磺酰脲类除草剂的三维药效团模型

磺酰脲类除草剂是七十年代末期[1，2]开发的一类超高效除草剂，杀草谱广，用量极低．它通过抑制植物体内乙酰乳酸合成酶（ALS，acetolactatesynthase）的活性[3]，破坏支链氨基酸缬氨酸、亮氨酸和异亮氨酸的合成，造成杂草的死亡．本文从三维角度出发，利用先进的三维分子设计软件APEX（ActivityPredictionExpertSystem）－3D[4]，建立破酸豚类除草剂药效团模型（biophoremodel），辅助设计、筛选活性化合物；再由药效团构造出模拟ALS酶活性位点（activesites）的空间结构，以该模拟结构为基点，以期设计出全新结构的ALS酶抑制剂的…     

Sulfonylurea类ALS/AHAS抑制剂作用方式的分子对接研究和新抑制剂的虚拟筛选

采用Dock5和Autodock3的组合, 从乙酰乳酸合成酶(ALS)的晶体结构出发, 对五个磺酰脲分子和三个类磺酰脲分子与ALS的相互作用方式进行了详细的分子对接研究, 并结合对ALS与氯嘧磺隆(类磺酰脲)共结晶的复合物晶体结构的分析得出了一个简化的药效团模型, 与前人利用其它手段得到的药效团模型一致. 结合此药效团模型并根据sulfonylurea类分子与ALS的作用机理, 我们对425个具有不同除草和杀虫作用的已知农药和ALS进行了分子对接研究和筛选, 从中发现了一些可能对ALS有抑制作用的农药分子. 此结果可以很好地解释这类农药的结构和活性的关系, 对设计、开发新ALS抑制剂的先导化合物提供依据和指导.     

基于药效团模型设计合成新型ALS抑制剂

以ALS抑制剂药效团模型为基础建立了提问结构,将药效团模型中的生物结构信息输入到多种小分子三维结构数据库(NCI-3D和ACD-3D数据库)中,分别搜寻出100多个符合特征结构信息的全新结构候选化合物.以这些命中结构的分子特征信息为基础设计合成了一系列新型的ALS抑制剂,初步生物活性测试结果表明,预期有生物活性的化合物显示出一定的ALS酶抑制剂活性.     

生物合理方法设计合成新型除草剂

采用生物合理的方法设计合成了光合作用抑制剂及ALS酶抑制剂,根据绿色红假单胞菌(Rps.viridis)光合反应中心X-衍射的晶体结构同源模建了高等植物豌豆(Pisumsativum)D1蛋白的结构模型,及其与抑制剂氰基丙烯酸(酰胺)与氢化脲嘧啶的复合物模型。研究了D1蛋白与抑制剂可能的作用位点。为了提高筛选的力度,还应用Wang树脂引入了组合合成的方法。对三类ALS抑制剂进行了2D-QSAR,3-DQSAR,作用模型及新抑制剂的设计研究。     

应用CoMFA研究磺酰脲类化合物的三维构效关系

用比较分子力场分析 (CoMFA)方法研究了磺酰脲类除草剂结构与活性的三维定量构效关系 ( 3D QSAR) ,并在此基础上对原有分子结构进行修饰改造 ,以获得较高活性的化合物 .并在三维等值线图的基础上得到了此类除草剂作用靶标ALS酶的模拟作用模型 ,为进一步合成出全新结构的ALS酶抑制剂的先导化合物提供了有益的启示和帮助 .     

超声辅助提取-液相色谱-串联质谱法同时测定油料作物中6种新型乙酰乳酸合成酶抑制剂类除草剂残留

将超声辅助提取与液相色谱-质谱联用技术相结合,建立了油料作物中6种新型乙酰乳酸合成酶（ALS）抑制剂类除草剂（甲基二磺隆、氯吡嘧磺、双草醚、嘧草醚、嘧苯胺磺隆和乙氧嘧磺隆）的痕量多残留检测技术。比较了超声辅助提取和QuEChERS提取2种方法对6种除草剂的提取回收率,并根据净化效果和吸附作用对十八烷基键合硅胶吸附剂（C18）、乙二胺-N-丙基硅烷（PSA）、石墨化炭黑（GCB）、弗罗里硅土（Florisil）和增强型基质去除吸附剂（EMR）5种吸附材料进行优化。结果表明,超声辅助提取可使6种化合物的提取回收率在90.0%以上,EMR对6种化合物的吸附作用较小,且可有效去除油脂干扰,减小基质效应。6种除草剂在0.05~500.0 μg/L范围内具有良好的线性,相关系数均大于0.9984。该方法检出限和定量限分别为0.08~0.8 μg/kg和0.25~2.5 μg/kg。6种化合物在油菜籽、大豆、花生米和葵花籽4种基质中3个加标水平下的加标回收率为70.7%~103.8%,相对标准偏差为0.8%~9.2%,可应用于油料作物中6种ALS抑制剂类除草剂的同时测定。     

氟化钠对大鼠血清微量元素的影响

为探讨氟化钠（NaF）对大鼠血清四种微量元素含量的影响,将80只2月龄SPF级SD大鼠,雌雄各半,随机分成8组：对照组[幼年（CS）、成年（AS）]和用药组[幼年高氟（CHS）、成年高氟（AHS）平订幼年低氟（CLS）、成年低氟（ALS）组,长期高氟（HS）和低氟（LS）组];对照组灌胃生理盐水,刖药组分别按相应时阃给予不同剂量的NaF灌胃。结果表明,与CS组相比,CYIS组和CLS组的P分别增加100％（P〈0．05）和193．8％（P〈0．05）;与As组相比,HS组的Ca、Zn分别下降了20．5％（P〈0．05）和40％（P〈0．05）,而P则增加了74％（P〈0．05）,LS组的Zn也下降了33．3％（P〈0．05）。提示：长期使用氟化钠可导致幼年大鼠血中化学元素代谢紊乱。     

新磺酰脲类除草活性构效关系的研究

磺酰脲类除草剂具有对环境友好和超高效的特点。本文采用X-衍射谱对其绝对构型进行分析,首次发现分子内氢键的存在。采用各种理论和软件计算,活性结构应符合三点要求：(a)分子内氢键使杂环和脲之间形成一个共轭体系;(b)羰基氧、磺酰氧和杂环氮形成分子中三个负电中心;(c)在磺酰胺与苯邻位取代基之间形成一个空穴。根据以上结论,构建了一个卡口模型,较合理地解释了磺酰脲类草活性的构效关系。建立了一个虚拟靶酶ALS的模拟作用模型,供进一步分子设计ALS抑制剂,包括一些非磺酰脲类先导化合物时参考。     

应用光谱技术无损检测油菜叶片中乙酰乳酸合成酶

应用可见/近红外光谱技术实现了油菜叶片中乙酰乳酸合成酶(ALS)的快速无损检测.对99个油菜样本进行光谱扫描,经过平滑、变量标准化、一阶求导等预处理后,应用偏最小二乘法(PLS)建立了ALS的预测模型.同时提取有效特征变量,作为反向传输人工神经网络(BPNN)和最小二乘-支持向量机(LS-SVM)的输入值,并建立相应的模型.用66个样本建模,33个样本验证.结果表明,LS-SVM模型能够获得最优的预测结果,预测集样本的相关系数(r)、预测标准差(RMSEP)和偏差(Bias)分别为0.998、 0.715和0.079,获得了满意的预测精度.结果表明,应用可见/近红外光谱技术结合LS-SVM检测油菜中乙酰乳酸合成酶是可行的,并能获得满意的预测精度,为进一步应用光谱技术进行油菜生长状况的大田监测奠定了基础.     

理科职前教师科学模型理解的调查研究

就科学模型的理解对553名理科职前教师进行问卷调查。结果发现：（1）职前教师对科学模型的认识处于中上水平,仍需进一步提高;（2）科学模型的多个维度之间职前教师的理解水平相当;（3）职前教师对科学模型的认识并非随年级逐渐递增,具有不稳定性、反复性;（4）专业学习内容的差异对教师科学模型的认识有着重要影响;（5）科学模型的认识性别差异不明显。基于此提出了关于理科职前教师教育中加强科学模型教学的3点启示。     

ALS抑制剂合理分子设计的研究进展

以乙酰乳酸合成酶为靶标合理设计开发新型超高效除草剂是当前除草剂化学研究中的重要领域。结合本课题组的研究工作,从ALS抑制剂的结构特征、分子力学与量子化学研究、定量构效关系(QSAR)与三维定量构效关系(3D-QSAR)研究、非线性QSAR研究以及新型除草剂的分子设计等几个方面对该领域的研究现状进行了总结报道,并对该领域的发展前景及存在的问题进行了展望。     

Elemental imbalance studies by INAA on extraneural tissues from amyotrophic lateral sclerosis patients

Human kidney and liver tissues were studied for generalized elemental imbalances in amyotrophic lateral sclerosis (ALS) by instrumental neutron activation analysis (INAA). Iron was significantly increased (p<0.05) in ALS kidneys and Co and Fe (marginal, p<0.10) were increased in ALS liver compared with their respective controls. Mercury values were almost two-fold higher for ALS kidney and 17% higher for ALS liver as compared with their respective controls. However, the Hg data exhibited large variations and ALS-control differences were not significant. Data from the present study are discussed with reference to the role of metallothioneins (MT) in ALS, and a possible linkage between a free radical mediated mechanism and degeneration of cells in ALS is also explored.     

三唑并嘧啶磺酰胺类除草剂的比较分子场法分析

用比较分子场分析方法,分析了三唑并嘧啶类化合物对乙酰乳酸合成酶(ALS)抑制活性的构效关系,推测其与ALs的空间结合模式.     

Comments on a recently published paper ‘some surprising properties of multivariate curve resolution‐alternating least squares (MCR‐ALS) algorithms’

Some of the results given in a recently published paper in this journal concerning some surprising properties of the multivariate curve resolution‐alternating least squares (MCR‐ALS) method are discussed. My results showed that the surprising properties of MCR‐ALS refer only to the slow linear convergence properties of ALS algorithms and to rounding error computer calculations. Results obtained by MCR‐ALS for the first data example were correct and no significant differences were observed in the resolved profiles. In the second more complex data example, large rotation ambiguities were present for the spectrum profile of the very minor second component which was not correctly estimated by MCR‐ALS. However, even in this case, the subspaces spanned by the MCR‐ALS solutions were also very close to the correct ones apart from slow convergence properties of the MCR‐ALS algorithm in this case. Copyright © 2009 John Wiley & Sons, Ltd.     

Sodium dodecyl sulfate versus acid-labile surfactant gel electrophoresis: comparative proteomic studies on rat retina and mouse brain

A long-chain derivative of 1,3-dioxolane sodium propyloxy sulfate, with similar denaturing and electrophoretic properties as SDS, and facilitated protein identification following polyacrylamide gel electrophoresis (PAGE) for Coomassie-stained protein bands, has been tested. Comparative acid-labile surfactant/sodium dodecyl sulfate two-dimensional (ALS/SDS 2-D)-PAGE experiments of lower abundant proteins from the proteomes of regenerating rat retina and mouse brain show that peptide recovery for mass spectrometry (MS) mapping is significantly enhanced using ALS leading to more successful database searches. ALS may influence some procedures in proteomic analysis such as the determination of protein content and methods need to be adjusted to that effect. The promising results of the use of ALS in bioanalytics call for detailed physicochemical investigations of surfactant properties.     

Application of maximum likelihood multivariate curve resolution to noisy data sets

In this work, two different maximum likelihood approaches for multivariate curve resolution based on maximum likelihood principal component analysis (MLPCA) and on weighted alternating least squares (WALS) are compared with the standard multivariate curve resolution alternating least squares (MCR‐ALS) method. To illustrate this comparison, three different experimental data sets are used: the first one is an environmental aerosol source apportionment; the second is a time‐course DNA microarray, and the third one is an ultrafast absorption spectroscopy. Error structures of the first two data sets were heteroscedastic and uncorrelated, and the difference between them was in the existence of missing values in the second case. In the third data set about ultrafast spectroscopy, error correlation between the values at different wavelengths is present. The obtained results confirmed that the resolved component profiles obtained by MLPCA‐MCR‐ALS are practically identical to those obtained by MCR‐WALS and that they can differ from those resolved by ordinary MCR‐ALS, especially in the case of high noise. It is shown that methods that incorporate uncertainty estimations (such as MLPCA‐ALS and MCR‐WALS) can provide more reliable results and better estimated parameters than unweighted approaches (such as MCR‐ALS) in the case of the presence of high amounts of noise. The possible advantage of using MLPCA‐MCR‐ALS over MCR‐WALS is then that the former does not require changing the traditional MCR‐ALS algorithm because MLPCA is only used as a preliminary data pretreatment before MCR analysis. Copyright © 2013 John Wiley & Sons, Ltd.     

Simultaneous Anodic Stripping Voltammetric Determination of Pb and Cd,Using a Vibrating Gold Microwire Electrode,Assisted by Chemometric Techniques

Simultaneous anodic stripping voltammetric determination of Pb and Cd is restricted on gold electrodes as a result of the overlapping of these two peaks. This work describes the quantitative determination of a binary mixture system of Pb and Cd, at low concentration levels (up to 15.0 and 10.0 µg L^?1 for Pb and Cd, respectively) by differential pulse anodic stripping voltammetry (DPASV; deposition time of 30 s), using a green electrode (vibrating gold microwire electrode) without purging in a chloride medium (0.5 M NaCl) under moderate acidic conditions (HCl 1.0 mM), assisted by chemometric tools. The application of multivariate curve resolution alternating least squares (MCR‐ALS) for the resolution and quantification of both metals is shown. The optimized MCR‐ALS models showed good prediction ability with concentration prediction errors of 12.4 and 11.4 % for Pb and Cd, respectively. The quantitative results obtained by MCR‐ALS were compared to those obtained with partial least squares (PLS) and classical least squares (CLS) regression methods. For both metals, PLS and MCR‐ALS results are comparable and superior to CLS. For Cd, as a result of the peak shift problem, the application of CLS was unsuitable. MCR‐ALS provides additional advantage compared to PLS since it estimates the pure response of the analytes signal. Finally, the built up multivariate calibration models, based either in MCR‐ALS or PLS regression, allowed to quantify concentrations of Pb and Cd in surface river water samples, with satisfactory results.     

Effect of UV radiation on some polymeric networks based on vinyl ester resin and modified lignin

Some semi-interpenetrating polymer networks (semi-IPNs) based on vinyl ester resin (VER) and ammonium lignosulfonate (ALS) modified lignin were synthesized and characterized using Fourier transform-infrared (FT-IR) spectroscopy, optical microscopy (OM) and differential scanning calorimetry (DSC) techniques. VER was synthesized starting from an epoxy resin in reaction with acrylic acid. The cross-linking reaction was initiated by UV radiation. The synthesized networks showed good compatibility, due to some possible interactions between the functional groups from VER and ALS components (OH, especially). A slight effect of photostabilization of the VER was noticed, due to the ALS structures which were incorporated into the resin matrix.     

Pattern recognition for the study of structure—activity relationships: Uses of the adaptive least-squares method and linear discriminant analysis

The adaptive least-squares method (ALS) and linear discriminant analysis (LDA) were applied to structure—activity correlation studies including the antitumor activity of mitomycin derivatives, the relative binding affinities of 100 steroids for five receptors, assignment of the pharmacological category of 80 diarylmethane-derived drugs, and discrimination of the adverse reaction of 98 miscellaneous drugs that may induce liver and/or blood diseases. Generally, more satisfactory results were obtained by the use of ALS than by LDA, both in recognition and in leave-one-out predictions. However, LDA was not always inferior to ALS in the applications, especially those related to classification of independent categories.