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91.
Summary A filamentous fungus,Mortierella alpina was incubated aerobically on a medium made from potato paste and dextrose at 20 °C for 20 days. The yield of arachidonic acid reached 11.8 g/kg medium, which is more than 10 times higher than that by any other method reported previously. The highest content of the acid was 67.4% of the total fatty acids. 相似文献
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Takuto Kojima Yasutomi Asano Osamu Kurasawa Yasuhiro Hirata Naoki Iwamura Tzu-Tshin Wong Bunnai Saito Yuta Tanaka Ryosuke Arai Kazuko Yonemori Yasufumi Miyamoto Yoji Sagiya Masahiro Yaguchi Sachio Shibata Akio Mizutani Osamu Sano Ryutaro Adachi Yoshinori Satomi Shinichi Imamura 《Bioorganic & medicinal chemistry》2018,26(9):2452-2465
We pursued serine palmitoyltransferase (SPT) inhibitors as novel cancer therapeutic agents based on a correlation between SPT inhibition and growth suppression of cancer cells. High-throughput screening and medicinal chemistry efforts led to the identification of structurally diverse SPT inhibitors 4 and 5. Both compounds potently inhibited SPT enzyme and decreased intracellular ceramide content. In addition, they suppressed cell growth of human lung adenocarcinoma HCC4006 and acute promyelocytic leukemia PL-21, and displayed good pharmacokinetic profiles. Reduction of 3-ketodihydrosphingosine, the direct downstream product of SPT, was confirmed under in vivo settings after oral administration of compounds 4 and 5. Their anti-tumor efficacy was observed in a PL-21 xenograft mouse model. These results suggested that SPT inhibitors might have potential to be effective cancer therapeutics. 相似文献
94.
Mice with endogenous TDP‐43 mutations exhibit gain of splicing function and characteristics of amyotrophic lateral sclerosis
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Pietro Fratta Jose M Brito‐Armas Bernadett Kalmar Agnieszka Ule Yichao Yu Nicol Birsa Cristian Bodo Toby Collins Alexander E Conicella Alan Mejia Maza Alessandro Marrero‐Gagliardi Michelle Stewart Joffrey Mianne Silvia Corrochano Warren Emmett Gemma Codner Michael Groves Ryutaro Fukumura Yoichi Gondo Mark Lythgoe Erwin Pauws Emma Peskett Philip Stanier Lydia Teboul Martina Hallegger Andrea Calvo Adriano Chiò Adrian M Isaacs Nicolas L Fawzi Eric Wang David E Housman Francisco Baralle Linda Greensmith Emanuele Buratti Vincent Plagnol Abraham Acevedo‐Arozena 《The EMBO journal》2018,37(11)
TDP‐43 (encoded by the gene TARDBP) is an RNA binding protein central to the pathogenesis of amyotrophic lateral sclerosis (ALS). However, how TARDBP mutations trigger pathogenesis remains unknown. Here, we use novel mouse mutants carrying point mutations in endogenous Tardbp to dissect TDP‐43 function at physiological levels both in vitro and in vivo. Interestingly, we find that mutations within the C‐terminal domain of TDP‐43 lead to a gain of splicing function. Using two different strains, we are able to separate TDP‐43 loss‐ and gain‐of‐function effects. TDP‐43 gain‐of‐function effects in these mice reveal a novel category of splicing events controlled by TDP‐43, referred to as “skiptic” exons, in which skipping of constitutive exons causes changes in gene expression. In vivo, this gain‐of‐function mutation in endogenous Tardbp causes an adult‐onset neuromuscular phenotype accompanied by motor neuron loss and neurodegenerative changes. Furthermore, we have validated the splicing gain‐of‐function and skiptic exons in ALS patient‐derived cells. Our findings provide a novel pathogenic mechanism and highlight how TDP‐43 gain of function and loss of function affect RNA processing differently, suggesting they may act at different disease stages. 相似文献
95.
Tomoyuki Ohe Ryutaro Umezawa Yumina Kitagawara Daisuke Yasuda Kyoko Takahashi Shigeo Nakamura Akiko Abe Shuichi Sekine Kousei Ito Kentaro Okunushi Hanae Morio Tomomi Furihata Naohiko Anzai Tadahiko Mashino 《Bioorganic & medicinal chemistry letters》2018,28(23-24):3708-3711
We synthesized six novel BBR derivatives that were designed to avoid metabolic activation via ipso-substitution and evaluated for their degree of toxicity and hURAT1 inhibition. It was found that all of the derivatives demonstrate lower cytotoxicity in mouse hepatocytes and lower levels of metabolic activation than BBR, while maintaining their inhibitory activity toward the uric acid transporter. We propose that these derivatives could serve as effective uricosuric agents that have much better safety profiles than BBR. 相似文献
96.
The effects of niflumic acid on ryanodinereceptors (RyRs) of frog skeletal muscle were studied by incorporatingsarcoplasmic reticulum (SR) vesicles into planar lipid bilayers. Frogmuscle had two distinct types of RyRs in the SR: one showed abell-shaped channel activation curve against cytoplasmicCa2+ or niflumic acid, and its mean open probability(Po) was increased by perchlorate at 20-30mM (termed "-like" RyR); the other showed a sigmoidalactivation curve against Ca2+ or niflumic acid, with noeffect on perchlorate (termed "-like" RyR). The unitaryconductance and reversal potential of both channel types wereunaffected after exposure to niflumic acid when clamped at 0 mV. Whenclamped at more positive potentials, the -like RyRchannel rectified this, increasing the unitary current. Treatment withniflumic acid did not inhibit the response of both channels toCa2+ release channel modulators such as caffeine,ryanodine, and ruthenium red. The different effects of niflumic acid onPo and the unitary current amplitude in both typesof channels may be attributable to the lack or the presence ofinactivation sites and/or distinct responses to agonists. 相似文献
97.
This study reports on the spatial and temporal patterns of seedling establishment in the Turkwel riverine forest, Kenya. Seedlings of the dominant tree species Acacia tortilis and Hyphaene compressa were mapped and monitored to assess the underlying causes of seedling recruitment and mortality. The broad‐scale distribution of A. tortilis was not correlated with any environmental variables, while H. compressa seedlings were confined to flood‐exposed sites in the arid downstream section of the floodplain. One year of monitoring showed that seedling recruitment of A. tortilis was evoked by prolonged rainfall, while seedling mortality was caused by desiccation, browsing and trampling. In contrast, seedling recruitment and mortality of H. compressa was largely unaffected by rainfall and livestock, probably due to the high moisture requirements of seeds and the tolerance of seedlings to disturbance. There were no effects of soils, light, or seedling density on the establishment of A. tortilis and H. compressa seedlings. This study demonstrates the importance of parallel mapping and monitoring of riverine seedlings in order to understand patterns and processes of forest regeneration in arid and semi‐arid floodplains. 相似文献
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Dax-1 as one of the target genes of Ad4BP/SF-1. 总被引:4,自引:0,他引:4
K Kawabe T Shikayama H Tsuboi S Oka K Oba T Yanase H Nawata K Morohashi 《Molecular endocrinology (Baltimore, Md.)》1999,13(8):1267-1284
100.