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51.
Wertz IE Kusam S Lam C Okamoto T Sandoval W Anderson DJ Helgason E Ernst JA Eby M Liu J Belmont LD Kaminker JS O'Rourke KM Pujara K Kohli PB Johnson AR Chiu ML Lill JR Jackson PK Fairbrother WJ Seshagiri S Ludlam MJ Leong KG Dueber EC Maecker H Huang DC Dixit VM 《Nature》2011,471(7336):110-114
Microtubules have pivotal roles in fundamental cellular processes and are targets of antitubulin chemotherapeutics. Microtubule-targeted agents such as Taxol and vincristine are prescribed widely for various malignancies, including ovarian and breast adenocarcinomas, non-small-cell lung cancer, leukaemias and lymphomas. These agents arrest cells in mitosis and subsequently induce cell death through poorly defined mechanisms. The strategies that resistant tumour cells use to evade death induced by antitubulin agents are also unclear. Here we show that the pro-survival protein MCL1 (ref. 3) is a crucial regulator of apoptosis triggered by antitubulin chemotherapeutics. During mitotic arrest, MCL1 protein levels decline markedly, through a post-translational mechanism, potentiating cell death. Phosphorylation of MCL1 directs its interaction with the tumour-suppressor protein FBW7, which is the substrate-binding component of a ubiquitin ligase complex. The polyubiquitylation of MCL1 then targets it for proteasomal degradation. The degradation of MCL1 was blocked in patient-derived tumour cells that lacked FBW7 or had loss-of-function mutations in FBW7, conferring resistance to antitubulin agents and promoting chemotherapeutic-induced polyploidy. Additionally, primary tumour samples were enriched for FBW7 inactivation and elevated MCL1 levels, underscoring the prominent roles of these proteins in oncogenesis. Our findings suggest that profiling the FBW7 and MCL1 status of tumours, in terms of protein levels, messenger RNA levels and genetic status, could be useful to predict the response of patients to antitubulin chemotherapeutics. 相似文献
52.
作物品种区域试验的评价体系及评价方法 总被引:28,自引:0,他引:28
从作物品种区域试验的实际需要出发,提出了区域试验的试验评价和品种评价的体系,并对具体评价方法和指标作了概述和比较,指出了其中尚待解决的难点,同时论述了区域试验中应注意的问题.表1,参29. 相似文献
53.
GAO Zhi-wei Ho Daniel W. C. WANG Xian-lai LI Guang-quan . Tianjin University Tianjin China . City University of Hong Kong Kowloon Hong Kong China 《系统科学与系统工程学报(英文版)》2000,(1)
1 IntroductionConsider a singular decentralized control system of the formEx(t) =Ax(t) ∑Ni=1Biui(t)yi =Cix(t) ,i∈ N ={ 1 ,2 ,… ,N}(1 )where x(t)∈ Rn is the state vector,ui(t)∈ Rmi and yi(t)∈ Rpi are respectively the localcontrol input and measure outputvectors of the ith control channel.The matrix E may besingular,i.e.,rank(E) 相似文献
54.
等离子熔积成形混相瞬态场的Level-Set方法模拟 总被引:1,自引:0,他引:1
提出了一种二维等离子熔积成形瞬态模型,该模型描述了液/气界面的自由表面发展,并模拟了熔池内流体流动和传热.采用Level—Set方法处理液/气界面边界条件,考虑了熔体流动的主要驱动力——表面张力梯度、表面曲率、浮力以及工件表面的对流散热等因素.用固液相统一模型来描述固/液界面处的熔融和凝固过程,并开发了相应的软件.对高温合金K163在不同扫描速度下的熔积层表面形貌、温度场以及熔池内流场进行了模拟分析. 相似文献
55.
自动识别和描述图像的内容是人工智能中一个重要的研究方向,它涉及计算机视觉和自然语言处理技术。针对这一难题,提出了一种由深层神经网络模型生成自然语言句子来描述图像内容的方法。该方法提出的模型由卷积神经网络(Convolution Neural Network,CNN)和循环神经网络(Recurrent Neural Network,RNN)组成,其中,CNN用来提取输入图像的特征生成固定长度的特征向量,该特征向量初始化RNN来生成句子。在MSCOCO图像描述数据集上的实验结果表明了该模型所生成句子的语法准确性和语义准确性,且优于先前的基线模型。 相似文献
56.
Sulem P Gudbjartsson DF Walters GB Helgadottir HT Helgason A Gudjonsson SA Zanon C Besenbacher S Bjornsdottir G Magnusson OT Magnusson G Hjartarson E Saemundsdottir J Gylfason A Jonasdottir A Holm H Karason A Rafnar T Stefansson H Andreassen OA Pedersen JH Pack AI de Visser MC Kiemeney LA Geirsson AJ Eyjolfsson GI Olafsson I Kong A Masson G Jonsson H Thorsteinsdottir U Jonsdottir I Stefansson K 《Nature genetics》2011,43(11):1127-1130
We tested 16 million SNPs, identified through whole-genome sequencing of 457 Icelanders, for association with gout and serum uric acid levels. Genotypes were imputed into 41,675 chip-genotyped Icelanders and their relatives, for effective sample sizes of 968 individuals with gout and 15,506 individuals for whom serum uric acid measurements were available. We identified a low-frequency missense variant (c.1580C>G) in ALDH16A1 associated with gout (OR = 3.12, P = 1.5 × 10(-16), at-risk allele frequency = 0.019) and serum uric acid levels (effect = 0.36 s.d., P = 4.5 × 10(-21)). We confirmed the association with gout by performing Sanger sequencing on 6,017 Icelanders. The association with gout was stronger in males relative to females. We also found a second variant on chromosome 1 associated with gout (OR = 1.92, P = 0.046, at-risk allele frequency = 0.986) and serum uric acid levels (effect = 0.48 s.d., P = 4.5 × 10(-16)). This variant is close to a common variant previously associated with serum uric acid levels. This work illustrates how whole-genome sequencing data allow the detection of associations between low-frequency variants and complex traits. 相似文献
57.
Extensive and coordinated transcription of noncoding RNAs within cell-cycle promoters 总被引:5,自引:0,他引:5
58.
Ping Kong Panagiota Christia Nikolaos G. Frangogiannis 《Cellular and molecular life sciences : CMLS》2014,71(4):549-574
Cardiac fibrosis is characterized by net accumulation of extracellular matrix proteins in the cardiac interstitium, and contributes to both systolic and diastolic dysfunction in many cardiac pathophysiologic conditions. This review discusses the cellular effectors and molecular pathways implicated in the pathogenesis of cardiac fibrosis. Although activated myofibroblasts are the main effector cells in the fibrotic heart, monocytes/macrophages, lymphocytes, mast cells, vascular cells and cardiomyocytes may also contribute to the fibrotic response by secreting key fibrogenic mediators. Inflammatory cytokines and chemokines, reactive oxygen species, mast cell-derived proteases, endothelin-1, the renin/angiotensin/aldosterone system, matricellular proteins, and growth factors (such as TGF-β and PDGF) are some of the best-studied mediators implicated in cardiac fibrosis. Both experimental and clinical evidence suggests that cardiac fibrotic alterations may be reversible. Understanding the mechanisms responsible for initiation, progression, and resolution of cardiac fibrosis is crucial to design anti-fibrotic treatment strategies for patients with heart disease. 相似文献
59.
60.
Richards JB Yuan X Geller F Waterworth D Bataille V Glass D Song K Waeber G Vollenweider P Aben KK Kiemeney LA Walters B Soranzo N Thorsteinsdottir U Kong A Rafnar T Deloukas P Sulem P Stefansson H Stefansson K Spector TD Mooser V 《Nature genetics》2008,40(11):1282-1284
We conducted a genome-wide association study for androgenic alopecia in 1,125 men and identified a newly associated locus at chromosome 20p11.22, confirmed in three independent cohorts (n = 1,650; OR = 1.60, P = 1.1 x 10(-14) for rs1160312). The one man in seven who harbors risk alleles at both 20p11.22 and AR (encoding the androgen receptor) has a sevenfold-increased odds of androgenic alopecia (OR = 7.12, P = 3.7 x 10(-15)). 相似文献