Lysosomal multienzyme complex: pros and cons of working together

The ubiquitous distribution of lysosomes and their heterogeneous protein composition reflects the versatility of these organelles in maintaining cell homeostasis and their importance in tissue differentiation and remodeling. In lysosomes, the degradation of complex, macromolecular substrates requires the synergistic action of multiple hydrolases that usually work in a stepwise fashion. This catalytic machinery explains the existence of lysosomal enzyme complexes that can be dynamically assembled and disassembled to efficiently and quickly adapt to the pool of substrates to be processed or degraded, adding extra tiers to the regulation of the individual protein components. An example of such a complex is the one composed of three hydrolases that are ubiquitously but differentially expressed: the serine carboxypeptidase, protective protein/cathepsin A (PPCA), the sialidase, neuraminidase-1 (NEU1), and the glycosidase β-galactosidase (β-GAL). Next to this ‘core’ complex, the existence of sub-complexes, which may contain additional components, and function at the cell surface or extracellularly, suggests as yet unexplored functions of these enzymes. Here we review how studies of basic biological processes in the mouse models of three lysosomal storage disorders, galactosialidosis, sialidosis, and GM1-gangliosidosis, revealed new and unexpected roles for the three respective affected enzymes, Ppca, Neu1, and β-Gal, that go beyond their canonical degradative activities. These findings have broadened our perspective on their functions and may pave the way for the development of new therapies for these lysosomal storage disorders.     

Semi-global stabilization via homogeneous output feedback for a class of nonlinear time-delay systems

The semi-global stabilization problem for a class of nonlinear systems with state time-delay is addressed in this paper. By using Lyapunov-Krasovskii functional method and homogeneous domination approach, a homogeneous observer and an output feedback controller with a scaling gain are designed. Then the scaling gain is adjusted such that the closed-loop system is semi-global asymptotically stable. A numerical example is presented to illustrate the effectiveness of the obtained results in this paper.     

馆藏图书资源借阅流通的统计分析

以武警指挥学院图书馆为例，对学员读者入馆和图书借阅情况进行了统计分析，揭示了读者的借阅需求和阅读倾向，提出了提高馆藏图书资源借阅流通率的合理化建议。     

探讨钢筋混凝土框架施工工艺

文章分析了钢筋混凝土框架结构施工中的工艺流程、质量控制工作，对工艺中存在的质量问题提出了相应的控制措施，以供工程技术人员参考。     

Enhanced mechanical properties of AZ31 magnesium alloy sheets by continuous bending process after V-bending

The effects of V-bending process, continuous bending process and combination process on the microstructure and mechanical properties and formability of an AZ31 magnesium alloy sheet were investigated. The experimental results showed that no twins were found in the microstructure of all samples after processes due to the fine grain. The V-bending and continuous bending processes were proved to be an effective approach to modify the mechanical properties and formability. While the samples after the combination process exhibited better mechanical properties and formability than the single processed sample. The yield strength significantly decreased with the value of 100 MPa and the fracture elongation enhanced to 18.3% at room temperature. The Erichsen value was 5.0 mm which was significantly increased by 117% compared with as-received sample. The superior formability of combination processed samples was mainly attributed to the smaller r-value and n-value.     

基尼系数法在乡镇企业发展空间非均衡测度中的应用

针对我国乡镇企业发展空间非均衡问题,选取2003-2012年乡镇企业总产值和乡镇企业营业收入2个指标数据,采用基尼系数法,分析了我国乡镇企业发展空间非均衡的特征、程度及其来源。结果表明:我国乡镇企业空间非均衡程度最大的是西部,其次是东部和中部地区最小。全国整体以及东、西部地区内部乡镇企业发展的空间非均衡程度均呈现进一步加深趋势,中部地区乡镇企业发展的空间均衡程度得到小幅缓解。区域间差距与剩余项差距反向变动是引致我国乡镇企业发展空间非均衡程度发生变动的重要因素。     

A second generation human haplotype map of over 3.1 million SNPs

We describe the Phase II HapMap, which characterizes over 3.1 million human single nucleotide polymorphisms (SNPs) genotyped in 270 individuals from four geographically diverse populations and includes 25-35% of common SNP variation in the populations surveyed. The map is estimated to capture untyped common variation with an average maximum r2 of between 0.9 and 0.96 depending on population. We demonstrate that the current generation of commercial genome-wide genotyping products captures common Phase II SNPs with an average maximum r2 of up to 0.8 in African and up to 0.95 in non-African populations, and that potential gains in power in association studies can be obtained through imputation. These data also reveal novel aspects of the structure of linkage disequilibrium. We show that 10-30% of pairs of individuals within a population share at least one region of extended genetic identity arising from recent ancestry and that up to 1% of all common variants are untaggable, primarily because they lie within recombination hotspots. We show that recombination rates vary systematically around genes and between genes of different function. Finally, we demonstrate increased differentiation at non-synonymous, compared to synonymous, SNPs, resulting from systematic differences in the strength or efficacy of natural selection between populations.     

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.