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.     

Structural insight into brassinosteroid perception by BRI1

Brassinosteroids are essential phytohormones that have crucial roles in plant growth and development. Perception of brassinosteroids requires an active complex of BRASSINOSTEROID-INSENSITIVE 1 (BRI1) and BRI1-ASSOCIATED KINASE 1 (BAK1). Recognized by the extracellular leucine-rich repeat (LRR) domain of BRI1, brassinosteroids induce a phosphorylation-mediated cascade to regulate gene expression. Here we present the crystal structures of BRI1(LRR) in free and brassinolide-bound forms. BRI1(LRR) exists as a monomer in crystals and solution independent of brassinolide. It comprises a helical solenoid structure that accommodates a separate insertion domain at its concave surface. Sandwiched between them, brassinolide binds to a hydrophobicity-dominating surface groove on BRI1(LRR). Brassinolide recognition by BRI1(LRR) is through an induced-fit mechanism involving stabilization of two interdomain loops that creates a pronounced non-polar surface groove for the hormone binding. Together, our results define the molecular mechanisms by which BRI1 recognizes brassinosteroids and provide insight into brassinosteroid-induced BRI1 activation.     

Skin collagen fiber-based radar absorbing materials

By using skin collagen fiber (CF) as raw material,Schiff base structure containing CF (Sa-CF) was synthesized through CF-salicylaldehyde reaction.Then a novel radar absorbing material (Fe-Sa-CF) was prepared by chelating reaction between Sa-CF and Fe 3+.The coaxial transmission and reflection method was used to analyze the complex permittivity and complex magnetic permeability of these CF-based materials,and the radar cross section (RCS) method was used to investigate their radar absorbing properties in the frequency range of 1.0-18.0 GHz.Experimental results indicated that the conductivity of CF increased from initial 1.08×10-11 to 2.86×10-6 S/cm after being transferred into Fe-Sa-CF,and its dielectric loss tangent (tanδ) in the frequency range of 1.0-17.0 GHz also increased.These facts suggest that the Fe-Sa-CF is electric-loss type radar absorbing material.In the frequency range of 3.0-18.0 GHz,Sa-CF (1.0 mm in thickness) exhibited somewhat radar absorbing property with maximum radar reflection loss (RL) of-4.73 dB.As for Fe-Sa-CF,the absorbing bandwidth was broadened,and the absorbing intensity significantly increased in the frequency range of 1.0-18.0 GHz where a maximum radar RL of-9.23 dB was observed.In addition,the radar absorbing intensity of Fe-Sa-CF can be further improved by increasing membrane thickness.When the thickness reached to 2.0 mm,the RL values of Fe-Sa-CF were-15.0-18.0 dB in the frequency range of 7.0-18.0 GHz.Consequently,a kind of novel radar absorbing material can be prepared by chemical modification of collagen fiber,which is characterized by thin thickness,low density,broad absorption bandwidth and high absorption intensity.     

基于系统动力学的海上交通应急救援效能分析

随着海上交通的日益频繁,海上交通突发事件的发生频率也在不断增加,应急救援工作越来越受到重视.为了提升应急救援效能,以海上交通突发事件的实际救援过程为切入点,从信息感知、协同研判、方案决策、救援行动4个维度构建海上交通应急救援效能影响因素指标体系,通过层次熵分法对指标权重进行赋值,建立海上交通应急救援效能的系统动力学(s...     

转炉流程轴承钢连铸坯非金属夹杂物的行为

探讨了BOF-LF-VD-CC流程生产的轴承钢连铸坯非金属夹杂物的物性、分布、特点,并通过示踪剂追踪分析了轴承钢夹杂物的来源,为轴承钢夹杂物的去除,提高转炉流程轴承钢质量提供了依据.研究表明,该生产流程可以获得T[O]的平均值为9.3×10-4%;显微夹杂体积分数为0.031%;>50μm的大型夹杂为1.5 mg/10 kg的洁净度较高的轴承钢连铸坯.夹杂物主要为<5μm的显微夹杂,它的分布特点决定了连铸坯中夹杂物的分布特点,显微夹杂主要是多元素复合脱氧产物与中间包液面二次氧化产物吸附集聚形成的复合物,其次是结晶器液面对钢液的污染,钢包液面影响较小.     

基于F&EI的新兴有机材料生产过程风险分析

新兴民营企业在运营流程中采取行政安全一手抓的管理模式,在新型有机材料生产和加工的过程中出现诸多新的安全问题.为规避此类问题带来的事故风险,以浙江某新兴材料企业为例,通过实地调研、定性分析和定量评估相结合的方法,对其物料、工艺、设备及维护过程中的危险源及有害因素进行风险分析.基于现场勘察获得引起生产加工过程中危险物质泄漏...     

沥青路面现场微波加热再生模型与实验

为了求解微波加热再生沥青混合料内的温度分布,研究了由于沥青混合料介电常数和比热容是温变参数,从而导致电磁场分布和吸收微波功率的非线性变化.建立了电磁场控制方程和热传递方程耦合的二维非线性热电耦合模型,提出了按微波周期为时间步长交替迭代求解该非线性模型的求解方法.使用了工作频率为2.45 GHz的微波系统,通过连续或间歇辐射加热方式,对不同体积的沥青混合料进行了加热实验.实验结果证实了微波加热再生通过辐射热传递能实现瞬间体积加热,具有快速、加热均匀、保证质量和无污染等特点.     

基于MVA的半导体生产过程质量分析方法

针对半导体晶圆生产中存在着位置间变异、晶圆间变异及批次间变异,提出了基于多变异分析(MVA)的工序质量分析方法.该方法通过建立基于方差分析晶圆生产工序质量的多变异分析模型,研究了晶圆生产过程中3种变异与总变异之间的定量关系.由定量关系推导出晶圆生产中的抽样规则,并提出了3种常用过程能力指数Cp,Cpk和Cpm的改进计算方法.通过在晶圆生产中的实际应用,证明了该方法中的抽样规则能捕获加工过程中主要随机变异,该方法计算获得的过程能力指数可较为真实地反映生产过程质量状况.     

高效液相色法同时测定丹参酮胶囊中隐丹参酮和丹参酮ⅡA含量

采用高效液相色谱法同时测定丹参酮胶囊中隐丹参酮和丹参酮ⅡA含量,建立丹参酮胶囊质量控制体系。采用C18柱分离测定;甲醇:水(80∶20)为流动相,检测波长:270nm;流速:1.0m l/m in。结果:隐丹参酮和丹参酮ⅡA分别在0.20~160μg(r>0.999 9)、0.21~1.68μg(r>0.999 8)质量范围内线性关系良好;回收率在98.7%~103.0%之间。