Sensitivity to antitubulin chemotherapeutics is regulated by MCL1 and FBW7

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.     

Sea surface temperature east of Australia： A predictor of tropical cyclone frequency over the western North Pacific？

The relationship between sea surface temperature (SST) east of Australia and tropical cyclone frequency over the western North Pacific (WNPTCF) is analyzed by use of observation data.The WNPTCF from June to October is correlated negatively to spring SST east of Australia.When the spring SST is in the positive phase,a cyclonic circulation anomaly in the upper troposphere and an anticyclonic circulation anomaly in the lower troposphere prevail over the western North Pacific from June to October,concurrent with an anomalous atmospheric subsidence and an enlarged vertical zonal wind shear.These conditions are unfavorable for tropical cyclone genesis,and thus WNPTCF decreases.The negative phase of the spring SST east of Australia leads to more tropical cyclones over the western North Pacific.The spring SST east of Australia may give rise to simultaneous change in tropical atmospheric circulation via the teleconnection wave train,and then subsequently affect atmospheric circulation variation over the western North Pacific.     

基于Wiener滤波器的波形比较方法及其在最坏情况分析中的应用

提出一种基于Wiener滤波器的波形比较方法,应用于数模混合电路的最坏情况分析.该方法能考虑一定的时间容限和信号容限,自动比较电路在不同的工艺参数、电压和温度(PVT)组合下的仿真波形,通过波形形状的比较来实现电路性能验证,有效地提高了电路验证效率.此方法成功地运用到波形比较软件系统中,并已在Intel技术开发(上海)公司内部推广使用.     

中药肾茶对家猫夏季饮水和血清尿素含量的影响

家猫饮水、排尿较少,泌尿系统疾病高发.肾茶是一种传统中药,具有良好的利尿作用.本研究采用10只家猫进行实验,结果显示:在饲粮中添加1％(质量分数)肾茶可以显著增加家猫的饮水量,降低血清尿素氮含量,但不影响家猫的体重和采食量.这表明肾茶有增加家猫排尿量、减少其泌尿系统疾病的潜在作用.     

含三阶色散的非线性薛定谔方程一个新的行波解

运用解析法求解含三阶色散光纤暗孤子的传输方程,得到孤子行波解,讨论含三阶色散光纤中暗孤子形成的条件以及三阶色散对暗孤子的中心位置、相位、振幅、频率的影响.     

基于系统参数估计时间序列的小波分析故障诊断方法

提出了一种失效性故障诊断的新方法.这种方法将基于解析模型的故障诊断技术和基于信号分析的故障诊断技术结合起来,对系统参数的递推最小二乘估计时间序列进行小波分析,得到故障特征值,兼有两种故障诊断技术的优点.本文还讨论了对于模型参数估计时间序列小波分析的基函数及尺度选取方法问题,仿真结果表明该方法的有效性和准确性非常明显,具有一定的实用价值.     

基于SolidWorks 渐开线齿轮的三维辅助设计

探讨了基于SolidW orks的二次开发技术,研究如何利用V isual Basic程序语言在SolidW orks中强大的三维绘图功能进行计算机三维辅助设计;并以渐开线齿轮的设计与绘制为例,提出了通过程序计算后利用SolidW orks曲线连接阵列点构建封闭齿廓的方法。实践证明该方法为其它CAD二次开发平台绘画渐开线齿轮提供可借鉴之处。     

基于BEMD-Copula-GARCH模型的股票投资组合VaR风险度量研究

鉴于股票波动具有显著的多尺度特征,本文引入二元经验模态分解(EMD)与二元CopulaGARCH算法,提出一种新的VaR风险度量模型,即BEMD-Copula-GARCH模型.具体地,新BEMD-Copula-GARCH模型可分为三个主要步骤:数据分析,分风险估计和总风险集成.首先,基于二元EMD模型,将复杂且相互作用的股票对分解为若干组较为简单且相互独立的分量,以降低建模难度.其次,引入二元Copula-GARCH模型,刻画各组分量间的相互关系,以度量股票投资组合在不同尺度上的分VaR值.最后,集成各分VaR值以得出最终VaR风险度量结果.实证研究以恒生指数与上证综指为数据样本构造投资组合,结果表明:本文所构建的新模型能有效度量投资组合风险,其估计精度显著优于DCC-GARCH和Copula-GARCH等现有模型.     

Generation of functional insulin-producing cells in the gut by Foxo1 ablation

Restoration of regulated insulin secretion is the ultimate goal of therapy for type 1 diabetes. Here, we show that, unexpectedly, somatic ablation of Foxo1 in Neurog3(+) enteroendocrine progenitor cells gives rise to gut insulin-positive (Ins(+)) cells that express markers of mature β cells and secrete bioactive insulin as well as C-peptide in response to glucose and sulfonylureas. Lineage tracing experiments showed that gut Ins(+) cells arise cell autonomously from Foxo1-deficient cells. Inducible Foxo1 ablation in adult mice also resulted in the generation of gut Ins(+) cells. Following ablation by the β-cell toxin streptozotocin, gut Ins(+) cells regenerate and produce insulin, reversing hyperglycemia in mice. The data indicate that Neurog3(+) enteroendocrine progenitors require active Foxo1 to prevent differentiation into Ins(+) cells. Foxo1 ablation in gut epithelium may provide an approach to restore insulin production in type 1 diabetes.     

具有混合执行器故障的多智能体分布式有限时间自适应协同容错控制

针对多智能体编队系统执行器发生故障时,所引起的参数不确定以及系统瞬态不稳定问题,本文采用径向基函数神经网络(radial basis function neural networks, RBFNNs)对不确定参数(未知函数)进行估计。同时,基于反推技术设计出合理的自适应容错控制器,并通过有限时间理论保证系统实现瞬态稳定。首先,本文采用10个智能体作为被控对象,基于有向通讯拓扑结构理论,构建了非线性多智能体系统模型。其次,基于RBFNNs逼近特性,采用反推技术与动态面技术相结合,设计出合理的容错控制器,补偿多智能体中出现的未知非线性执行器故障,并采用有限时间理论解决系统瞬态不稳定问题。接着,基于Lyapunov稳定性理论分析了控制器的稳定性和快速收敛性。最后,通过两种算例对比,验证了所设计的控制器性能优于传统的反推技术,为工程实践提供了一种有效的研究思路。