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.     

Human metabolic individuality in biomedical and pharmaceutical research

Genome-wide association studies (GWAS) have identified many risk loci for complex diseases, but effect sizes are typically small and information on the underlying biological processes is often lacking. Associations with metabolic traits as functional intermediates can overcome these problems and potentially inform individualized therapy. Here we report a comprehensive analysis of genotype-dependent metabolic phenotypes using a GWAS with non-targeted metabolomics. We identified 37 genetic loci associated with blood metabolite concentrations, of which 25 show effect sizes that are unusually high for GWAS and account for 10-60% differences in metabolite levels per allele copy. Our associations provide new functional insights for many disease-related associations that have been reported in previous studies, including those for cardiovascular and kidney disorders, type 2 diabetes, cancer, gout, venous thromboembolism and Crohn's disease. The study advances our knowledge of the genetic basis of metabolic individuality in humans and generates many new hypotheses for biomedical and pharmaceutical research.     

Role of sulphuric acid, ammonia and galactic cosmic rays in atmospheric aerosol nucleation

Atmospheric aerosols exert an important influence on climate through their effects on stratiform cloud albedo and lifetime and the invigoration of convective storms. Model calculations suggest that almost half of the global cloud condensation nuclei in the atmospheric boundary layer may originate from the nucleation of aerosols from trace condensable vapours, although the sensitivity of the number of cloud condensation nuclei to changes of nucleation rate may be small. Despite extensive research, fundamental questions remain about the nucleation rate of sulphuric acid particles and the mechanisms responsible, including the roles of galactic cosmic rays and other chemical species such as ammonia. Here we present the first results from the CLOUD experiment at CERN. We find that atmospherically relevant ammonia mixing ratios of 100 parts per trillion by volume, or less, increase the nucleation rate of sulphuric acid particles more than 100-1,000-fold. Time-resolved molecular measurements reveal that nucleation proceeds by a base-stabilization mechanism involving the stepwise accretion of ammonia molecules. Ions increase the nucleation rate by an additional factor of between two and more than ten at ground-level galactic-cosmic-ray intensities, provided that the nucleation rate lies below the limiting ion-pair production rate. We find that ion-induced binary nucleation of H(2)SO(4)-H(2)O can occur in the mid-troposphere but is negligible in the boundary layer. However, even with the large enhancements in rate due to ammonia and ions, atmospheric concentrations of ammonia and sulphuric acid are insufficient to account for observed boundary-layer nucleation.     

基于三维CAD的机械制图课程改革中的习题配置

工程设计现在已发展到全数字阶段,能使设计、制造一体化过程得以实现的核心是三维实体模型,二维投影图已满足不了形势发展的需求.因此,基于三维CAD绘图技术,我院开展了机械制图课程"3D实体教学法"的教学改革,其思路一是直接从3D实体图形开始学习,而不是传统的从投影概念、2D投影视图开始学习,二是以3D实体造型而不是传统的以画法几何作为教学的基本核心.在此基础上,提出了一种以"使学生成为自主学习者"为目标,突出"三维"和"设计"新思想,在习题配置这一环节上所进行的配套措施,以此来深化教学改革.     

基于三维CAD的机械制图教学中的"美育"

三维CAD技术的迅速发展,为欣赏现代工程图学具有美的特性提供了一个有效的方式.介绍了"机械制图"课程教学中如何渗透"美育"的具体举措,旨在配合、支持和丰富基于三维CAD的"工程制图"课程改革,激发学生对该门课程更多的兴趣,使学生的专业能力与审美能力得到和谐发展.     

略论辛词的艺术特色

南宋词人中最耀眼的莫过于辛弃疾.他创造性地继承了苏轼词的创作个性,他的作品对于词这种体裁的独立地位的确立起到了非常重要的作用.他作为当时的文坛领袖,不仅作品数量多,而且质量上乘.他的作品反映了一个生在屈辱时代的英雄深刻而丰富的思想内涵.     

日本江户幕府中后期的幕藩体制与商品经济

江户中后期,幕藩制社会无论在经济构造还是政治体制上都发生了重要的变化.经济上幕府和各藩都出现了财政危机,政治上农民的反抗斗争不断,幕藩体制进入到危机期.与之相对,江户初期的幕藩制商品流通机构的绝对优势地位,也开始受到农村商品经济和各藩独立领国商品经济发展的冲击而发生动摇.为了解决危机,幕府在经济上一方面通过加强对商品市场统制,利用株仲间控制全国的商品流通,压制商品经济在农村和各藩的发展;一方面又开始转变初期"重本抑末"的倾向,积极地吸收商品经济的成果振兴幕府经济.因此这一时期幕藩体制已开始成为商品经济自由发展的障碍.     

人胰高血糖素样肽-1串联体的克隆及其表达

为大量获取人胰高血糖素样肽-1,利用基因串联的方法构建了人胰高血糖素样肽-1的一组串联体.将化学合成的人胰高血糖素样肽-1（human glucagon like peptide-1, hGLP-1）cDNA基因插入质粒载体pET-32a(⁺)中,构建成硫氧还蛋白（thioredoxin）及六聚组氨酸（hexahistidine）与rhGLP-1的融合表达载体pET32-GLP-1.在此基础上将该融合基因序列进行同向串联,获得二串和三串的表达载体pET32-GLP-1-2 和pET32-GLP-1-3.将该三种表达载体转化大肠杆菌BLR(DE3)后获得相应的基因工程菌.结果表明：三种基因工程菌经发酵和IPTG诱导后均正确表达目的蛋白,目的蛋白表达量随着基因串数的增加而得到一定提高,重组蛋白经分离纯化后进行生物学活性测试具有明显的降低血糖浓度作用.     

中距协同空战决策过程二次聚类重构与评估

未来空战将以中距空战为主,找出导致中距空战结果的原因是开展贴近实际的中距空战智能决策需解决的重要问题。针对空战训练过程中记录数据分布的复杂特点,建立了中距协同空战训练评估模型,提出了基于高阶导数聚类和相对模糊熵聚类的二次聚类方法,计算编队协同决策集,实现编队中距协同空战决策过程重构。以编队协同搜索和协同机动决策的角度,寻找编队协同决策与中距空战结果的相关性,并通过实例评估验证了聚类算法的合理性。     

钢筋混凝土框架结构节点施工中常见的几个问题

在钢筋混凝土框架结构施工中,在梁柱节点处出现诸如混凝土强度等级不同、核心区箍筋施工、混凝土保护层厚度等问题,在实际的施工过程中,要根据具体情况采取措施,使施工能够满足规范要求,从而保证工程质量。