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.     

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.     

回归模型的相关性检验

基于经验似然的方法构造了检验统计量,对非参数回归模型中的误差进行了相关性假设检验,获得了零假设下检验统计量的渐近分布为χ2分布.模拟计算表明相关性假设检验的经验似然方法具有较好的功效.     

π0与N- (N-)重整化链传播子的"精确"收敛公式与辐射修正

采用中性介子π0与核子(N-)反核子-N强相互作用Lorentz不变耦合模型,对π0与N- (N-)两类重整化链图传播子函数级数收敛性问题作了全面考察与深入研究,并利用链图传播子函数的精确理论计算结果,通过相关理论分析、推导后获得重整化链图传播子函数级数"精确"收敛公式;在此基础上又对两类重整化链图传播子"辐射修正"问题作了理论计算与分析.     

水钢高炉最佳炉料结构的试验

采用正交试验方法研究了现有原燃料及设备条件下水钢高炉的最佳炉料结构;在此基础上进一步优化炉料结构,并对它们的冶金性能进行了试验.结果表明:目前水钢高炉最佳炉料结构为86%的烧结矿(二元碱度为1.8)配加14%的印度块矿与越南块矿的混合矿(混合比例为1:1);此种炉料结构的软熔性能好,还原性能达到优良水平,炉渣碱度合适,但低温还原粉化性能不佳;若采用二元碱度为1.7的烧结矿,使炉渣的碱度低于1.2,则熟料率达到90%的炉料结构是完全可行的.     

New crystal structure of molecular complex 1-piperidine carboxylate-piperidinium-H<Subscript>2</Subscript>O studied by X-ray single crystal diffraction

Piperidine absorbs CO2 and H2O in air to form a molecular complex： piperidium-l-piperidinecarboxylate-H2O. The structure of the complex was characterized by X-ray single crystal diffraction. The crystal structure was determined to be triclinic, space group P1^-with a=0.648 6（8） nm, b=0.809 200） nm, c= 1.357 1（16） nm, a=96.96706）°, β =102.506（15）°,γ=104.202 05）°, Z=2. The complex is stabilized via five hydrogen bonds between the three components, N-O electrostatic interaction and O-O interaction （electron transfer） betweenl-piperidinecarboxylate and H2O. Due to electron transference of carbamate ion, the oxygen atom in water molecule is strongly negatively charged and the O-H bond is considerably shorter than that of the free molecule of water. The formation of the molecular complex is a reversible process and will decompose upon heating. The mechanism of formation and stabilization is further investigated herein.     

An Adaptive Model and Algorithm for an Electrohydraulic Position Servo System in Auto Gauge Control for Aluminum Hot Tandem Mill

The electrohydraulic servo position control system (HPC) is the core of an auto gap control for a modern fourhigh continuous hot strip mill. The actuators are loaded with considerable external disturbances, rolling forces, and the system stiffness and position accuracy will become hypersensitive to the leakage and the compressibility of the oil. Many efforts have being made to increase the position accuracies. The conventional resources are proportion integral differential (PID) controller. But the PID controller is faint for a considerable external disturbance. In this paper, by introducing the adaptive control strategy of model reference the reciprocities of the system structure with the loads were analyzed. With the Lyapunov energy function, an adaptive control algorithm applied to improve the system accuracy was formulated. The system simulations and the selection of parameters of the model were also discussed. The simulations show the static state errors at 0.02%. Finally, the industrial experimental result was given.     

交互式语音地球仪照明结构研究

简述了交互式语音地球仪结构原理;研究了地球仪上首都的无歧义显示、发光二极管的布置以及首 都显示分辨率;制成了交互式语音地球仪。     

基于人的信息处理模型分析操作人员视觉信息处理过程

报告了由知觉、思维、运动３个处理器和短期记忆、工作记忆和长期记忆构成的研究用计算机实现 人的信息处理模型;把人的信息处理模型安装在一台PC机上,模拟生产操作人员监视锅炉厂模拟机计算机屏幕 的过程表明,视觉信息处理过程取决于画面因素、人的身心状态和知觉处理器参数等与实际生产操作人员的行 为特征相符。此模型可以用来分析工业生产中人为操作失误的发生机制,以预防和减少事故发生。     

伐昔洛韦联合微米光治疗28例带状疱疹的临床观察

目的:观察伐昔洛韦(valacyclovir)联合微米光治疗28例带状疱疹的临床疗效.方法:将54例带状疱疹患者随机分为两组,试验组28例口服伐昔洛韦(商品名:维德思)1 000 mg,每日3次,共服7d后改为每次500 mg,每日3次,继续服用7d.同时皮肤照射微米光每日一次,共照射14 d.对照组26例口服阿昔洛韦,200 mg,每日5次,同样每日照射微米光,与试验组一致,共14 d.观察记录第1、3、5、7、10、14天时止疱、结痂、疼痛及不良反应,第14天根据评分表评定总疗效.结果:试验组痊愈率为82.1％,对照组为46.2％,差异有统计学意义(P＜0.01),试验组有效率为96.4％,对照组为73.1％ (P ＜0.05).全部患者无严重不良反应发生,疗程结束后查肝肾功能无明显改变.结论:伐昔洛韦(维德思)联合微米光能明显缩短带状疱疹病程、加快水疱干枯结痂、促进皮损愈合、减少神经痛的程度及持续时间,降低后遗神经痛的发生率.