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411.
The anti-metabolite 5-fluorouracil (5-FU) is employed clinically to manage solid tumors including colorectal and breast cancer.
Intracellular metabolites of 5-FU can exert cytotoxic effects via inhibition of thymidylate synthetase, or through incorporation
into RNA and DNA, events that ultimately activate apoptosis. In this review, we cover the current data implicating DNA repair
processes in cellular responsiveness to 5-FU treatment. Evidence points to roles for base excision repair (BER) and mismatch
repair (MMR). However, mechanistic details remain unexplained, and other pathways have not been exhaustively interrogated.
Homologous recombination is of particular interest, because it resolves unrepaired DNA intermediates not properly dealt with
by BER or MMR. Furthermore, crosstalk among DNA repair pathways and S-phase checkpoint signaling has not been examined. Ongoing
efforts aim to design approaches and reagents that (i) approximate repair capacity and (ii) mediate strategic regulation of
DNA repair in order to improve the efficacy of current anticancer treatments.
Received 08 September 2008; received after revision 25 September 2008; accepted 03 October 2008 相似文献
412.
In the sixties James Watson suggested a twosite model for the ribosome comprising the P site for the peptidyl transfer RNA
(tRNA) before peptide-bond formation and the A site, where decoding takes place according to the codon exposed there. In the
eighties a third tRNA binding site was detected, the E site, which was specific for deacylated tRNA and turned out to be a
universal feature of ribosomes. However, despite having three tRNA binding sites, only two tRNAs occupy the ribosome at a
time during protein synthesis: at the A and P sites before translocation (PRE state) and at the P and E sites after translocation
(POST state). The importance of having two tRNAs in the POST state has been revealed during the last 25 years, showing that
the E site contributes two fundamental features: (i) the fact that incorporation of a wrong amino acid is not harmful for
the cell (only 1 in about 400 misincorporations destroys the function of a protein) stems from the presence of an E-tRNA;
(ii) maintenance of the reading frame is one of the most remarkable achievements of the ribosome, essential for faithful translation
of the genetic information. The presence of the POST state E-tRNA prevents loss of the reading frame.
Received 14 March 2006; received after revision 8 June 2006; accepted 4 August 2006 相似文献
413.
Estrada K Styrkarsdottir U Evangelou E Hsu YH Duncan EL Ntzani EE Oei L Albagha OM Amin N Kemp JP Koller DL Li G Liu CT Minster RL Moayyeri A Vandenput L Willner D Xiao SM Yerges-Armstrong LM Zheng HF Alonso N Eriksson J Kammerer CM Kaptoge SK Leo PJ Thorleifsson G Wilson SG Wilson JF Aalto V Alen M Aragaki AK Aspelund T Center JR Dailiana Z Duggan DJ Garcia M Garcia-Giralt N Giroux S Hallmans G Hocking LJ Husted LB Jameson KA Khusainova R Kim GS Kooperberg C Koromila T Kruk M Laaksonen M 《Nature genetics》2012,44(5):491-501
Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10(-4), Bonferroni corrected), of which six reached P < 5 × 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility. 相似文献
414.
用气象色谱方法对高原鼢鼠油脂中亚油酸含量进行了定量分析,并对方法的准确度进行了检验。结果发现:高原鼢鼠油脂中亚油酸含量为10.84%±0.38%,皂化和酯化最佳时间分别为15min和7min,亚油酸甲酯标准曲线回归系数r=0.9999,亚油酸甲酯色谱峰面积的相对偏差为0.0124,样品亚油酸甲酯回收率为95.08%。 相似文献
415.
Barton A Thomson W Ke X Eyre S Hinks A Bowes J Plant D Gibbons LJ;Wellcome Trust Case Control Consortium;YEAR Consortium;BIRAC Consortium Wilson AG Bax DE Morgan AW Emery P Steer S Hocking L Reid DM Wordsworth P Harrison P Worthington J 《Nature genetics》2008,40(10):1156-1159
The WTCCC study identified 49 SNPs putatively associated with rheumatoid arthritis at P = 1 x 10(-4) - 1 x 10(-5) (tier 3). Here we show that three of these SNPs, mapping to chromosome 10p15 (rs4750316), 12q13 (rs1678542) and 22q13 (rs3218253), are also associated (trend P = 4 x 10(-5), P = 4 x 10(-4) and P = 4 x 10(-4), respectively) in a validation study of 4,106 individuals with rheumatoid arthritis and an expanded reference group of 11,238 subjects, confirming them as true susceptibility loci in individuals of European ancestry. 相似文献
416.
Yong Hu Samuel M.L.Teicher Brenden R.Ortiz Yang Luo Shuting Peng Linwei Huai Junzhang Ma Nicholas C.Plumb Stephen D.Wilson Junfeng He Ming Shi 《科学通报(英文版)》2022,(5):495-500
Exotic quantum phenomena may appear in material systems with multiple orders or phases,where the mutual interactions can give rise to new physics beyond that of... 相似文献
417.
R.P.Wilson 《浙江海洋学院学报(自然科学版)》2001,20(Z1):16-22
在确定鱼类对潜在营养源的利用或营养物需求的研究中,常存在一些问题.本文将讨论这些问题,并提出这类实验的一般步骤.
1、饲料 商用饲料需注明饲料及厂家的全称.实验饲料需列出所有原料的标准名称及国际饲料号.精饲料及添加剂需列出原料供应商及地址.基础饲料应能提供实验鱼所需的全部营养.除了所测成分外,饲料的组成应是恒定的.最好能根据消化率数据确定饲料配方.饲料制作的步骤应描述清楚.饲料使用前应冷冻保存.饲料应采用国际上接受的方法进行化学分析.
2、实验条件
应描述饲养单元的大小、位置、水源及水处理方法、水温、流速、溶氧、水质参数、光照条件、实验鱼的详细情况及其他实验条件.养鱼系统包括流水、循环过滤水及静水系统.静水系统不能用于营养需求实验,循环水系统亦不宜用于维生素及无机盐需求量实验.
3、实验设计 每一饲养单元是一个重复,单元内的个体不能看作重复样.每一处理至少需要3个重复.实验鱼需经过一段时间暂养才能用于实验.实验周期至少8周,微营养物需求实验需要12-20周.实验期增重率应在200%-500%以上.饲养单元应随机分配于各个处理.投喂方式可以是饱食或限食.若采用限食投喂,投喂水平应接近饱食.
4、数据评价 如果对照鱼生长率较预期的低,或死亡率较高,或实验结果与预期的不同,则有必要重复实验.需求量实验应得到剂量反应曲线,否则须重新设计实验.建议采用拐点法或回归法确定最低需求量. 相似文献
418.
龙门山造山带-川西前陆盆地系统构造事件研究 总被引:12,自引:0,他引:12
通过对构造事件形成的产物 (岩浆岩、各种矿物等 )进行氩 -氩年龄测定、裂变径迹年龄测定、ESR年龄测定和计算机模拟 ,得出龙门山造山带 -川西前陆盆地系统自印支期以来 ,共发生了 7次构造事件 :(1)卡尼期末的构造事件 (D1 ) ,形成 S1 和 F1 ,并有区域低温动热变质作用 ;(2 )诺利期末的构造事件 (安县运动 ,D2 ) ,产生川西前陆盆地上三叠统须四段与下伏地层不整合接触和须四段砾岩的分布 ,并有较强的岩浆作用 ;(3)燕山期 (12 0~ 130 Ma,D3) ,有较强的岩浆作用和变质作用 ;(4 )喜马拉雅期 6 0 Ma左右的构造事件 (D4) ;(5 )喜马拉雅期 30~ 40Ma的构造事件 (D5 ) ;(6 )喜马拉雅期 2 0~ 2 5 Ma的构造事件 (D6 ) ;(7)喜马拉雅期 10 Ma的构造事件 (D7)。后 4次构造事件使龙门山造山带 -川西前陆盆地系统发生强烈的冲断作用和隆升作用 相似文献
419.
The Toll-like receptor 2 is recruited to macrophage phagosomes and discriminates between pathogens. 总被引:82,自引:0,他引:82
D M Underhill A Ozinsky A M Hajjar A Stevens C B Wilson M Bassetti A Aderem 《Nature》1999,401(6755):811-815
Macrophages orchestrate innate immunity by phagocytosing pathogens and coordinating inflammatory responses. Effective defence requires the host to discriminate between different pathogens. The specificity of innate immune recognition in Drosophila is mediated by the Toll family of receptors; Toll mediates anti-fungal responses, whereas 18-wheeler mediates anti-bacterial defence. A large number of Toll homologues have been identified in mammals, and Toll-like receptor 4 is critical in responses to Gram-negative bacteria. Here we show that Toll-like receptor 2 is recruited specifically to macrophage phagosomes containing yeast, and that a point mutation in the receptor abrogates inflammatory responses to yeast and Gram-positive bacteria, but not to Gram-negative bacteria. Thus, during the phagocytosis of pathogens, two classes of innate immune receptors cooperate to mediate host defence: phagocytic receptors, such as the mannose receptor, signal particle internalization, and the Toll-like receptors sample the contents of the vacuole and trigger an inflammatory response appropriate to defence against the specific organism. 相似文献
420.