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排序方式: 共有90条查询结果,搜索用时 15 毫秒
41.
42.
David A. DeGoey David A. Betebenner David J. Grampovnik Dachun Liu John K. Pratt Michael D. Tufano Wenping He Preethi Krishnan Tami J. Pilot-Matias Kennan C. Marsh Akhteruzzaman Molla Dale J. Kempf Clarence J. Maring 《Bioorganic & medicinal chemistry letters》2013,23(12):3627-3630
Efforts to improve the genotype 1a potency and pharmacokinetics of earlier naphthyridine-based HCV NS5A inhibitors resulted in the discovery of a novel series of pyrido[2,3-d]pyrimidine compounds, which displayed potent inhibition of HCV genotypes 1a and 1b in the replicon assay. SAR in this system revealed that the introduction of amides bearing an additional ‘E’ ring provided compounds with improved potency and pharmacokinetics. Introduction of a chiral center on the amide portion resulted in the observation of a stereochemical dependence for replicon potency and provided a site for the attachment of functional groups useful for improving the solubility of the series. Compound 21 was selected for administration in an HCV-infected chimpanzee. Observation of a robust viral load decline provided positive proof of concept for inhibition of HCV replication in vivo for the compound series. 相似文献
43.
Petra Leidinger Christina Backes Stephanie Deutscher Katja Schmitt Sabine C Mueller Karen Frese Jan Haas Klemens Ruprecht Friedemann Paul Cord St?hler Christoph JG Lang Benjamin Meder Tamas Bartfai Eckart Meese Andreas Keller 《Genome biology》2013,14(7):R78
Background
Alzheimer disease (AD) is the most common form of dementia but the identification of reliable, early and non-invasive biomarkers remains a major challenge. We present a novel miRNA-based signature for detecting AD from blood samples.Results
We apply next-generation sequencing to miRNAs from blood samples of 48 AD patients and 22 unaffected controls, yielding a total of 140 unique mature miRNAs with significantly changed expression levels. Of these, 82 have higher and 58 have lower abundance in AD patient samples. We selected a panel of 12 miRNAs for an RT-qPCR analysis on a larger cohort of 202 samples, comprising not only AD patients and healthy controls but also patients with other CNS illnesses. These included mild cognitive impairment, which is assumed to represent a transitional period before the development of AD, as well as multiple sclerosis, Parkinson disease, major depression, bipolar disorder and schizophrenia. miRNA target enrichment analysis of the selected 12 miRNAs indicates an involvement of miRNAs in nervous system development, neuron projection, neuron projection development and neuron projection morphogenesis. Using this 12-miRNA signature, we differentiate between AD and controls with an accuracy of 93%, a specificity of 95% and a sensitivity of 92%. The differentiation of AD from other neurological diseases is possible with accuracies between 74% and 78%. The differentiation of the other CNS disorders from controls yields even higher accuracies.Conclusions
The data indicate that deregulated miRNAs in blood might be used as biomarkers in the diagnosis of AD or other neurological diseases. 相似文献44.
Hutchinson DK Flentge CA Donner PL Wagner R Maring CJ Kati WM Liu Y Masse SV Middleton T Mo H Montgomery D Jiang WW Koev G Beno DW Stewart KD Stoll VS Molla A Kempf DJ 《Bioorganic & medicinal chemistry letters》2011,21(6):1876-1879
A series of quinoline derivatives was synthesized as potential bioisosteric replacements for the benzothiadiazine moiety of earlier Hepatitis C NS5B polymerase inhibitors. Several of these compounds exhibited potent activity in enzymatic and replicon assays. 相似文献
45.
Zhen Liu Franck Lebrin Janita A. Maring Sander van den Driesche Stieneke van der Brink Maarten van Dinther Midory Thorikay Sabrina Martin Kazuki Kobayashi Lukas J. A. C. Hawinkels Laurens A. van Meeteren Evangelia Pardali Jeroen Korving Michelle Letarte Helen M. Arthur Charles Theuer Marie-José Goumans Christine Mummery Peter ten Dijke 《PloS one》2014,9(1)
ENDOGLIN (ENG) is a co-receptor for transforming growth factor-β (TGF-β) family members that is highly expressed in endothelial cells and has a critical function in the development of the vascular system. Mutations in Eng are associated with the vascular disease known as hereditary hemorrhagic telangiectasia type l. Using mouse embryonic stem cells we observed that angiogenic factors, including vascular endothelial growth factor (VEGF), induce vasculogenesis in embryoid bodies even when Eng deficient cells or cells depleted of Eng using shRNA are used. However, ENG is required for the stem cell-derived endothelial cells to organize effectively into tubular structures. Consistent with this finding, fetal metatarsals isolated from E17.5 Eng heterozygous mouse embryos showed reduced VEGF-induced vascular network formation. Moreover, shRNA-mediated depletion and pharmacological inhibition of ENG in human umbilical vein cells mitigated VEGF-induced angiogenesis. In summary, we demonstrate that ENG is required for efficient VEGF-induced angiogenesis. 相似文献
46.
Viktoria Gloy Wolfgang Langhans Jacquelien JG Hillebrand Nori Geary Lori Asarian 《Biology of sex differences》2011,2(1):1-13
Background
Men are at an increased risk of dying from heart failure caused by inflammatory heart diseases such as atherosclerosis, myocarditis and dilated cardiomyopathy (DCM). We previously showed that macrophages in the spleen are phenotypically distinct in male compared to female mice at 12 h after infection. This innate immune profile mirrors and predicts the cardiac immune response during acute myocarditis.Methods
In order to study sex differences in the innate immune response, five male and female BALB/c mice were infected intraperitoneally with coxsackievirus B3 (CVB3) or phosphate buffered saline and their spleens were harvested 12 h later for microarray analysis. Gene expression was determined using an Affymetrix Mouse Gene 1.0 ST Array. Significant gene changes were verified by quantitative real-time polymerase chain reaction or ELISA.Results
During the innate immune response to CVB3 infection, infected males had higher splenic expression of genes which are important in regulating the influx of cholesterol into macrophages, such as phospholipase A2 (PLA2) and the macrophage scavenger receptor compared to the infected females. We also observed a higher expression in infected males compared to infected females of squalene synthase, an enzyme used to generate cholesterol within cells, and Cyp2e1, an enzyme important in metabolizing cholesterol and steroids. Infected males also had decreased levels of the translocator protein 18 kDa (TSPO), which binds PLA2 and is the rate-limiting step for steroidogenesis, as well as decreased expression of the androgen receptor (AR), which indicates receptor activation. Gene differences were not due to increased viral replication, which was unaltered between sexes.Conclusions
We found that, compared to females, male mice had a greater splenic expression of genes which are important for cholesterol metabolism and activation of the AR at 12 h after infection. Activation of the AR has been linked to increased cardiac hypertrophy, atherosclerosis, myocarditis/DCM and heart failure in male mice and humans. 相似文献47.
Yuansha Chen Peter Bystricky Jacob Adeyeye Pinaki Panigrahi Afsar Ali Judith A Johnson CA Bush JG MorrisJr OC Stine 《BMC microbiology》2007,7(1):20
Background
In V. cholerae, the biogenesis of capsule polysaccharide is poorly understood. The elucidation of capsule structure and biogenesis is critical to understanding the evolution of surface polysaccharide and the internal relationship between the capsule and LPS in this species. V. cholerae serogroup O31 NRT36S, a human pathogen that produces a heat-stable enterotoxin (NAG-ST), is encapsulated. Here, we report the covalent structure and studies of the biogenesis of the capsule in V. cholerae NRT36S. 相似文献48.
Andrew JG Simpson 《Genome biology》2000,1(1):reports411.1-reports4112
A meeting report of the sessions on human, eukaryotic and bacterial genome sequencing at the American Society for Microbiology and Institut Pasteur joint conference: Genomes 2000 International Conference on Microbial and Model Genomes, Paris, April 11-15, 2000 相似文献
49.
André B. P. van Kuilenburg Judith Meijer Adri N. P. M. Mul Rutger Meinsma Veronika Schmid Doreen Dobritzsch Raoul C. M. Hennekam Marcel M. A. M. Mannens Marion Kiechle Marie-Christine Etienne-Grimaldi Heinz-Josef Klümpen Jan Gerard Maring Veerle A. Derleyn Ed Maartense Gérard Milano Raymon Vijzelaar Eva Gross 《Human genetics》2010,128(5):529-538
Dihydropyrimidine dehydrogenase (DPD) is the initial enzyme acting in the catabolism of the widely used antineoplastic agent 5-fluorouracil (5FU). DPD deficiency is known to cause a potentially lethal toxicity following administration of 5FU. Here, we report novel genetic mechanisms underlying DPD deficiency in patients presenting with grade III/IV 5FU-associated toxicity. In one patient a genomic DPYD deletion of exons 21–23 was observed. In five patients a deep intronic mutation c.1129–5923C>G was identified creating a cryptic splice donor site. As a consequence, a 44 bp fragment corresponding to nucleotides c.1129–5967 to c.1129–5924 of intron 10 was inserted in the mature DPD mRNA. The deleterious c.1129–5923C>G mutation proved to be in cis with three intronic polymorphisms (c.483 + 18G>A, c.959–51T>G, c.680 + 139G>A) and the synonymous mutation c.1236G>A of a previously identified haplotype. Retrospective analysis of 203 cancer patients showed that the c.1129–5923C>G mutation was significantly enriched in patients with severe 5FU-associated toxicity (9.1%) compared to patients without toxicity (2.2%). In addition, a high prevalence was observed for the c.1129–5923C>G mutation in the normal Dutch (2.6%) and German (3.3%) population. Our study demonstrates that a genomic deletion affecting DPYD and a deep intronic mutation affecting pre-mRNA splicing can cause severe 5FU-associated toxicity. We conclude that screening for DPD deficiency should include a search for genomic rearrangements and aberrant splicing. 相似文献
50.
G Inesi E Maring A J Murphy B H McFarland 《Archives of biochemistry and biophysics》1970,138(1):285-294