RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia

Epigenetic pathways can regulate gene expression by controlling and interpreting chromatin modifications. Cancer cells are characterized by altered epigenetic landscapes, and commonly exploit the chromatin regulatory machinery to enforce oncogenic gene expression programs. Although chromatin alterations are, in principle, reversible and often amenable to drug intervention, the promise of targeting such pathways therapeutically has been limited by an incomplete understanding of cancer-specific dependencies on epigenetic regulators. Here we describe a non-biased approach to probe epigenetic vulnerabilities in acute myeloid leukaemia (AML), an aggressive haematopoietic malignancy that is often associated with aberrant chromatin states. By screening a custom library of small hairpin RNAs (shRNAs) targeting known chromatin regulators in a genetically defined AML mouse model, we identify the protein bromodomain-containing 4 (Brd4) as being critically required for disease maintenance. Suppression of Brd4 using shRNAs or the small-molecule inhibitor JQ1 led to robust antileukaemic effects in vitro and in vivo, accompanied by terminal myeloid differentiation and elimination of leukaemia stem cells. Similar sensitivities were observed in a variety of human AML cell lines and primary patient samples, revealing that JQ1 has broad activity in diverse AML subtypes. The effects of Brd4 suppression are, at least in part, due to its role in sustaining Myc expression to promote aberrant self-renewal, which implicates JQ1 as a pharmacological means to suppress MYC in cancer. Our results establish small-molecule inhibition of Brd4 as a promising therapeutic strategy in AML and, potentially, other cancers, and highlight the utility of RNA interference (RNAi) screening for revealing epigenetic vulnerabilities that can be exploited for direct pharmacological intervention.     

多孔介质太阳能吸热器的非稳态传热

为了研究塔式太阳能多孔介质吸热器的非稳态传热特性,建立了该吸热器的非稳态传热模型,通过最小二乘拟合提出适合该类型吸热器多孔介质的体积对流换热系数模型,采用数值方法求解,分别分析典型的非稳态无量纲温度场以及平均颗粒直径、孔隙率、厚度与入口空气速度对非稳态无量纲温度场的影响.结果表明:为了减小吸热器的热应力破坏,相关参数选...     

CaWO4:Eu3+,M3+(M=Tb,Sm,Bi,Dy)的水热合成及发光性能研究

利用水热合成法制备CaWO4∶Eu3+以及CaWO4∶Eu3+,M3+(M=Tb,Sm,Bi,Dy)系列钨酸盐基荧光粉,利用XRD表征产物CaWO4∶Eu3+(5%)的晶体结构,结果表明其结构和CaWO4的标准物相结构相似,为四方晶系结构;研究了CaWO4∶Eu3+的发光性能以及第二掺杂离子M3+(M=Tb,Sm,Bi...     

乳酸膨润土及其在聚乳酸材料中的应用

为扩展聚乳酸的应用范围,用乳酸与碱性钙基膨润土反应制备出剥离型乳酸膨润土,并用该材料与聚乳酸通过氯仿溶液铸膜法制备出聚乳酸/乳酸膨润土复合膜.用扫描电镜(SEM)观察膜的形态,万能力学试验机测定膜的拉伸强度和断裂伸长率,差示扫描量热法(DSC)和热重分析(TGA)研究膜的热性能.测试结果表明,添加1％的乳酸膨润土以剥离...     

公路下充填开采的相似材料及数值模拟研究

针对公路下大量压煤的实际情况,为尝试性地探索公路下采煤的合适方法,利用相似材料模拟实验对公路下充填开采进行了研究,通过实验得到了公路在充填开采状态下所产生的移动和变形值;同时利用有限元软件ADINA进行三维数值模拟,将数值模拟与相似材料模拟实验的结果进行了对比分析,并研究了开采时煤层倾角、采深对公路稳定性的影响.研究表...     

基于网络药理学与GC-MS探讨竹叶花椒挥发油干预高脂血症的作用机制

目的 基于气相色谱-质谱联用结合网络药理学方法,探讨竹叶花椒挥发油干预高脂血症的活性成分及作用机制,为竹叶花椒挥发油中功能性成分研究及其干预高脂血症的作用机制提供理论基础。方法 首先通过GC-MS鉴定竹叶花椒挥发油的化学成分,再借助数据库获取化学成分对应靶点和高脂血症疾病靶点。又通过Venn图、蛋白-蛋白相互作用分析、GO分析、KEGG代谢通路富集分析和构建“靶点-通路-活性成分”网络得到竹叶花椒挥发油干预高脂血症的关键靶点。最后采用分子对接软件AutoDock对竹叶花椒挥发油主要活性化合物与关键靶点进行半柔性对接验证。结果 在竹叶花椒挥发油中鉴定出29个化学成分,得到37个干预高脂血症的核心靶点,该核心靶点涉及细胞对脂质的反应、脂质的定位调节和对脂多糖的反应等方面。KEGG富集分析与“靶点-通路-活性成分”网络进一步得到PPARA、RXRA、TNF、NR1H3、PPARG和IL-6等28个关键靶点,也得到金合欢醇、亚油酸和α-石竹烯等7个主要活性成分。分子对接结果表明关键靶点与主要活性成分有较好的结合能力,结合能均小于-7.0 kJ/mol。结论 竹叶花椒挥发油中的多种功能性成分可能...     

干湿循环作用下深部砂岩强度劣化及能量演化规律

为研究干湿循环对深部砂岩的强度劣化机制和能量演化规律,对经历不同干湿循环次数的砂岩进行基本物理参数的测定、单轴压缩试验和扫描电子显微镜(scanning electron microscope,SEM)观测,探讨砂岩单轴抗压强度劣化及单轴压缩过程中能量演化规律.试验结果表明:随着干湿循环次数的增加,单轴抗压强度和弹性模...     

基于优化肌电特征的无声语音信号识别

提出了一种基于遗传算法(GA)和fisher投影的最佳可鉴别基的求解方法.将原始特征向量向着最佳可鉴别基投影可得到具有最佳可分性的新的特征向量.从颧肌和二腹肌前腹的皮肤表面检测无声发出6个汉语元音的表面肌电信号(SEMG),以该肌电信号的AR模型系数、倒谱系数和美尔倒谱系数作为原始特征向量.使用遗传算法找出了原始特征的次优组合,并组成新的特征向量.将GA找出的次优特征向量向着fisher最佳可鉴别基投影可得到最佳鉴别特征向量.最后用改进的BP神经网络作为分类器得到了较好的识别效果.