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991.
Fibroblast growth factor (FGF) signalling has been implicated in the generation of mesoderm and neural fates in chordate embryos including ascidians and vertebrates. In Ciona, FGF9/16/20 has been implicated in both of these processes. However, in FGF9/16/20 knockdown embryos, notochord fate recovers during later development. It is thus not clear if FGF signalling is an essential requirement for notochord specification in Ciona embryos. We show that FGF-MEK-ERK signals act during two distinct phases to establish notochord fate. During the first phase, FGF signalling is required during an asymmetric cell division to promote notochord at the expense of neural identity. Consistently, ERK1/2 is specifically activated in the notochord precursors following this cell division. Sustained activation of ERK1/2 is then required to maintain notochord fate. We demonstrate that FGF9/16/20 acts solely during the initial induction step and that, subsequently, FGF8/17/18 together with FGF9/16/20 is involved in the following maintenance step. These results together with others' show that the formation of a large part of the mesoderm cell types in ascidian larvae is dependent on signalling events involving FGF ligands. 相似文献
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Bai Linquan Ohnishi Yasuo Kim Eung-Soo 《Journal of industrial microbiology & biotechnology》2019,46(3-4):313-317
Journal of Industrial Microbiology & Biotechnology - Discovery and development of natural products (NPs) have played important roles in the fields of human medicine and other biotechnology... 相似文献
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Chia Chi M. Ho Nan Guo Jonathan T. Sockolosky Aaron M. Ring Kipp Weiskopf Engin ?zkan Yasuo Mori Irving L. Weissman K. Christopher Garcia 《The Journal of biological chemistry》2015,290(20):12650-12663
CD47 is a cell surface protein that transmits an anti-phagocytic signal, known as the “don''t-eat-me” signal, to macrophages upon engaging its receptor signal regulatory protein α (SIRPα). Molecules that antagonize the CD47-SIRPα interaction by binding to CD47, such as anti-CD47 antibodies and the engineered SIRPα variant CV1, have been shown to facilitate macrophage-mediated anti-tumor responses. However, these strategies targeting CD47 are handicapped by large antigen sinks in vivo and indiscriminate cell binding due to ubiquitous expression of CD47. These factors reduce bioavailability and increase the risk of toxicity. Here, we present an alternative strategy to antagonize the CD47-SIRPα pathway by engineering high affinity CD47 variants that target SIRPα, which has restricted tissue expression. CD47 proved to be refractive to conventional affinity maturation techniques targeting its binding interface with SIRPα. Therefore, we developed a novel engineering approach, whereby we augmented the existing contact interface via N-terminal peptide extension, coined “Velcro” engineering. The high affinity variant (Velcro-CD47) bound to the two most prominent human SIRPα alleles with greatly increased affinity relative to wild-type CD47 and potently antagonized CD47 binding to SIRPα on human macrophages. Velcro-CD47 synergizes with tumor-specific monoclonal antibodies to enhance macrophage phagocytosis of tumor cells in vitro, with similar potency as CV1. Finally, Velcro-CD47 interacts specifically with a subset of myeloid-derived cells in human blood, whereas CV1 binds all myeloid, lymphoid, and erythroid populations interrogated. This is consistent with the restricted expression of SIRPα compared with CD47. Herein, we have demonstrated that “Velcro” engineering is a powerful protein-engineering tool with potential applications to other systems and that Velcro-CD47 could be an alternative adjuvant to CD47-targeting agents for cancer immunotherapy. 相似文献
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Taiki Katayama Manabu Kanno Naoki Morita Tomoyuki Hori Takashi Narihiro Yasuo Mitani Yoichi Kamagata 《Applied and environmental microbiology》2014,80(3):1126-1131
Medium- and long-chain fatty acids are present in organisms in esterified forms that serve as cell membrane constituents and storage compounds. A large number of organisms are known to accumulate lipophilic materials as a source of energy and carbon. We found a bacterium, designated GK12, that intrinsically accumulates free fatty acids (FFAs) as intracellular droplets without exhibiting cytotoxicity. GK12 is an obligatory anaerobic, mesophilic lactic acid bacterium that was isolated from a methanogenic reactor. Phylogenetic analysis based on 16S rRNA gene sequences showed that GK12 is affiliated with the family Erysipelotrichaceae in the phylum Firmicutes but is distantly related to type species in this family (less than 92% similarity in 16S rRNA gene sequence). Saturated fatty acids with carbon chain lengths of 14, 16, 18, and 20 were produced from glucose under stress conditions, including higher-than-optimum temperatures and the presence of organic solvents that affect cell membrane integrity. FFAs were produced at levels corresponding to up to 25% (wt/wt) of the dry cell mass. Our data suggest that FFA accumulation is a result of an imbalance between excess membrane fatty acid biosynthesis due to homeoviscous adaptation and limited β-oxidation activity due to anaerobic growth involving lactic acid fermentation. FFA droplets were not further utilized as an energy and carbon source, even under conditions of starvation. A naturally occurring bacterium that accumulates significant amounts of long-chain FFAs with noncytotoxicity would provide useful strategies for microbial biodiesel production. 相似文献
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Kazuya Sakata Masaki Ohmuraya Kimi Araki Chigure Suzuki Satoshi Ida Daisuke Hashimoto Jung Wang Yasuo Uchiyama Hideo Baba Ken-ichi Yamamura 《Experimental Animals》2014,63(1):45-53
Serine protease inhibitor Kazal type 1 (SPINK1; mouse homologue
Spink3) was initially discovered as a trypsin-specific inhibitor in the
pancreas. However, previous studies have suggested that SPINK1/Spink3 is
expressed in a wide range of normal tissues and tumors, although precise characterization
of its gene expression has not been described in adulthood. To further analyze
Spink3 expression, we generated two mouse lines in which either
lacZ or Cre recombinase genes were inserted into the
Spink3 locus by Cre-loxP technology. In
Spink3lacZ mice, β-galactosidase activity was found in
acinar cells of the pancreas and kidney, as well as epithelial cells of the bronchus in
the lung, but not in the gastrointestinal tract or liver.
Spink3cre knock-in mice were crossed with Rosa26 reporter
(R26R) mice to monitor Spink3 promoter activity. In
Spink3cre;R26R mice, β-galactosidase activity was found in
acinar cells of the pancreas, kidney, lung, and a small proportion of cells in the
gastrointestinal tract and liver. These data suggest that Spink3 is widely expressed in
endoderm-derived tissues, and that Spink3cre knock-in mice are
a useful tool for establishment of a conditional knockout mice to analyze Spink3 function
not only in normal tissues, but also in tumors that express
SPINK1/Spink3. 相似文献