Model informed precision medicine of Chinese herbal medicines formulas-A multi-scale mechanistic intelligent model

Recent trends suggest that Chinese herbal medicine formulas(CHM formulas)are promising treatments for complex diseases.To characterize the precise syndromes,precise diseases and precise targets of the precise targets between complex diseases and CHM formulas,we developed an artificial intelligence-based quantitative predictive algorithm(DeepTCM).DeepTCM has gone through multilevel model calibration and validation against a comprehensive set of herb and disease data so that it accurately captures the complex cellular signaling,molecular and theoretical levels of traditional Chinese medicine(TCM).As an example,our model simulated the optimal CHM formulas for the treatment of coronary heart disease(CHD)with depression,and through model sensitivity analysis,we calculated the balanced scoring of the formulas.Furthermore,we constructed a biological knowledge graph representing interactions by associating herb-target and gene-disease interactions.Finally,we experimentally confirmed the therapeutic effect and pharmacological mechanism of a novel model-predicted intervention in humans and mice.This novel multiscale model opened up a new avenue to combine“disease syndrome”and“macro micro”system modeling to facilitate translational research in CHM formulas.

Research progress of traditional Chinese medicine in the treatment of endocrine metabolic diseases in 2023

This study aimed to provide a comprehensive review of the research progress in Chinese medicine in the treatment of endocrine metabolic diseases in 2023,covering traditional Chinese medicine(TCM)monomers,TCM extracts,and TCM combinations,including non-alcoholic fatty liver disease,type 2 diabetes mellitus and its complications,obesity,hyperuricaemia,and thyroid disorders.After systematic sorting and summary,we found that in 2023,the research focusing on the application of TCM for endocrine metabolic diseases was still on the mechanism of action at the cellular and molecular levels,which not only influenced the classical pathways of lipid metabolism,but also delved into the key mechanisms of anti-inflammation,anti-oxidation,anti-insulin resistance,and so on.Additionally,TCM has shown remarkable results in the treatment of endocrine metabolic diseases by improving intestinal flora disorders and abnormal cellular iron death.These research results provide valuable ideas,methods,and tools for TCM in the prevention and treatment of endocrine metabolic diseases,and provide important references and guidance for future research and practice.

Research on the development methodology for clinical practice guidelines for organic integration of traditional Chinese medicine and Western medicine

Integrated traditional Chinese medicine(TCM)and Western medicine(WM)is a new medical science grounded in the knowledge bases of both TCM and WM,which then forms a unique modern medical system in China.Integrated TCM and WM has a long history in China,and has made important achievements in the process of clinical diagnosis and treatment.However,the methodological defects in currently published clinical practice guidelines(CPGs)limit its development.The organic integration of TCM and WM is a deeper integration of TCM and WM.To realize the progression of"integration"to"organic integration",a targeted and standardized guideline development methodology is needed.Therefore,the purpose of this study is to establish a standardized development procedure for clinical practice guidelines for the organic integration of TCM and WM to promote the systematic integration of TCM and WM research results into clinical practice guidelines in order to achieve optimal results as the whole is greater than the sum of the parts.

Integration of traditional,complementary,and alternative medicine with modern biomedicine:the scientization,evidence,and challenges for integration of traditional Chinese medicine

Traditional medicine has garnered significant global recognition,with an estimated 80%of the global population using it.Therefore,it is essential to fully understand the integration of traditional medicines into current healthcare systems.This review aims to provide a comprehensive overview of the standard process to modernize traditional medicine scientifically in the context of modern biomedicine,further termed here as“scientization”.Specifically,we aim to summarize the advancements made in understanding the efficacy,effectiveness,and underlying mechanisms of herbal medicine.We also examined the transition from experience-to evidence-based medicine during acupuncture.Furthermore,we explore the development of universal safety and quality control standards.Finally,we discuss international trade and export markets for Chinese medical products.The development and integration of traditional medicine have allowed it to further improve human health,resulting in a more comprehensive health solution for the global population.

Chinese Medicine,Acupuncture and Science

Ever since the introduction of Western biomedicine into China, there has been friction between proponents of this new approach, and proponents of the traditional medical practices that had evolved over thousands of years in China. For the most part, this friction has been couched in the unexamined assumption that Western medicine is based on science, while Chinese medicine is not. This article will examine that assumption, which in this author’s opinion is unjustified and incorrect. Having practiced acupuncture for the past 50 years, after receiving my doctoral degrees in medicine and physiology, my thinking on this topic has also evolved over time. I will begin this article with some historical information that bears on the topic under discussion, followed by my personal ideas about how to resolve the confiicts that have arisen.

Bio-soft matter derived from traditional Chinese medicine:Characterizations of hierarchical structure,assembly mechanism,and beyond

Structural and functional explorations on bio-soft matter such as micelles,vesicles,nanoparticles,aggregates or polymers derived from traditional Chinese medicine(TCM)has emerged as a new topic in the field of TCM.The discovery of such cross-scaled bio-soft matter may provide a unique perspective for unraveling the new effective material basis of TCM as well as developing innovative medicine and biomaterials.Despite the rapid rise of TCM-derived bio-soft matter,their hierarchical structure and assembly mechanism must be unambiguously probed for a further in-depth understanding of their pharmacological activity.In this review,the current emerged TCM-derived bio-soft matter assembled from either small molecules or macromolecules is introduced,and particularly the unambiguous elucidation of their hierarchical structure and assembly mechanism with combined electron microscopic and spectroscopic techniques is depicted.The pros and cons of each technique are also discussed.The future challenges and perspective of TCM-derived bio-soft matter are outlined,particularly the requirement for their precise in situ structural determination is highlighted.

Comparative efficacy and safety of Chinese patent medicines of iron deficiency anemia during pregnancy:A network meta-analysis

BACKGROUND Iron deficiency anemia(IDA)is a prevalent nutritional disorder during pregnancy.Clinical studies indicate that incorporating Chinese patent medicines(CPMs)with oral iron(OI)in treating IDA in pregnancy can reduce adverse effects and improve clinical outcomes.Nonetheless,the comparative efficacy of different CPMs remains unclear.AIM To assess the safety and effectiveness of different CPMs for treating IDA during pregnancy using network meta-analysis.METHODS We conducted a search for randomized controlled trials(RCTs)that combined CPM and OI for IDA treatment in pregnancy,spanning from 2013 to the present.Data analysis was performed using Rev Man 5.3 and Stata 14.0 on literature that satisfied the quality criteria.RESULTS The analysis included 45 RCTs,encompassing 4422 pregnant patients with IDA.Six CPMs were examined,including Shengxuebao Mixture,Shengxuening Tablets(SXN),Yiqi Weixue CPMs(YQWX),Jianpi Shengxue CPMs(JPSX),Yiqi Buxue Tablets,and Compound Hongyi Buxue Oral Liquid(FFHY).Findings indicated that FFHY+OI significantly improved the clinical effective rate.SXN+OI was most effective in boosting red blood cells counts and hemoglobin levels.YQWX+OI showed superior results in improving serum ferritin,and SXN+OI was most effective in increasing serum iron levels.JPSX+OI was optimal in reducing adverse pregnancy outcomes,while YQBX+OI effectively minimized adverse events.A cluster analysis suggested that SXN+OI could be the potentially optimal therapeutic regimen for IDA in pregnancy.CONCLUSION This study demonstrates that the combination of OI with CPMs offers better outcomes than OI alone.Based on clinical efficacy and other measured outcomes,SXN+OI emerges as the most effective treatment modality for improving the health of pregnant patients with IDA.

Growth of Chinese Medicine in Iran: Past, Present, and Prospects

The international recognition of traditional Chinese medicine(TCM)has continuously increased,and that medical practice has gradually become incorporated into the medical systems of many nations.As an important country in the Belt and Road Initiative,Iran has enormous potential for cooperation with China in medical and health care.High-level officials of the two countries attach great importance to cooperation in both areas.Despite the recent rapid development of TCM in Iran,that medical practice still faces many problems;examples here are the lack of practitioners of TCM as well as the paucity of comprehensive cooperation among herbal medicine factories,publishing houses,traditional medicine colleges,and universities in the two countries.The present study collected and analyzed materials related to the practice of TCM in Iran;it made a deep examination of the current situation,problems,and development prospects regarding TCM in Iran with the aim of providing ideas and references to promote the international development of that form of medicine.Following an analysis of the development trends of TCM in Iran in recent years,it became evident that the prospects for TCM in that country are extensive,and the practice has excellent potential.

Matching traditional Chinese medicine and western medicine-based research:Advanced nutraceutical development for proactive gastric cancer prevention

Gastric cancer(GC),the third leading cause of cancer-related death globally,is complex and heterogeneous.This review explores multidisciplinary investigations of traditional Chinese medicine(TCM)combined with Western medical practices,emphasizing the development of nutraceuticals for cancer prevention.Using advanced analytical chemistry and food chemistry techniques,this study investigated how TCM components may be optimized for nutraceutical development.Focusing on molecular interactions with GC pathways,particularly the NF-κB,PI3K/Akt,and Wnt/β-catenin pathways,we examined the effects of TCM polyherbal formulas,extracts,and isolated compounds.These agents modulate apoptosis and cellular proliferation,underscoring their potential in preventive strategies.The convergence of nutraceutical and medicine food homology studies highlights a significant shift towards integrating TCM-derived compounds in a preventive health framework.This approach aims not only to enhance efficacy and reduce side effects but also to champion a preventive paradigm using personalized medicine to advance proactive health maintenance and disease prevention.The combination of TCM and western medical practices offers promising avenues for future research and practical applications in GC prevention.

Knee osteoarthritis:A review of animal models and intervention of traditional Chinese medicine

Background:Knee osteoarthritis(KOA)characterized by degeneration of knee cartilage and subsequent bone hyperplasia is a prevalent joint condition primarily affecting aging adults.The pathophysiology of KOA remains poorly understood,as it involves complex mechanisms that result in the same outcome.Consequently,researchers are interested in studying KOA and require appropriate animal models for basic research.Chinese herbal compounds,which consist of multiple herbs with diverse pharmacological properties,possess characteristics such as multicomponent,multipathway,and multitarget effects.The potential benefits in the treatment of KOA continue to attract attention.Purpose:This study aims to provide a comprehensive overview of the advantages,limitations,and specific considerations in selecting different species and methods for KOA animal models.This will help researchers make informed decisions when choosing an animal model.Methods:Online academic databases(e.g.,PubMed,Google Scholar,Web of Science,and CNKI)were searched using the search terms“knee osteoarthritis,”“animal models,”“traditional Chinese medicine,”and their combinations,primarily including KOA studies published from 2010 to 2023.Results:Based on literature retrieval,this review provides a comprehensive overview of the methods of establishing KOA animal models;introduces the current status of advantages and disadvantages of various animal models,including mice,rats,rabbits,dogs,and sheep/goats;and presents the current status of methods used to establish KOA animal models.Conclusion:This study provides a review of the animal models used in recent KOA research,discusses the common modeling methods,and emphasizes the role of traditional Chinese medicine compounds in the treatment of KOA.

Mechanism of traditional Chinese medicine in the treatment of psoriasis with depression:A review

Psoriasis is a kind of immune-mediated, chronic, inflammatory skin disease, which is often associated with different degrees of psychological disorders. Specifically, there is a significant correlation between psoriasis and depression, and they show the relationships of reciprocal causation and mutual promotion. Psoriasis with depression is more harmful than simple psoriasis, and its prognosis is worse, which brings a huge burden to the family and society and is worthy of clinical attention. Based on the pathogenic factors of western medicine and pathogenesis of traditional Chinese medicine in psoriasis with depression, the paper summarized and elaborated the research progress on the mechanism of traditional Chinese medicine in the treatment of psoriasis with depression, in order to provide new ideas for clinical treatment.

The Making of a Health Profession:How Chinese Medicine Became a Nationally Registered Allied Health Profession in Australia

In 2012, traditional Chinese medicine(TCM) practitioners in Australia became nationally-registered allied health professionals in three categories: acupuncturist, Chinese herbal medicine practitioner, and Chinese herbal medicine dispenser. Australia was the first Western country to introduce national registration for Chinese medicine, followed by Portugal and, recently, New Zealand. The practice of TCM in Australia can be traced back to the beginning of Chinese immigration to Australia during the Victorian Gold Rush which began in the 1850s. The process which led to national registration commenced in the early 1970s with the establishment of the first acupuncture courses. Decades of gradual development of courses from unaccredited part-time diplomas to accredited bachelor degrees, and the development, by the profession, of national consensus on educational standards were essential elements in the process which led to registration. Professional associations, such as the Australian Acupuncture and Chinese Medicine Association Ltd.(AACMA), also developed a framework of professional selfregulation, including Codes of Ethics, Codes of Conduct, ongoing professional development requirements and Infection Control Guidelines, and provided leadership in the development of the profession. After decades of tribalism and division within the TCM profession, the National Academic Standards Committee brought almost all stakeholders together to reach a consensus on the Australian Guidelines for Traditional Chinese Medicine Education which were published by AACMA in 2001. Professional associations also collaborated on joint submissions to the government in support of registration, which was introduced first in the state of Victoria in 2000, and subsequently became national in 2012. Despite national registration, some barriers still remain, and professional associations continue to lobby the federal government for inclusion in Medicare, chronic disease management scheme, and Veterans Affairs.

A harmonisation approach to traditional Chinese medicine registration in Asian countries

The traditional Chinese medicine(TCM)industry is critical to not only for public health but also for economic growth.According to the European Union(EU)directives,under the EU framework for(traditional)herbal medicinal products,herbal medicines with long history of use can be registered in EU.However,there is a condition in this directive in which only those that have at least 10e15 years in the EU market are accepted for registration and/or marketing authorization.In author opinion,the condition of 10-15 years of use in EU countries set within the EU regulatory framework is with consideration of the genetic differences which can result in variation in adverse drug responses among different world populations.With this concept in mind,it is reasonable to project the principal of the EU directive to the Asian countries where TCM is originated.Countries like China,Singapore,Japan and South Korea that have well established drug registration framework are in best position in executing the best practice and facilitate harmonization of registration for TCM within the region.Furthermore,the registration process itself allows more safety and efficacy data to be collected systemically before and after product registration/marketing authorization.These are valuable information for future drug development.The therapeutic value of TCM is limitless,it has been left out in the EU regulatory framework,and the opportunity for it to be expanded and carried forward in modern medicines is shadowed by the limited number of TCM that are qualified to be registered under the EU regulatory framework.An early establishment of a harmonized risk-based registration process for TCM in Asian countries is important.This will strengthen the database to substantiate the history of safe use and further preserving and expanding the therapeutic values of TCM within and beyond the Asian region.

Chinese herbal medicine for the treatment of endocrine therapyrelated osteoporosis among patients with breast cancer:A systematic review and meta-analysis

Objective To assess the efficacy and safety of combining traditional Chinese medicine(TCM),specifically Chinese herbal medicine(CHM),with Western medicine(WM),compared to WM alone to treat breast cancer endocrine therapy-related osteoporosis(BCET-OP)by meta-analysis.Methods Thirty-eight randomized controlled trials involving 2170 participants were analyzed.Eight databases were searched for articles published between inception and December 2023.Quality assessment was performed using the Risk of Bias 2 tool.Results Significant increases were observed in the TCM-WM group in lumbar vertebrae bone mineral density(BMD)(P<.001,mean difference(MD)=0.07,95%confidence interval(CI):0.06 to 0.08),lumbar vertebrae T-score(P=.0005,MD=0.21,95%CI:0.09 to 0.33)and collum femoris BMD(P=.01,MD=0.10,95%CI:0.02 to 0.19).No significant difference was observed between the groups in the collum femoris T-score and estradiol levels.Bone gla-protein levels were significantly increased in the TCM-WM group(P=.0002,MD=0.52,95%CI:0.25 to 0.79).Beta-CrossLaps decreased significantly in the TCM-WM group(P=.0008,MD=−0.10,95%CI:−0.16 to−0.04).No significant difference was observed between the TCM-WM and WM groups in alkaline phosphatase,in procollagen type I N-terminal propeptide,and in the Kupperman index.The visual analog score(VAS)was decreased in the TCM-WM group compared to the WM group(P<.001,MD=−1.40,95%CI:−1.94 to−0.87).No significant difference in adverse events was observed between the two groups.Conclusion Combining CHM with WM in patients with BCET-OP significantly improved BMD,T-score,and certain bone turnover markers and reduced the VAS score,indicating potential benefits for bone health and related pain.Adverse event analysis revealed no differences between the groups,supporting the feasibility of the combination therapy.However,further research,particularly in diverse populations,is required.

Inhibition of hepatitis B virus via selective apoptosis modulation by Chinese patent medicine Liuweiwuling Tablet

BACKGROUND Liuweiwuling Tablet(LWWL)is a Chinese patent medicine approved for the treatment of chronic inflammation caused by hepatitis B virus(HBV)infection.Previous studies have indicated an anti-HBV effect of LWWL,specifically in terms of antigen inhibition,but the underlying mechanism remains unclear.AIM To investigate the potential mechanism of action of LWWL against HBV.METHODS In vitro experiments utilized three HBV-replicating and three non-HBV-replicating cell lines.The in vivo experiment involved a hydrodynamic injectionmediated mouse model with HBV replication.Transcriptomics and metabolomics were used to investigate the underlying mechanisms of action of LWWL.RESULTS In HepG2.1403F cells,LWWL(0.8 mg/mL)exhibited inhibitory effects on HBV DNA,hepatitis B surface antigen and pregenomic RNA(pgRNA)at rates of 51.36%,24.74%and 50.74%,respectively.The inhibition rates of LWWL(0.8mg/mL)on pgRNA/covalently closed circular DNA in HepG2.1403F,HepG2.2.15 and HepG2.A64 cells were 47.78%,39.51%and 46.74%,respectively.Integration of transcriptomics and metabolomics showed that the anti-HBV effect of LWWL was primarily linked to pathways related to apoptosis(PI3K-AKT,CASP8-CASP3 and P53 pathways).Apoptosis flow analysis revealed that the apoptosis rate in the LWWL-treated group was significantly higher than in the control group(CG)among HBV-replicating cell lines,including HepG2.2.15(2.92%±1.01%vs 6.68%±2.04%,P<0.05),HepG2.A64(4.89%±1.28%vs 8.52%±0.50%,P<0.05)and HepG2.1403F(3.76%±1.40%vs 7.57%±1.35%,P<0.05)(CG vs LWWL-treated group).However,there were no significant differences in apoptosis rates between the non-HBV-replicating HepG2 cells(5.04%±0.74%vs 5.51%±1.57%,P>0.05),L02 cells(5.49%±0.80%vs 5.48%±1.01%,P>0.05)and LX2 cells(6.29%±1.54%vs 6.29%±0.88%,P>0.05).TUNEL staining revealed a significantly higher apoptosis rate in the LWWL-treated group than in the CG in the HBVreplicating mouse model,while no noticeable difference in apoptosis rates between the two groups was observed in the non-HBV-replicating mouse model.CONCLUSION Preliminary results suggest that LWWL exerts a potent inhibitory effect on wild-type and drug-resistant HBV,potentially involving selective regulation of apoptosis.These findings offer novel insights into the anti-HBV activities of LWWL and present a novel mechanism for the development of anti-HBV medications.

Chinese herbal medicine combined with Western medicine for Mycoplasma pneumoniae pneumonia in children:An overview of systematic reviews

Objective:To summarize the characteristics and evaluate the quality of the methodology and evidence within systematic reviews(SRs)of Chinese herbal medicine(CHM)for Mycoplasma pneumoniae pneumonia(MPP)inchildren.Methods:SRs of randomized controlled trials were searched using PubMed,the Cochrane Library,Embase,the Chinese National Knowledge Infrastructure Databases(CNKI),the Chinese Scientific Journals Database(VIP),Wanfang,and the SinoMed Database.SRs on the use of CHM alone or in combination with Western medications for MPP in children were included.The study compared the effects of Western medicine alone with those of CHM.The evidence quality using the A Measurement Tool to Assess Systematic Reviews(AMSTAR)2,the Preferred Reporting Items for Systematic Reviews and Meta-Analyses(PRISMA)2020,and the Grading of Recommendations,Assessment,Development,and Evaluation(GRADE)criteria.The primary indicators were the total effective rate,fever subsidence time,and cough disappearance time.The secondary outcomes were pulmonary rale disappearance time,average hospitalization time,lung X-ray infiltrate disappearance time,immunological indices,and inflammatory cytokine levels.Results:Twelve relevant SRs were included;75%(9/12)were assessed as very low quality,and 25%(3/12)Were rated as low quality using the AMSTAR 2 criteria.According to the PRISMA 2020 checklist,the average SR score was 20.3 out of a 27 point maximum.In all SRs,CHM demonstrated improvement in symptoms and signs among children with MPP.The evidence quality using the GRADE criteria ranged from"very low"(>50%)to"moderate"(<5%).The most common downgrading factor was imprecision,followed by publication bias and inconsistency.Conclusion:This overview highlights the limited quality of the methodology and evidence of the included SRs.Although the included studies showed the beneficial effects of CHM on MPP in children,it was difficult to draw firm conclusions owing to methodological flaws.

Modern technology-based exploration of mechanism of traditional Chinese medicine in prevention and treatment of gastric cancer

This review comments on the article“To explore the mechanism of Yigong San anti-gastric cancer and immune regulation”.We are interested that the article applied network pharmacology and bioinformatics techniques to elucidate the mechanism of action of Yigong Sang,a traditional Chinese medicine(TCM),in the treatment of gastric cancer(GC).The mechanism of action of Yigong Sang in the treatment of GC has not yet been elucidated because it is composed of multiple Chinese medicines with multiple components and multiple targets.The emergence of network pharmacology and bioinformatics analysis helps explain the mechanism of action of TCM in preventing and treating GC,and provides a possibility for TCM to transform from empirical to evidence-based medicine.This is of great significance for the application of TCM in oncology,new drug development,formula optimization,and the improvement of clinical efficacy.

HHO optimized support vector machine classifier for traditional Chinese medicine syndrome differentiation of diabetic retinopathy

AIM:To develop a classifier for traditional Chinese medicine(TCM)syndrome differentiation of diabetic retinopathy(DR),using optimized machine learning algorithms,which can provide the basis for TCM objective and intelligent syndrome differentiation.METHODS:Collated data on real-world DR cases were collected.A variety of machine learning methods were used to construct TCM syndrome classification model,and the best performance was selected as the basic model.Genetic Algorithm(GA)was used for feature selection to obtain the optimal feature combination.Harris Hawk Optimization(HHO)was used for parameter optimization,and a classification model based on feature selection and parameter optimization was constructed.The performance of the model was compared with other optimization algorithms.The models were evaluated with accuracy,precision,recall,and F1 score as indicators.RESULTS:Data on 970 cases that met screening requirements were collected.Support Vector Machine(SVM)was the best basic classification model.The accuracy rate of the model was 82.05%,the precision rate was 82.34%,the recall rate was 81.81%,and the F1 value was 81.76%.After GA screening,the optimal feature combination contained 37 feature values,which was consistent with TCM clinical practice.The model based on optimal combination and SVM(GA_SVM)had an accuracy improvement of 1.92%compared to the basic classifier.SVM model based on HHO and GA optimization(HHO_GA_SVM)had the best performance and convergence speed compared with other optimization algorithms.Compared with the basic classification model,the accuracy was improved by 3.51%.CONCLUSION:HHO and GA optimization can improve the model performance of SVM in TCM syndrome differentiation of DR.It provides a new method and research idea for TCM intelligent assisted syndrome differentiation.

The Dissemination and Development of Chinese Medicine in Pakistan

The article focuses on the dissemination and development of Chinese medicine in Pakistan.Religious records show that Chinese medicine was introduced to Pakistan as early as 1,400 years ago,while Hijama(Chinese cupping)was used by Prophet Hazrat Muhammad to cure different types of diseases.Exchanges and cooperations between China and Pakistan continue to the present day.Acupuncture and moxibustion therapy,cupping therapy and herbal medicine are practiced with significant merits in today’s Pakistan.In the future,with the proposal of the Belt and Road Initiative and the landmark project of China-Pakistan Economic Corridor,Chinese medicine can be strengthened through cooperations at the herbal medicine trade level,the research and development level,the educational level,and the social association level.

Unveiling the anticancer effect of traditional Chinese herbal medicine

In this issue of World Journal of Gastroenterology,Huang et al reported that Calculus bovis(CB),a traditional Chinese herbal medicine,impedes the growth of liver cancers in vivo.Through further in vitro studies,they showed that CB suppressed the M2 polarization of tumor-associated macrophages by suppressing the Wnt signaling pathway,which consequently inhibited the growth of liver cancer.Although the effects of traditional Chinese herbal medicine are often not scientifically proven,Huang et al successfully identified the molecular mechanism involved in the anticancer effect of CB,and it is anticipated that the molecular mechanisms involved in the effects of other traditional Chinese herbal medicines will be scientifically elucidated,as demonstrated in this article.