高通量筛选技术在农用杀菌剂创制研究中的应用

高通量筛选技术是发现创新药物的重要技术手段之一,在医药研究领域已经得到了广泛的应用,但在农药研究领域还处于初始阶段。综述了近年来高通量筛选技术在农用杀菌剂创制中的应用,并展望了其发展前景。     

No time to lose--high throughput screening to assess nanomaterial safety

Nanomaterials hold great promise for medical, technological and economical benefits. Knowledge concerning the toxicological properties of these novel materials is typically lacking. At the same time, it is becoming evident that some nanomaterials could have a toxic potential in humans and the environment. Animal based systems lack the needed capacity to cope with the abundance of novel nanomaterials being produced, and thus we have to employ in vitro methods with high throughput to manage the rush logistically and use high content readouts wherever needed in order to gain more depth of information. Towards this end, high throughput screening (HTS) and high content screening (HCS) approaches can be used to speed up the safety analysis on a scale that commensurate with the rate of expansion of new materials and new properties. The insights gained from HTS/HCS should aid in our understanding of the tenets of nanomaterial hazard at biological level as well as assist the development of safe-by-design approaches. This review aims to provide a comprehensive introduction to the HTS/HCS methodology employed for safety assessment of engineered nanomaterials (ENMs), including data analysis and prediction of potentially hazardous material properties. Given the current pace of nanomaterial development, HTS/HCS is a potentially effective means of keeping up with the rapid progress in this field--we have literally no time to lose.     

Druggability Assessment for Selected Serine Proteases in a Pharmaceutical Industry Setting

Target druggability assessment is an integral part of the early target characterization and selection process in pharmaceutical industry. Here, we investigate a set of five different serine proteases from the blood coagulation cascade. The aim of this study is twofold. Firstly, leveraging the wealth of available in-house high-throughput screening (HTS) data, we analyze HTS hit rates and discuss their predictive value for the development of small molecule (SMOL) candidates. Purely structure-activity relationship (SAR) based druggability ratings are compared with computational protein-structure based druggability assessments. Secondly, we evaluate the impact of using conformational ensembles from molecular dynamics (MD) simulations instead of single static crystal structures as basis for computational druggability assessments. Based on this study, we recommend incorporating molecular dynamics routinely into the early target characterization process, especially if only a single X-ray structure is available.     

Improving the thermal stability of polysulfidic crosslinks by hexamethylene-1, 6-bis(thiosulfate) disodium salt as the curing agent of natural rubber

When vulcanized with sulfur, the natural rubber (NR) usually accompanies reversion, and the proportion of polysulfidic crosslinks decreases considerably, leading to significantly performance decay. In the rubber industry, hexamethylene-1, 6-bis(thiosulfate) disodium salt (HTS) is used as a multifunctional agent to improve not only the reversion and fatigue properties of NR, but also the adhesive properties between NR and steel cords. However, there is few research about the working mechanism of HTS. In this work, HTS is added to belt compounds in doses of 0 to 5 phr. The cure characteristics, crosslinking structures, physical-mechanical properties, dynamic viscoelastic behavior, and T-pull adhesion forces of the NR composites are investigated. The results show that the total crosslinking density and T-pull adhesion forces of the composites both pass through a maximum and then decrease with the increasing dosage of HTS. Meanwhile, the formation of hybrid crosslinks during the prolonged cure time enhances the thermal stability and retention of the polysulfidic crosslinks of the NR composites. Surprisingly, the reduction in the proportion of polysulfidic crosslinks from optimum cure time (Tc₉₀) to 60 min just reaches 15.9% with the addition of 5 phr HTS, whereas that value is 30.9% without adding HTS, which shows the excellent antireversion ability of the HTS in the belt compound. Our work reveals some new features of HTS, which can lead to a more profound understanding of HTS.     

钛硅分子筛的改性对环己烷氧化反应的影响

使用不同改性液H_2SO_4-H_2O_2、(NH_4)_2CO_3-H_2O_2、(NH_4)HF_2-H_2O_2和(NH_4)_2CO_3+(NH_4)HF_2-H_2O_2混合溶液对中空钛硅分子筛进行改性。采用XRD、UV-Vis和拉曼光谱进行表征分析,考察改性前后钛硅分子筛在环己烷氧化反应的催化性能。结果表明,改性过程没有破坏钛硅分子筛的MFI拓扑结构,但提高了钛硅分子筛相对结晶度,并脱除了部分锐钛矿相TiO_2;与未改性钛硅分子筛相比,环己醇和环己酮选择性及H_2O_2有效利用率明显提高,以改性液(NH_4)_2CO_3+(NH_4)HF_2-H_2O_2改性钛硅分子筛效果最佳,醇酮选择性提高12.78个百分点,H_2O_2有效利用率提高17.33个百分点;(NH_4)_2CO_3+(NH_4)HF_2-H_2O_2混合溶液改性钛硅分子筛显著降低H_2O_2用量,在己内酰胺生产过程中有很好的应用前景。     

A Review of the Influence of Grain Boundary Geometry on the Electromagnetic Properties of Polycrystalline YBa2Cu3O7−x Films

Shortly after the discovery of high-temperature superconducting (HTS) materials in the late 1980s, it was revealed that grain boundaries in these complex oxides are strong barriers to current flow. This fact has remained one of the most significant challenges to a viable HTS conductor, and necessitated the development of technologies capable of producing biaxially textured substrates in long lengths. Multiple studies have reported that the critical current density ( J _c) across grain boundaries in the perovskite-like superconductor YBa₂Cu₃O_{7− x} (YBCO) falls off exponentially below the intragrain J _c beyond a critical misorientation angle θ_c of only ≈2°–3°. Here we review our recent work demonstrating that certain grain boundary geometries permit significant enhancements of J _c well beyond the conventional J _c(θ) limit, and also that the grain boundary structure in YBCO films is tied closely to the films' deposition technique. Pulsed laser deposition, a physical vapor deposition technique, results in a columnar grain structure and planar grain boundaries that exhibit the typical J _c(θ) dependence. Ex situ growth processes, where the YBCO film is converted from a previously deposited precursor, can result in laminar grain growth with highly meandered grain boundaries. These latter grain boundary structures are directly correlated to greatly improved J _c values over a wide range of applied magnetic fields. Consequently, very high J _c values are possible in polycrystalline HTS wire even when significant misorientations between grains are present.     

Effect of reaction temperature on CVD-made TiO2 primary particle diameter

The effect of chemical reaction rate on the generation of titania nanoparticles by chemical vapor deposition using two different precursors was investigated by FTIR, XRD, and microscopy. The size of the primary particle exhibited a minimum with increasing reactor temperature. At lower reaction temperatures, the continuous and gradual formation of titania monomers occurred followed by coagulation and/or surface reaction on the existing particles. In addition, unreacted precursor condensed at the reactor exit. As the reaction temperature increased, the rate of monomer production increased, the dominant characteristics of particle growth were coagulation and sintering. The reactor temperature where the minimum primary particle diameter was produced was different for the two precursors due to differences in chemical reaction rates. Phase composition as well as the primary particle diameter of product titania were affected by the chemical reaction rate. Particle-laden reactor wall enhanced the precursor conversion at low reactor temperatures, where surface reactions compete effectively with gas-phase precursor conversion.     

Adaptation of high-throughput screening in drug discovery-toxicological screening tests

High-throughput screening (HTS) is one of the newest techniques used in drug design and may be applied in biological and chemical sciences. This method, due to utilization of robots, detectors and software that regulate the whole process, enables a series of analyses of chemical compounds to be conducted in a short time and the affinity of biological structures which is often related to toxicity to be defined. Since 2008 we have implemented the automation of this technique and as a consequence, the possibility to examine 100,000 compounds per day. The HTS method is more frequently utilized in conjunction with analytical techniques such as NMR or coupled methods e.g., LC-MS/MS. Series of studies enable the establishment of the rate of affinity for targets or the level of toxicity. Moreover, researches are conducted concerning conjugation of nanoparticles with drugs and the determination of the toxicity of such structures. For these purposes there are frequently used cell lines. Due to the miniaturization of all systems, it is possible to examine the compound's toxicity having only 1-3 mg of this compound. Determination of cytotoxicity in this way leads to a significant decrease in the expenditure and to a reduction in the length of the study.     

统计学方法处理RNA干扰文库的高通量筛选实验数据

RNA干扰是真核生物中普遍存在的基因转录后水平调控机制,已成为基因治疗的重要手段。RNA干扰文库的高通量筛选实现了对大量预测的药物靶点的快速筛选,在现代药物开发中起到重要作用。尽管这种高新技术的存在,对于高通量筛选产生的大量数据的处理仍然依赖于简单的数据统计和基本的统计学分析,易忽视筛选过程的系统性和随机性误差,从而对最终筛选结果的鉴定产生影响。文章提出一个完整的高通量筛选数据处理流程,并讨论各个阶段可供选择的基于现代统计学数据分析的方法。     

球形和圆柱形变换催化剂宏观活性评价新方法

运用“ 催化反应单元” 概念提出了球形私圆柱形变换催化剂的宏观活性评价新方法, 即催化剂分层整齐排列各粒、各层间填充细小惰性颗粒的排列方式和消除了内外扩散影响的反应器结构以这种方法所做的活性评价试验结果置信度高, 其二级反应速率常数k_T有解析解, 可以此作为变换催化剂宏观活性评价标准与催化剂的填充层数无关.     

Preliminary experiments on metallisation of ceramic oxide superconductors

Abstract

The present paper briefly reports on preliminary experiments on two new methods for the metallisation of ceramic oxide high temperature superconductors )HTS compounds): sinter-permeate silver and chemically precipitated silver. By using well characterised HTS samples for the measurement of superconducting properties it is shown that successful metallisation and jointing were obtained. The two methods are considered to have potential for further development and application in this field.     

制备与使用条件对中变催化剂性能的影响

本文讨论了铁铬系中变催化剂在空气升温过程中超温现象的原因、制备过程中残存低价铁与高价铬对催化剂性能的影响以及提高铁铬系催化剂还原态强度的途径。     

Characterization and carbonylic hydrogenation of methyl oleate over Ru-Sn/Al2O3: Effects of metal precursor and chlorine removal

Hydrogenation of methyl oleate to oleyl alcohol was evaluated over Ru-Sn/Al₂O₃ catalysts, prepared from different precursors, at 270 °C and 5.0 MPa. Two kinds of metal precursors were employed: chlorine-free precursors and inorganic chlorides. In addition, several methods for chlorine removal of metal-chloride-based catalysts were studied. Catalysts were characterized by EDX, XRF, DRX, BET and TPR analyses. Selectivity toward unsaturated alcohol was higher with the bimetallic catalyst based on chlorine-free precursors than with the catalyst based on metal chlorides, owing that chlorine avoids, at certain extent, an effective interaction between ruthenium and tin species. However, the most selective catalyst was the bimetallic one based on chloride precursors and reduced with NaBH₄, due to elimination of residual chlorine and higher dispersion of Ru-Sn species.     

基于Co(Ⅱ)配合物前驱体的微纳米Co_3O_4功能材料的研究进展

金属有机骨架化合物(MOFs)是由有机配体和金属节点通过自组装形成的一类具有周期性结构和较大比表面积的材料。目前,选择MOFs材料作为前驱体,经高温焙烧合成纳米金属氧化物或纳米复合金属氧化物材料是一大研究热点。综述了近年来以Co基配位聚合物为前驱体制备纳米Co_3O_4或Co_3O_4/碳纳米复合材料的方法,以及Co_3O_4纳米材料在锂离子电池负极材料、超级电容器、电催化析氧反应、气敏材料及催化剂材料等研究领域的应用,并对其今后的发展进行了展望。     

Nicotinamide Phosphoribosyltransferase as a Key Molecule of the Aging/Senescence Process

Aging is a phenomenon underlined by complex molecular and biochemical changes that occur over time. One of the metabolites that is gaining strong research interest is nicotinamide adenine dinucleotide, NAD⁺, whose cellular level has been shown to decrease with age in various tissues of model animals and humans. Administration of NAD⁺ precursors, nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR), to supplement NAD⁺ production through the NAD⁺ salvage pathway has been demonstrated to slow down aging processes in mice. Therefore, NAD⁺ is a critical metabolite now understood to mitigate age-related tissue function decline and prevent age-related diseases in aging animals. In human clinical trials, administration of NAD⁺ precursors to the elderly is being used to address systemic age-associated physiological decline. Among NAD⁺ biosynthesis pathways in mammals, the NAD⁺ salvage pathway is the dominant pathway in most of tissues, and NAMPT is the rate limiting enzyme of this pathway. However, only a few activators of NAMPT, which are supposed to increase NAD⁺, have been developed so far. In this review, we will focus on the importance of NAD⁺ and the possible application of an activator of NAMPT to promote successive aging.     

Synthesis and pyrolysis of non-oxide precursors for ZrC/SiC and HfC/SiC composite ceramics

Multiphase ceramics like ZrC/SiC are promising candidates as ultra-high temperature ceramics for applications in extreme environments. In this work, non-oxide precursors for ZrC/SiC and HfC/SiC composite ceramics were synthesized by a one-pot reaction of three components – metal source, silicon source, and activating reagent. Molecular structures of the precursors were identified by ¹H NMR and FTIR. Transformation process of the precursors to the ZrC/SiC ceramics was investigated via XRD and SEM. After heat-treatment at 1600 °C under argon, the obtained ZrC/SiC and HfC/SiC ceramics features a particle size of 100–200 nm and high metal content without excess carbon. The elemental composition of pyrolyzed ceramics can be tuned by varying the ratio of the reagents in the synthesis of precursors. This strategy also inspires a facile fabrication of composite ceramics with other elemental compositions.     

A High-Throughput Screening Method for the Directed Evolution of Hydroxynitrile Lyase towards Cyanohydrin Synthesis

Chiral cyanohydrins are useful intermediates in the pharmaceutical and agricultural industries. In nature, hydroxynitrile lyases (HNLs) are a kind of elegant tool for enantioselective hydrocyanation of carbonyl compounds. However, currently available methods for demonstrating hydrocyanation are still stalled at precise, but low-throughput, GC or HPLC analyses. Herein, we report a chromogenic high-throughput screening (HTS) method that is feasible for the cyanohydrin synthesis reaction. This method was highly anti-interference and sensitive, and could be used to directly profile the substrate scope of HNLs either in cell-free extract or fermentation clear broth. This HTS method was also validated by generating new variants of PcHNL5 that presented higher catalytic efficiency and stronger acidic tolerance in variant libraries.     

In situ synthesis of organic–inorganic hybrids or nanocomposites from sol–gel chemistry in molten polymers

This survey is dedicated to the synthesis of nanocomposites and organic–inorganic hybrids from sol–gel chemistry under polymer processing. Depending on the nature and reactivity of the inorganic precursors as well as the processing parameters, different types of filler and functionality can be created. These points are discussed for the in situ synthesis of silica and titanium oxide. The influence of the nature of the polymer matrix, its affinity with the initial inorganic precursors or the inorganic phase during growth is evidenced in the case of the study of polyamide/silica composites. In addition, other parameters, such as the addition of water during polymer processing, are shown to increase the rate of the conversion of the hydrolysis–condensation reactions of the inorganic precursor, and thereby affect the final morphology. Another important finding of this survey demonstrate the potential for in situ synthesis of functional nanofillers using appropriate inorganic precursors. This represents a new and original way to prepare new polymer materials with functionalities relevant to a number of applications, such as optical, mechanical reinforcement, fire retardancy and biocide properties.     

Design and Nanofabrication of Superconductor Ceramic Strands and Customized Leads

We made possible an engineering application of the 18-year-old Nobel Prize-winning discovery of High Temperature Superconductor (HTS) ceramic particles. Guided by certain theories of physics and nano-science, we created the ceramic-silicone nanofabrication method where a silicone additive controls both the nanostructural evolution of the magnetically oriented HTS ceramic nano-grains by a 3D polymeric matrix scaffold and thermally induced nano-phase transformation. These result in the sintered granular superconductor ceramic composite material with the desirable superconducting nano-phase composition and 3D nanostructure including vortex-pinning network. The prototype HTS samples were nanofabricated in the form of adhesion substrate coated strands or surfaces or variously shaped bulk leads.     

Managing laboratory automation: integration and informatics in drug discovery

Drug discovery today requires the focused use of laboratory automation and other resources in combinatorial chemistry and high-throughput screening (HTS). The ultimate value of both combinatorial chemistry and HTS technologies and the lasting impact they will have on the drug discovery process is a chapter that remains to be written. Central to their success and impact is how well they are integrated with each other and with the rest of the drug discovery processes-informatics is key to this success. This presentation focuses on informatics and the integration of the disciplines of combinatorial chemistry and HTS in modern drug discovery. Examples from experiences at Neurogen from the last five years are described.