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.     

Copy number variation and selection during reprogramming to pluripotency

The mechanisms underlying the low efficiency of reprogramming somatic cells into induced pluripotent stem (iPS) cells are poorly understood. There is a clear need to study whether the reprogramming process itself compromises genomic integrity and, through this, the efficiency of iPS cell establishment. Using a high-resolution single nucleotide polymorphism array, we compared copy number variations (CNVs) of different passages of human iPS cells with their fibroblast cell origins and with human embryonic stem (ES) cells. Here we show that significantly more CNVs are present in early-passage human iPS cells than intermediate passage human iPS cells, fibroblasts or human ES cells. Most CNVs are formed de novo and generate genetic mosaicism in early-passage human iPS cells. Most of these novel CNVs rendered the affected cells at a selective disadvantage. Remarkably, expansion of human iPS cells in culture selects rapidly against mutated cells, driving the lines towards a genetic state resembling human ES cells.     

CSP生产Ti微合金化高强钢中纳米碳化物

采用光学金相、电子显微术和化学相分析的方法并结合热力学计算,分析了紧凑式带钢生产(CSP)的Ti微合金化高强钢中的析出物及其析出规律.研究发现:高强钢中存在微米尺寸的立方TiN析出和大量纳米尺寸的析出物粒子;钢中MX相(M=Ti,Mo,Cr;X=C,N)的质量分数为0.0927%,其中10 nm以下的析出物占26.9%;均热之前和均热过程TiN已基本全部析出,连轧前TiC不具备析出的热力学条件;降低钢中N和S含量、严格控制卷取温度可增加TiC的体积分数,降低γ→α相变温度可以阻止细小碳化物长大.结果表明,析出物总的沉淀强化效果约为156 MPa,并能通过化学成分和工艺的控制进一步增强.     

二氧化碳在转炉炼钢中的应用研究

对炼钢温度下CO2与熔池元素的反应机理进行了研究,并进行了相关热力学和动力学分析.利用30 t转炉进行顶底复吹CO2气体的炼钢工艺试验.试验结果表明:采用顶底复吹CO2试验炉次烟尘量减少了11.15%,烟尘TFe降低了12.98%,炉渣铁损降低了3.10%,试验终点钢液中[N]、[P]含量分别降低了50%和23.33%.转炉顶底复吹CO2气体炼钢工艺是完全可行的,为转炉炼钢节能降耗提供了新方法.     

Frictional ageing from interfacial bonding and the origins of rate and state friction

Earthquakes have long been recognized as being the result of stick-slip frictional instabilities. Over the past few decades, laboratory studies of rock friction have elucidated many aspects of tectonic fault zone processes and earthquake phenomena. Typically, the static friction of rocks grows logarithmically with time when they are held in stationary contact, but the mechanism responsible for this strengthening is not understood. This time-dependent increase of frictional strength, or frictional ageing, is one manifestation of the 'evolution effect' in rate and state friction theory. A prevailing view is that the time dependence of rock friction results from increases in contact area caused by creep of contacting asperities. Here we present the results of atomic force microscopy experiments that instead show that frictional ageing arises from the formation of interfacial chemical bonds, and the large magnitude of ageing at the nanometre scale is quantitatively consistent with what is required to explain observations in macroscopic rock friction experiments. The relative magnitude of the evolution effect compared with that of the 'direct effect'--the dependence of friction on instantaneous changes in slip velocity--determine whether unstable slip, leading to earthquakes, is possible. Understanding the mechanism underlying the evolution effect would enable us to formulate physically based frictional constitutive laws, rather than the current empirically based 'laws', allowing more confident extrapolation to natural faults.     

Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140?mm?Hg systolic blood pressure or ≥90?mm?Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.     

Gough-Stewart并联机器人刚体动力学模型

综合采用拉格朗日方程和牛顿-欧拉公式推导了Gough-Stewart并联机器人机构逆动力学模型的封闭解形式.通过选择合适的分支广义坐标,简化了拉格朗日函数对广义坐标的偏导求解,得到了求导矩阵的解析表达式.分析了分支角速度、角加速度轴向分量对机构动力学的影响,仿真结果表明：当机构运动加速度及分支轴向惯量较小时,可以忽略该...     

Amplitudes, rates, periodicities and causes of temperature variations in the past 2485 years and future trends over the central-eastern Tibetan Plateau

Amplitudes, rates, periodicities, causes and future trends of temperature variations based on tree rings for the past 2485 years on the central-eastern Tibetan Plateau were analyzed. The results showed that extreme climatic events on the Plateau, such as the Medieval Warm Period, Little Ice Age and 20th Century Warming appeared synchronously with those in other places worldwide. The largest amplitude and rate of temperature change occurred during the Eastern Jin Event (343-425 AD), and not in the late 20th century. There were significant cycles of 1324 a, 800 a, 199 a, 110 a and 2-3 a in the 2485-year temperature series. The 1324 a, 800 a, 199 a and 110 a cycles are associated with solar activity, which greatly affects the Earth surface temperature. The long-term trends (>1000 a) of temperature were controlled by the millennium-scale cycle, and amplitudes were dominated by multi-century cycles. Moreover, cold intervals corresponded to sunspot minimums. The prediction indicated that the temperature will decrease in the future until to 2068 AD and then increase again.