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101.
Zhe Nie Victoria Feher Srinivasa Natala Christopher McBride Andre Kiryanov Benjamin Jones Betty Lam Yan Liu Stephen Kaldor Jeffrey Stafford Kouki Hikami Noriko Uchiyama Tomohiro Kawamoto Yuichi Hikichi Shin-ichi Matsumoto Nobuyuki Amano Lilly Zhang David Hosfield Takashi Ichikawa 《Bioorganic & medicinal chemistry letters》2013,23(12):3662-3666
Using structure-based drug design, we identified and optimized a novel series of pyrimidodiazepinone PLK1 inhibitors resulting in the selection of the development candidate TAK-960. TAK-960 is currently undergoing Phase I evaluation in adult patients with advanced solid malignancies. 相似文献
102.
Prostaglandins are biologically active substances used in a wide range of medical treatments. Prostaglandins have been supplied mainly by chemical synthesis; nevertheless, the high cost of prostaglandin production remains a factor. To lower the cost of prostaglandin production, we attempted to produce prostaglandins using a liverwort, Marchantia polymorpha L., which accumulates arachidonic acid, which is known as a substrate of prostaglandins. Here we report the first bioproduction of prostaglandins in plant species by introducing a cyclooxygenase gene from a red alga, Gracilaria vermiculophylla into the liverwort. The transgenic liverworts accumulated prostaglandin F2α, prostaglandin E2 and prostaglandin D2 which were not detected in the wild-type liverwort. Moreover, we succeeded in drastically increasing the bioproduction of prostaglandins using an in vitro reaction system with the extracts of transgenic liverworts. 相似文献
103.
Hirotaka Kashiwagi Yoshiyuki Ono Masateru Ohta Susumu Itoh Fumihiko Ichikawa Suguru Harada Satoshi Takeda Nobuo Sekiguchi Masaki Ishigai Tadakatsu Takahashi 《Bioorganic & medicinal chemistry》2013,21(7):1823-1833
In an extension of our study on gamma hydroxy carboxylic acid analogs, we explored a series of nonsecosteroidal vitamin D receptor (VDR) agonists in which 1,3-diol of 1,25(OH)2D3 had been replaced by aryl acetic acid. These analogs showed very potent activity in vitro compared with 1,25(OH)2D3. An X-ray analysis of 8d showed that the inserted phenyl ring well mimicked the folded methylene linker of the gamma hydroxy carboxylic acid moiety but the carboxylic acid of 8d interacted with VDR in a different manner from gamma hydroxy carboxylic acids. Through our in vivo screening in an osteoporosis rat model using immature rats, we identified a potent active vitamin D3 analog, compound 7e. In mature rats of the same model, compound 7e also showed good PK profiling and excellent ability to prevent bone mineral density loss without severe hypercalcemia. Our nonsecosteroidal VDR agonist 7e (CH5036249) could be a possible new drug candidate for treating osteoporosis in human. 相似文献
104.
Miho Morimoto Junko Morimoto Yoshiaki Moriya Futoshi Nakamura 《Landscape and Ecological Engineering》2013,9(2):259-270
Recently, the conversion of plantations into natural forests has attracted increasing attention, but little is known about how to convert a windthrown plantation into a natural forest. We examined the initial 3-year effects of salvage logging, site preparation, planting, and weeding in comparison with the effects of legacy retention after a typhoon blowdown on the changes in terrestrial environments and plant compositions and the similarity of the species composition to that of the intact natural forest. Our major findings are as follows: (1) A homogeneous, sunny, and flat environment continued for 3 years in the planted and weeded plot, whereas a heterogeneous environment was observed in the legacy retention plot; however, the light environment changed slightly in the planted plot. (2) The species composition in the planted plots changed greatly due to invasion by annual, biennial, and perennial herbs and early successional trees. Alien species also invaded the planted row. Conversely, the species composition changed little in the legacy retention, which was likely due to the presence of residual plants that prevented shade-intolerant species from being established. (3) The legacy retention, followed by the residual row, was the closest to the natural forest with respect to species composition, whereas the planted row was the most dissimilar from the natural forest. Legacy retention appears to be the most appropriate way to restore a natural forest immediately after a windthrow, yet supplemental planting may be necessary to restore the desired broadleaved species. 相似文献
105.
Yasuhiro Ogawa Makoto Tanaka Miho Tanabe Toshihiro Suzuki Tadayasu Togawa Tomoko Fukushige Takuro Kanekura Hitoshi Sakuraba Kazuhiko Oishi 《PloS one》2013,8(1)
Sandhoff disease (SD) is a glycosphingolipid storage disease that arises from mutations in the Hexb gene and the resultant deficiency in β-hexosaminidase activity. This deficiency results in aberrant lysosomal accumulation of the ganglioside GM2 and related glycolipids, and progressive deterioration of the central nervous system. Dysfunctional glycolipid storage causes severe neurodegeneration through a poorly understood pathogenic mechanism. Induced pluripotent stem cell (iPSC) technology offers new opportunities for both elucidation of the pathogenesis of diseases and the development of stem cell-based therapies. Here, we report the generation of disease-specific iPSCs from a mouse model of SD. These mouse model-derived iPSCs (SD-iPSCs) exhibited pluripotent stem cell properties and significant accumulation of GM2 ganglioside. In lineage-directed differentiation studies using the stromal cell-derived inducing activity method, SD-iPSCs showed an impaired ability to differentiate into early stage neural precursors. Moreover, fewer neurons differentiated from neural precursors in SD-iPSCs than in the case of the wild type. Recovery of the Hexb gene in SD-iPSCs improved this impairment of neuronal differentiation. These results provide new insights as to understanding the complex pathogenic mechanisms of SD. 相似文献
106.
Tokujiro Uchida Nagara Ohno Miho Asahara Yoshitsugu Yamada Osamu Yamaguchi Makoto Tomita Koshi Makita 《PloS one》2013,8(7)
Purpose
Postoperative respiratory failure is a major problem which can prolong the stay in the intensive care unit in patients undergoing cardiac surgery. We measured the serum levels of the soluble isoform of the receptor for advanced glycation end products (sRAGE), and we studied its association with postoperative respiratory failure.Methods
Eighty-seven patients undergoing elective cardiac surgery were enrolled in this multicenter observational study in three university hospitals. Serum biomarker levels were measured perioperatively, and clinical data were collected for 7 days postoperatively. The duration of mechanical ventilation was studied for 28 days.Results
Serum levels of sRAGE elevated immediately after surgery (median, 1751 pg/mL; interquartile range (IQR) 1080–3034 pg/mL) compared with the level after anesthetic induction (median, 884 pg/mL; IQR, 568–1462 pg/mL). Postoperative sRAGE levels in patients undergoing off-pump coronary artery bypass grafting (median, 1193 pg/mL; IQR 737–1869 pg/mL) were significantly lower than in patients undergoing aortic surgery (median, 1883 pg/mL; IQR, 1406–4456 pg/mL; p = 0.0024) and valve surgery (median, 2302 pg/mL; IQR, 1447–3585 pg/mL; p = 0.0005), and postoperative sRAGE correlated moderately with duration of cardiopulmonary bypass (rs = 0.44, p<0.0001). Receiver operating characteristic curve analysis demonstrated that postoperative sRAGE had a predictive performance with area under the curve of 0.81 (95% confidence interval 0.71–0.88) for postoperative respiratory failure, defined as prolonged mechanical ventilation >3 days. The optimum cutoff value for prediction of respiratory failure was 3656 pg/mL, with sensitivity and specificity of 62% and 91%, respectively.Conclusions
Serum sRAGE levels elevated immediately after cardiac surgery, and the range of elevation was associated with the morbidity of postoperative respiratory failure. Early postoperative sRAGE levels appear to be linked to cardiopulmonary bypass, and may have predictive performance for postoperative respiratory failure; however, large-scale validation studies are needed. 相似文献107.
108.
Satoshi Yamamoto Kenji Minami Keiichi Fukaya Kohji Takahashi Hideki Sawada Hiroaki Murakami Satsuki Tsuji Hiroki Hashizume Shou Kubonaga Tomoya Horiuchi Masamichi Hongo Jo Nishida Yuta Okugawa Ayaka Fujiwara Miho Fukuda Shunsuke Hidaka Keita W. Suzuki Masaki Miya Hitoshi Araki Hiroki Yamanaka Atsushi Maruyama Kazushi Miyashita Reiji Masuda Toshifumi Minamoto Michio Kondoh 《PloS one》2016,11(3)
Recent studies in streams and ponds have demonstrated that the distribution and biomass of aquatic organisms can be estimated by detection and quantification of environmental DNA (eDNA). In more open systems such as seas, it is not evident whether eDNA can represent the distribution and biomass of aquatic organisms because various environmental factors (e.g., water flow) are expected to affect eDNA distribution and concentration. To test the relationships between the distribution of fish and eDNA, we conducted a grid survey in Maizuru Bay, Sea of Japan, and sampled surface and bottom waters while monitoring biomass of the Japanese jack mackerel (Trachurus japonicus) using echo sounder technology. A linear model showed a high R2 value (0.665) without outlier data points, and the association between estimated eDNA concentrations from the surface water samples and echo intensity was significantly positive, suggesting that the estimated spatial variation in eDNA concentration can reflect the local biomass of the jack mackerel. We also found that a best-fit model included echo intensity obtained within 10–150 m from water sampling sites, indicating that the estimated eDNA concentration most likely reflects fish biomass within 150 m in the bay. Although eDNA from a wholesale fish market partially affected eDNA concentration, we conclude that eDNA generally provides a ‘snapshot’ of fish distribution and biomass in a large area. Further studies in which dynamics of eDNA under field conditions (e.g., patterns of release, degradation, and diffusion of eDNA) are taken into account will provide a better estimate of fish distribution and biomass based on eDNA. 相似文献
109.
Maiko Matsushita Yohei Otsuka Naoya Tsutsumida Chiaki Tanaka Akane Uchiumi Koji Ozawa Takuma Suzuki Daiju Ichikawa Hiroyuki Aburatani Shinichiro Okamoto Yutaka Kawakami Yutaka Hattori 《PloS one》2016,11(1)
The homeobox protein, PEPP2 (RHOXF2), has been suggested as a cancer/testis (CT) antigen based on its expression pattern. However, the peptide epitope of PEPP2 that is recognized by cytotoxic T cells (CTLs) is unknown. In this study, we revealed that PEPP2 gene was highly expressed in myeloid leukemia cells and some other hematological malignancies. This gene was also expressed in leukemic stem-like cells. We next identified the first reported epitope peptide (PEPP2271-279). The CTLs induced by PEPP2271-279 recognized PEPP2-positive target cells in an HLA-A*24:02-restricted manner. We also found that a demethylating agent, 5-aza-2’-deoxycytidine, could enhance PEPP2 expression in leukemia cells but not in blood mononuclear cells from healthy donors. The cytotoxic activity of anti-PEPP2 CTL against leukemic cells treated with 5-aza-2’-deoxycytidine was higher than that directed against untreated cells. These results suggest a clinical rationale that combined treatment with this novel antigen-specific immunotherapy together with demethylating agents might be effective in therapy-resistant myeloid leukemia patients. 相似文献
110.