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211.
212.
Setti EL Venkatraman S Palmer JT Xie X Cheung H Yu W Wesolowski G Robichaud J 《Bioorganic & medicinal chemistry letters》2006,16(16):4296-4299
The synthesis and biological profile of a novel series of potent and selective inhibitors of cysteine protease cathepsin K (Cat K) are described. Pharmacokinetic evaluation of 12 indicated that some members of this series could be suitable candidates to develop new orally active therapeutic agents for the treatment of osteoporosis. 相似文献
213.
Cole DC Stock JR Chopra R Cowling R Ellingboe JW Fan KY Harrison BL Hu Y Jacobsen S Jennings LD Jin G Lohse PA Malamas MS Manas ES Moore WJ O'Donnell MM Olland AM Robichaud AJ Svenson K Wu J Wagner E Bard J 《Bioorganic & medicinal chemistry letters》2008,18(3):1063-1066
Proteolytic cleavage of amyloid precursor protein by beta-secretase (BACE-1) and gamma-secretase leads to formation of beta-amyloid (A beta) a key component of amyloid plaques, which are considered the hallmark of Alzheimer's disease. Small molecule inhibitors of BACE-1 may reduce levels of A beta and thus have therapeutic potential for treating Alzheimer's disease. We recently reported the identification of a novel small molecule BACE-1 inhibitor N-[2-(2,5-diphenyl-pyrrol-1-yl)-acetyl]guanidine (3.a.1). We report here the initial hit-to-lead optimization of this hit and the SAR around the aryl groups occupying the S(1) and S(2') pockets leading to submicromolar BACE-1 inhibitors. 相似文献
214.
Perrier H Bayly C Laliberté F Huang Z Rasori R Robichaud A Girard Y Macdonald D 《Bioorganic & medicinal chemistry letters》1999,9(3):323-326
The synthesis and in vitro activity of a series of substituted furans as a novel structural class of PDE4 inhibitors is described. Comparison of emetic threshold with known PDE4 inhibitors is presented. 相似文献
215.
Zhou P Yan Y Bernotas R Harrison BL Huryn D Robichaud AJ Zhang GM Smith DL Schechter LE 《Bioorganic & medicinal chemistry letters》2005,15(5):1393-1396
The preparation of a novel class of 4-(2-aminoethoxy)-N-(phenylsulfonyl)indoles which exhibit high affinity towards the 5-HT6 receptor is reported here. Among these compounds, 4-(2-methylaminoethoxy)-N-(phenylsulfonyl)indole 5g showed superior affinity (Ki = 1 nM) towards the 5-HT6 receptor as well as excellent selectivity (> 2000-fold) against the closely related subtype 5-HT7 receptor. 相似文献
216.
Robichaud GA Barbeau B Fortin JF Rothstein DM Tremblay MJ 《The Journal of biological chemistry》2002,277(26):23733-23741
Human immunodeficiency virus type-1 (HIV-1) preferentially replicates in CD4-expressing T cells bearing a "memory" (CD45RO+) rather than a "naive" (CD45RA+/CD62L+) phenotype. Yet the basis for the higher susceptibility of these cells to HIV-1 infection remains unclear. Because the nature of the CD45 isoform itself can affect biochemical events in T cells, we set out to determine whether these isoforms could differently modulate HIV-1 long terminal repeat (LTR) activity and thereby replication. Through the use of CD4+ Jurkat T cells specifically expressing distinct CD45 isoforms (i.e. CD45RABC or CD45RO), we demonstrated that a difference in CD45 isoform expression conferred preferential replication of HIV-1 to CD45RO-expressing T cell clones following a physiological CD3/CD28 stimulation. Closer analysis indicated that higher HIV-1 LTR activation levels were consistently observed in CD45RO-positive cells, which was paralleled by more pronounced nuclear factor of activated T cells (NFAT) activation in these same cells. Specific involvement of NFAT1 was revealed in studied Jurkat clones by mobility shift analyses. In addition, preferential activation of the LTR and viral replication in CD45RO T cells was FK506- and cyclosporin A-sensitive. These results underscore the importance of NFAT in HIV-1 regulation and for the first time identify the role of the CD45 isoform in limiting productive HIV-1 replication to the human CD4 memory T cell subset. 相似文献
217.
Robichaud AL 《Bioethics》2003,17(1):59-68
In the clinical setting, not enough attention is paid to the role that emotion plays. It is at worst ignored or avoided, isolating those who are suffering, at best treated as something to help another to endure. This is the result, in part, of an impoverished idea that views emotion as mere feelings. However, emotions are not just feelings, they are cognitive. If we look beneath the surface, emotions can provide information about values and beliefs, some of which may be false or unreasonable. When they are motivating decisions that seriously affect the lives of others, there is a moral obligation to ferret them out and correct or deal with them. Attention needs to be paid to the emotions of healthcare providers as well as to the emotions of patients and their loved ones, and more done to train healthcare providers to deal effectively and productively with emotion – their own and others'. A son tearfully requests everything be done for his dying father. He fears limiting treatment means his father will be ignored. A physician orders another course of chemotherapy because she cannot bear for this patient to die. The patient, fearing he will painfully suffocate to death, agrees. Paying attention to emotions and bringing to light the beliefs and values behind them can only enhance the care and consideration of all involved. 相似文献
218.
The effects of amino acids, abscisic acid (ABA), polyethylene glycol (PEG), and elevated sucrose were tested on the maturation and germination of American chestnut (Castanea dentata) somatic embryos. Somatic embryos from three lines were matured over an eight week period through a two-stage process. After maturation, somatic embryos were randomly divided into three groups to measure dry weight/ fresh weight ratios, starch levels, and germination rates. Prior to transfer to germination medium, somatic embryos received a four week cold treatment. While some treatments with amino acids, elevated sucrose, PEG or ABA increased either dry weight/fresh weight ratios, starch content or both, only addition of 25mM L-asparagine significantly increased germination rate and taproot length, and this response was only obtained with one of the three lines tested. Six plants survived the transfer to potting mix, acclimatization to greenhouse conditions and field planting. 相似文献
219.
Roy RL Morin Y Courtenay SC Robichaud P 《Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology》2004,139(2):235-244
Male smooth flounder (Pleuronectes putnami) were induced to produce vitellogenin (VTG) by injection of 17beta-estradiol (E2). Anion exchange chromatography of precipitated plasma from E2-injected resulted in a single peak consisting of VTG. Smooth flounder VTG has an approximate molecular mass of approximately 520 kDa, determined by gel filtration with molecular weight standards. Purified VTG was used to develop a homologous enzyme-linked immunosorbent assay (ELISA). The flounder VTG ELISA is an indirect antigen competition assay with a detection limit of 15 ng.ml(-1) and a useful range of 30-950 ng.ml(-1) of diluted sample. Intra- and inter-assay precision (as %CV, n=7) ranged from 1.3% to 6.0% and 5.1%, respectively. The ELISA was evaluated using plasma samples collected from a smooth flounder population captured in the Saint Lawrence Estuary. The ELISA is sensitive enough to differentiate males and non-vitellogenic females from vitellogenic individuals during early vitellogenesis. 相似文献
220.
Patrick Knott Eden Pappo Michelle Cameron JC deMauroy Charles Rivard Tomasz Kotwicki Fabio Zaina James Wynne Luke Stikeleather Josette Bettany-Saltikov Theodoros B Grivas Jacek Durmala Toru Maruyama Stefano Negrini Joseph P O’Brien Manuel Rigo 《Scoliosis》2014,9(1):1-9
This 2012 Consensus paper reviews the literature on side effects of x-ray exposure in the pediatric population as it relates to scoliosis evaluation and treatment. Alternative methods of spinal assessment and imaging are reviewed, and strategies for reducing the number of radiographs are developed. Using the Delphi technique, SOSORT members developed consensus statements that describe how often radiographs should be taken in each of the pediatric and adolescent sub-populations. 相似文献