目的:应用计算机系统生物学方法预测生脉散的分子靶标,并为生脉散的分子机制提供线索。方法:采用TCMGeneDIT数据库系统,文本挖掘人参、麦冬、五味子各自所能影响的基因或蛋白质数据;收集生脉散中五味子醇甲、五味子醇乙、戈米辛D、五味...目的:应用计算机系统生物学方法预测生脉散的分子靶标,并为生脉散的分子机制提供线索。方法:采用TCMGeneDIT数据库系统,文本挖掘人参、麦冬、五味子各自所能影响的基因或蛋白质数据;收集生脉散中五味子醇甲、五味子醇乙、戈米辛D、五味子乙素、γ-五味子素、20(S)-人参皂苷Rh、人参皂苷Rk3等14种血中移行成分,采用Accelrys公司Discovery Studio 2.5版完成分子构建,并上载至PharmMapper服务器进行靶标预测;从BIND,BioGRID,DIP,HPRD,IntAct,MINT等分子相互作用数据库中收集与预测靶标有直接相互作用的蛋白质,进行综合分析。结果:已有的实验发现,五味子有10个血中移行成分,人参只有4个血中移行成分;人参与55个基因相关,五味子与1个基因相关,没有基因与麦冬相关。人参的4种血中移行成分不但可直接作用于实验证实的靶标,还能影响相关靶标发挥广泛的生物学效应。五味子的10种血中移行成分只能通过影响相关靶标而发挥间接的治疗作用。结论:结果可为生脉散的后续研究提供有用的线索,促进生脉散的分子作用机制研究,为中药复方的系统研究提供参考。展开更多
Stoichiometry-based analyses of meta- bolic networks have aroused significant interest of systems biology researchers in recent years. It is necessary to develop a more convenient modeling platform on which users can ...Stoichiometry-based analyses of meta- bolic networks have aroused significant interest of systems biology researchers in recent years. It is necessary to develop a more convenient modeling platform on which users can reconstruct their network models using completely graphical operations, and explore them with powerful analyzing modules to get a better understanding of the properties of metabolic systems. Herein, an in silico platform, FluxExplorer, for metabolic modeling and analyses based on stoichiometry has been developed as a publicly available tool for systems biology research. This platform integrates various analytic approaches, in- cluding flux balance analysis, minimization of meta- bolic adjustment, extreme pathways analysis, shadow prices analysis, and singular value decom- position, providing a thorough characterization of the metabolic system. Using a graphic modeling process, metabolic networks can be reconstructed and modi- fied intuitively and conveniently. The inconsistencies of a model with respect to the FBA principles can be proved automatically. In addition, this platform sup- ports systems biology markup language (SBML). FluxExplorer has been applied to rebuild a metabolic network in mammalian mitochondria, producing meaningful results. Generally, it is a powerful and very convenient tool for metabolic network modeling and analysis.展开更多
This research provides, to the authors’ knowledge, the first integrative model of oxidative stress and C1 metabolism in plants. Increased oxidative stress can cause irreversible damage to photosynthetic components an...This research provides, to the authors’ knowledge, the first integrative model of oxidative stress and C1 metabolism in plants. Increased oxidative stress can cause irreversible damage to photosynthetic components and is harmful to plants. Perturbations at the genetic level may increase oxidative stress and upregulate antioxidant systems in plants. One of the key mechanisms involved in oxidative stress regulation is the ascorbate-glutathione cycle which operates in chloroplasts as well as the mitochondria and is responsible for removal of reactive oxygen species (ROS) generated during photosynthetic operations and respiration. In this research, the complexity of molecular pathway systems of oxidative stress is modeled and then integrated with a previously developed in silico model of C1 metabolism system. This molecular systems integration provides two important results: 1) demonstration of the scalability of the CytoSolve®?Collaboratory™, a computational systems biology platform that allows for modular integration of molecular pathway models, by coupling the in silico model of oxidative stress with the in silico model of C1 metabolism, and 2) derivation of new insights on the effects of oxidative stress on C1 metabolism relative to formaldehyde (HCHO), a toxic molecule, and glutathione (GSH), an important indicator of oxidative homeostasis in living systems. Previous in silico modeling of C1 metabolism, without oxidative stress, observed complete removal of formaldehyde via formaldehyde detoxification pathway and no change in glutathione concentrations. The results from this research of integrative oxidative stress with C1 metabolism, however, demonstrate significant upregulation of formaldehyde concentrations, with concomitant downregulation and depletion of glutathione. Sensitivity analysis indicates that kGSH-HCHO, the rate constant of GSH-HCHO binding, VSHMT, the rate of formation of sarcosine from glycine, and , the rate of superoxide formation significantly affect formaldehyde homeostasis in the 展开更多
An integrative computational, in silico, model of C1 metabolism is developed from molecular pathway systems identified from a recent, comprehensive systematic bioinformatics review of C1 metabolism. C1 metabolism is e...An integrative computational, in silico, model of C1 metabolism is developed from molecular pathway systems identified from a recent, comprehensive systematic bioinformatics review of C1 metabolism. C1 metabolism is essential for all organisms to provide one-carbon units for methylation and other types of modifications, as well as for nucleic acid, amino acid, and other biomolecule syntheses. C1 metabolism consists of three important molecular pathway systems: 1) methionine biosynthesis, 2) methylation cycle, and 3) formaldehyde detoxification. Each of the three molecular pathway systems is individually modeled using the CytoSolve?? Collaboratory?, a proven and scalable computational systems biology platform for in silico modeling of complex molecular pathway systems. The individual models predict the temporal behavior of formaldehyde, formate, sarcosine, glutathione (GSH), and many other key biomolecules involved in C1 metabolism, which may be hard to measure experimentally. The individual models are then coupled and integrated dynamically using CytoSolve to produce, to the authors’ knowledge, the first comprehensive computational model of C1 metabolism. In silico modeling of the individual and integrated C1 metabolism models enables the identification of the most sensitive parameters involved in the detoxification of formaldehyde. This integrative model of C1 metabolism, giving its systems-based nature, can likely serve as a platform for: 1) generalized research and study of C1 metabolism, 2) hypothesis generation that motivates focused and specific in vitro and in vivo testing in perhaps a more efficient manner, 3) expanding a systems biology understanding of plant bio-molecular systems by integrating other known molecular pathway systems associated with C1 metabolism, and 4) exploring and testing the potential effects of exogenous inputs on the C1 metabolism system.展开更多
The complex mechanisms of the internal operation of cellular functions have not been fully resolved and these functions are regulated by multiple effects,such as transcription regulation,signal transduction,and enzyme...The complex mechanisms of the internal operation of cellular functions have not been fully resolved and these functions are regulated by multiple effects,such as transcription regulation,signal transduction,and enzyme catalysis,forming complex interactive mechanisms.This makes the construction of a whole-cell computational model,containing various complex cellular functions,very challenging.However,biological models have played a significant role in the field of systems biology,such as guiding gene-target mining and studying cell metabolic characteristics.Therefore,there is increasing research interest in the construction of whole-cell computational models.Combining two classical languages of systems biology,this review expounds on the development and challenges of whole-cell computational modeling from the two classical methods of steady-state and dynamic modeling.Finally,we propose a new approach for constructing whole-cell computational models.展开更多
Recent trend on biological data at a molecular level is omics data analysis for both bulk and single cells, in eluding genomics, proteomics, metabolomics, and epigenetics data (Wang and Zhang, 2017;Zhang et al., 2017;...Recent trend on biological data at a molecular level is omics data analysis for both bulk and single cells, in eluding genomics, proteomics, metabolomics, and epigenetics data (Wang and Zhang, 2017;Zhang et al., 2017;Zhao and Li, 2017;Cheng and Leung, 2018). Rapid accumulation of such high-dimensional biological data is driving the system-level study from describing complex phenomena to understanding molecular mechanisms (Park et al., 2018;Sun et al., 2018) and from analyzi ng in dividual components to understanding their networks and systems (Chen et al., 2009;Chen, 2017).展开更多
Microorganisms have been the main sources for the production of chemicals.Production of chemicals requires the development of low-cost and higher-yield processes.Towards this goal,microbial strains with higher levels ...Microorganisms have been the main sources for the production of chemicals.Production of chemicals requires the development of low-cost and higher-yield processes.Towards this goal,microbial strains with higher levels of production should be first considered.Metabolic engineering has been used extensively over the past two to three decades to increase production of these chemicals.Advances in omics technology and computational simulation are allowing us to perform metabolic engineering at the systems level.By combining the results of omics analyses and computational simulation,systems biology allows us to understand cellular physiology and characteristics,which can subsequently be used for designing strategies.Here,we review the current status of metabolic engineering based on systems biology for chemical production and discuss future prospects.展开更多
A model of a hypertorus communication grid has been constructed in the form of an infinite Petri net. A grid cell represents either a packet switching device or a bioplast cell. A parametric expression is obtained to ...A model of a hypertorus communication grid has been constructed in the form of an infinite Petri net. A grid cell represents either a packet switching device or a bioplast cell. A parametric expression is obtained to allow a finite specification of an infinite Petri net. To prove properties of an ideal communication protocol, we derive an infinite Diophantine system of equations from it, which is subsequently solved. Then we present the programs htgen and ht-mcrl2-gen, developed in the C language, which generate Petri net and process algebra models of a hypertorus with a given number of dimensions and grid size. These are the inputs for the respective modeling tools Tina and mCRL2, which provide model visualization, step simulation, state space generation and reduction, and structural analysis techniques. Benchmarks to compare the two approaches are obtained. An ad-hoc induction-like technique on invariants,obtained for a series of generated models, allows the calculation of a solution of the Diophantine system in a parametric form.It is proven that the basic solutions of the infinite system have been found and that the infinite Petri net is bounded and conservative. Some remarks regarding liveness and liveness enforcing techniques are also presented.展开更多
文摘目的:应用计算机系统生物学方法预测生脉散的分子靶标,并为生脉散的分子机制提供线索。方法:采用TCMGeneDIT数据库系统,文本挖掘人参、麦冬、五味子各自所能影响的基因或蛋白质数据;收集生脉散中五味子醇甲、五味子醇乙、戈米辛D、五味子乙素、γ-五味子素、20(S)-人参皂苷Rh、人参皂苷Rk3等14种血中移行成分,采用Accelrys公司Discovery Studio 2.5版完成分子构建,并上载至PharmMapper服务器进行靶标预测;从BIND,BioGRID,DIP,HPRD,IntAct,MINT等分子相互作用数据库中收集与预测靶标有直接相互作用的蛋白质,进行综合分析。结果:已有的实验发现,五味子有10个血中移行成分,人参只有4个血中移行成分;人参与55个基因相关,五味子与1个基因相关,没有基因与麦冬相关。人参的4种血中移行成分不但可直接作用于实验证实的靶标,还能影响相关靶标发挥广泛的生物学效应。五味子的10种血中移行成分只能通过影响相关靶标而发挥间接的治疗作用。结论:结果可为生脉散的后续研究提供有用的线索,促进生脉散的分子作用机制研究,为中药复方的系统研究提供参考。
文摘Stoichiometry-based analyses of meta- bolic networks have aroused significant interest of systems biology researchers in recent years. It is necessary to develop a more convenient modeling platform on which users can reconstruct their network models using completely graphical operations, and explore them with powerful analyzing modules to get a better understanding of the properties of metabolic systems. Herein, an in silico platform, FluxExplorer, for metabolic modeling and analyses based on stoichiometry has been developed as a publicly available tool for systems biology research. This platform integrates various analytic approaches, in- cluding flux balance analysis, minimization of meta- bolic adjustment, extreme pathways analysis, shadow prices analysis, and singular value decom- position, providing a thorough characterization of the metabolic system. Using a graphic modeling process, metabolic networks can be reconstructed and modi- fied intuitively and conveniently. The inconsistencies of a model with respect to the FBA principles can be proved automatically. In addition, this platform sup- ports systems biology markup language (SBML). FluxExplorer has been applied to rebuild a metabolic network in mammalian mitochondria, producing meaningful results. Generally, it is a powerful and very convenient tool for metabolic network modeling and analysis.
文摘This research provides, to the authors’ knowledge, the first integrative model of oxidative stress and C1 metabolism in plants. Increased oxidative stress can cause irreversible damage to photosynthetic components and is harmful to plants. Perturbations at the genetic level may increase oxidative stress and upregulate antioxidant systems in plants. One of the key mechanisms involved in oxidative stress regulation is the ascorbate-glutathione cycle which operates in chloroplasts as well as the mitochondria and is responsible for removal of reactive oxygen species (ROS) generated during photosynthetic operations and respiration. In this research, the complexity of molecular pathway systems of oxidative stress is modeled and then integrated with a previously developed in silico model of C1 metabolism system. This molecular systems integration provides two important results: 1) demonstration of the scalability of the CytoSolve®?Collaboratory™, a computational systems biology platform that allows for modular integration of molecular pathway models, by coupling the in silico model of oxidative stress with the in silico model of C1 metabolism, and 2) derivation of new insights on the effects of oxidative stress on C1 metabolism relative to formaldehyde (HCHO), a toxic molecule, and glutathione (GSH), an important indicator of oxidative homeostasis in living systems. Previous in silico modeling of C1 metabolism, without oxidative stress, observed complete removal of formaldehyde via formaldehyde detoxification pathway and no change in glutathione concentrations. The results from this research of integrative oxidative stress with C1 metabolism, however, demonstrate significant upregulation of formaldehyde concentrations, with concomitant downregulation and depletion of glutathione. Sensitivity analysis indicates that kGSH-HCHO, the rate constant of GSH-HCHO binding, VSHMT, the rate of formation of sarcosine from glycine, and , the rate of superoxide formation significantly affect formaldehyde homeostasis in the
文摘An integrative computational, in silico, model of C1 metabolism is developed from molecular pathway systems identified from a recent, comprehensive systematic bioinformatics review of C1 metabolism. C1 metabolism is essential for all organisms to provide one-carbon units for methylation and other types of modifications, as well as for nucleic acid, amino acid, and other biomolecule syntheses. C1 metabolism consists of three important molecular pathway systems: 1) methionine biosynthesis, 2) methylation cycle, and 3) formaldehyde detoxification. Each of the three molecular pathway systems is individually modeled using the CytoSolve?? Collaboratory?, a proven and scalable computational systems biology platform for in silico modeling of complex molecular pathway systems. The individual models predict the temporal behavior of formaldehyde, formate, sarcosine, glutathione (GSH), and many other key biomolecules involved in C1 metabolism, which may be hard to measure experimentally. The individual models are then coupled and integrated dynamically using CytoSolve to produce, to the authors’ knowledge, the first comprehensive computational model of C1 metabolism. In silico modeling of the individual and integrated C1 metabolism models enables the identification of the most sensitive parameters involved in the detoxification of formaldehyde. This integrative model of C1 metabolism, giving its systems-based nature, can likely serve as a platform for: 1) generalized research and study of C1 metabolism, 2) hypothesis generation that motivates focused and specific in vitro and in vivo testing in perhaps a more efficient manner, 3) expanding a systems biology understanding of plant bio-molecular systems by integrating other known molecular pathway systems associated with C1 metabolism, and 4) exploring and testing the potential effects of exogenous inputs on the C1 metabolism system.
基金This work was fnancially supported by the National Key R&D Program of China(No.2019YFA0904300).
文摘The complex mechanisms of the internal operation of cellular functions have not been fully resolved and these functions are regulated by multiple effects,such as transcription regulation,signal transduction,and enzyme catalysis,forming complex interactive mechanisms.This makes the construction of a whole-cell computational model,containing various complex cellular functions,very challenging.However,biological models have played a significant role in the field of systems biology,such as guiding gene-target mining and studying cell metabolic characteristics.Therefore,there is increasing research interest in the construction of whole-cell computational models.Combining two classical languages of systems biology,this review expounds on the development and challenges of whole-cell computational modeling from the two classical methods of steady-state and dynamic modeling.Finally,we propose a new approach for constructing whole-cell computational models.
文摘Recent trend on biological data at a molecular level is omics data analysis for both bulk and single cells, in eluding genomics, proteomics, metabolomics, and epigenetics data (Wang and Zhang, 2017;Zhang et al., 2017;Zhao and Li, 2017;Cheng and Leung, 2018). Rapid accumulation of such high-dimensional biological data is driving the system-level study from describing complex phenomena to understanding molecular mechanisms (Park et al., 2018;Sun et al., 2018) and from analyzi ng in dividual components to understanding their networks and systems (Chen et al., 2009;Chen, 2017).
基金the National Natural Science Foundation of China(Grant No.30770066,200876181,and 20831006)Natural Science Foundation of Guangdong Province(No.07003631)the Project of Science and Technology of Guangdong Province(No.2007A010900001)for their financial support.
文摘Microorganisms have been the main sources for the production of chemicals.Production of chemicals requires the development of low-cost and higher-yield processes.Towards this goal,microbial strains with higher levels of production should be first considered.Metabolic engineering has been used extensively over the past two to three decades to increase production of these chemicals.Advances in omics technology and computational simulation are allowing us to perform metabolic engineering at the systems level.By combining the results of omics analyses and computational simulation,systems biology allows us to understand cellular physiology and characteristics,which can subsequently be used for designing strategies.Here,we review the current status of metabolic engineering based on systems biology for chemical production and discuss future prospects.
文摘A model of a hypertorus communication grid has been constructed in the form of an infinite Petri net. A grid cell represents either a packet switching device or a bioplast cell. A parametric expression is obtained to allow a finite specification of an infinite Petri net. To prove properties of an ideal communication protocol, we derive an infinite Diophantine system of equations from it, which is subsequently solved. Then we present the programs htgen and ht-mcrl2-gen, developed in the C language, which generate Petri net and process algebra models of a hypertorus with a given number of dimensions and grid size. These are the inputs for the respective modeling tools Tina and mCRL2, which provide model visualization, step simulation, state space generation and reduction, and structural analysis techniques. Benchmarks to compare the two approaches are obtained. An ad-hoc induction-like technique on invariants,obtained for a series of generated models, allows the calculation of a solution of the Diophantine system in a parametric form.It is proven that the basic solutions of the infinite system have been found and that the infinite Petri net is bounded and conservative. Some remarks regarding liveness and liveness enforcing techniques are also presented.
