Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2

TET2 is a close relative of TET1, an enzyme that converts 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) in DNA. The gene encoding TET2 resides at chromosome 4q24, in a region showing recurrent microdeletions and copy-neutral loss of heterozygosity (CN-LOH) in patients with diverse myeloid malignancies. Somatic TET2 mutations are frequently observed in myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), MDS/MPN overlap syndromes including chronic myelomonocytic leukaemia (CMML), acute myeloid leukaemias (AML) and secondary AML (sAML). We show here that TET2 mutations associated with myeloid malignancies compromise catalytic activity. Bone marrow samples from patients with TET2 mutations displayed uniformly low levels of 5hmC in genomic DNA compared to bone marrow samples from healthy controls. Moreover, small hairpin RNA (shRNA)-mediated depletion of Tet2 in mouse haematopoietic precursors skewed their differentiation towards monocyte/macrophage lineages in culture. There was no significant difference in DNA methylation between bone marrow samples from patients with high 5hmC versus healthy controls, but samples from patients with low 5hmC showed hypomethylation relative to controls at the majority of differentially methylated CpG sites. Our results demonstrate that Tet2 is important for normal myelopoiesis, and suggest that disruption of TET2 enzymatic activity favours myeloid tumorigenesis. Measurement of 5hmC levels in myeloid malignancies may prove valuable as a diagnostic and prognostic tool, to tailor therapies and assess responses to anticancer drugs.     

PTC124 targets genetic disorders caused by nonsense mutations

Nonsense mutations promote premature translational termination and cause anywhere from 5-70% of the individual cases of most inherited diseases. Studies on nonsense-mediated cystic fibrosis have indicated that boosting specific protein synthesis from <1% to as little as 5% of normal levels may greatly reduce the severity or eliminate the principal manifestations of disease. To address the need for a drug capable of suppressing premature termination, we identified PTC124-a new chemical entity that selectively induces ribosomal readthrough of premature but not normal termination codons. PTC124 activity, optimized using nonsense-containing reporters, promoted dystrophin production in primary muscle cells from humans and mdx mice expressing dystrophin nonsense alleles, and rescued striated muscle function in mdx mice within 2-8 weeks of drug exposure. PTC124 was well tolerated in animals at plasma exposures substantially in excess of those required for nonsense suppression. The selectivity of PTC124 for premature termination codons, its well characterized activity profile, oral bioavailability and pharmacological properties indicate that this drug may have broad clinical potential for the treatment of a large group of genetic disorders with limited or no therapeutic options.     

Generalization of the linguistic aggregation operator and its application in decision making

A generalization of the linguistic aggregation functions (or operators) is presented by using generalized and quasiarithmetic means.Firstly,the linguistic weighted generalized mean (LWGM) and the linguistic generalized ordered weighted averaging (LGOWA) operator are introduced.These aggregation functions use linguistic information and generalized means in the weighted average (WA) and in the ordered weighted averaging (OWA) function.They are very useful for uncertain situations where the available information cannot be assessed with numerical values but it is possible to use linguistic assessments.These aggregation operators generalize a wide range of aggregation operators that use linguistic information such as the linguistic generalized mean (LGM),the linguistic OWA (LOWA) operator and the linguistic ordered weighted quadratic averaging (LOWQA) operator.We also introduce a further generalization by using quasi-arithmetic means instead of generalized means obtaining the quasi-LWA and the quasi-LOWA operator.Finally,we develop an application of the new approach where we analyze a decision making problem regarding the selection of strategies.     

基于收益管理的班轮联盟舱位互换与分配优化

运用收益管理原理方法,研究了联盟条件下班轮公司舱位互换与分配问题,构建了综合考虑班轮联盟多条航线、不同种类和不同尺寸的集装箱等因素的舱位互换与分配随机优化共赢模型,运用机会约束方法加以求解,算例分析验证了模型和算法的适用性和有效性,结果表明舱位互换与分配优化可以明显地提高班轮联盟的总收益,联盟内舱位互换与分配数量及其总收益与合同客户需求量呈负相关、与现货市场需求量呈正相关,从而可为班轮公司制定舱位互换与分配策略提供科学的决策参考.     

Perfluoroalkyl substances in the blood samples from a male population of Sweden

Temporal trends of perfluoroalkyl substances （PFASs） have been determined in the blood samples from several countries globally including a female population in Sweden recently, yet little is known about the time trends in the blood levels of these compounds in Swedish male populations over recent years. In this study, the fourteen target PFASs consisted of four perfluorosulfonates （PFSAs） and ten perfluorocarboxylates （PFCAs） in the whole blood samples, collected from 153 Swedish elderly men during the period between 2008 and 2010, were analyzed via ultra-performance liquid chromatography-tandem mass spectrometry （UPLC-MS/MS）. As the dominant PFASs contaminants in the blood samples, perfluorooctane sulfo- nate （PFOS） showed the highest geometric mean （GM） at 8.5 ng/mL, ranging from 1.7 to 29 ng/mL, while blood perfluorooctanoic acid （PFOA） contained the GM of 1.8 ng/mL, ranging from 0.35 to 6.4 ng/mL. Both the levels of these two compounds were lower than those determined in the blood samples of Swedish elderly pop- ulations derived from the late 1990s. According to the temporal trend analysis, over the three years, the blood levels of PFOS in Swedish male populations declined 16 % per annum, while those of perfluoroundecanoic acid （PFUnDA） increased 6.1% per annum, which were con- sistent with those reported previously for the populations from other countries.     

吡罗昔康-Cu(Ⅱ)-牛血清白蛋白相互作用的荧光光谱法研究

应用荧光光谱法研究了生理条件下吡罗昔康对牛血清白蛋白,Cu(Ⅱ)对牛血清白蛋白以及Cu(Ⅱ)对吡罗昔康和牛血清白蛋白荧光光谱特性的影响.结果表明:Cu(Ⅱ)和吡罗昔康均可使牛血清白蛋白的荧光强度发生静态猝灭,并且在Cu(Ⅱ)存在下,吡罗昔康对牛血清白蛋白的荧光猝灭作用显著增强.根据荧光猝灭双倒数图计算吡罗昔康和牛血清白蛋白的结合常数为3.18×103 L/mol,结合位点数为0.75;二元配合物Cu(Ⅱ)与牛血清白蛋白之间的结合常数为1.13×103 L/mol,结合位点数为0.74.     

基于IDS 80图形系统的液压和气动设备符号库

我们在此给出一个在意大利IDS—80图形计算机系统上实观的符号库。我们扼要地概述了该库的构造和使用方法。这个库是一个遵循机械设计统一标准UNI的标准符号库并且我们的方法(模型扩张)是新的和有价值的。     

大型水利枢纽砼运输浇筑系统的GPSS模型及仿真研究

本文应用系统仿真原理和GPSS(General Purpose Simulation System——通用仿真系统)仿真语言构造了大型水利枢纽混凝土工程的运输浇筑系统的GPSS模型，并通过计算机运行对该系统进行了仿真研究，得出了具有一定实用价值的结果，为大型水利枢纽的可行性研究、设计、施工提供了参考．