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Discovery of Potent, selective and Reversible Caspase-3 Inhibitors

合成化学 2004年第Z1期12卷 13-13页

作者： André Giroux john Colucci Christopher I. Bayly Daniel J. Mckay sophie Roy s.eve xanthoudakis.john vaillancourt Dita M. Rasper john Tam Paul Tawa Donald W. Nicholson Robert J. Zamboni Department of Medicinal Chemistry Department of Biochemistry and Molecular Biology Merck Frosst Centre for Therapeutic Research Merck Frosst Canada & Co. P.O. Box 1005 Pointe-Claire-DorvalQuebec Canada H9R 4P8

Recent studies towards understanding the molecular mechanisms of apoptosis have revealed the importance of a group of cysteinyl aspartate specific proteases, the caspases, in the programmed cell death process (Hengartner, M.O. Nature 2000, 407, 770). Caspase-3, in particular,has been characterized as the dominant effector caspase involved in the proteolytic cleavage of a variety of protein substrates including cytoskeletal proteins, kinases and DNA repair enzymes during apoptosis (Nicholson, D. W. Cell Death Differ. 1999, 6, 1028). The development of potent and selective caspase-3 inhibitors has thus emerged as an attractive therapeutic target. In the presentation,the identification of a series of potent, selective and reversible non-peptidyl caspase-3 inhibitors containing a pyrazinone core (1) will be presented. sAR optimization at R1, R2, R3 and R4 led to the discovery of inhibitors such as 2 with excellent in vitro activities (IC50 against rh-caspase-3: 5 nM; IC50 against camptothecin induced apoptotic cell death in NT2 cells: 20 nM). Compounds such as 2 also displayed excellent in vivo activities in a number of animal models of acute injuries (see: Methot, N. et al, J. Exp. Med. 2004, 119, 199; Toulmond, s. et al, British J. Pharm. 2004, 141,689; Holtzman,D.M. et al, JBC, 2002, 277, 30128), and selected examples will be discussed during the presentation.

关键词： programmed cell death cytoskeletal proteins molecular mechanisms identification of animal models DNA repair in vitro

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The making of an agricultural classic: farmers of forty centuries or permanent agriculture in China, Korea and Japan, 1911-2011

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Agricultural sciences 2011年第3期2卷 175-180页

作者： john Paull 不详

Few agriculture books achieve the status of ‘classic’. F. H. King’s book Farmers of Forty Centuries or Permanent Agriculture in China, Korea and Japan was privately published in Wisconsin, UsA, in 1911. The book had an inauspicious start, and the longevity and acclaim that this book has since achieved must have been, then, barely conceivable. The author was dead, the book was incomplete, and there was no commercial publisher. Yet through a combination of perhaps luck and circumstance the book was ‘resurrected’ in 1927 by a London publisher, Jonathan Cape, who then kept it in print for more than two decades. The London issue of King’s book was favourably cited in the 1930s and 1940s by leading agriculture and organic agriculture writers including: Lord North- bourne, eve Balfour, Viscount Lymington, Albert and Louise Howard in Britain;Ehrenfried Pfeiffer in switzerland;Jerome Rodale in the UsA;and stanton Hicks in Australia. These endorsements served to entrench King’s book as a ‘classic’. Jerome Rodale reintroduced the book to a Us audience with an edition published by his Organic Gardening Press, c.1949. King’s book arose out of his discontent with the views promulgated by the Us Department of Agriculture (UsDA), he differentiated the Asian agriculture he encountered as ‘permanent agriculture’, he provided a detailed account of the ancien régime organic agriculture of China, Korea and Japan, he called for a “world movement” for agricultural reform, and his book was been taken as a validation of the principles of organic agriculture. At least twenty six impressions of Farmers of Forty Centuries have been published in the past century, ten of these appeared during the first nine decades, while 16 have appeared in the past decade.

关键词： Organic Agriculture Organic Farming Biodynamic Agriculture Franklin Hiram King Cyril Hopkins Jonathan Cape London.

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Raisingthe Bar:strongman Gym Open in Haizhu

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城市漫步（GBA版） 2023年第12期 36-39页

作者： Kirby john Carney 不详

We meet Ginour on the eve of his strongman competition at his fitness resort for the first-ever iteration of this particular China strongman *** venue certainly feels that *** place is a fitness fanatic's paradise,wit... 详细信息

关键词： strong resort iteration

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Phased,chromosome-scale genome assemblies of tetraploid potato reveal a complex genome,transcriptome,and predicted proteome landscape underpinning genetic diversity

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Molecular Plant 2022年第3期15卷 520-536页

作者： Genevieve Hoopes Xiaoxi Meng john P.Hamilton sai Reddy Achakkagari Fernanda de Alves Freitas Guesdes Marie E.Bolger Joseph J.Coombs Danny Esselink Natalie R.Kaiser Linda Kodde Maria Kyriakidou Brian Lavrijssen Natascha van Lieshout Rachel shereda Heather K.Tuttle Brieanne vaillancourt Joshua C.Wood Jan Mde Boer Nolan Bornowski Peter Bourke David Douches Herman Jvan Eck Dave Ellis Max J.Feldman Kyle M.Gardner Johannes C.P.Hopman Jiming Jiang Walter s.De Jong Joseph C.Kuhl Richard G.Novy stan Oome Vidyasagar sathuvalli Ek Han Tan Remco A.Ursum M.Isabel Vales Kelly Vining Richard G.F.Visser Jack Vossen G.Craig Yencho Noelle L.Anglin Christian W.B.Bachem Jeffrey B.Endelman Laura M.shannon Martina V.stromvik Helen H.Tai Bjorn Usadel C.Robin Buell Richard Finkers Department of Plant Biology Michigan State UniversityEast LansingMI 48824USA Department of Horticultural science University of MinnesotaSt.PaulMN 55108USA Department of Plant science McGill UniversitySainte-Anne-de-BellevueQC H9X 3V9Canada Plant Breeding Wageningen University&ResearchPlant Breeding6708 PB Wageningenthe Netherlands IBG-4 Bioinformatics Forschungszentrum JülichWilhelm Johnen Str52428 JülichGermany Department of Plant Soiland Microbial SciencesMichigan State UniversityEast LansingMI 48824USA Bayer Crop science WoodlandCA 95695USA Averis seeds B.V. 9640 AA Veendamthe Netherlands International Potato Center 1895 Avenida La MolinaLimaPeru UsDA-ARs ProsserWA 99350USA Agriculture and Agri-Food Canada Fredericton Research and Development Centre FrederictonNB E3B 4Z7Canada school of Integrative Plant science Cornell UniversityIthacaNY 14853-1901USA Department of Plant sciences University of IdahoMoscowID 83844USA UsDA-ARs Small Grains and Potato Germplasm ResearchAberdeenID 83210USA HZPC Research B.V. Edisonweg 58501 XG Jourethe Netherlands Department of Crop and soil science Oregon State UniversityHermistonOR 97838USA school of Biology and Ecology University of Maine5735 Hitchner Hall OronoME 04469USA Department of Horticultural sciences Texas A&M UniversityCollege StationTX 77843-2133USA Department of Horticulture Oregon State UniversityCorvallisOR 97331USA Department of Horticultural science North Carolina State UniversityRaleighNC 27695-7609USA Department of Horticulture University of Wisconsin-MadisonMadisonWI 53706USA Department of Horticulture Michigan State UniversityEast LansingMI 48824USA Institute for Biological Data science Heinrich Heine UniversityDusseldorf40225 DusseldorfGermany Plant Resilience Institute Michigan State UniversityEast LansingMI 48824USA Present address:GenNovation B.V. Wageningenthe Netherlands

Cultivated potato is a clonally propagated autotetraploid species with a highly heterogeneous *** assemblies of six cultivars including two chromosome-scale phased genome assemblies revealed extensive allelic diversity,including altered coding and transcript sequences,preferential allele expression,and structural variation that collectively result in a highly complex transcriptome and predicted proteome,which are distributed across the homologous *** species contribute to the extensive allelic diversity in tetraploid cultivars,demonstrating ancestral introgressions predating modern breeding *** a clonally propagated autotetraploid that undergoes limited meiosis,dysfunctional and deleterious alleles are not purged in tetraploid *** a quarter of the loci bore mutations are predicted to have a high negative impact on protein function,complicating breeder’s efforts to reduce genetic *** stCDF1 locus controls maturity,and analysis of six tetraploid genomes revealed that 12 allelic variants of stCDF1 are correlated with maturity in a dosage-dependent *** of the complexity of the tetraploid potato genome with its rampant structural variation and embedded deleterious and dysfunctional alleles will be key not only to implementing precision breeding of tetraploid cultivars but also to the construction of homozygous,diploid potato germplasm containing favorable alleles to capitalize on heterosis in F1 hybrids.

关键词： potato allele diversity phased assembly polyploid pan-genome wild introgressions

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2006年迟到一闰秒(英文)

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大学英语 2006年第2期 7-9页

作者： john Roach 李同良浙江嘉兴职业技术学院外语系

For those of you counting the seconds until 2006, add *** world's top timekeepers will insert an extra second-or leap second-just before midnight in coordinated universal time (UTC)2 on New Year's.eve. UTC is determin... 详细信息

关键词： ITU IAU

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