Recent Advances in Physicochemical and ADMET Profiling in Drug Discovery

The drastic increase in the cost for discovering and developing a new drug along with the high attrition rate of development candidates led to shifting drug‐discovery strategy to parallel assessment of comprehensive drug physicochemical, and absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties alongside efficacy. With the proposal of a profiling paradigm and utilization of integrated risk assessment, one can exponentially enhance the predictive power of in vitro tools by taking into consideration the interplay among profiling parameters. In particular, this article will review recent advances in accurate assessment of solubility and other physicochemical parameters. The proper interpretation of these experimental data is crucial for rapid and meaningful risk assessment and rational optimization of drug candidates in drug discovery. The impact of these tools on assisting drug‐discovery teams in establishing in vitro–in vivo correlation (IVIVC) as well as structure–property relationship (SPR) will be presented.     

Improving discrimination of outer membrane proteins by fusing different forms of pseudo amino acid composition

Integral membrane proteins are central to many cellular processes and constitute approximately 50% of potential targets for novel drugs. However, the number of outer membrane proteins (OMPs) present in the public structure database is very limited due to the difficulties in determining structure with experimental methods. Therefore, discriminating OMPs from non-OMPs with computational methods is of medical importance as well as genome sequencing necessity. In this study, some sequence-derived structural and physicochemical features of proteins were incorporated with amino acid composition to discriminate OMPs from non-OMPs using support vector machines. The discrimination performance of the proposed method is evaluated on a benchmark dataset of 208 OMPs, 673 globular proteins, and 206 α-helical membrane proteins. A high overall accuracy of 97.8% was observed in the 5-fold cross-validation test. In addition, the current method distinguished OMPs from globular proteins and α-helical membrane proteins with overall accuracies of 98.2 and 96.4%, respectively. The prediction performance is superior to the state-of-the-art methods in the literature. It is anticipated that the current method might be a powerful tool for the discrimination of OMPs.     

First investigation of ultraoligotrophic alpine Lake Puma Yumco in the pre-Himalayas,China

Lake Puma Yumco is a typical alpine lake (altitude 5030m) located in the pre-Himalayas of Tibet, China, and this study was the first limnological investigation ever conducted on it. Lake Puma Yumco (28°34N, 90°24E) has the following morphometric properties: maximum length 31km, maximum width 14km, mean width 9km, shoreline 90km, surface area 280km², and shoreline development 1.5. Transparency was approximately 10m, even in the thawing season. The extinction coefficient of the lake water was calculated as 0.15m^–1. Annual maximum transparency was estimated from the depth of the Chara zone to be 30m. Dissolved oxygen was 7mg O₂ l^–1 and showed saturated values, and salinity was 360mgl^–1. The chemical type of the lake water was Mg-Ca-HCO₃-SO₄, and it was slightly alkaline in character. Total nitrogenous nutrients (sum of ammonia, nitrite, nitrate, and urea nitrogen), phosphate, and silicate were extremely low at 1, 0.02, and 9µM, respectively. Dissolved organic carbon, nitrogen, and phosphorus concentrations were 160, 11, and 0.08µM and the molar ratio was calculated as 2100:140:1. Chlorophyll a concentration was 0.2mgm^–3. Phytoplankton and zooplankton were dominated by Aphanocapsa sp. and Diaptomidae. Both nitrogen and phosphorus appear to be the limiting parameters for phytoplankton growth. Organic carbon and nitrogen contents in lake sediments were low and the sediments contained a large amount of CaCO₃. The grain size of sediment was that of silt-sand in most cases. The present results indicate that the pre-Himalayan alpine freshwater Lake Puma Yumco is an ultraoligotrophic lake.     

过氧化氢对铜锌超氧化物歧化酶活性及某些理化性质的影响

用H_2O_2作用于牦牛红细胞铜锌超氧化物歧化酶。观察到酶活性随H_2O_2浓度升高及作用时间增加而下降;酶分子连接的铜和锌有所丢失;PAGE图谱中三条酶活性带成为四条酶活性带;等电点下降;680nm处表征二价铜光学性质的可见光吸收减弱;紫外吸收增加,表现为增色效应;内源性荧光减弱;在含有3.0mol/LKCl的PH3.8—5.4琥珀酸缓冲液中溶解度下降;酶对胰蛋白酶水解的敏感性增加。     

不同夏季水位时黑龙滩水库的理化性状

对黑龙滩水库夏季不同水位时理化性状进行差异显著性分析以及外源性输入和理化性状在库区的变化过程比较分析,得出高水位时输入水中Ｍｇ,Ｃａ,Ｓｏ,Ｎｏ＾－３,ＴＮ,硬度及电导率均显著高于低水位时,而ＣＯＤＣｒ和ＮＨ＾＋４含量则显著低于低水位时;高水位时理化指标在库区的变化幅度比低水位时高,说明高水位时生物活动强度比低水位时高。     

Maternal control of calcium concentration in the larval nursery of the bromeliad crab,Metopaulias depressus (Grapsidae)

It has been proposed that parental care in invertebrates controls for physicochemical conditions. This suggests that the parent detects deviations from optimal conditions and responds by correcting the deviation for the benefit of the offspring. In the bromeliad crab, Metopaulias depressus, mothers accumulate snail shells (CaCO₃) in the leaf axil containing the larvae, which results in an increase in Ca²⁺ and pH, both beneficial to the young. I tested the hypotheses that mothers: (i) control for calcium levels and only collect shells when calcium is too low; (ii) always collect shells, independent of the calcium content of the nursery; (iii) collect shells if encountered, but increase their activity if the calcium content becomes critical. In a field experiment, I reduced the initial calcium concentration in the nurseries of one group and increased it in another group. In both groups mothers collected shells. However, they collected significantly more shell mass per day in the group with reduced levels than in the group with high levels. The results support hypothesis (iii) and unequivocally demonstrate maternal control of physicochemical conditions in the nursery. This is the first proof that crustacean mothers actively regulate abiotic conditions for their offspring.     

广东省地方稻种品质性状表型多样性及其形成的生态因子分析

（广东省农业科学院水稻研究所,广州 510640） 摘要 为了进一步完善广东地方稻种资源的鉴定评价,并为该资源在水稻品质育种中的有效利用提供科学依据,我们以国家作物种质库编目的2974份广东地方稻种为研究对象,其9个品质性状数据为基础,研究了广东地方稻种品质性状的区域分布特点,并对总体和不同稻作区品质性状多样性进行了比较分析.同时对部分生态因子与品质性状的相关性进行了初探。结果显示,广东地方稻种资源品质性状具有丰富的多样性。其糙、精米率较高,蛋白质含量丰富多样,胶稠度的变异幅度大,直链淀粉含量适中达国标的材料偏少;中南稻作区为广东优质地方稻种的主要集中地;不同稻作区的品质性状多样性表现各异;直链淀粉含量、碱消值及胶稠度是影响广东地方稻种品质形成的主要指标;湿度和温度的地域差异是广东地方稻种稻米品质多样性的主要成因。本研究结果充分说明,广东地方稻种中具有优异品质性状资源的利用对改良现有品质的稻米品质和拓宽遗传基础具有十分重要的意义。