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91.
Takeo Kawahara Naoe Hotta Yukiko Ozawa Seiichi Kato Keiko Kano Yukihiro Yokoyama Masato Nagino Takashi Takahashi Kiyoshi Yanagisawa 《PloS one》2013,8(12)
Elucidation of how pancreatic cancer cells give rise to distant metastasis is urgently needed in order to provide not only a better understanding of the underlying molecular mechanisms, but also to identify novel targets for greatly improved molecular diagnosis and therapeutic intervention. We employed combined proteomic technologies including mass spectrometry and isobaric tags for relative and absolute quantification peptide tagging to analyze protein profiles of surgically resected human pancreatic ductal adenocarcinoma tissues. We identified a protein, dihydropyrimidinase-like 3, as highly expressed in human pancreatic ductal adenocarcinoma tissues as well as pancreatic cancer cell lines. Characterization of the roles of dihydropyrimidinase-like 3 in relation to cancer cell adhesion and migration in vitro, and metastasis in vivo was performed using a series of functional analyses, including those employing multiple reaction monitoring proteomic analysis. Furthermore, dihydropyrimidinase-like 3 was found to interact with Ezrin, which has important roles in cell adhesion, motility, and invasion, while that interaction promoted stabilization of an adhesion complex consisting of Ezrin, c-Src, focal adhesion kinase, and Talin1. We also found that exogenous expression of dihydropyrimidinase-like 3 induced activating phosphorylation of Ezrin and c-Src, leading to up-regulation of the signaling pathway. Taken together, the present results indicate successful application of combined proteomic approaches to identify a novel key player, dihydropyrimidinase-like 3, in pancreatic ductal adenocarcinoma tumorigenesis, which may serve as an important biomarker and/or drug target to improve therapeutic strategies. 相似文献
92.
Yuzuru Itoh Shun-ichi Sekine Shiro Suetsugu Shigeyuki Yokoyama 《Nucleic acids research》2013,41(13):6729-6738
Selenocysteine (Sec) is translationally incorporated into proteins in response to the UGA codon. The tRNA specific to Sec (tRNASec) is first ligated with serine by seryl-tRNA synthetase (SerRS). In the present study, we determined the 3.1 Å crystal structure of the tRNASec from the bacterium Aquifex aeolicus, in complex with the heterologous SerRS from the archaeon Methanopyrus kandleri. The bacterial tRNASec assumes the L-shaped structure, from which the long extra arm protrudes. Although the D-arm conformation and the extra-arm orientation are similar to those of eukaryal/archaeal tRNASecs, A. aeolicus tRNASec has unique base triples, G14:C21:U8 and C15:G20a:G48, which occupy the positions corresponding to the U8:A14 and R15:Y48 tertiary base pairs of canonical tRNAs. Methanopyrus kandleri SerRS exhibited serine ligation activity toward A. aeolicus tRNASec
in vitro. The SerRS N-terminal domain interacts with the extra-arm stem and the outer corner of tRNASec. Similar interactions exist in the reported tRNASer and SerRS complex structure from the bacterium Thermus thermophilus. Although the catalytic C-terminal domain of M. kandleri SerRS lacks interactions with A. aeolicus tRNASec in the present complex structure, the conformational flexibility of SerRS is likely to allow the CCA terminal region of tRNASec to enter the SerRS catalytic site. 相似文献
93.
Shigeru Kitanishi Masaki Nishio Kazuhiko Uehara Rikiya Ogawa Tatsuya Yokoyama Kaneaki Edo 《Environmental Biology of Fishes》2013,96(4):567-572
In this study, the level of genetic diversity of captive populations of the itasenpara bitterling (Acheilognathus longipinnis) was assessed to obtain information useful for successful captive breeding and reintroduction; this analysis was performed using mitochondrial DNA (mtDNA) sequence data. Comparison of the captive and wild populations showed low levels of genetic diversity within the captive population and significant genetic differentiation among the captive populations and also between the wild and captive populations, suggesting at chance effect during the founding process for the captive population and a subsequent genetic drift. Therefore, for successful reintroduction, it is important that the reintroduced population reflects all the genetic diversity available from the captive populations, and that releasing a large number of individuals that consist of all captive populations. 相似文献
94.
Akemi Shodai Toshifumi Morimura Akemi Ido Tsukasa Uchida Takashi Ayaki Rina Takahashi Soichiro Kitazawa Sakura Suzuki Mikako Shirouzu Takanori Kigawa Yutaka Muto Shigeyuki Yokoyama Ryosuke Takahashi Ryo Kitahara Hidefumi Ito Noriko Fujiwara Makoto Urushitani 《The Journal of biological chemistry》2013,288(21):14886-14905
Aggregation of TAR DNA-binding protein of 43 kDa (TDP-43) is a pathological signature of amyotrophic lateral sclerosis (ALS). Although accumulating evidence suggests the involvement of RNA recognition motifs (RRMs) in TDP-43 proteinopathy, it remains unclear how native TDP-43 is converted to pathogenic forms. To elucidate the role of homeostasis of RRM1 structure in ALS pathogenesis, conformations of RRM1 under high pressure were monitored by NMR. We first found that RRM1 was prone to aggregation and had three regions showing stable chemical shifts during misfolding. Moreover, mass spectrometric analysis of aggregated RRM1 revealed that one of the regions was located on protease-resistant β-strands containing two cysteines (Cys-173 and Cys-175), indicating that this region served as a core assembly interface in RRM1 aggregation. Although a fraction of RRM1 aggregates comprised disulfide-bonded oligomers, the substitution of cysteine(s) to serine(s) (C/S) resulted in unexpected acceleration of amyloid fibrils of RRM1 and disulfide-independent aggregate formation of full-length TDP-43. Notably, TDP-43 aggregates with RRM1-C/S required the C terminus, and replicated cytopathologies of ALS, including mislocalization, impaired RNA splicing, ubiquitination, phosphorylation, and motor neuron toxicity. Furthermore, RRM1-C/S accentuated inclusions of familial ALS-linked TDP-43 mutants in the C terminus. The relevance of RRM1-C/S-induced TDP-43 aggregates in ALS pathogenesis was verified by immunolabeling of inclusions of ALS patients and cultured cells overexpressing the RRM1-C/S TDP-43 with antibody targeting misfolding-relevant regions. Our results indicate that cysteines in RRM1 crucially govern the conformation of TDP-43, and aberrant self-assembly of RRM1 at amyloidogenic regions contributes to pathogenic conversion of TDP-43 in ALS. 相似文献
95.
Effective population control of Japanese wild boar (Sus scrofa leucomystax) requires reliable information about population dynamics. Fertility rate is the fundamental component of reproduction to evaluate population dynamics. However, little is known regarding the fertility rate of Japanese wild boar. The traditional hunting practices make it difficult to obtain pregnant females and calculate the fertility rate by checking fetuses as is performed in other countries. Therefore, we focused on the corpora albicans (CA) as the CA remains in the ovaries of postpartum females after pregnancy. This study aimed to evaluate the utility of CA and estimate the fertility rate of Japanese wild boars using CA. Histological analysis of ovaries enabled us to discriminate type 1 CA, which remains for 1 year after breeding. Type 1 CA is a superior indicator compared with lactation in the non-pregnancy season because it allows verification of postpartum females over a long period. The fertility rate was calculated by the combination of pregnant and postpartum females using fetuses and type 1 CA from April to November. The fertility rate of the females captured after the second pregnancy season was 90.3 % during the pregnancy period and 100 % during the non-pregnancy period. The high fertility rate of adult females suggests that intensive adult female harvesting is needed. Our new method to determine fertility rates contributes to developing a monitoring system to adequately control Japanese wild boar population. 相似文献
96.
Nao Kusuhashi Yukiyasu Tsutsumi Haruo Saegusa Kenji Horie Tadahiro Ikeda Kazumi Yokoyama Kazuyuki Shiraishi 《Proceedings. Biological sciences / The Royal Society》2013,280(1759)
We here describe a new Early Cretaceous (early Albian) eutherian mammal, Sasayamamylos kawaii gen. et sp. nov., from the ‘Lower Formation’ of the Sasayama Group, Hyogo Prefecture, Japan. Sasayamamylos kawaii is characterized by a robust dentary, a distinct angle on the ventral margin of the dentary at the posterior end of the mandibular symphysis, a lower dental formula of 3–4 : 1 : 4 : 3, a robust lower canine, a non-molariform lower ultimate premolar, and a secondarily reduced entoconid on the molars. To date, S. kawaii is the earliest known eutherian mammal possessing only four premolars, which demonstrates that the reduction in the premolar count in eutherians started in the late Early Cretaceous. The occurrence of S. kawaii implies that the relatively rapid diversification of eutherians in the mid-Cretaceous had already started by the early Albian. 相似文献
97.
Minoru Tanaka Xin Li Hidemasa Hikawa Takafumi Suzuki Katsuhiko Tsutsumi Masashi Sato Osamu Takikawa Hideharu Suzuki Yuusaku Yokoyama 《Bioorganic & medicinal chemistry》2013,21(5):1159-1165
Indoleamine 2,3-dioxygenase (IDO) plays a significant role in several disorders such as Alzheimer’s disease, age-related cataracts and tumors. A series of novel tryptoline derivatives were synthesized and evaluated for their inhibitory activity against IDO. Substituted tryptoline derivatives (11a, 11c, 11e, 12b and 12c) were demonstrated to be more potent than known inhibitor MTH-Trp. Suzuki–Miyaura cross-coupling reaction of 11a–d with phenylboronic acid proceeded in high yields. In most cases, C5 and C6 substitutions on the corresponding indole ring were well tolerated. The tryptoline derivative 11c is a promising chemical lead for the discovery of novel IDO inhibitors. 相似文献
98.
Masaki Setoguchi Shin Iimura Yuuichi Sugimoto Yoshiyuki Yoneda Jun Chiba Toshiyuki Watanabe Fumihito Muro Yutaka Iigo Gensuke Takayama Mika Yokoyama Tomoe Taira Misato Aonuma Tohru Takashi Atsushi Nakayama Nobuo Machinaga 《Bioorganic & medicinal chemistry》2013,21(1):42-61
We have carried out the optimization of substituents at the C-3 or the C-5 position on the pyrrolidine ring of VLA-4 antagonist 3 with 2-(phenylamino)-7-fluorobenzoxazolyl moiety for the purpose of improving in vivo efficacy while maintaining good aqueous solubility. As a result, we successfully increased in vitro activity in the presence of 3% human serum albumin and achieved an exquisite lipophilic and hydrophilic balance of compounds suitable for oral administrative regimen. The modification resulted in the identification of zwitterionic compound 7n with (5S)-[methoxy(methyl)amino]methylpyrrolidine, which significantly alleviated bronchial hyper-responsiveness to acetylcholine chloride at 12.5 mg/kg, p.o. in a murine asthma model and showed favorable aqueous solubility (JP1, 89 μg/mL; JP2, 462 μg/mL). Furthermore, this compound showed good oral bioavailability (F = 54%) in monkeys. 相似文献
99.
100.
Various saccharides were hydrolyzed with the purified amyloglucosidase of Endornyces sp. IFO 0111.Glucose was the only reducing product in the digest of soluble starch. The amyloglucosidase could hydrolyze starch and amylose only incompletely though it had the ability to split α-d-(1→6) bonds and hydrolyzed amylopectin and glycogen to high extents.It hydrolyzed maito-oligosaccharides by stepwise removal of glucose units from the nonreducing end of the molecules. 相似文献