学生参与实验准备对检验实验教学质量的影响

优质的实验准备是保证检验实验教学质量的关键。学生参与实验准备可有效地提高实验教学质量。探讨实验教学中存在的问题及改革要点，指导学生参与实验的方法和意义，教学研究和尝试表明，学生参与实验准备有助于促进师生交流，从而促使调动积极性，激发实验兴趣，实现提高实验教学质量。     

提高高职药学专业药剂学实验实效性的实践

药剂学是高职药学专业主干专业课程之一，实验教学在整个教学中占有重要地位。对如何提高药剂学实验实效性的方面，通过多年的实践，制定一系列方案：确定实验课程目标，制定药剂学实验基本操作规程，精选实验内容，确立药剂实验考试规程与评分标准等。在实施实验教学过程中，以学生为中心，强化过程控制与成品质量评价、开放化实践教学、对学生进行综合实训等，全面系统培养学生的实验技能，提升药剂学实验教学实效性，取得良好的教学效果。     

谈药剂学实验教学改革

药剂学是药学专业的一门主干专业课，实验教学在整个教学过程中占有非常重要的地位。我们对实验教学进行了改革，优化实验教学内容，改革教学模式，对于小设计实验多以在学生实验报告和实验过程中以讨论的形式体现。尽可能地开放实验室，为学生提供实验场所。并建立综合性实验考核制度，从实验预习报告、实验技能、实验报告与结果、专题设计及其它等五个方面进行考核。     

实验准备在医学微生物学设计性实验教学中的作用

实验教学是培养学生创新意识和创新能力的一个重要手段，在医学微生物学实验教学中如何重新整合教学内容，改革教学方法，开设综合性、设计性甚至探索性实验是我们需要认真研究的课题。我们在2002级医学、麻醉、口腔专业本科微生物学实验教学中抽出约25％的实验学时(10学时)，进行一项设计性实验，并且开放了实验室，进行医学微生物学设计性实验在实验教学改革中的探索新尝试。     

加强实验教学改革不断提高学生的综合素质

实验教学是高等学校培养学生实践能力和创新精神的重要教学环节之一。通过实验教学改革，打破常规的课程框架的实验教学模式，按实验技术归类重组综合性实验教学新模式，开设综合性实验和适当开设部分设计性实验，不断提高学生的综合素质和能力。     

中药化学实验教学改革

为适应培养高素质人才的需要，增强学生分析问题、解决问题的能力，针对中药化学实验教学中存在的问题，对中药化学实验教学内容和方法，作了相应的调整和改革，使学生的创新能力在实验中得到锻炼和培养。     

实验《乙酸乙酯制备》的改进

“乙酸乙酯制备”是有机化学实验中常规的实验项目，也是大多数有机化学实验教材中常见的内容，其反应原理是乙醇和乙酸的混合物在浓硫酸催化作用下进行的酯化反应。通过实验过程，使学生对有机化学实验基本知识加深认识，基本操作、基本技能得到运用和锻炼。在实际工作当中，我发现本实验有可以改进的地方，并且在实验教学当中运用，实验效果明显，降低了实验成本，提高了乙酸乙酯的产率，而且减少了环境污染。     

中药药剂学开放性实验体会

针对实验教学中存在的问题，通过改革传统实验教学方法，结合学校实施的开放式实验教学方案，调动了学生实验积极性，对本科生的科研素质培养有很重要的意义。     

浅谈高校实验课的教学艺术

我们在长期的生物化学实验教学中根据实验教学的本质 ,注重实验教学艺术的关键环节 ,作了如下探讨。1　实验教学准备的艺术做好实验前的准备工作是搞好实验教学的前提。原来的实验准备工作常常是从试剂的配制到仪器的调试乃至仪器的摆放 ,由教师独立完成 ,学生不知其所以然 ,也不必问其所以然。为了在整个实验教学中 ,突出学生的主体地位 ,形成高昂的实验热情 ,我们要求学生 :第一 ,预习实验内容 (可参考其它资料 ) ,明确实验目的 ,了解实验操作步骤、要点、及注意事项 ,书写预习笔记 ,使学生对本次实验有一个较全面的了解 ,做到心中有数 ,…     

学生参与开放性实验的前期调查

为更好地开展开放性实验教学，掌握学生的思想动态，笔者进行了有关开放性实验的认识、教学内容的组织、教学方式的安排、实验成绩的评定等方面的问卷调查，通过分析，发现问题，找出不足，从而制定并完善开放性实验的实施方案。     

Microfluidic technologies in drug discovery

Microfluidic systems are increasingly used as tools in various stages of the drug discovery process. Microscale systems offer several obvious advantages, such as low sample consumption and significantly reduced analysis or experiment time. These technologies raise the possibility of massive parallelization and concomitant reduction in cost per acquired data point. In addition, fluids in confined spaces display unique behaviors that can be used to acquire information not accessible using macroscopic systems. This article will focus on the implementation of microfluidic systems and technologies in the process of drug discovery.     

Structure-based drug discovery and protein targets in the CNS

Structure-based methods are having an increasing role and impact in drug discovery. The crystal structures of an increasing number of therapeutic targets are becoming available. These structures can transform our understanding of how these proteins perform their biological function and often provide insights into the molecular basis of disease. In addition, the structures can help the discovery process. Methods such as virtual screening and experimental fragment screening can provide starting hit compounds for a discovery project. Crystal structures of compounds bound to the protein can direct or guide the medicinal chemistry optimisation to improve drug-like properties - not only providing ideas on how to improve binding affinity or selectivity, but also showing where the compound can be modified in attempting to modulate physico-chemical properties and biological efficacy. The majority of drug discovery projects against globular protein targets now use these methods at some stage.This review provides a summary of the range of structure-based drug discovery methods that are in use and surveys the suitability of the methods for targets currently identified for CNS drugs. Until recently, structure-based discovery was difficult or unknown for these targets. The recent determination of the structures of a number of GPCR proteins, together with the steady increase in structures for other membrane proteins, is opening up the possibility for these structure-based methods to find increased use in drug discovery for CNS diseases and conditions.     

In-depth mutation and SNP discovery using DHPLC gene scanning

Denaturing high-performance liquid chromatography (DHPLC) is a new technology used in the discovery of genetic variations (mutations), such as single-base substitutions (or single nucleotide polymorphisms) and small deletions or insertions. These genetic variations can be routinely detected by DHPLC gene scanning at the germ-line and somatic levels. Epigenetic alterations, such as changes in DNA methylation status at defined loci, can also be assessed using DHPLC-based methodologies. The biological impact of these genetic variations depends on the location and identity of the DNA sequence alteration. The discovery of functionally relevant genetic variations can be exploited throughout the drug discovery and development processes. Examples of the application of DHPLC for sequence variant detection will be presented and discussed, with emphasis on target validation by candidate gene scanning and mutation detection in disease pathway genes, as well as the discovery of therapeutically significant mutations associated with drug metabolism and resistance.     

The future of predictive biosimulation in drug discovery

Biosimulation and mathematical modeling are powerful approaches for characterizing complex biological systems and their dynamic evolution. The modeling process enables research scientists to systematically identify critical gaps in their knowledge and explicitly formulate candidate hypotheses to span them. Biosimulations are being used to explore “what if” scenarios that can lead to recommendations for designing the best, most informative ‘next experiment.’ This targeted approach to assay development, data interpretation and decision making promises to dramatically narrow the ‘predictability gap’ between drug discovery and clinical development.     

Computational Advances for the Development of Allosteric Modulators and Bitopic Ligands in G Protein-Coupled Receptors

Allosteric modulators of G protein-coupled receptors (GPCRs), which target at allosteric sites, have significant advantages against the corresponding orthosteric compounds including higher selectivity, improved chemical tractability or physicochemical properties, and reduced risk of receptor oversensitization. Bitopic ligands of GPCRs target both orthosteric and allosteric sites. Bitopic ligands can improve binding affinity, enhance subtype selectivity, stabilize receptors, and reduce side effects. Discovering allosteric modulators or bitopic ligands for GPCRs has become an emerging research area, in which the design of allosteric modulators is a key step in the detection of bitopic ligands. Radioligand binding and functional assays ([³⁵S]GTPγS and ERK1/2 phosphorylation) are used to test the effects for potential modulators or bitopic ligands. High-throughput screening (HTS) in combination with disulfide trapping and fragment-based screening are used to aid the discovery of the allosteric modulators or bitopic ligands of GPCRs. When used alone, these methods are costly and can often result in too many potential drug targets, including false positives. Alternatively, low-cost and efficient computational approaches are useful in drug discovery of novel allosteric modulators and bitopic ligands to help refine the number of targets and reduce the false-positive rates. This review summarizes the state-of-the-art computational methods for the discovery of modulators and bitopic ligands. The challenges and opportunities for future drug discovery are also discussed.Key words: allosteric modulators, bitopic ligands, computational approaches, drug discovery, drug target discovery, G protein-coupled receptors     

The future of crystallography in drug discovery

Introduction: X-ray crystallography plays an important role in structure-based drug design (SBDD), and accurate analysis of crystal structures of target macromolecules and macromolecule–ligand complexes is critical at all stages. However, whereas there has been significant progress in improving methods of structural biology, particularly in X-ray crystallography, corresponding progress in the development of computational methods (such as in silico high-throughput screening) is still on the horizon. Crystal structures can be overinterpreted and thus bias hypotheses and follow-up experiments. As in any experimental science, the models of macromolecular structures derived from X-ray diffraction data have their limitations, which need to be critically evaluated and well understood for structure-based drug discovery.

Areas covered: This review describes how the validity, accuracy and precision of a protein or nucleic acid structure determined by X-ray crystallography can be evaluated from three different perspectives: i) the nature of the diffraction experiment; ii) the interpretation of an electron density map; and iii) the interpretation of the structural model in terms of function and mechanism. The strategies to optimally exploit a macromolecular structure are also discussed in the context of ‘Big Data' analysis, biochemical experimental design and structure-based drug discovery.

Expert opinion: Although X-ray crystallography is one of the most detailed ‘microscopes' available today for examining macromolecular structures, the authors would like to re-emphasize that such structures are only simplified models of the target macromolecules. The authors also wish to reinforce the idea that a structure should not be thought of as a set of precise coordinates but rather as a framework for generating hypotheses to be explored. Numerous biochemical and biophysical experiments, including new diffraction experiments, can and should be performed to verify or falsify these hypotheses. X-ray crystallography will find its future application in drug discovery by the development of specific tools that would allow realistic interpretation of the outcome coordinates and/or support testing of these hypotheses.     

质谱在蛋白质生物标志物发现中的应用策略

生物标志物是可被客观测量并能用于评价正常生物过程、病理过程及治疗反应的指标。生物标志物的发现是对其研究的第一步，其实质就是筛选出在不同的生物学状态或进程中的差异化物质。在这一阶段中，分析策略所考虑的重点是高通量化和定性(和/或半定量)性能。目前，生物标志物研究的热点已转移至蛋白质层面上。在蛋白质生物标志物的发现中，质谱以不同的策略和方式得到了广泛的应用，并仍在不断进步中。本文对蛋白质生物标志物的发现过程中常用的及新型的质谱应用策略进行了归纳阐述。     

An intravenous formulation decision tree for discovery compound formulation development

Discovery and pre-clinical animal efficacy assessment formulation development efforts are challenged by limited compound availability and stringent timelines. The implementation and use of a systematic discovery formulation scheme can facilitate this important process. We observed that nearly 85% of Pfizer, Ann Arbor discovery compounds (n>300) submitted for discovery and pre-clinical injectable formulation development in the year 2000 could be formulated by pH adjustment, cosolvent addition, or a combination of the two approaches. Based on the vehicle data generated by this laboratory, a discovery formulation decision tree, that utilizes the solubilization approaches described above, is proposed. The proposed decision tree can be adapted and modified by pharmaceutical scientists to conform to best practices put forth by their institutions for discovery animal studies requiring injectable dosage forms.     

A behavioural and pharmacological examination of phenylethylamine-induced anorexia and hyperactivity--comparisons with amphetamine

The discovery that trace amine beta-phenylethylamine (PEA) has a number of properties in common with amphetamine (AMPH) has led to the suggestion that PEA may be a neuromodulator of catecholamine release or an "endogenous amphetamine." The present study compared PEA-induced behavioural changes (anorexia and hyperactivity) with AMPH-induced changes in feeding and motor activity. The first experiment examined the effects of PEA (0-35 mg/kg) on the temporal profile of feeding. The results from this experiment revealed important differences between the effects of PEA as compared with AMPH, in particular PEA failed to increase the rate of eating that is characteristic of AMPH-induced anorexia. The second experiment concurrently measured food intake and motor activity following equi-anorectic doses of PEA and AMPH and pretreatment with the neuroleptic pimozide. Pimozide attenuated PEA-induced hyperactivity, AMPH-induced hyperactivity and AMPH-induced anorexia, but failed to attenuate PEA-induced anorexia. These findings are discussed in relation to the possible mechanisms of action of PEA and AMPH.     

Potential biological targets for bioassay development in drug discovery of Sturge–Weber syndrome

Sturge–Weber Syndrome (SWS) is a neurocutaneous disease with clinical manifestations including ocular (glaucoma), cutaneous (port‐wine birthmark), neurologic (seizures), and vascular problems. Molecular mechanisms of SWS pathogenesis are initiated by the somatic mutation in GNAQ. Therefore, no definite treatments exist for SWS and treatment options only mitigate the intensity of its clinical manifestations. Biological assay design for drug discovery against this syndrome demands comprehensive knowledge on mechanisms which are involved in its pathogenesis. By analysis of the interrelated molecular targets of SWS, some in vitro bioassay systems can be allotted for drug screening against its progression. Development of such platforms of bioassay can bring along the implementation of high‐throughput screening of natural or synthetic compounds in drug discovery programs. Regarding the fact that study of molecular targets and their integration in biological assay design can facilitate the process of effective drug discovery; some potential biological targets and their respective biological assay for SWS drug discovery are propounded in this review. For this purpose, some biological targets for SWS drug discovery such as acetylcholinesterase, alkaline phosphatase, GABAergic receptors, Hypoxia‐Inducible Factor (HIF)‐1α and 2α are suggested.