Reactivity profiles of ligands of mammalian retinoic acid receptors: A preliminary COREPA analysis

Retinoic acid and associated derivatives comprise a class of endogenous hormones that bind to and activate different families of retinoic acid receptors (RARs, RXRs), and control many aspects of vertebrate development. Identification of potential RAR and RXR ligands is of interest both from a pharmaceutical and toxicological perspective. The recently developed COREPA (COmmon REactivity PAttern) algorithm was used to establish reactivity profiles for a limited data set of retinoid receptor ligands in terms of activation of three RARs ( f , g , n ) and an RXR ( f ). Conformational analysis of a training set of retinoids and related analogues in terms of thermodynamic stability of conformers and rotational barriers showed that these chemicals tend to be quite flexible. This flexibility, and the observation that relatively small energy differences between conformers can result in significant variations in electronic structure, highlighted the necessity of considering all energetically reasonable conformers in defining common reactivity profiles. The derived reactivity patterns for three different subclasses of the RAR ( f , g , n ) were similar in terms of their global electrophilicity (nucleophilicity) and steric parameters. However, the profile of active chemicals with respect to interaction with the RXR- f differed qualitatively from that of the RARs. Variations in reactivity profiles for the RAR versus RXR families would be consistent with established differences in their affinity for endogenous retinoids, likely reflecting functional differences in the receptors.     

Quantitative prediction of biodegradability,metabolite distribution and toxicity of stable metabolites

An evaluation of the capability of organic chemicals to mineralize is an important factor to consider when assessing their fate in the environment. Microbial degradation can convert a toxic chemical into an innocuous one, and vice versa , or alter the toxicity of a chemical. Moreover, primary biodegradation can convert chemicals into stable products that can be difficult to mineralize. In this paper, we present some new results obtained on the basis of a recently developed probabilistic approach to modeling biodegradation based on microbial transformation pathways. The metabolic transformations and their hierarchy were calibrated by making use of the ready biodegradability data from the MITI-I test and expert knowledge for the most probable transformation pathways. A model was developed and integrated into an expert software system named CATABOL that is able to predict the probability of biodegradation of organic chemicals directly from their structure. CATABOL simulates the effects of microbial enzyme systems, generates the most plausible transformation pathways, and quantitatively predicts the persistence and toxicity of the biodegradation products. A subset of 300 organic chemicals were selected from Canada's Domestic Substances List and subjected to CATABOL to compare predicted properties of the parent chemicals with their respective first stable metabolite. The results show that most of the stable metabolites have a lower acute toxicity to fish and a lower bioaccumulation potential compared to the parent chemicals. In contrast, the metabolites appear to be generally more estrogenic than the parent chemicals.     

A model validation and consensus building environment

Over half of the failures in drug development are due to problems with the absorption, distribution, metabolism, excretion, and toxicity, or ADME/Tox properties of a candidate compound. The utilization of in silico tools to predict ADME/Tox and physicochemical properties holds great potential for reducing the attrition rate in drug research and development, as this technology can prioritize candidate compounds in the pharmaceutical R&D pipeline. However, a major concern surrounding the use of in silico ADME/Tox technology is the reliability of the property predictions. Bio-Rad Laboratories, Inc. has created a computational environment that addresses these concerns. This environment is referred to as KnowItAll®. Within this platform are encoded a number of ADME/Tox predictors, the ability to validate these predictors with/without in-house data and models, as well as build a ‘consensus’ model that may be a much better model than any of the individual predictive model. The KnowItAll® system can handle two types of predictions: real number and categorical classification.     

Interactions between apolar,basic and acidic model oils and a calcite surface

Abstract

In this study, the atomic force microscopy colloidal probe technique was employed to investigate the interaction between apolar, basic and acidic model oil probes and a calcite surface in solutions containing different concentrations of NaCl, CaCl₂ and Na₂SO₄. In the presence of SO₄^2?, hydration and structural forces were observed between apolar model oil probes and a calcite surface on approach. Relatively low adhesion forces were observed between the basic model oil probes and the calcite surface, while higher adhesion forces were observed between the acidic model oil probes and the calcite surface. Furthermore, the adhesion forces between the basic model oil probes and the calcite surface significantly increased in the presence of SO₄^2?, while the adhesion force between the acidic model oil probes and the calcite surface decreased in the presence of Ca²⁺ or SO₄^2?. The differences in the adhesion forces are related to electrostatic attraction and ion bridging forces between the model oil probes and the calcite surface.     

木质素及其模型化合物的加氢脱氧反应研究进展

随着化石能源的不断枯竭,以及所产生的环境问题-温室效应及其高硫含量引起的酸雨,迫使人类寻找新型替代能源.在众多可再生能源中,生物质因其碳中性,易获取,作为唯一可转化为液体燃料的可再生资源,正日益受到重视.全球每年生物质产出高达1.7×1011t,其中,含75%的碳水化合物如纤维素、甲壳素和淀粉,20%木质素,其他占     

带连续变利率风险模型最终破产概率上界

考虑了带二元连续变利息力的Sparre Andersen风险模型.研究了积累值盈余过程的表达式与性质;在利率递增环境下,利用推广后的调节系数方程组与递归技术推导了最终破产概率的上界,结论表明得到的破产概率上界是更为一般的Lundberg指数上界.     

Nature of Alkali- and Coinage-Metal Bonds versus Hydrogen Bonds

We have quantum chemically studied the structure and nature of alkali- and coinage-metal bonds (M-bonds) versus that of hydrogen bonds between A−M and B⁻ in archetypal [A−M⋅⋅⋅B]⁻ model systems (A, B=F, Cl and M=H, Li, Na, Cu, Ag, Au), using relativistic density functional theory at ZORA-BP86-D3/TZ2P. We find that coinage-metal bonds are stronger than alkali-metal bonds which are stronger than the corresponding hydrogen bonds. Our main purpose is to understand how and why the structure, stability and nature of such bonds are affected if the monovalent central atom H of hydrogen bonds is replaced by an isoelectronic alkali- or coinage-metal atom. To this end, we have analyzed the bonds between A−M and B⁻ using the activation strain model, quantitative Kohn-Sham molecular orbital (MO) theory, energy decomposition analysis (EDA), and Voronoi deformation density (VDD) analysis of the charge distribution.     

Study of ozone generation in an atmospheric dielectric barrier discharge reactor

Ozone (O₃) generation in a dielectric barrier discharge (DBD) reactor driven by a pulsed power supply was investigated at atmospheric pressure and room temperature. An O₃ generation efficiency model is established in which discharge power, O₂ concentration, gas flow rate, and volume of the discharge space are included. Constants in the O₃ generation efficiency model were obtained by fitting the model with experiment results. O₃ concentration can be simply calculated from the energy density and initial O₂ concentration. Comparison on O₃ concentrations from calculation with references is given.     

基于GA的主汽温系统内模控制研究

主汽温控制系统是典型的大迟延、大惯性、时变控制系统,一直以来都是火电厂自动控制的难点。为此将内模控制引入主汽温控制系统,并提出采用遗传算法对滤波器参数优化整定,该方法简单易行,相较于传统PID参数整定方法具有一定的优越性。并对内模控制为主控制器的IMC-PI控制系统进行SIMULINK仿真,与PID-PI控制系统进行对比,仿真结果表明IMC-PID控制系统相比于传统PID-P串级控制系统过渡时间短、超调量小、鲁棒性好等特点。其控制效果好于常规串级 PID 控制系统,适用于大迟延、大惯性过程的控制,并且易于在工业上实现。     

A novel graphene nanoribbon field effect transistor with two different gate insulators

In this paper, a novel structure for a dual-gated graphene nanoribbon field-effect transistor (GNRFET) is offered, which combines the advantages of high and low dielectric constants. In the proposed Two Different Insulators GNRFET (TDI-GNRFET), the gate dielectric at the drain side is a material with low dielectric constant to form smaller capacitances, while in the source side, there is a material with high dielectric constant to improve On-current and reduce the leakage current. Simulations are performed based on self-consistent solutions of the Poisson equation coupled with Non-Equilibrium Green's Function (NEGF) formalism in the ballistic regime. We assume a tight-binding Hamiltonian in the mode space representation. The results demonstrate that TDI-GNRFET has lower Off-current, higher On-current and higher transconductance in comparison with conventional low-K GNRFET. Furthermore, using a top-of-the-barrier two-dimensional circuit model, some important circuit parameters are studied. It is found that TDI-GNRFET has smaller capacitances, lower intrinsic delay time and shorter power delay product (PDP) in comparison with high-K GNRFET. Moreover, mobile charge and average velocity are improved in comparison with low dielectric constant GNRFET. The results show that the TDI-GNRFET can provide Drain Induced Barrier Lowering (DIBL) and Subthreshold Swing near their theoretical limits.