Advances in Basic Theory Research of Mongolian Medicine and Prospects of Its Combination with Systems Biology Research

This paper sorted out the relevant literature on the basic theory of Mongolian medicine,explored the research methods and ideas of the basic theory of Mongolian medicine,and elaborated the idea of combining systems biology to study part of the basic theory of Mongolian medicine.Through searching classic works and research papers in academic journals,this paper sorted out and summarized the research progress of the basic theory of Mongolian medicine and the existing problems in the current research,analyzed its characteristics,combined with systems biology methods to systematically explain some content in the basic theory,reveal its scientific connotation,and provide a basis for further research.

Systems biology approaches for studying the pathogenesis of non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is a progressive disease of increasing public health concern. In western populations the disease has an estimated prevalence of 20%-40%, rising to 70%-90% in obese and type II diabetic individuals. Simplistically, NAFLD is the macroscopic accumulation of lipid in the liver, and is viewed as the hepatic manifestation of the metabolic syndrome. However, the molecular mechanisms mediating both the initial development of steatosis and its progression through non-alcoholic steatohepatitis to debilitating and potentially fatal fibrosis and cirrhosis are only partially understood. Despite increased research in this field, the development of non-invasive clinical diagnostic tools and the discovery of novel therapeutic targets has been frustratingly slow. We note that, to date, NAFLD research has been dominated by in vivo experiments in animal models and human clinical studies. Systems biology tools and novel computational simulation techniques allow the study of large-scale metabolic networks and the impact of their dysregulation on health. Here we review current systems biology tools and discuss the benefits to their application to the study of NAFLD. We propose that a systems approach utilising novel in silico modelling and simulation techniques is key to a more comprehensive, better targeted NAFLD research strategy. Such an approach will accelerate the progress of research and vital translation into clinic.

Comparative systems biology between human and animal models based on next-generation sequencing methods

Animal models provide myriad benefits to both experimental and clinical research.Unfortunately,in many situations,they fall short of expected results or provide contradictory results.In part,this can be the result of traditional molecular biological approaches that are relatively inefficient in elucidating underlying molecular mechanism.To improve the efficacy of animal models,a technological breakthrough is required.The growing availability and application of the high-throughput methods make systematic comparisons between human and animal models easier to perform.In the present study,we introduce the concept of the comparative systems biology,which we define as“comparisons of biological systems in different states or species used to achieve an integrated understanding of life forms with all their characteristic complexity of interactions at multiple levels”.Furthermore,we discuss the applications of RNA-seq and ChIP-seq technologies to comparative systems biology between human and animal models and assess the potential applications for this approach in the future studies.

Comparative systems biology between human and animal models based on next-generation sequencing methods

Animal models provide myriad benefits to both experimental and clinical research. Unfortunately, in many situations, they fall short of expected results or provide contradictory results. In part, this can be the result of traditional molecular biological approaches that are relatively inefficient in elucidating underlying molecular mechanism. To improve the efficacy of animal models, a technological breakthrough is required. The growing availability and application of the high-throughput methods make systematic comparisons between human and animal models easier to perform. In the present study, we introduce the concept of the comparative systems biology, which we define as "comparisons of biological systems in different states or species used to achieve an integrated understanding of life forms with all their characteristic complexity of interactions at multiple levels". Furthermore, we discuss the applications of RNA-seq and ChIP-seq technologies to comparative systems biology between human and animal models and assess the potential applications for this approach in the future studies.

Developmental systems biology flourishing on new technologies

Organism development is a systems level process. It has benefited greatly from the recent technological advances in the field of systems biology. DNA microarray, phenome, interactome and transcriptome mapping, the new generation of deep sequencing technologies, and faster and better computational and modeling approaches have opened new frontiers for both systems biologists and developmental biologists to reexamine the old developmental biology questions, such as pattern formation, and to tackle new problems, such as stem cell reprogramming. As showcased in the International Developmental Systems Biology Symposium organized by Chinese Academy of Sciences, developmental systems biology is flourishing in many perspectives, from the evolution of developmental systems, to the underlying genetic and molecular pathways and networks, to the genomic, epigenomic and noncoding levels, to the computational analysis and modeling. We believe that the field will continue to reap rewards into the future with these new approaches.

In-Silico Analysis &In-Vivo Results Concur on Glutathione Depletion in Glyphosate Resistant GMO Soy, Advancing a Systems Biology Framework for Safety Assessment of GMOs

This study advances previous efforts towards development of computational systems biology, in silico, methods for biosafety assessment of genetically modified organisms (GMOs). C1 metabolism is a critical molecular system in plants, fungi, and bacteria. In our previous research, critical molecular systems of C1 metabolism were identified and modeled using CytoSolve?, a platform for in silico analysis. In addition, multiple exogenous molecular systems affecting C1 metabolism such as oxidative stress, shikimic acid metabolism, glutathione biosynthesis, etc. were identified. Subsequent research expanded the C1 metabolism computational models to integrate oxidative stress, suggesting glutathione (GSH) depletion. Recent integration of data from the EPSPS genetic modification of Soy, also known as Roundup Ready Soy (RRS), with C1 metabolism predicts similar GSH depletion and HCHO accumulation in RRS. The research herein incorporates molecular systems of glutathione biosynthesis and glyphosate catabolism to expand the extant in silico models of C1 metabolism. The in silico results predict that Organic Soy will have a nearly 250% greater ratio of GSH and GSSG, a measure of glutathione levels, than in RRS that are glyphosate-treated glyphosate-resistant Soy versus the Organic Soy. These predictions also concur with in vivo greenhouse results. This concurrence suggests that these in silico models of C1 metabolism may provide a viable and validated platform for biosafety assessment of GMOs, and aid in selecting rational criteria for informing in vitro and in vivo efforts to more accurately decide in the problem formulation phase whose parameters need to be assessed so that conclusion on “substantial equivalence” or material difference of a GMO and its non-GMO counterpart can be drawn on a well-grounded basis.

An Effective Numerical Calculation Method for Multi-Time-Scale Mathematical Models in Systems Biology

The improvements of high-throughput experimental devices such as microarray and mass spectrometry have allowed an effective acquisition of biological comprehensive data which include genome, transcriptome, proteome, and metabolome (multi-layered omics data). In Systems Biology, we try to elucidate various dynamical characteristics of biological functions with applying the omics data to detailed mathematical model based on the central dogma. However, such mathematical models possess multi-time-scale properties which are often accompanied by time-scale differences seen among biological layers. The differences cause time stiff problem, and have a grave influence on numerical calculation stability. In the present conventional method, the time stiff problem remained because the calculation of all layers was implemented by adaptive time step sizes of the smallest time-scale layer to ensure stability and maintain calculation accuracy. In this paper, we designed and developed an effective numerical calculation method to improve the time stiff problem. This method consisted of ahead, backward, and cumulative algorithms. Both ahead and cumulative algorithms enhanced calculation efficiency of numerical calculations via adjustments of step sizes of each layer, and reduced the number of numerical calculations required for multi-time-scale models with the time stiff problem. Backward algorithm ensured calculation accuracy in the multi-time-scale models. In case studies which were focused on three layers system with 60 times difference in time-scale order in between layers, a proposed method had almost the same calculation accuracy compared with the conventional method in spite of a reduction of the total amount of the number of numerical calculations. Accordingly, the proposed method is useful in a numerical analysis of multi-time-scale models with time stiff problem.

Stress Knowledge Map:A knowledge graph resource for systems biology analysis of plant stress responses

Stress Knowledge Map(SKM;https://skm.nib.si)is a publicly available resource containing two complementary knowledge graphs that describe the current knowledge of biochemical,signaling,and regulatory molecular interactions in plants:a highly curated model of plant stress signaling(PSS;543 reactions)and a large comprehensive knowledge network(488390 interactions).Both were constructed by domain experts through systematic curation of diverse literature and database resources.SKM provides a single entry point for investigations of plant stress response and related growth trade-offs,as well as interactive explorations of current knowledge.PSS is also formulated as a qualitative and quantitative model for systems biology and thus represents a starting point for a plant digital twin.Here,we describe the features of SKM and show,through two case studies,how it can be used for complex analyses,including systematic hypothesis generation and design of validation experiments,or to gain new insights into experimental observations in plant biology.

Design and construction of microbial cell factories based on systems biology

Environmental sustainability is an increasingly important issue in industry.As an environmentally friendly and sustainable way,constructing microbial cell factories to produce all kinds of valuable products has attracted more and more attention.In the process of constructing microbial cell factories,systems biology plays a crucial role.This review summarizes the recent applications of systems biology in the design and construction of microbial cell factories from four perspectives,including functional genes/enzymes discovery,bottleneck pathways identification,strains tolerance improvement and design and construction of synthetic microbial consortia.Systems biology tools can be employed to identify functional genes/enzymes involved in the biosynthetic pathways of products.These discovered genes are introduced into appropriate chassis strains to build engineering microorganisms capable of producing products.Subsequently,systems biology tools are used to identify bottleneck pathways,improve strains tolerance and guide design and construction of synthetic microbial consortia,resulting in increasing the yield of engineered strains and constructing microbial cell factories successfully.

Bridging the Traditional Chinese Medicine Pattern Classification and Biomedical Disease Diagnosis with Systems Biology

Being the unique core of traditional Chinese medicine （TCM）, pattern classification exerts a direct effect on the efficacy and safety of herbal interventions. In this article, the authors integrated the pattern classification and disease diagnosis with many approaches from systems biology, integration of pattern classification with biomedical diagnosis by systems biology is not only a new direction of personalized medicine development, but also provides a new drug development model. In the further study, the pattern classifications of major diseases will be the focus of research.

Application of Systems Biology Technology in Research of Traditional Chinese Medicine

Systems biology is an emerging science of the 21st century and its method and design of study resemble those of traditional Chinese medicine (TCM). Adopting systems biology technology will help to understand TCM Syndromes and modernize Chinese herbal medicine. The technology platforms of systems biology, especially proteomics can provide useful tools for exploring essence of TCM syndromes and understanding principle of herbal formulation. Moreover, compared with methods of molecular biology, such as genomics and proteomics, metabolomics provide more direct, rapid, concise and effective methods for study of kidney disease especially in the case of prevention and treatment with TCM.

Integrated Systems Biology and Chemical Biology Approach to Exploring Mechanisms of Traditional Chinese Medicines

After thousands of years of development, traditional Chinese medicines （TCMs） have evolved into a complete scientific system characterized by multiple components, targets, and pathways, which mediates numerous pharmacological activities and efficacies. The development of ＂-omics＂ technology, including systems biology and network pharmacology, has enabled the illustration of TCMs from a more systematic view. Although the network adequately reflects the overall philosophy of TCMs, its complexity hinders the relevant research to a hover. In addition, the strategies involved appear to be in contrast to the original concise and efficacious disease therapy oriented focus on classic Chinese material medica （CMM）. Based on the established holistic view and reductionism, in this review, we discuss an integrated systems biology and chemical biology research approach that will facilitate and accelerate the understanding of the mechanisms of TCMs. Furthermore, we are optimistic that it will elucidate the associated interactions between active natural products and their targets, and ultimately improve the strategies for complex disease therapies.

Biomedical Mechanisms of Blood Stasis Syndrome of Coronary Heart Disease by Systems Biology Approaches

The prevalence of coronary heart disease （CHD） is increasing, and has been a severe burden on society and family worldwide. New ideas need to be achieved for developing more efficacious and safe therapies to treat CHD. Chinese medicine （CM） uses multicomponent drugs to prevent disease and ameliorate symptoms based on patients＇ different syndromes. The benefit of CM in CHD has recently been proven by increasing clinical evidence. More importantly, linking CM syndrome differentiation and biomedical diagnosis might provide innovative thinking for treating CHD. According to epidemiological investigations, blood stasis syndrome （BSS） is the major type of syndrome in CHD. Investigating the biomedical mechanisms of BSS of CHD is a topic of CM research. Because the holistic perspective of systems biology is well matched with CM, the application of omics techniques and other integrative approaches appears inherently appropriate. A wide range of omics techniques, including transcriptomics and proteomics, have been used in studies of BSS of CHD to search for a common ground of understanding. These approaches could be useful for understanding BSS of CHD from clinical and biological viewpoints. Nevertheless, current studies mainly contain results from a single approach, and they have not achieved the holistic, systematic and integrative concept of system biology. Therefore, we discuss the progress and challenges in exploring the biomedical mechanisms of BSS of CHD by systems biology approaches. With further development of systems biology, a better platform to study BSS of CHD may be provided, and biomarkers for BSS of CHD and therapeutic targets may be found. The study of BSS of CHD by systems biology approaches will also be beneficial for developing personalized treatment for BSS of CHD patients.

Lessons Learned as President of the Institute for Systems Biology(2000–2018)

I stepped down as president of the Institute for Systems Biol- ogy （ISB） on Jan 1, 2018. As I think about my 17-year term as President, I am astounded at how much I have learned, not only about science but also about, among other things, what it takes to build a unique world-class institution.

Systems Biology Application in Research on Sustainable Utilization of Chinese Materia Medica Resources

This paper reviews the progress of systems biology applied to researching on sustainable utilization of Chinese materia medica （CMM） resources in the following aspects： identification and evaluation of CMM resources, analysis of biosynthesis and their regulation of active ingredients in medicinal plants, metabolic engineering and synthetic biology research of medicinal plants, and molecular breeding of medicinal plants. Development of systems biology is currently leading to extremely broad applications in the field of CMM resources, and systems biology wiil become a significant approach for the sustainable utilization of CMM resources.

Strategy of Systems Biology for Visualizing the “Black Box” of Traditional Chinese Medicine

Traditional Chinese medicine(TCM)has been practiced for thousands of years in China.TCM formula,usually composed of several or even dozens of herbal medicines,is the main form of TCM practicing,which is extremely complex due to multiple components and therapeutic targets,especially the characteristics of formula compatibility.Thus,it is an enormous challenge for the modernization of TCM.Systems biology is a strategy for investigating the complex interactions between genes,mRNA,proteins,and metabolites by using integrated omics approaches.In recent years,systems biology has been increasingly adopted in TCM study.This review comprehensively summarized status of syndrome and application of TCM formulae in clinical and preclinical studies and discussed the advances of systems biology in TCM research.Then,a"Disease-Syndrome-Formulae-Effect"strategy was proposed for TCM research.Combination of systems biology and"Disease-Syndrome-Formulae-Effect"strategy provided a novel approach to understand the complex interactions among biological systems,drugs,and complex diseases from a network perspective,thus facilitating the modernization of TCM.The objective of this manuscript is to provide comprehensive and up-to-date review on the application of systems biology in TCM research,as well as the perspective of TCM modernization with systems biology.

Understanding channel tropism in traditional Chinese medicine in the context of systems biology

Channel tropism is investigated and developed through long-term clinical practice.In recent years,the development of channel tropism theory has attracted increasing attention.This study analyzed channel tropism theory and the problems associated with it.Results showed that this theory and systems biology have a similar holistic viewpoint.Systems biology could provide novel insights and platform in the study of channel tropism.Some problems in channel tropism theory,including pharmacology and action mechanism,were investigated.

Application of Bioinformatics and Systems Biology in Medicinal Plant Studies

One important purpose to investigate medicinal plants is to understand genes and enzymes that govern the biological metabolic process to produce bioactive compounds. Genome wide high throughput technologies such as genomics, transcriptomics, proteomics and metabolomics can help reach that goal. Such technologies can produce a vast amount of data which desperately need bioinformatics and systems biology to process, manage, distribute and understand these data. By dealing with the 'omics' data, bioinformatics and systems biology can also help improve the quality of traditional medicinal materials, develop new approaches for the classification and authentication of medicinal plants, identify new active compounds, and cultivate medicinal plant species that tolerate harsh environmental conditions. In this review, the application of bioinformatics and systems biology in medicinal plants is briefly introduced.

Application of systems biology to the study of chronic kidney disease

Chronic kidney disease （CKD） is a major public health problem that affects about 10% of the general population. Current approaches to characterize the category and progression of CKD are normally based on renal histopathological results and clinical parameters. However, this information is not sufficient to predict CKD progression risk reliably or to guide preventive interventions. Nowadays, the appearance of systems biology has brought forward the concepts of ＂-omics＂ technologies, including genomics, transcriptomics, proteomics, and metabolomics. Systems biology, together with molecular analysis approaches such as microarray analysis, genome-wide association studies （GWAS）, and serial analysis of gene expression （SAGE）, has provided the framework for a comprehensive analysis of renal disease and serves as a starting point for generating novel molecular diagnostic tools for use in nephrology. In particular, analysis of urinary mRNA and protein levels is rapidly evolving as a non-invasive approach for CKD monitoring. All these systems biological molecular approaches are required for application of the concept of ＂personalized medicine＂ to progressive CKD, which will result in tailoring therapy for each patient, in contrast to the ＂one-size-fits-all＂ therapies currently in use.

Metabolic engineering based on systems biology for chemicals production

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.