计算系统生物学:理论、方法及在药物研发中的应用

计算系统生物学是一个多学科交叉的新兴领域,旨在通过整合海量数据建立其生物系统相互作用的复杂网络。数据的整合和模型的建立需要发展合适的数学方法和软件工具,这也是计算系统生物学的主要任务。生物系统模型有助于从整体上理解生物体的内在功能和特性。同时,生物网络模型在药物研发中的应用也越来越受到制药企业以及新药研发机构的重视,如用于特异性药物作用靶点的预测和药物毒性评估等。该文简要介绍计算系统生物学的常见网络和计算模型,以及建立模型所用的研究方法,并阐述其在建模和分析中的作用及面临的问题和挑战。     

Assay and biological relevance of endogenous histamine and its metabolites: application of microseparation techniques

This review provides an overview of the assay methods used to determine the presence of endogenous histamine (HA) including its metabolites, and also discusses their biological significance. Firstly, this review briefly summarizes the biological significance of HA and its biological pathways. Next, the assay methods with microseparation techniques, such as gas-chromatography (GC), liquid-chromatography (LC), capillary electrophoresis (CE) and capillary electrochromatography (CEC) are looked at from a developmental viewpoint. Finally, the use of these methods, including flow cytometry techniques, for the determination of HA and its metabolites in biological samples, such as blood, urine, brain and cells, is described. The merits and demerits associated with each of these various methods are also discussed, along with their applications.     

A simple method to analyze the similarity of biological sequences based on the fuzzy theory

In this paper, we propose a simple method to analyze the similarity of biological sequences. By taking the average contents of biological sequences and their information entropies as the variables, the fuzzy method is used to cluster them. From the results of application, it finds that the method is relatively easy and rapid. Unlike other methods such as the graphical representation methods, which is usually very complex to compute some invariants of matric derived from graphical representation, our method pays more attention to the information of biological sequences themselves. Especially with the help of the software (SPSS), it seems to be very convenient. Therefore, it may be used to study the new biological sequences such as their evolution relationship and structures.     

定量评价天敌控害功能的生态能学方法

由于昆虫的能量完全来自于寄主,因此昆虫摄入的能量相当于食物的被取食消耗量。生态能量学方法的基本原理就是捕食性天敌完全依靠捕食猎物(害虫)而获取能量。显然,捕食性天敌摄入的能量就相当于为猎物(害虫)的被捕食消耗量,也即是捕食性天敌摄入量等于猎物(害虫)的被捕食消耗量。由此,可通过研究捕食性天敌和害虫种群的能量动态,定量分析捕食性天敌对害虫的控制作用。本文详细论述了生态能量学方法的基本原理、测算方法,并以棉田捕食性瓢虫类捕食作用为例,介绍了该方法的应用,为定量评价天敌的控害作用提供了一种新方法。     

High throughput platform to explore RNA–protein interactomes

RNA binding proteins (RBPs) and RNA interaction is an emerging topic in molecular biology. Many reports showed that such interactions contribute to many cellular processes as well as disease development. Several standard in vitro and in vivo methods were developed to fulfill the needs of this RBP–RNA interaction study to explore their biological functions. However, these methods have their limitations in terms of throughput. In this review, we emphasize two important high throughput methods to studying RBP–RNA interactions, affinity purification and protein microarray. These methods have recently become robust techniques regarding their efficiency in systematically analyzing RBP–RNA interactions. Here, we provide technique overviews, strategies and applications of these methods during biological research. Although these technologies are just beginning to be explored, they will be most important methods in this study.     

真菌内共生细菌研究进展

自真菌内共生细菌在1970年被首次发现以来,各个时期的学者都采用当时流行的研究方法关注宿主真菌及其内共生细菌之间的关联现象。近年来科技手段日益多样,对二者相互作用的探索逐渐成为新的研究热点,随着研究的不断拓展和深入,越来越多的生物学现象和原理被揭示。本文在真菌内共生细菌的研究方法、定殖位置、形态、分类、宿主类群、共生关联的建立、生物学功能、宿主治愈、分离和重新植入等方面进行综述,并在此基础上进行展望,以期为真菌内共生细菌的广泛深入研究提供借鉴。     

A biologically inspired validity measure for comparison of clustering methods over metabolic data sets

In the biological domain, clustering is based on the assumption that genes or metabolites involved in a common biological process are coexpressed/coaccumulated under the control of the same regulatory network. Thus, a detailed inspection of the grouped patterns to verify their memberships to well-known metabolic pathways could be very useful for the evaluation of clusters from a biological perspective. The aim of this work is to propose a novel approach for the comparison of clustering methods over metabolic data sets, including prior biological knowledge about the relation among elements that constitute the clusters. A way of measuring the biological significance of clustering solutions is proposed. This is addressed from the perspective of the usefulness of the clusters to identify those patterns that change in coordination and belong to common pathways of metabolic regulation. The measure summarizes in a compact way the objective analysis of clustering methods, which respects coherence and clusters distribution. It also evaluates the biological internal connections of such clusters considering common pathways. The proposed measure was tested in two biological databases using three clustering methods.     

Fluorescent lipid probes: properties and application

This review is devoted to fluorescent lipid probes: the characteristics of their fluorophores; the main methods of their synthesis; and the potentialities, scope, and limitations of their use in studies of biological systems (cells, membranes and their models, enzymes of lipid metabolism, etc.). Particular attention is paid to the lipid specificity of the probes, i.e., the correspondence of their physicochemical characteristics and behavior in biological systems to those of natural lipids.     

Towards genome-scale structure prediction for transmembrane proteins

In this paper we briefly review some of the recent progress made by ourselves and others in developing methods for predicting the structures of transmembrane proteins from amino acid sequence. Transmembrane proteins are an important class of proteins involved in many diverse biological functions, many of which have great impact in terms of disease mechanism and drug discovery. Despite their biological importance, it has proven very difficult to solve the structures of these proteins by experimental techniques, and so there is a great deal of pressure to develop effective methods for predicting their structure. The methods we discuss range from methods for transmembrane topology prediction to new methods for low resolution folding simulations in a knowledge-based force field. This potential is designed to reproduce the properties of the lipid bilayer. Our eventual aim is to apply these methods in tandem so that useful three-dimensional models can be built for a large fraction of the transmembrane protein domains in whole proteomes.     

酶分子设计常用策略和进展

酶分子的生物学功能很大程度上是由其三维空间结构和所处溶剂环境共同决定的。因此,优化酶分子的结构性质以及探索其性质最优的溶剂环境是改善酶分子功能以及进行理性设计的一个可行途径。从实际应用的角度来看,分子设计方法可以为酶工程提供一种有效的解决方案。目前,酶分子设计有两个重要的研究方向,包括提高酶分子的催化活力和优化其稳定性。同时,对酶分子设计方法的研究也有助于对蛋白质生物学机理的探索。在近些年的学术界酶分子设计案例中,生物信息学方法得到广泛的应用。本文系统地总结基于生物信息学的酶分子设计方法的背景、策略和一些经典案例。     

Biological control of snail-borne diseases: a review

The need for alternatives to chemical control of snail-borne diseases and the growing interest in biological control methods are noted. Two groups of natural enemies of snails reviewed as especially promising for biological control are competing and predatory snails, and predatory fly larvae. Potentially useful natural enemies of the intramolluscan stages of trematodes include microsporidian infections and antagonistic trematode larvae. More unusual methods of biological control include the use of a toxic plant product (endod) and genetic manipulation of snails to decrease their susceptibility to trematode infection. The disappointing progress in biological control of snail-borne diseases in the past is attributed largely to delay in recognizing the need for alternatives to chemical control and to lack of interdisciplinary communication.     

生物人类学和人体组成学的渊源关系

随着人体组成学中文版的发行和人体组成测量培训班在中国的举行, 中国生物人类学家对人体组成测量方法在科研中的运用有了更大的兴趣。该文对人类学家,如Jindr?ich Matiegka和Stanley MarionGarn在人体组成学发展中的历史贡献做了基本的介绍。此外, 作者还以Garn博士的工作为例, 去激励中国生物人类学家开展人体组成学的研究工作。文章讨论了人体组成成分的测量方法在生物人类学中的用途, 并介绍了人体组成学的基本理论和概念及近年来人体组成学的变化: 如影像技术的发展, 影像技术作为"金标准"对评估其他人体组成测量方法的用途, 双能量x线吸收法的优势, 生物电阻分析法的广泛运用, 和多种人体组成测量方法相辅相成的现象。作者对常用的人体组成测量方法的优缺点做了比较, 并指出人体组成成分测量是人体测量方法的自然延续, 人体组成学和生物人类学的关系渊源已久; 因此中国人类学家应当更多地利用人体组成测量方法对人体差异做更深入的研究, 并注重人体差异同健康疾病和生物医学的关系, 以便让生物人类学更好地为当今社会服务。     

Detection and determination of antimalarial drugs and their metabolites in body fluids

This review of methods for determining antimalarial drugs in biological fluids has focused on the various analytical techniques for the assay of chloroquine, quinine, amodiaquine, mefloquine, proguanil, pyrimethamine, sulphadoxine, primaquine and some of their metabolites. The methods for determining antimalarials and their metabolites in biological samples have changed rapidly during the last eight to ten years with the increased use of chromatographic techniques. Chloroquine is still the most used antimalarial drug, and various methods of different complexity exist for the determination of chloroquine and its metabolites in biological fluids. The pharmacokinetics of chloroquine and other antimalarials have been updated using these new methods.The various analytical techniques have been discussed, from simple colorimetric methods of intermediate selectivity and sensitivity to highly sophisticated, selective and sensitive chromatographic methods applied in a modern analytical laboratory. Knowledge concerning the method for a particular study is determined by the type of application and the facilities, equipment and personnel available. Often is it useful to apply various methods when conducting a clinical study in malaria-endemic areas. Field-adapted methods for the analysis of urine samples can be applied at the study site for screening, and corresponding blood samples can be preserved for subsequent analysis in the laboratory. Selecting samples for laboratory analysis is based on clinical, parasitological and field-assay data. The wide array of methods available for chloroquine permit carefully tailored approaches to acquire the necessary analytical information in clinical field studied concerning the use of this drug. The development of additional field-adapted and field-interfaced methods for other commonly used antimalarials will provide similar flexibility in field studies of these drugs.     

Express control of toxic substances and pathogenic microorganisms. Immune analysis and immune sensors

In the review the overall characteristics of biological warfare components, which represent danger to people in the case of their application by military or terrorist groups are discussed. The main part of the review is devoted to modern approaches of antibody obtaining and, in particular, preparation of specific recombinant immunoglobulins as well as to different immune chemical methods of determination of individual toxins and pathogenic microorganisms. A special attention is paid to existing data about the development of rapid, selective, high sensitive, simple and fully automated instrumental methods on the basis of biosensor technology which is designed for the control of components of biological warfare in environmental objects. Additionally industrially manufactured biosensors and their characteristics are given and analyzed.     

Biological methods for speciation of heavy metals: different approaches

Heavy metals are found in their different forms in the environment. The distribution, mobility, and toxicity of metals are strongly related to these different forms. This necessitates the exploration of different methods for the remediation and speciation of heavy metals. Some direct and indirect physico-chemical methods such as filtration, chemical precipitation, ion-exchange, electro deposition, and membrane systems have been used for the last four decades. However, it is only in last few years that reliable biological methods have also been used. The biological methods include the use of microorganisms (fungi, algae, bacteria), plants (live or dead) and biopolymers. The use of these methods for the speciation of heavy metals is reviewed here.     

Separation methods for antiviral phosphorus-containing drugs

Among antiviral drugs, phosphorus-containing compounds, foscarnet and cidofovir, present adverse effects including renal toxicity. Since their main therapeutic target is the treatment of CMV retinitis, which needs lifelong maintenance therapy, accurate analytical methods are required for drug monitoring. According to the high hydrophilic property of the two compounds, ion pair reversed-phase HPLC methods were proposed for their separation in drug formulations and biological samples. Their lack of UV absorption at wavelengths above 205 nm does not allow the use of this detection technique for biological fluids. Electrochemical detection methods (coulometry and amperometry) led to a quantification limit of 15 μM for foscarnet. Fluorescent derivatives obtained by modification of cidofovir cytosine nucleus with α-haloketones offered advantage over UV detection and allowed to reach a detection limit of 5 ng/ml, making possible investigations on the drug time-course in biological fluids.     

History and perspectives of bioanalytical methods for chemical warfare agent detection

This paper provides a short historical overview of the development of bioanalytical methods for chemical warfare (CW) agents and their biological markers of exposure, with a more detailed overview of methods for organophosphorus nerve agents. Bioanalytical methods for unchanged CW agents are used primarily for toxicokinetic/toxicodynamic studies. An important aspect of nerve agent toxicokinetics is the different biological activity and detoxification pathways for enantiomers. CW agents have a relatively short lifetime in the human body, and are hydrolysed, metabolised, or adducted to nucleophilic sites on macromolecules such as proteins and DNA. These provide biological markers of exposure. In the past two decades, metabolites, protein adducts of nerve agents, vesicants and phosgene, and DNA adducts of sulfur and nitrogen mustards, have been identified and characterized. Sensitive analytical methods have been developed for their detection, based mainly on mass spectrometry combined with gas or liquid chromatography. Biological markers for sarin, VX and sulfur mustard have been validated in cases of accidental and deliberate human exposures. The concern for terrorist use of CW agents has stimulated the development of higher throughput analytical methods in support of homeland security.     

Chiral C3 epoxides and halohydrins: Their preparation and synthetic application

Epichlorohydrin, 3-chloro-1,2-propanediol and glycidol are versatile chiral C3 syntons in organic synthesis. For the production of these, more efficient and more practical methods are required and many studies have been reported. In this review, biological and synthetic preparations of their synthons and microbial dehalogenation of halohydrins connected with the biological methods are described. Several of their synthetic applications are also introduced.     

Determining protein–protein functional associations by functional rules based on gene ontology and KEGG pathway

Protein–protein interactions (PPIs) describe the direct physical contact of two proteins that usually results in specific biological functions or regulatory processes. The characterization and study of PPIs through the investigation of their pattern and principle have remained a question in biological studies. Various experimental and computational methods have been used for PPI studies, but most of them are based on the sequence similarity with current validated PPI participators or cellular localization patterns. Most methods ignore the fact that PPIs are defined by their specific biological functions. In this study, we constructed a novel rule-based computational method using gene ontology and KEGG pathway annotation of PPI participators that correspond to the complicated biological effects of PPIs. Our newly presented computational method identified a group of biological functions that are tightly associated with PPIs and provided a new function-based tool for PPI studies in a rule manner.