Evaluation of the hepatotoxicological effects of a drug in an in vivo/in vitro model

Both in vivo and in vitro models have certain disadvantages for the study of the chronic hepatotoxicity of drugs. The aim of this work was to evaluate a new approach based on an in vivo/in vitro model. After chronic in vivo treatment of rats with Vincamine and Vindeburnol (an eburnamenine derivative which exhibits hepatotoxic properties in man) liver cells were isolated, and functional and metabolic disorders (metabolic utilization of fructose and protein biosynthesis) were studied to determine injury. The results showed no modification of blood parameters, but a direct relationship between the dose of Vindeburnol administered in vivo and the metabolic disorders observed in vitro, evidencing the high sensitivity and reliability of this model.     

Biosynthesis of 1-aminocyclopropanecarboxylic acid: Steric course of the reaction at the C-4 position

Summary Under the action of the appropriate synthase from ripe tomatoes a 11 mixture of (3S, 4R)-[3,4-²H₂] and (3R, 4S)-[3,4-²H₂]-(2S)-adenosylmethionine is transformed into a 11 mixture of the two meso forms of [²H₂]-1-aminocyclopropanecarboxylic acid, a result which proves the operation of an inversion mechanism and which is consistent with direct nucleophilic displacement of the leaving group in the substrate.     

Quantitative genetic models of sexual selection

Summary Quantitative genetic models of sexual selection have disporven some of the central tenets of both the handicap mechanism and the sexy son hypothesis. These results suggest that the good genes approach to sexual selection may generally lead to erroneous results.Runaway sexual selection seems possible under a wide variety of circumstances. Quantittive genetic models have revealed runaway processes for sexually selected attributes expressed in both sexes and for attributes of parental care. Furthermore, the runaway could occur simultaneously in a series of populations that straddle an environmental gradient. While the models support the feasibility of runaway processes, empirical studies are needed to evaluate whether runaways actually happen. Estimates of critical genetic parameters are particularly needed, as well as measures of natural and sexual selection acting on the same population.The models also show that sexual selection has tremendous potential to produce population differentiation, particularly in epigamic traits. Differentiation is promoted by indeterminancy of evolutionary outcome, transient differences among populations during the final slow approach to equilibrium, sampling drift among equilibrium populations, and the tendency of sexual selection to amplify geographic variation arising from spatial differences in natural selection. Recent work with two- and three-locus models of sexual selection has produced results that parallel the results of the polygenic models^36–38,58. Thus the feature of indeterminate equilibria (outcome dependent on initial conditions) is common to both types of model.     

A major metabolite of Δ1-tetrahydrocannabinol reduces its cataleptic effect in mice

Summary The results described here demonstrate that THC-induced catalepsy in mice can be substantially inhibited by the prior administration of ¹-THC-7-oic acid, the major metabolite of THC in most species including humans. This raises the possibility that the intensity and duration of action of THC may depend to a large degree on the levels of this metabolite at the sites of action.We thank the National Institute on Drug Abuse for supporting this project by grants DA-02043 and DA-02052 and for supplying all of the cannabinoids. One of us (S.B.) is also the recipient of a Research Scientist Award from NIDA. We are grateful to Kristen Carlson and Thomas Honeyman for helpful suggestions in preparing this report.     

Structure of the human CLC-7/Ostm1 complex reveals a novel state

CLC-7 functions as a Cl?/H+ exchanger in lysosomes. Defects in CLC-7 and its β-subunit, Ostm1, result in osteopetrosis and neurodegeneration. Here, we present the cryogenic electron microscopy (cryo-EM) structure of the human CLC-7/Ostm1 complex (HsCLC-7/Ostm1) at a resolution of 3.6 ?. Our structure reveals a new state of the CLC-7/Ostm1 heterotetramer, in which the cytoplasmic domain of CLC-7 is absent, likely due to high flexibility. The disordered cytoplasmic domain is probably not able to restrain CLC-7 subunits and thus allow their relative movements. The movements result in an approximately half smaller interface between the CLC-7 transmembrane domains than that in a previously reported CLC-7/Ostm1 structure with a well-folded cytoplasmic domain. Key interactions involving multiple osteopetrosis-related residues are affected by the interface change.     

基于PiggyBac转座系统的低溢漏诱导型Tet-On过表达体系的建立及应用

为避免诱导基因稳定表达的Tet-On诱导表达系统溢漏表达,实现简便且高效的外源基因稳定诱导表达, 本研究拟在Tet-On调控的转录水平基础上,将基于稳定配体Shield-1的不稳定结构域FK506结合蛋白引入目的基因的N端,从蛋白水平控制其本底表达水平.为验证该系统的效果,本研究以荧光蛋白TdTomato为报告基因,经流式分析结果证明优化后的体系较原体系的溢漏表达在蛋白水平上降低7倍左右.将该系统应用于基于小鼠胚胎干细胞的体外牙向分化模型,在诱导因子Dox和稳定配体Shield-1的协同作用下,诱导表达牙齿发育相关转录因子Hand2提高了牙向分化诱导的完成度.     

|x|在扩展的Chebyshev结点的有理插值

研究|x|在扩展的Chebyshev结点的有理插值,得到逼近阶为O(1/(nln n)).通过数值计算发现相同逼近阶的误差与结点的密集度、结点所在曲线的凹凸性有关.     

固定时间扩张状态观测器下的四旋翼飞行器滑模控制策略

针对滑模控制中系统状态接近滑模面后存在的抖颤现象,提出一种基于固定时间扩张状态观测器(FTESO)的二阶滑模控制策略.首先,设计全驱动子系统及欠驱动子系统的控制结构中的二阶滑模控制器;然后,通过FTESO对内部的参数不确定及外部扰动进行观测,在一定时间上限内收敛到观测值,利用观测值对控制器进行补偿,从而减少甚至消除抖颤现象;最后,通过李亚普诺夫函数保证设计的四旋翼飞行器系统的闭环稳定性,并进行仿真实验.结果表明：文中提出的控制策略具有优越性.     

循环荷载作用下NaCl溶液对黏土动力特性影响及微观机理分析

针对黏土易与水结合,孔隙溶液环境变化对黏土动力特性有较大影响的问题,使用GDS真/动三轴仪对黏土试样进行模拟交通循环荷载下的分级加载试验,研究不同浓度NaCl孔隙溶液、振动频率对土体应力-应变关系和动弹性模量的影响,分析骨干曲线及弹性模量的发展规律,并结合电镜扫描,分析NaCl溶液浓度和振动频率改变前后试样的孔隙分布规律,得到微观孔径与动力特性的关系。结果表明,随着NaCl溶液浓度和振动频率的升高,应力-应变曲线和动弹性模量曲线呈上移趋势;阻尼比-动应变曲线随振动频率的增加而上升,随NaCl溶液浓度的增加而下降;NaCl溶液浓度升高,水化反应产生的胶体增多,微填充作用可有效减少小孔隙,振动频率增加则使得片状颗粒间距被压缩,层状结构减少,土体更加密实,有效减少大孔隙。研究得出的含NaCl溶液黏土受孔隙溶液浓度与振动频率变化的影响规律,可为研究其他环境下黏土的强度变化提供参考。     

3—己烯—1—醇及其酯类的合成和香气研究

介绍了叶醇(cis-3-己烯-1-醇)及其异构体的实用合成路线。由顺反混合(或全反式)3-己烯-1-醇制备了一系列羧酸酯,研究了这些化合物的结构与香气的关系,从中发现一些有实用价值的新香料。