mutant of Escherichia coli 下载免费PDF全文
Takehiro Sugawara Sakura Onoue Hiroaki Takimoto Kazuyoshi Kawahara 《Microbiology and immunology》2018,62(8):497-506
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Akito Y. Kawahara David Plotkin Chris A. Hamilton Harlan Gough Ryan St Laurent Hannah L. Owens Nicholas T. Homziak Jesse R. Barber 《Organisms Diversity & Evolution》2018,18(1):13-27
Lepidoptera (butterflies and moths) are one of the most taxonomically diverse insect orders with nearly 160,000 described species. They have been studied extensively for centuries and are found on nearly all continents and in many environments. It is often assumed that adult butterflies are strictly diurnal and adult moths are strictly nocturnal, but there are many exceptions. Despite the broad interest in butterflies and moths, a comprehensive review of diel (day-night) activity has not been conducted. Here, we synthesize existing data on diel activity in Lepidoptera, trace its evolutionary history on a phylogeny, and show where gaps lie in our knowledge. Diurnality was likely the ancestral condition in Lepidoptera, the ancestral heteroneuran was likely nocturnal, and more than 40 transitions to diurnality subsequently occurred. Using species diversity estimates across the order, we predict that roughly 75-85% of Lepidoptera are nocturnal. We also define the three frequently used terms for activity in animals (diurnal, nocturnal, crepuscular), and show that literature on the activity of micro-moths is significantly lacking. Ecological factors leading to nocturnality/diurnality is a compelling area of research and should be the focus of future studies. 相似文献
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