Tyrosine 842 in the activation loop is required for full transformation by the oncogenic mutant FLT3-ITD

The type III receptor tyrosine kinase FLT3 is frequently mutated in acute myeloid leukemia. Oncogenic FLT3 mutants display constitutive activity leading to aberrant cell proliferation and survival. Phosphorylation on several critical tyrosine residues is known to be essential for FLT3 signaling. Among these tyrosine residues, Y842 is located in the so-called activation loop. The position of this tyrosine residue is well conserved in all receptor tyrosine kinases. It has been reported that phosphorylation of the activation loop tyrosine is critical for catalytic activity for some but not all receptor tyrosine kinases. The role of Y842 residue in FLT3 signaling has not yet been studied. In this report, we show that Y842 is not important for FLT3 activation or ubiquitination but plays a critical role in regulating signaling downstream of the receptor as well as controlling receptor stability. We found that mutation of Y842 in the FLT3-ITD oncogenic mutant background reduced cell viability and increased apoptosis. Furthermore, the introduction of the Y842 mutation in the FLT3-ITD background led to a dramatic reduction in in vitro colony forming capacity. Additionally, mice injected with cells expressing FLT3-ITD/Y842F displayed a significant delay in tumor formation, compared to FLT3-ITD expressing cells. Microarray analysis comparing gene expression regulated by FLT3-ITD versus FLT3-ITD/Y842F demonstrated that mutation of Y842 causes suppression of anti-apoptotic genes. Furthermore, we showed that cells expressing FLT3-ITD/Y842F display impaired activity of the RAS/ERK pathway due to reduced interaction between FLT3 and SHP2 leading to reduced SHP2 activation. Thus, we suggest that Y842 is critical for FLT3-mediated RAS/ERK signaling and cellular transformation.     

自动化码头运输设备充电策略优化的仿真研究

随着自动化集装箱码头成为当今码头的发展趋势,AGV(automated guided vehicle) 作为自动化码头中使用最为广泛的水平运输工具,合理制定其充电策略至关重要。针对当前自动化集装箱码头中AGV充电策略的不足,提出一种以离线充电为主在线充电为辅的充电策略,并且针对在线充电站点位置选择问题提出一种利用热区图选择有效在线充电站点的快捷方法。在使用该种充电策略情况下,通过大量仿真实验得出在码头工作任务量不变的前提下可减少AGV数量配置的结果,说明自动化集装箱码头水平搬运效率得到提高,证明该充电策略具有有效性。     

HD分子X1Σ+g, B1Σ+u和C1Πu态的势能函数

使用SAC/SAC-CI方法，利用D95++**、6-311++g**以及cc-PVTZ等基组，对HD分子的基态(X1Σ+g)、第二激发态(B1Σ+u)和第三激发态(C1Πu)的平衡结构和谐振频率进行了优化计算．通过对3个基组的计算结果的比较，得出了cc-PVTZ基组为三个基组中的最优基组的结论；使用cc-PVTZ基组，利用SAC的GSUM(Group Sum of Operators)方法对基态(X1Σ+g)、SAC-CI的GSUM方法对激发态(B1Σ+u)和(C1Πu)进行单点能扫描计算，用正规方程组拟合Murrell-Sorbie函数，得到了相应电子态的完整势能函数；从得到的势能函数计算了与基态(X1Σ+g)、第二激发态(B1Σ+u)和第三激发态(C1Πu)相对应的光谱常数(Be, αe, ωe 和ωeχe)，结果与实验数据基本吻合．     

Simultaneous mineralization of CO2 and recovery of soluble potassium using earth-abundant potassium feldspar

CO2 capture and storage(CCS) is an important strategy in combatting anthropogenic climate change.However,commercial application of the CCS technique is currently hampered by its high energy expenditure and costs.To overcome this issue,CO2 capture and utilization(CCU) is a promising CO2 disposal method.We,for the first time,developed a promising method to mineralize CO2 using earth-abundant potassium feldspar in order to effectively reduce CO2 emissions.Our experiments demonstrate that,after adding calcium chloride hexahydrate as an additive,the K-feldspar can be transformed to Ca-silicates at 800 C,which can easily mineralize CO2 to form stable calcium carbonate and recover soluble potassium.The conversion of this process reached 84.7%.With further study,the pretreatment temperature can be reduced to 250 C using hydrothermal method by adding the solution of triethanolamine(TEA).The highest conversion can be reached 40.1%.The process of simultaneous mineralization of CO2 and recovery of soluble potassium can be easily implemented in practice and may provide an economically feasible way to tackle global anthropogenic climate change.     

Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes

Calorie restriction extends lifespan and produces a metabolic profile desirable for treating diseases of ageing such as type 2 diabetes. SIRT1, an NAD+-dependent deacetylase, is a principal modulator of pathways downstream of calorie restriction that produce beneficial effects on glucose homeostasis and insulin sensitivity. Resveratrol, a polyphenolic SIRT1 activator, mimics the anti-ageing effects of calorie restriction in lower organisms and in mice fed a high-fat diet ameliorates insulin resistance, increases mitochondrial content, and prolongs survival. Here we describe the identification and characterization of small molecule activators of SIRT1 that are structurally unrelated to, and 1,000-fold more potent than, resveratrol. These compounds bind to the SIRT1 enzyme-peptide substrate complex at an allosteric site amino-terminal to the catalytic domain and lower the Michaelis constant for acetylated substrates. In diet-induced obese and genetically obese mice, these compounds improve insulin sensitivity, lower plasma glucose, and increase mitochondrial capacity. In Zucker fa/fa rats, hyperinsulinaemic-euglycaemic clamp studies demonstrate that SIRT1 activators improve whole-body glucose homeostasis and insulin sensitivity in adipose tissue, skeletal muscle and liver. Thus, SIRT1 activation is a promising new therapeutic approach for treating diseases of ageing such as type 2 diabetes.     

Genome-wide detection and characterization of positive selection in human populations

With the advent of dense maps of human genetic variation, it is now possible to detect positive natural selection across the human genome. Here we report an analysis of over 3 million polymorphisms from the International HapMap Project Phase 2 (HapMap2). We used 'long-range haplotype' methods, which were developed to identify alleles segregating in a population that have undergone recent selection, and we also developed new methods that are based on cross-population comparisons to discover alleles that have swept to near-fixation within a population. The analysis reveals more than 300 strong candidate regions. Focusing on the strongest 22 regions, we develop a heuristic for scrutinizing these regions to identify candidate targets of selection. In a complementary analysis, we identify 26 non-synonymous, coding, single nucleotide polymorphisms showing regional evidence of positive selection. Examination of these candidates highlights three cases in which two genes in a common biological process have apparently undergone positive selection in the same population:LARGE and DMD, both related to infection by the Lassa virus, in West Africa;SLC24A5 and SLC45A2, both involved in skin pigmentation, in Europe; and EDAR and EDA2R, both involved in development of hair follicles, in Asia.     

塔里木河流域中下游典型地物光谱变化规律

由于塔里木河流域中下游距离河道在垂直向的差别,以及气候与人为因素的影响,使植被的空间分布具有异构性.典型地物光谱变化的研究为中下游生态环境的遥感监测提供了基础,实验研究表明:绿色全荣植物中,棉花由于其具有明显绿峰、水分吸收谷和近红外的高反射峰而更加容易识别,其他植物主要差别则集中在550,680,1420 nm附近的反射峰、吸收谷和1920～2500 nm之间的反射率;与绿色植被相比,枯枝的光谱在可见光部分的绿峰和红光吸收谷不明显,但在可见光部分波形有所差别,而与流沙土壤光谱相比,各波段反射率变化较大;对比不同荣枯比例的植物光谱发现,同一种植物随着荣枯配比的变化,除可见光绿峰、近红外反射峰和各水分吸收谷变化外,最明显的是在近红外1420～1820 nm之间和短波红外1920～2500 nm之间反射率随着枯枝的比例增加而明显升高;关于土壤光谱,中下游各断面占主要类型的流沙土光谱相差不大,但是盐碱土和含有一定水分的盐碱土则变化较大,而且反射率基本低于流沙土,结壳土则除在近红外和短波红外部分变化更加平缓而有所差别外,其余波段接近流沙土;同样的土壤背景下,近红外和短波红外部分反射率的差别能够在一定程度上反映覆盖度的变化.