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91.
Lupberger J Zeisel MB Xiao F Thumann C Fofana I Zona L Davis C Mee CJ Turek M Gorke S Royer C Fischer B Zahid MN Lavillette D Fresquet J Cosset FL Rothenberg SM Pietschmann T Patel AH Pessaux P Doffoël M Raffelsberger W Poch O McKeating JA Brino L Baumert TF 《Nature medicine》2011,17(5):589-595
Hepatitis C virus (HCV) is a major cause of liver disease, but therapeutic options are limited and there are no prevention strategies. Viral entry is the first step of infection and requires the cooperative interaction of several host cell factors. Using a functional RNAi kinase screen, we identified epidermal growth factor receptor and ephrin receptor A2 as host cofactors for HCV entry. Blocking receptor kinase activity by approved inhibitors broadly impaired infection by all major HCV genotypes and viral escape variants in cell culture and in a human liver chimeric mouse model in vivo. The identified receptor tyrosine kinases (RTKs) mediate HCV entry by regulating CD81-claudin-1 co-receptor associations and viral glycoprotein-dependent membrane fusion. These results identify RTKs as previously unknown HCV entry cofactors and show that tyrosine kinase inhibitors have substantial antiviral activity. Inhibition of RTK function may constitute a new approach for prevention and treatment of HCV infection. 相似文献
92.
Hamaï A Duperrier-Amouriaux K Pignon P Raimbaud I Memeo L Colarossi C Canzonieri V Perin T Classe JM Campone M Jézéquel P Campion L Ayyoub M Valmori D 《PloS one》2011,6(6):e21129
The highly immunogenic human tumor antigen NY-ESO-1 (ESO) is a target of choice for anti-cancer immune therapy. In this study, we assessed spontaneous antibody (Ab) responses to ESO in a large cohort of patients with primary breast cancer (BC) and addressed the correlation between the presence of anti-ESO Ab, the expression of ESO in the tumors and their characteristics. We found detectable Ab responses to ESO in 1% of the patients. Tumors from patients with circulating Ab to ESO exhibited common characteristics, being mainly hormone receptor (HR)− invasive ductal carcinomas of high grade, including both HER2− and HER2+ tumors. In line with these results, we detected ESO expression in 20% of primary HR− BC, including both ESO Ab+ and Ab− patients, but not in HR+ BC. Interestingly, whereas expression levels in ESO+ BC were not significantly different between ESO Ab+ and Ab− patients, the former had, in average, significantly higher numbers of tumor-infiltrated lymph nodes, indicating that lymph node invasion may be required for the development of spontaneous anti-tumor immune responses. Thus, the presence of ESO Ab identifies a tumor subtype of HR− (HER2− or HER2+) primary BC with frequent ESO expression and, together with the assessment of antigen expression in the tumor, may be instrumental for the selection of patients for whom ESO-based immunotherapy may complement standard therapy. 相似文献
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Wenyi Yan a bc Shenghai Ye b Qingsheng Jin b Longjun Zeng c Yu Peng c Dawei Yan c Weibing Yang c Donglei Yang c Zuhua He c Yanjun Dong a Xiaoming Zhang b a College of Life Environment Sciences Shanghai Normal University Shanghai China b Institute of Crop Nuclear Technology Utilization Zhejiang Academy of Agricultural Sciences Hangzhou China c Institute of Plant Physiology & Ecology Shanghai Institutes for Biological Sciences Chinese Academy of Sciences Shanghai China 《Acta Genetica Sinica》2010,(1)
Plant senescence plays diverse important roles in development and environmental responses.However,the molecular basis of plant senescence is remained largely unknown.A rice spontaneous mutant with the character of early senescence and male sterility (sms) was found in the breeding line NT10-748.In order to identify the gene SMS1 and the underlying mechanism,we preliminarily analyzed physiological and biochemical phenotypes of the mutant.The mutant contained lower chlorophyll content compared with the wild t... 相似文献
96.
Pawel Nowak Derek C. Cole Ann Aulabaugh Jonathan Bard Rajiv Chopra Rebecca Cowling Kristi Y. Fan Baihua Hu Steve Jacobsen Minakshi Jani Guixan Jin Mei-Chu Lo Michael S. Malamas Eric S. Manas Rani Narasimhan Peter Reinhart Albert J. Robichaud Joseph R. Stock Joan Subrath Kristine Svenson John W. Ellingboe 《Bioorganic & medicinal chemistry letters》2010,20(2):632-635
8,8-Diphenyl-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine (1) was identified through HTS, as a weak (micromolar) inhibitor of BACE1. X-Ray crystallographic studies indicate the 2-aminoimidazole ring forms key H-bonding interactions with Asp32 and Asp228 in the catalytic site of BACE1. Lead optimization using structure-based focused libraries led to the identification of low nanomolar BACE1 inhibitors such as 20b with substituents which extend from the S1 to the S3 pocket. 相似文献
97.
Quantification of facial skeletal shape variation in fibroblast growth factor receptor‐related craniosynostosis syndromes 下载免费PDF全文
98.
Viviana Lo Martire Alessandro Silvani Stefano Bastianini Chiara Berteotti Giovanna Zoccoli 《PloS one》2012,7(10)
The central neural pathways underlying the physiological coordination between thermoregulation and the controls of the wake-sleep behavior and cardiovascular function remain insufficiently understood. Growing evidence supports the involvement of hypocretin (orexin) peptides in behavioral, cardiovascular, and thermoregulatory functions. We investigated whether the effects of ambient temperature on wake-sleep behavior and cardiovascular control depend on the hypothalamic neurons that release hypocretin peptides. Orexin-ataxin3 transgenic mice with genetic ablation of hypocretin neurons (n = 11) and wild-type controls (n = 12) were instrumented with electrodes for sleep scoring and a telemetric blood pressure transducer. Simultaneous sleep and blood pressure recordings were performed on freely-behaving mice at ambient temperatures ranging between mild cold (20°C) and the thermoneutral zone (30°C). In both mouse groups, the time spent awake and blood pressure were higher at 20°C than at 30°C. The cold-related increase in blood pressure was significantly smaller in rapid-eye-movement sleep (REMS) than either in non-rapid-eye-movement sleep (NREMS) or wakefulness. Blood pressure was higher in wakefulness than either in NREMS or REMS at both ambient temperatures. This effect was significantly blunted in orexin-ataxin3 mice irrespective of ambient temperature and particularly during REMS. These data demonstrate that hypocretin neurons are not a necessary part of the central pathways that coordinate thermoregulation with wake-sleep behavior and cardiovascular control. Data also support the hypothesis that hypocretin neurons modulate changes in blood pressure between wakefulness and the sleep states. These concepts may have clinical implications in patients with narcolepsy with cataplexy, who lack hypocretin neurons. 相似文献
99.
Nancy B. Y. Tsui Peiyong Jiang Katherine C. K. Chow Xiaoxi Su Tak Y. Leung Hao Sun K. C. Allen Chan Rossa W. K. Chiu Y. M. Dennis Lo 《PloS one》2012,7(10)
Background
Fetal DNA in maternal urine, if present, would be a valuable source of fetal genetic material for noninvasive prenatal diagnosis. However, the existence of fetal DNA in maternal urine has remained controversial. The issue is due to the lack of appropriate technology to robustly detect the potentially highly degraded fetal DNA in maternal urine.Methodology
We have used massively parallel paired-end sequencing to investigate cell-free DNA molecules in maternal urine. Catheterized urine samples were collected from seven pregnant women during the third trimester of pregnancies. We detected fetal DNA by identifying sequenced reads that contained fetal-specific alleles of the single nucleotide polymorphisms. The sizes of individual urinary DNA fragments were deduced from the alignment positions of the paired reads. We measured the fractional fetal DNA concentration as well as the size distributions of fetal and maternal DNA in maternal urine.Principal Findings
Cell-free fetal DNA was detected in five of the seven maternal urine samples, with the fractional fetal DNA concentrations ranged from 1.92% to 4.73%. Fetal DNA became undetectable in maternal urine after delivery. The total urinary cell-free DNA molecules were less intact when compared with plasma DNA. Urinary fetal DNA fragments were very short, and the most dominant fetal sequences were between 29 bp and 45 bp in length.Conclusions
With the use of massively parallel sequencing, we have confirmed the existence of transrenal fetal DNA in maternal urine, and have shown that urinary fetal DNA was heavily degraded. 相似文献100.