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.     

Structural definition of a conserved neutralization epitope on HIV-1 gp120

The remarkable diversity, glycosylation and conformational flexibility of the human immunodeficiency virus type 1 (HIV-1) envelope (Env), including substantial rearrangement of the gp120 glycoprotein upon binding the CD4 receptor, allow it to evade antibody-mediated neutralization. Despite this complexity, the HIV-1 Env must retain conserved determinants that mediate CD4 binding. To evaluate how these determinants might provide opportunities for antibody recognition, we created variants of gp120 stabilized in the CD4-bound state, assessed binding of CD4 and of receptor-binding-site antibodies, and determined the structure at 2.3 A resolution of the broadly neutralizing antibody b12 in complex with gp120. b12 binds to a conformationally invariant surface that overlaps a distinct subset of the CD4-binding site. This surface is involved in the metastable attachment of CD4, before the gp120 rearrangement required for stable engagement. A site of vulnerability, related to a functional requirement for efficient association with CD4, can therefore be targeted by antibody to neutralize HIV-1.     

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.     

区域城乡协调发展的综合评价——以宁波为例

城乡之间的协调表现在很多方面.要全面、客观地评价一个地区的城乡协调发展情况,必须建立科学合理的评价指标体系,选择恰当的评价方法.本文结合宁波市的实际情况,讨论了城乡协调发展的内涵和目标,提出了城乡协调发展评价指标体系和方法,揭示了宁波市近年城乡协调发展方面存在的问题和未来可能的变化态势.     

微束X射线荧光分析谱仪及其对松针中元素的分布分析

介绍了一种小型的微束X射线荧光分析谱仪,它是由导管X光透镜和能量色散X射线荧光分析谱仪组成.谱仪具有较高的空间分辨率和能量分辨率.使用本谱仪对松树针叶进行了微区分析,得出各种元素沿松针长度方向和横切面径向的分布规律.结果表明使用X光透镜的微束X射线荧光分析方法可以实现植物样品的微区分析,有助于进一步了解植物的生长与元素迁移的关系.     

旅游流规模结构的Zipf特征与差异度对比研究——以四川省为例

以1996年至2004年入境旅游统计数据为样本,借用齐夫(Zipf)参数和差异度、均衡度指标,对四川省入境旅游流规模结构的齐夫(Zipf)特征和差异度进行了对比研究.结果发现齐夫(Zipf)参数可对旅游流规模结构进行分段处理,并以此分析各标度区内旅游流规模结构的空间分布形态;对不满足Zipf法则的无效标度区内部结构只能借助差异度和均衡度指标予以完成,但由于该指标既不能很好说明旅游流规模结构的标度分段特征,又无法反映旅游流结构的空间分布形态,故只能在分析旅游流规模结构时对齐夫(Zipf)参数起补充作用;用Zipf参数和差异度、均衡度指标定量研究旅游流规模结构所得到的结果与客观实际相符合,从而证明了Zipf定律、差异度、均衡度指标均可作为旅游流规模结构分析的有效手段或工具,这对丰富旅游流的分析方法具有重要意义.     

对象迁移自动机在TDT中的聚类研究

对象迁移自动机(OMA)是一种能够较好地解决话题识别与跟踪(TDT)中聚类问题的方法,但是,传统OMA模型由于聚类速度慢等缺点,难以满足TDT实时和增量聚类的要求.针对这一问题,本文一方面改进传统的OMA模型中自动机的动作设计,同时提出文档选择策略,加快了OMA的聚类速度.改进的方法在中等文档集上进行了实验,实验结果表明,该方法具有较好的聚类效果.