\\n\\n
IntechOpen was founded by scientists, for scientists, in order to make book publishing accessible around the globe. Over the last two decades, this has driven Open Access (OA) book publishing whilst levelling the playing field for global academics. Through our innovative publishing model and the support of the research community, we have now published over 5,700 Open Access books and are visited online by over three million academics every month. These researchers are increasingly working in broad technology-based subjects, driving multidisciplinary academic endeavours into human health, environment, and technology.
\\n\\nBy listening to our community, and in order to serve these rapidly growing areas which lie at the core of IntechOpen's expertise, we are launching a portfolio of Open Science journals:
\\n\\nAll three journals will publish under an Open Access model and embrace Open Science policies to help support the changing needs of academics in these fast-moving research areas. There will be direct links to preprint servers and data repositories, allowing full reproducibility and rapid dissemination of published papers to help accelerate the pace of research. Each journal has renowned Editors in Chief who will work alongside a global Editorial Board, delivering robust single-blind peer review. Supported by our internal editorial teams, this will ensure our authors will receive a quick, user-friendly, and personalised publishing experience.
\\n\\n"By launching our journals portfolio we are introducing new, dedicated homes for interdisciplinary technology-focused researchers to publish their work, whilst embracing Open Science and creating a unique global home for academics to disseminate their work. We are taking a leap toward Open Science continuing and expanding our fundamental commitment to openly sharing scientific research across the world, making it available for the benefit of all." Dr. Sara Uhac, IntechOpen CEO
\\n\\n"Our aim is to promote and create better science for a better world by increasing access to information and the latest scientific developments to all scientists, innovators, entrepreneurs and students and give them the opportunity to learn, observe and contribute to knowledge creation. Open Science promotes a swifter path from research to innovation to produce new products and services." Alex Lazinica, IntechOpen founder
\\n\\nIn conclusion, Natalia Reinic Babic, Head of Journal Publishing and Open Science at IntechOpen adds:
\\n\\n“On behalf of the journal team I’d like to thank all our Editors in Chief, Editorial Boards, internal supporting teams, and our scientific community for their continuous support in making this portfolio a reality - we couldn’t have done it without you! With your support in place, we are confident these journals will become as impactful and successful as our book publishing program and bring us closer to a more open (science) future.”
\\n\\nWe invite you to visit the journals homepage and learn more about the journal’s Editorial Boards, scope and vision as all three journals are now open for submissions.
\\n\\nFeel free to share this news on social media and help us mark this memorable moment!
\\n\\n\\n"}]',published:!0,mainMedia:{caption:"",originalUrl:"/media/original/237"}},components:[{type:"htmlEditorComponent",content:'
After years of being acknowledged as the world's leading publisher of Open Access books, today, we are proud to announce we’ve successfully launched a portfolio of Open Science journals covering rapidly expanding areas of interdisciplinary research.
\n\n\n\nIntechOpen was founded by scientists, for scientists, in order to make book publishing accessible around the globe. Over the last two decades, this has driven Open Access (OA) book publishing whilst levelling the playing field for global academics. Through our innovative publishing model and the support of the research community, we have now published over 5,700 Open Access books and are visited online by over three million academics every month. These researchers are increasingly working in broad technology-based subjects, driving multidisciplinary academic endeavours into human health, environment, and technology.
\n\nBy listening to our community, and in order to serve these rapidly growing areas which lie at the core of IntechOpen's expertise, we are launching a portfolio of Open Science journals:
\n\nAll three journals will publish under an Open Access model and embrace Open Science policies to help support the changing needs of academics in these fast-moving research areas. There will be direct links to preprint servers and data repositories, allowing full reproducibility and rapid dissemination of published papers to help accelerate the pace of research. Each journal has renowned Editors in Chief who will work alongside a global Editorial Board, delivering robust single-blind peer review. Supported by our internal editorial teams, this will ensure our authors will receive a quick, user-friendly, and personalised publishing experience.
\n\n"By launching our journals portfolio we are introducing new, dedicated homes for interdisciplinary technology-focused researchers to publish their work, whilst embracing Open Science and creating a unique global home for academics to disseminate their work. We are taking a leap toward Open Science continuing and expanding our fundamental commitment to openly sharing scientific research across the world, making it available for the benefit of all." Dr. Sara Uhac, IntechOpen CEO
\n\n"Our aim is to promote and create better science for a better world by increasing access to information and the latest scientific developments to all scientists, innovators, entrepreneurs and students and give them the opportunity to learn, observe and contribute to knowledge creation. Open Science promotes a swifter path from research to innovation to produce new products and services." Alex Lazinica, IntechOpen founder
\n\nIn conclusion, Natalia Reinic Babic, Head of Journal Publishing and Open Science at IntechOpen adds:
\n\n“On behalf of the journal team I’d like to thank all our Editors in Chief, Editorial Boards, internal supporting teams, and our scientific community for their continuous support in making this portfolio a reality - we couldn’t have done it without you! With your support in place, we are confident these journals will become as impactful and successful as our book publishing program and bring us closer to a more open (science) future.”
\n\nWe invite you to visit the journals homepage and learn more about the journal’s Editorial Boards, scope and vision as all three journals are now open for submissions.
\n\nFeel free to share this news on social media and help us mark this memorable moment!
\n\n\n'}],latestNews:[{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"8090",leadTitle:null,fullTitle:"Who Wants to Retire and Who Can Afford to Retire?",title:"Who Wants to Retire and Who Can Afford to Retire?",subtitle:null,reviewType:"peer-reviewed",abstract:"Worldwide life expectancy has increased and, as such, this book examines different aspects of aging from societal and political perspectives. Written by reputable academics working at universities around the world (Australia, New Zealand, Portugal, Taiwan, Tanzania, Russia), this book takes a kaleidoscope view of how different societies handle their aging population.",isbn:"978-1-83962-477-3",printIsbn:"978-1-83962-476-6",pdfIsbn:"978-1-83962-478-0",doi:"10.5772/intechopen.77921",price:119,priceEur:129,priceUsd:155,slug:"who-wants-to-retire-and-who-can-afford-to-retire-",numberOfPages:154,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"90fe30d224594414bb156e42afa47f5e",bookSignature:"Ingrid Muenstermann",publishedDate:"December 9th 2020",coverURL:"https://cdn.intechopen.com/books/images_new/8090.jpg",numberOfDownloads:3994,numberOfWosCitations:0,numberOfCrossrefCitations:2,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:3,numberOfDimensionsCitationsByBook:0,hasAltmetrics:1,numberOfTotalCitations:5,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"November 27th 2019",dateEndSecondStepPublish:"March 24th 2020",dateEndThirdStepPublish:"May 23rd 2020",dateEndFourthStepPublish:"August 11th 2020",dateEndFifthStepPublish:"October 10th 2020",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"77112",title:"Dr.",name:"Ingrid",middleName:null,surname:"Muenstermann",slug:"ingrid-muenstermann",fullName:"Ingrid Muenstermann",profilePictureURL:"https://mts.intechopen.com/storage/users/77112/images/system/77112.jpg",biography:"Ingrid Muenstermann was born in 1938 in Hamburg, Germany, and settled in Australia in 1973. For many years she worked as a secretary in the medical field, but discovered the rewards of becoming an academic after achieving a PhD in Social Sciences. She is a sociologist at heart and is casually employed at Flinders University of South Australia. Dr. Muenstermann has a special interest in all things equity. Of particular interest have been, and still are, new settlers to Australia with a special focus on German immigrants. The decline of the natural environment and increased societal self-interest led her to consider universal social responsibility. Lately the concept of aging and how to retire gracefully, that is, to maintain a certain standard of living, have been on her mind. She hopes to research different areas of life in the not too distant future.",institutionString:"Flinders University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"3",institution:{name:"Flinders University",institutionURL:null,country:{name:"Australia"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1337",title:"Social Welfare",slug:"social-policy-social-welfare"}],chapters:[{id:"70904",title:"Addressing the Pension Decumulation Phase of Employee Retirement Planning",doi:"10.5772/intechopen.90807",slug:"addressing-the-pension-decumulation-phase-of-employee-retirement-planning",totalDownloads:627,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Longevity increases and population ageing create challenges for all societal institutions, particularly those providing retirement income, healthcare, and long-term care services. At the individual level, an obvious question is how to ensure all retirees have an adequate, secure, stable, and predictable lifelong income stream that will allow them to maintain a target standard of living for, however, long the individual lives. In this chapter, we review and discuss the main pension decumulation options by explicitly modelling consumers’ behaviour and objectives though an objective function based on utility theory accounting for consumption and bequest motives and different risk preferences. Using a Monte-Carlo simulation approach calibrated to US financial market and mortality data, our results suggest that purchasing a capped participating longevity-linked life annuity at retirement including embedded longevity and financial options that allow the annuity provider to periodically revise annuity payments if observed survivorship and portfolio outcomes deviate from expected (or guaranteed) values at contract initiation deliver superior welfare results when compared with classical annuitization and non-annuitization decumulation strategies.",signatures:"Jorge Miguel Ventura Bravo",downloadPdfUrl:"/chapter/pdf-download/70904",previewPdfUrl:"/chapter/pdf-preview/70904",authors:[null],corrections:null},{id:"71712",title:"The Age Pension Means Tests: Contorting Australian Retirement",doi:"10.5772/intechopen.91856",slug:"the-age-pension-means-tests-contorting-australian-retirement",totalDownloads:565,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:1,abstract:"Most Australian retirees are likely to be subject to the Age Pension assets or income test at some point. Evidence is that many retirees adapt their consumption to increase Age Pension entitlements, but long-term implications are difficult to determine—even if the current rules were to remain in place. This chapter evaluates the current approach to means testing against the principles set out in a Department of Social Services discussion paper on this topic. We evaluate the implied “effective marginal tax rates” (EMTRs) on the assets of part pensioners who are subject to the assets test. We find that depending on a variety of parameters such as assumed future earnings rates, demographic status, drawdown strategy and the base level of assets held, the EMTRs are high enough to explain material distortions to savings decisions of those still in employment, and the spending and investment decisions of retirees. Optimal decisions in this context require contorted retirement strategies that do not appear to be in anyone’s interest. Some possible remedies are suggested, which should include incorporating the value of the principal residence within the assets test. The chapter therefore illustrates the application of principled analysis to policy issues of this sort.",signatures:"Anthony Asher and John De Ravin",downloadPdfUrl:"/chapter/pdf-download/71712",previewPdfUrl:"/chapter/pdf-preview/71712",authors:[null],corrections:null},{id:"71935",title:"Pathways to Retirement in Taiwan: Do Ethnicity and Cohort Matter?",doi:"10.5772/intechopen.92147",slug:"pathways-to-retirement-in-taiwan-do-ethnicity-and-cohort-matter-",totalDownloads:359,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Studies about retirement often neglect ethnic identity. This research utilized the “Taiwan Longitudinal Study in Aging” data from 1989 to 1996 when political and social changes in the country occurred to examine the influence of ethnicity (dominant Mainlanders versus Southern Min, Hakka, and various indigenous people) on Taiwanese men’s working status at age 60 and above. We asked three questions: (1) Are Mainlanders more likely to retire earlier than non-Mainlanders? (2) Does working in the public versus the private sector affect the age of retirement and does this differ by ethnicity? (3)What factors determine retirement ages of two cohorts? Using chi-square and t-tests, results of a comparison of two cohorts (n = 1254 and n = 526 for the 1989 and 1996 cohorts, respectively) showed that being a Mainlander, being unmarried, older age, self-reported poor health, and functional limitation were associated with a higher likelihood of earlier retirement. In logistic regression models, public sector work mediated and moderated the effect of ethnicity on the likelihood of earlier retirement only in the older cohort, where Mainlander public sector workers had the greatest likelihood of earlier retirement, indicating that the incentive structure of public pensions contributes to earlier retirement. The results are consistent with cumulative advantage theory. To delay the retirement age for public sector workers, policymakers could reduce public pension incentives.",signatures:"Fang-Yi Huang and Monika Ardelt",downloadPdfUrl:"/chapter/pdf-download/71935",previewPdfUrl:"/chapter/pdf-preview/71935",authors:[null],corrections:null},{id:"71893",title:"Alternatives to Serve the Interests of Russian Pensioners",doi:"10.5772/intechopen.92163",slug:"alternatives-to-serve-the-interests-of-russian-pensioners",totalDownloads:420,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:1,abstract:"The results of the analysis of statistical data on the Russian labor market, employment and wages, as well as the specific features of the Russian pension system, provide the basis for several important conclusions. Firstly, the living standards of the majority of Russian pensioners do not meet their needs as the Russian pension system is focused on the achievement of minimum living standards. Secondly, the regulation on the functioning of the pension system established by Russian legislation is often violated by the regulators without coordination with economic entities and citizens, participants of the pension system, which prevents future pensioners from feeling protected upon retirement. For this reason, citizens of the retirement age do not seek to retire even when they reach the retirement age. The growth rate of working pensioners (who pay taxes, including insurance deductions to the Pension Fund of Russia and private pension funds) confirms this. Thirdly, there is a need to create a socially-comfortable environment for pensioners, to counteract the psychological problems of older people their sense of “uselessness” to society. The article proposes practical measures to mitigate the negative phenomena in the pension provision of Russian citizens.",signatures:"Elena Ivanovna Kulikova",downloadPdfUrl:"/chapter/pdf-download/71893",previewPdfUrl:"/chapter/pdf-preview/71893",authors:[null],corrections:null},{id:"71593",title:"Called to Plan: Changing Patterns and Perceptions of Retirement for Australian and New Zealand Faith-Based Ministers",doi:"10.5772/intechopen.91901",slug:"called-to-plan-changing-patterns-and-perceptions-of-retirement-for-australian-and-new-zealand-faith-",totalDownloads:536,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The rising tide of aging citizens globally suggests a compelling argument for increasing understanding of factors impacting retirement. Factors such as health and finance have been identified as principal, but these results generally apply to homogenous groups with little reference to the impact of culture and tradition. This study adopted an ex post-facto, cross-sectional, self-reporting survey from working faith-based ministers in Australia and New Zealand to ascertain personal and professional factors affecting retirement perception in specific context including results for age-related differences. Results from four areas of foci show participants generally regarded retirement as a positive season. They were, however, less confident about their preparedness and mostly dissatisfied with the level of planning for retirement. Significant differences were noted in age-related groups with health and financial considerations constituting the primary differences. Increased understanding of changing patterns and perceptions for specific groups including age differences, potentially aids the response of state and society to the ageing phenomenon.",signatures:"Bernadene Erasmus and Peter John Morey",downloadPdfUrl:"/chapter/pdf-download/71593",previewPdfUrl:"/chapter/pdf-preview/71593",authors:[null],corrections:null},{id:"72847",title:"Lifestyles, Health, and Life Satisfaction among the Portuguese Seniors",doi:"10.5772/intechopen.93250",slug:"lifestyles-health-and-life-satisfaction-among-the-portuguese-seniors",totalDownloads:454,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"This chapter focuses on the interaction between lifestyles, health, and life satisfaction of Portuguese seniors. The aim of the analysis is to find the main determinants of health and life satisfaction and to verify the importance of lifestyle variables as determinants of health and life satisfaction. We used data collected by the National Health Survey of 2014 and estimated two ordered probits. The main results show that not all lifestyle variables are meaningful in explaining self-assessed health and life satisfaction. The determinants of the health status include education and income; however, it can be assumed that overall good health, family, or close people and income contribute to life satisfaction. A general profile of the Portuguese seniors is provided; however, the results obtained here are changing as a new scenario is emerging, generation X enters old age.",signatures:"Aida Isabel Tavares",downloadPdfUrl:"/chapter/pdf-download/72847",previewPdfUrl:"/chapter/pdf-preview/72847",authors:[{id:"196819",title:"Prof.",name:"Aida Isabel",surname:"Tavares",slug:"aida-isabel-tavares",fullName:"Aida Isabel Tavares"}],corrections:null},{id:"73975",title:"Retired but Not Tired: Entrepreneurial Motives and Performance among Retired Public Servants in Tanzania",doi:"10.5772/intechopen.94281",slug:"retired-but-not-tired-entrepreneurial-motives-and-performance-among-retired-public-servants-in-tanza",totalDownloads:413,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Venturing into a business venture at an old age is an interesting phenomenon. Retirees seem to consider this decision as imperative as it provides them with a source of earning and keeps them active post-retirement. Despite a plethora of research on entrepreneurship, there is a paucity of research on entrepreneurial behavior and performance retired public servants. The current study examines the motive and performance of businesses owned by retired public servants in Tanzania, one of the developing economies. The study used a survey of 90 randomly selected public servants who retired between 2012 and 2016. The descriptive and probit regression analyses were used to examine the entrepreneurial performance and factors associated with it. The results of the analysis suggest that the performance of the businesses is generally not good, as the majority made losses for the past 3 years consecutively. As for the determinants of performance, the study observed that age and source of capital negatively affect performance, whereas education and planning/preparations for business establishment positively influenced entrepreneurial performance. The findings imply that employees, employers and social security industry have a role to play in creating awareness and preparing public service employees for life after retirement especially in sustaining post-retirement income. Lumpsum pension and monthly allowance may be necessary, but the knowledge to manage them through profitable business ventures my be sufficient for a better post-retirement life.",signatures:"Anselm Namala and Mursali A. Milanzi",downloadPdfUrl:"/chapter/pdf-download/73975",previewPdfUrl:"/chapter/pdf-preview/73975",authors:[null],corrections:null},{id:"72453",title:"The End of the Retirement “Age”: How the New World of Work Is Transforming the Old World of Retirement",doi:"10.5772/intechopen.92273",slug:"the-end-of-the-retirement-age-how-the-new-world-of-work-is-transforming-the-old-world-of-retirement",totalDownloads:620,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:1,abstract:"The nature of work is undergoing fundamental transformation in the twenty-first century with drivers including digitalization, automation, and new forms of work organization. This chapter explores how the concept of retirement itself is increasingly redundant in relation to the new world of work. Of course, working lives inevitably do come to an end, but for whom, and at what point, and under what personal and social financial conditions, is this end point? Many people will want, and be required by public policy, to continue their working lives well into later life. In addition, the new dynamics of work and employment unfolding may enable this later life engagement. But in the “post-work” world predicted by many scholars, will later life employment be a possibility for them, and even for many people in their middle and younger years? This chapter explores the implications of the future of work for how traditional models of working lives and retirement need to be restructured and examines the one vital reform to ensure everyone can sustain a decent life in the new highly volatile world of work.",signatures:"Veronica Sheen",downloadPdfUrl:"/chapter/pdf-download/72453",previewPdfUrl:"/chapter/pdf-preview/72453",authors:[null],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"5598",title:"People's Movements in the 21st Century",subtitle:"Risks, Challenges and Benefits",isOpenForSubmission:!1,hash:"34b65e63d50ff8998006a76b46081adf",slug:"people-s-movements-in-the-21st-century-risks-challenges-and-benefits",bookSignature:"Ingrid Muenstermann",coverURL:"https://cdn.intechopen.com/books/images_new/5598.jpg",editedByType:"Edited by",editors:[{id:"77112",title:"Dr.",name:"Ingrid",surname:"Muenstermann",slug:"ingrid-muenstermann",fullName:"Ingrid Muenstermann"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6630",title:"Social Responsibility",subtitle:null,isOpenForSubmission:!1,hash:"2f6cc315119ed59e44cce41a717d6316",slug:"social-responsibility",bookSignature:"Ingrid Muenstermann",coverURL:"https://cdn.intechopen.com/books/images_new/6630.jpg",editedByType:"Edited by",editors:[{id:"77112",title:"Dr.",name:"Ingrid",surname:"Muenstermann",slug:"ingrid-muenstermann",fullName:"Ingrid Muenstermann"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophile",surname:"Theophanides",slug:"theophile-theophanides",fullName:"Theophile Theophanides"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"314",title:"Regenerative Medicine and Tissue Engineering",subtitle:"Cells and Biomaterials",isOpenForSubmission:!1,hash:"bb67e80e480c86bb8315458012d65686",slug:"regenerative-medicine-and-tissue-engineering-cells-and-biomaterials",bookSignature:"Daniel Eberli",coverURL:"https://cdn.intechopen.com/books/images_new/314.jpg",editedByType:"Edited by",editors:[{id:"6495",title:"Dr.",name:"Daniel",surname:"Eberli",slug:"daniel-eberli",fullName:"Daniel Eberli"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"57",title:"Physics and Applications of Graphene",subtitle:"Experiments",isOpenForSubmission:!1,hash:"0e6622a71cf4f02f45bfdd5691e1189a",slug:"physics-and-applications-of-graphene-experiments",bookSignature:"Sergey Mikhailov",coverURL:"https://cdn.intechopen.com/books/images_new/57.jpg",editedByType:"Edited by",editors:[{id:"16042",title:"Dr.",name:"Sergey",surname:"Mikhailov",slug:"sergey-mikhailov",fullName:"Sergey Mikhailov"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1373",title:"Ionic Liquids",subtitle:"Applications and Perspectives",isOpenForSubmission:!1,hash:"5e9ae5ae9167cde4b344e499a792c41c",slug:"ionic-liquids-applications-and-perspectives",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/1373.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],ofsBooks:[]},correction:{item:{id:"66303",slug:"corrigendum-to-rural-landscape-architecture-traditional-versus-modern-fa-ade-designs-in-western-spai",title:"Corrigendum to: Rural Landscape Architecture: Traditional versus Modern Façade Designs in Western Spain",doi:null,correctionPDFUrl:"https://cdn.intechopen.com/pdfs/66303.pdf",downloadPdfUrl:"/chapter/pdf-download/66303",previewPdfUrl:"/chapter/pdf-preview/66303",totalDownloads:null,totalCrossrefCites:null,bibtexUrl:"/chapter/bibtex/66303",risUrl:"/chapter/ris/66303",chapter:{id:"57545",slug:"rural-landscape-architecture-traditional-versus-modern-fa-ade-designs-in-western-spain",signatures:"María Jesús Montero-Parejo, Jin Su Jeong, Julio Hernández-Blanco\nand Lorenzo García-Moruno",dateSubmitted:"September 6th 2017",dateReviewed:"October 11th 2017",datePrePublished:"December 20th 2017",datePublished:"September 19th 2018",book:{id:"6066",title:"Landscape Architecture",subtitle:"The Sense of Places, Models and Applications",fullTitle:"Landscape Architecture - The Sense of Places, Models and Applications",slug:"landscape-architecture-the-sense-of-places-models-and-applications",publishedDate:"September 19th 2018",bookSignature:"Amjad Almusaed",coverURL:"https://cdn.intechopen.com/books/images_new/6066.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"110471",title:"Prof.",name:"Amjad",middleName:"Zaki",surname:"Almusaed",slug:"amjad-almusaed",fullName:"Amjad Almusaed"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"221245",title:"Dr.",name:"María Jesús",middleName:null,surname:"Montero-Parejo",fullName:"María Jesús Montero-Parejo",slug:"maria-jesus-montero-parejo",email:"cmontero@unex.es",position:null,institution:null},{id:"223556",title:"Dr.",name:"Jin Su",middleName:null,surname:"Jeong",fullName:"Jin Su Jeong",slug:"jin-su-jeong",email:"jsbliss@gmail.com",position:null,institution:null},{id:"223557",title:"Prof.",name:"Julio",middleName:null,surname:"Hernández-Blanco",fullName:"Julio Hernández-Blanco",slug:"julio-hernandez-blanco",email:"juliohb@unex.es",position:null,institution:null},{id:"223558",title:"Prof.",name:"Lorenzo",middleName:null,surname:"García-Moruno",fullName:"Lorenzo García-Moruno",slug:"lorenzo-garcia-moruno",email:"lgmoruno@unex.es",position:null,institution:null}]}},chapter:{id:"57545",slug:"rural-landscape-architecture-traditional-versus-modern-fa-ade-designs-in-western-spain",signatures:"María Jesús Montero-Parejo, Jin Su Jeong, Julio Hernández-Blanco\nand Lorenzo García-Moruno",dateSubmitted:"September 6th 2017",dateReviewed:"October 11th 2017",datePrePublished:"December 20th 2017",datePublished:"September 19th 2018",book:{id:"6066",title:"Landscape Architecture",subtitle:"The Sense of Places, Models and Applications",fullTitle:"Landscape Architecture - The Sense of Places, Models and Applications",slug:"landscape-architecture-the-sense-of-places-models-and-applications",publishedDate:"September 19th 2018",bookSignature:"Amjad Almusaed",coverURL:"https://cdn.intechopen.com/books/images_new/6066.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"110471",title:"Prof.",name:"Amjad",middleName:"Zaki",surname:"Almusaed",slug:"amjad-almusaed",fullName:"Amjad Almusaed"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"221245",title:"Dr.",name:"María Jesús",middleName:null,surname:"Montero-Parejo",fullName:"María Jesús Montero-Parejo",slug:"maria-jesus-montero-parejo",email:"cmontero@unex.es",position:null,institution:null},{id:"223556",title:"Dr.",name:"Jin Su",middleName:null,surname:"Jeong",fullName:"Jin Su Jeong",slug:"jin-su-jeong",email:"jsbliss@gmail.com",position:null,institution:null},{id:"223557",title:"Prof.",name:"Julio",middleName:null,surname:"Hernández-Blanco",fullName:"Julio Hernández-Blanco",slug:"julio-hernandez-blanco",email:"juliohb@unex.es",position:null,institution:null},{id:"223558",title:"Prof.",name:"Lorenzo",middleName:null,surname:"García-Moruno",fullName:"Lorenzo García-Moruno",slug:"lorenzo-garcia-moruno",email:"lgmoruno@unex.es",position:null,institution:null}]},book:{id:"6066",title:"Landscape Architecture",subtitle:"The Sense of Places, Models and Applications",fullTitle:"Landscape Architecture - The Sense of Places, Models and Applications",slug:"landscape-architecture-the-sense-of-places-models-and-applications",publishedDate:"September 19th 2018",bookSignature:"Amjad Almusaed",coverURL:"https://cdn.intechopen.com/books/images_new/6066.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"110471",title:"Prof.",name:"Amjad",middleName:"Zaki",surname:"Almusaed",slug:"amjad-almusaed",fullName:"Amjad Almusaed"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}}},ofsBook:{item:{type:"book",id:"11625",leadTitle:null,title:"Intensive Animal Farming - A Cost-Effective Tactic",subtitle:null,reviewType:"peer-reviewed",abstract:"
\r\n\tIntensive animal farming, also known as factory farming, is an advanced technique to maximize production while reducing the cost of production. Intensive animal farming is a very recent development in agribusiness which involves the high stocking of animals like cattle, poultry, and fish on a large scale and the use of advanced biotechnology to enhance production. Livestock, particularly cattle and poultry are important contributors to total food production in the world. Intensive animal farming is very important from the food security perspective as it involves a dense population of animals on small land and increases food production.
\r\n\r\n\tIntensive animal farming benefits global trade but it also has some harmful impacts on human health. To lessen the harmful effects of intensive farming, farmers should improve the health, welfare, and productivity of their animals through animal health planning and disease control measures that are less dependent on veterinary medicines without jeopardizing animal welfare.
\r\n\r\n\tIntensive animal farming is very prevalent in developed countries and the aim is to produce large quantities of milk, meat, and eggs at low cost. Intensive farming involves mass production through modernized feeding systems and improved breeding and health programs.
",isbn:"978-1-80356-102-8",printIsbn:"978-1-80356-101-1",pdfIsbn:"978-1-80356-103-5",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,isSalesforceBook:!1,hash:"c7c16a12a60f1131a1635594b98e2f11",bookSignature:"Dr. Shumaila Manzoor and Dr. Muhammad Abubakar",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11625.jpg",keywords:"Livestock, Animal Husbandry, Poultry Farming, Cattle Farming, Pasture Strengthening, Rotational Grazing, Concentrated Animal Feeding, Biotechnology, Antibiotic Resistance, Zoonotic Diseases, Socio-Economics Impact, Animal Welfare",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"January 27th 2022",dateEndSecondStepPublish:"February 24th 2022",dateEndThirdStepPublish:"April 25th 2022",dateEndFourthStepPublish:"July 14th 2022",dateEndFifthStepPublish:"September 12th 2022",remainingDaysToSecondStep:"3 months",secondStepPassed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"Scientist from the National Veterinary Laboratory, Pakistan, with experience of over 10 years in various areas of veterinary disease diagnosis. Dr. Manzoor’s expertise on Transboundary animal diseases (TADs) is well recognized and she has worked with FAO control programs of TADs in the country.",coeditorOneBiosketch:"An Editor-in-Chief of two journals and a Senior Scientist from the National Veterinary Laboratory with over 15 years of experience in various areas of veterinary sciences.",coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"174519",title:"Dr.",name:"Shumaila",middleName:null,surname:"Manzoor",slug:"shumaila-manzoor",fullName:"Shumaila Manzoor",profilePictureURL:"https://mts.intechopen.com/storage/users/174519/images/system/174519.jpg",biography:"Dr. Shumaila Manzoor, a scientist and laboratory worker from the National Veterinary Laboratory, Islamabad, Pakistan, has experience over 10 years in various areas of veterinary disease diagnosis. Her expertise on the Transboundary animal diseases (TADs) is well recognized and she has worked with FAO control programs of TADs in the country. She has been involved in conduct of various trainings for field as well as laboratory staff. She has published research papers, review articles and book chapters on different areas of veterinary disease diagnosis and control. She has been peer reviewer for two different journals of veterinary science “Research journal for Veterinary Practitioners and Veterinary Sciences; Research and Reviews” for over 03 years.",institutionString:"National Veterinary Laboratory",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:null}],coeditorOne:{id:"112070",title:"Dr.",name:"Muhammad",middleName:null,surname:"Abubakar",slug:"muhammad-abubakar",fullName:"Muhammad Abubakar",profilePictureURL:"https://mts.intechopen.com/storage/users/112070/images/system/112070.jpg",biography:"Dr. Muhammad Abubakar, a scientist from the National Veterinary Laboratory, Islamabad, Pakistan, has more than fifteen years of experience in various fields of veterinary sciences. His main area of expertise is transboundary animal diseases (TADs) and antimicrobial resistance (AMR). He has worked in academics as well as in the field of implementing disease control programs. He has worked with local and international projects to establish diagnostic laboratories for TADs. He has also conducted various training for field as well as laboratory staff. Dr. Abubakar has published numerous research papers, review articles, and book chapters on different subjects in the veterinary sciences, especially TADs like avian influenza, foot-and-mouth disease, and peste des petits ruminants. He is the co-editor of The Role of Biotechnology in Improvement of Livestock. He is currently an editor in chief for the Research Journal for Veterinary Practitioners and Veterinary Sciences: Research and Reviews.",institutionString:"National Veterinary Laboratory",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"6",totalChapterViews:"0",totalEditedBooks:"6",institution:null},coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"5",title:"Agricultural and Biological Sciences",slug:"agricultural-and-biological-sciences"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"444312",firstName:"Sara",lastName:"Tikel",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/444312/images/20015_n.jpg",email:"sara.t@intechopen.com",biography:"As an Author Service Manager, my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"6418",title:"Hyperspectral Imaging in Agriculture, Food and Environment",subtitle:null,isOpenForSubmission:!1,hash:"9005c36534a5dc065577a011aea13d4d",slug:"hyperspectral-imaging-in-agriculture-food-and-environment",bookSignature:"Alejandro Isabel Luna Maldonado, Humberto Rodríguez Fuentes and Juan Antonio Vidales Contreras",coverURL:"https://cdn.intechopen.com/books/images_new/6418.jpg",editedByType:"Edited by",editors:[{id:"105774",title:"Prof.",name:"Alejandro Isabel",surname:"Luna Maldonado",slug:"alejandro-isabel-luna-maldonado",fullName:"Alejandro Isabel Luna Maldonado"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10359",title:"Landraces",subtitle:"Traditional Variety and Natural Breed",isOpenForSubmission:!1,hash:"0600836fb2c422f7b624363d1e854f68",slug:"landraces-traditional-variety-and-natural-breed",bookSignature:"Amr Elkelish",coverURL:"https://cdn.intechopen.com/books/images_new/10359.jpg",editedByType:"Edited by",editors:[{id:"231337",title:"Dr.",name:"Amr",surname:"Elkelish",slug:"amr-elkelish",fullName:"Amr Elkelish"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophile",surname:"Theophanides",slug:"theophile-theophanides",fullName:"Theophile Theophanides"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"314",title:"Regenerative Medicine and Tissue Engineering",subtitle:"Cells and Biomaterials",isOpenForSubmission:!1,hash:"bb67e80e480c86bb8315458012d65686",slug:"regenerative-medicine-and-tissue-engineering-cells-and-biomaterials",bookSignature:"Daniel Eberli",coverURL:"https://cdn.intechopen.com/books/images_new/314.jpg",editedByType:"Edited by",editors:[{id:"6495",title:"Dr.",name:"Daniel",surname:"Eberli",slug:"daniel-eberli",fullName:"Daniel Eberli"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"57",title:"Physics and Applications of Graphene",subtitle:"Experiments",isOpenForSubmission:!1,hash:"0e6622a71cf4f02f45bfdd5691e1189a",slug:"physics-and-applications-of-graphene-experiments",bookSignature:"Sergey Mikhailov",coverURL:"https://cdn.intechopen.com/books/images_new/57.jpg",editedByType:"Edited by",editors:[{id:"16042",title:"Dr.",name:"Sergey",surname:"Mikhailov",slug:"sergey-mikhailov",fullName:"Sergey Mikhailov"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1373",title:"Ionic Liquids",subtitle:"Applications and Perspectives",isOpenForSubmission:!1,hash:"5e9ae5ae9167cde4b344e499a792c41c",slug:"ionic-liquids-applications-and-perspectives",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/1373.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"76224",title:"Roles of the Serotoninergic System in Coping with Traumatic Stress",doi:"10.5772/intechopen.97221",slug:"roles-of-the-serotoninergic-system-in-coping-with-traumatic-stress",body:'\nFollowing exposure to traumatic events as a succession of inescapable stressful stimuli or life-threatening accidents, most people adapt and cope with the stress and return to their normal life when the stressful event (s) has (ve) stopped. However a minority of them, 6-8% of people [1, 2] develop PTSD characterized by a variety of symptoms precisely defined by “the American Psychiatric Association’s Diagnostic and Statistical manual of Mental Disorders” [3]. It includes intrusive memories of the traumatic event, nightmares, irritability, sleep impairment, attention deficit and/or emotional withdrawal. Post-traumatic stress disorder is often associated with several comorbidities such as inflammation [4], chronic pain and heightened risk of neurodegenerative disease. This disorder is more often than we believe difficult to treat as many patients suffer from it during several years after the traumatic event has stopped. For instance, 40 years after the Vietnam War, 11% of the veterans still experienced PTSD [5]. This disorder is primarily due to an overload of traumatic sensory stimuli inducing continuous overproduction of cortisol in the brain and body [6] generating secondary cascades of deregulations that prevent a return to the original homeostatic biological state by the parasympathetic brake, essential for the patient [6, 7, 8]. These biological impairments lead to the anchoring of fear memories in the limbic cerebral circuits which include primarily the amygdala complex (AMY) handling the emotional processing related to stress associated with memory processing of the hippocampal-cortical circuits [6, 9, 10].
\nThe fact that a minority of people undergoing traumatic events don’t recover and develop long-lasting PTSD suggests that among the population different genetic/epigenetic predispositions unique for each individual impact the way patients are able to cope or not with stressful events [6]. Impairments of the limbic circuitry and activity are among the key features explaining various PTSD symptoms. Numerous examples have shown that the serotoninergic system is well positioned to modulate the activity of the amygdalo-hippocampal-prefrontal hub. The serotoninergic system is widely known to play a critical role in mood regulation and it is not surprising that different pharmacological treatments initially proposed to relieve PTSD symptoms modulate serotoninergic systems [11, 12, 13, 14]. Among them serotonin reuptake inhibitors (SSRIs; i.e. citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline) causing high extracellular 5-HT levels are classically used for their anxiolytic effects and treatment of depression and for their relative minor side effects [12, 13, 14, 15].
\nWe will review how the limbic system is modulated by changes in 5-HT homeostasis by acting through 5-HT transporter or receptors during development and in adults.
\nWe analyze knowledge obtained from relevant adult rodent models and extend them to human data when possible. Indeed, rodent models, appear useful for understanding the etiology of PTSD, as the “fear circuitry” and the endocrine responses to stress are fairly conserved across species. However, they lack the complexity of the cognitive treatment mediated by highly developed cortical circuits observed in primates [6, 16, 17, 18]. We will also review literature clearly demonstrating that imbalance in the serotonergic system during development associated or not with genetic alterations may modify the way patients are able to cope with stressful events.
\nRegardless of its intensity, stress induces primarily stimulation of the Hypothalamic-Pituitary-Adrenal (HPA) axis that coordinates the body-brain biological response through a highly regulated neurohormonal cascade. Corticotrophin releasing hormone (CRH) or factor (CRF) is released from hypothalamic neurons, letting adrenocorticotropic hormone (ACTH) out of pituitary cells, which in turn stimulates the secretion of cortisol (CORT) into the bloodstream by the adrenal cortex. Cortisol activates glucocorticoid receptors (GR) that are widely distributed in the brain, mainly along the HPA axis itself and in major limbic structures such as the amygdala complex (AMY), the hippocampal formation (HIP) and the prefrontal cortex (PFC). When the stress is qualified as « adaptive », activation of hypothalamic GR decreases HPA axis activity, creating a negative feedback loop leading to corticoid levels returning to normal with the stress responses turned off [6, 7, 8, 19]. In parallel the HPA axis interacts with the limbic structures afore mentioned which in turn participate to the feedback inhibition and feed-forward stimulation of the HPA axis that regulate stress responses [20, 21, 22]. When stressful events are perceived as particularly severe and/or persistent, the stressors can cause long-lasting changes in active stimulation of the HPA axis modifying the “body-brain” responses to CORT and CRH. In this context, corticoids flowing continuously in the brain and the body generate long lasting modifications/alterations of the limbic and cortical circuits contributing to induce a large array of PTSD symptoms [6, 7, 8] (Figure 1).
\nThe « reward/action » versus the « fear/inhibitory » circuits. Following a threat (stressor), sensory information arising from sensory stimuli is conveyed to the thalamus (light green) that relays information to the lateral amygdala (LA) of the amydgala complex (AMY; orange). The amygdala, in concert with the hippocampal and cortical memory circuits (blue), attributes an emotional valence to the stressor. When adaptive behaviour is possible, the basal nucleus (BA) of the amygdala complex is activated leading to stimulation of the « reward/action » systems (dark green) that includes the ventral tegmental area (VTA), the accumbens nucleus and the striatum. Action is also modulated by cognitive prefrontal circuits. If the threat is inescapable the central amygdala (CE) is activated, inducing an inhibition of the motor system (gray) and freezing behaviour (red). In parallel, the hypothalamus-pituitary-adrenal axis (HPA axis; yellow) induces a surge of neurohormones leading to the liberation of cortisol/corticosterone (violet) in the brain and body. When adaptive behaviour is possible and efficient, cortisol/corticosterone return to normal levels. If the stressor is too strong, HPA axis retrocontrol is blunted and cortisol production continues. In addition, inflammatory cytokines are released. Cortisol damages the prefrontal cortex and hippocampus that become hypotrophic. AMY is by contrast hypersollicitated and increased synaptic complexity of glutamatergic neurons induces its hypertrophy. Monoamines, including serotonin, that send axons in almost every brain regions mentioned are potent modulators (violet) of the reward/action and fear/freezing circuits.
The amygdala complex is considered as “a hub” of cerebral emotional processing, receiving inputs from sensory areas (including sensory thalamus), autonomic system, HIP and cortical regions such as the infra-limbic (IL) prefrontal cortex. By « computing » information stored in the HIP and cortical structures, AMY attributes an emotional valence to the event and plays a crucial role in fear learning and extinction [10, 23, 24]. In patients suffering PTSD, exaggerated responses to emotional stimuli induce hyperactivation of AMY, which become hypertrophic by the increased complexity of their glutamatergic neurons [6, 25]. Then in PTSD, the different subnuclei of AMY are modified in their connections and their complex regulation of inhibitory GABA neurons network. The basolateral nucleus (BLA) that receives sensory information stimulates abnormally the central nucleus (CE), which regulates the output of fear behavior [10, 26, 27, 28]. Different Pavlovian rodent models analyzed the neural basis for encoding association of two stimuli, a neutral stimulus (a sound, a light) and a painful stimulus (a footshock). They revealed that the lateral nucleus of the amygdala (LA) receives inputs of both stimuli, conveyed information to the basal nucleus (BA), then to the output CE which coordinates the expression of defensive behaviors such as freezing [29, 30, 31]. Recently, it was suggested that the BA may not be implicated in the defensive behavior but rather in avoidance [32]. The extended amygdala as the bed nucleus of the stria terminalis (BNST) is also largely implicated in anxiety [10, 26, 28] and its role will be developed later. The reciprocal connections of AMY with HIP and PFC, in particular IL cortex (in rodents) that participate in the inhibition of learned fears are defective in PTSD patients leading to the persistence of fearful memories and other emotional symptoms [24].
\nThe HIP is known to play a critical role in learning and memory integrating contextual information to regulate behavior (Reviewed by [33]). In PTSD, it mediates memory-related problems including persistent re-experiencing of traumatic events and impaired context-dependent modulation of memory as well as increased salience of negative emotional memories deficits in working and verbal memory [6, 34]. Studies in rats have shown that the dorsal HIP (homologous to the human posterior HIP) is mostly associated with cognitive performance while the ventral HIP (homologous to the human anterior HIP) rather participates in the regulation of stress response and affect [35]. Hippocampal volume is reduced in individuals with PTSD compared to controls. The HIP morphology is highly plastic and size reduction could indicate predisposition for PTSD while increase in volume may underlie positive responses to treatment. The HIP reciprocal connections to other brain areas are critical in these regulations; importantly, the HIP interacts with the AMY to regulate emotional arousal and consolidation of fear memories (as previously mentioned [10, 27, 36] and with the PFC to regulate memory [37].
\nThe prefrontal part (PFC) of the frontal lobe plays essential roles in attention, working memory, decision-making and regulation of emotion [38]. Its role is crucial for PTSD patients in the regulation of fear, learning, expression, and extinction [39]. Interestingly the anterior cingulate cortex (ACC) and the medial PFC (mPFC) display abnormal levels of activation in PTSD patients [40]. The human ventromedial PFC (vmPFC; analogous to the IL cortex in rodents) plays a key role in the extinction of fearful memories by processing “safety signals” and interacting with the AMY to inhibit fear expression [41]. In PTSD patients, impaired vmPFC activation leads to altered emotional processing and impaired retention of fear extinction learning. Other cortical structures such as the insular cortex (visceral regulation) intervene in the emotional processing and interoception that are altered in PTSD patients.
\nGoing back to everyday life stress regulation, the response to an adaptive stress involves motivation and action giving rise to pleasure by activation of
Serotonin is synthesized from the essential amino-acid L-tryptophan. In the blood stream, L-tryptophan is linked to serum-albumin but a free proportion that decreases with age and physiological status freely crosses the BBB (10% at postnatal day 12 when BBB is thought fully functional in rat [48]). In 5-HT-producing cells, tryptophan is then transported, accumulated and hydroxylated by the tryptophan hydroxylase (Tph) enzymes. Tryptophan hydroxylase type 2 (Tph2) is expressed in serotoninergic neurons of the raphe nuclei and myenteric neurons [49, 50] while Tph1 is expressed in the gut enterochromaffin cells, the pineal gland and various peripheral tissues [51, 52] and possibly in the placenta depending on the species [53]. 5-hydroxytryptophan is then further decarboxylated into 5-HT by the aromatic amino-acid decarboxylase (AADC). It has been shown that the availability of tryptophan to synthesize 5-HT depends on the inflammatory status of the organism. Interestingly, patients suffering PTSD develop a pro-inflammatory status with increased circulating pro-inflammatory cytokines [6]. Indoleamine 2,3-dioxygenase (IDO) is generated following inflammation and can lead to 5-HT depletion in the organism [54]. Such a state may impact the levels of 5-HT in PTSD patients and favor the emergence of depressive-like status.
\n5-HT producing cells express the SERT and vesicular monoamine transporter type 2 (VMAT2) allowing respectively 5-HT uptake and storage in those cells [55]. In the CNS these transporters regulate the level of 5-HT, not only at the synaptic cleft, but also when 5-HT is release along 5-HT-containing (5-HT+) axons in a « volume-transmission » manner [56]. The use of SSRIs have been used for treatment of PTSD symptoms [6]. In various rodent models, SSRIs were shown to relieve some of the PTSD-like symptoms (reviewed in [57]). Indeed, administration of SSRIs or ketamine ameliorate PTSD-like behavioral deficits in restraint paired forced swimming test (or other stressors) [58]. These models are attempting to reproduce unpredictable stress as those observed by soldiers experiencing war zones [59, 60, 61]. Similarly, exposure to a predator induces hyperarousal, avoidance and fear, [62, 63, 64] increases anxiety-like behavior and reduces fear extinction. In these models, animals also respond to sertraline reducing anxiety-like behavior and cue avoidance [65, 66]. Interestingly, SSRI treatment appears efficient only when administered chronically, at least for 3-6 month in patients. Initially depressive symptoms worsen by 5-HT increase activating the inhibitory 5-HT1 autoreceptors in the raphe nuclei, before they get desensitized following chronic treatment. Alternatively, the delayed therapeutic effects of SSRIs may be due to neuroplastic changes that need time to develop in mature brain [62, 67].
\n5-HT is catabolized by monoamine oxidases A or B (MAOA or MAOB; located in the mitochondria and by catechol-O-methyltransferase (COMT) [68, 69]. MAOA has higher affinity for 5-HT than MAOB and is co-expressed with MAOB in rodent serotoninergic neurons [70]. MAOs are also expressed by many non-aminergic structures, in particular MAOB is expressed in glial cells throughout the brain [71] and our unpublished results). MAOA mRNA has been detected in the deep layers of the rodent prefrontal cortex [72]. MAOs may thus regulate the amount of 5-HT locally, throughout the brain and in the peripheral tissues where they are also expressed [70, 71]. Interestingly, MAOs expression and protein synthesis are tightly regulated and have been shown to be sensitive to environmental factors such as inflammation [73] and stress. Indeed, glucocorticoids increase MAOA in the brain through the stimulation of the Kruppel-like factor11 and cell-division associated 7-Like protein pathways [74]. Animals under chronic stress show increased MAOA and 5-HIAA/5-HT ratio suggesting a higher 5-HT turnover levels [75]. MAOA inhibitors have been shown to reverse the decreased neurogenesis and dendritic plasticity in the hippocampus of chronically stressed rats [76].
\nAt least fourteen 5-HT receptor subtypes have been identified in the mammalian brain and periphery ([77, 78, 79]; see [80] for the latest classification). Isoform diversity, alternative splicing of some subtypes and RNA editing add to the complexity of serotoninergic receptor functions. With the exception of 5-HT3 receptors, all 5-HT receptors are coupled to G-proteins. According to their second messenger coupling pathways, 5-HT receptors have been categorized into four groups. 5-HT1 and 5-HT5 receptors are coupled to Gi/Go proteins and exert their inhibitory effects on adenylate cyclase, inhibiting cAMP formation. Within the raphe nuclei, 5-HT1A receptors are acting as autoreceptors inhibiting the release of 5-HT by serotoninergic neurons. After the start of SSRI treatment, they are proposed to be responsible for the initial worsening of depressive symptoms [13, 81]. 5-HT2 receptors are coupled to Gq proteins and stimulate phospholipase C to increase the hydrolysis of inositol phosphates and elevate intracellular Ca2+. 5-HT4,6,7 receptors are coupled to Gs proteins and are positively linked to adenylate cyclase and increase cAMP formation. 5-HT3 receptors are ligand-gated ion channel receptors and are a unique 5-HT receptor able to mediate fast response to neurotransmitter release [82]. It is generally admitted that, in the limbic structures 5-HT1A receptors are mainly expressed by glutamatergic neurons. 5-HT3 receptors are expressed by subtypes of interneurons expressing mainly the vasoactive intestinal peptide (VIP), cholecystokinin (CCK) or calretinin (CR) (but never expressing parvalbumin (PV) and rarely somatostatin (SOM)). 5-HT2 receptors are expressed in both neuronal populations [83, 84, 85]. 5-HT7 receptor expression has been shown in the deep layers of the rodent prefrontal cortex. For additional precision, see also [86].
\nDifferent subsets of 5-HT+ neurons of brainstem raphe nuclei (average of 26 000 neurons in rodents) send diffuse axonal networks to specific brain areas throughout the brain. Pioneer studies using 5-HT or SERT Immunolabeling, coupled or not to retrograde tracing [87, 88, 89] provided a general description of these 5-HT projections towards numerous areas including the cerebral cortex. More recently, anterograde tracing (injection of adeno-associated viruses) in raphe nuclei of mice conditionally expressing the green fluorescent protein/channel rhodopsin under the control of the SERT or TPH2 promoter [47, 90, 91] have provided evidence that limbic structures receive 5-HT afferences from topographically organized subpopulations of dorsal DR (the largest 5-HT+ nuclei in rodent and primates) and median raphe nuclei (MnR). Using genetic activation of specific 5-HT+ projections, some studies allowed to correlate activation/inhibition of specific 5-HT+ subgroups/afferences to behaviour. Interestingly they revealed that DR and MnR 5-HT+ neurons should be apprehended as neuronal populations having the ability to release a large numbers of neurotransmitters and neuropeptides in addition to 5-HT [92, 93]. Such a diversity in subtypes, targeting and functions is already underlined by the complexity observed in 5-HT+ developmental programming (i.e. specification and axonal targeting; see [93, 94]).
\nAs a whole, it is generally admitted that exposure to a severe/inescapable shock as in predator exposure, social defeat or other stress conditions [95] induces a surge of 5-HT in the vicinity of DR/MnR and in the corticolimbic structures such as the AMY, HIP and mPFC. Only a few studies have reported a decrease of serotoninergic activity following severe stressful situation. That may match with the genuine possibility of specific individual/strain to cope with stress [96]. Interestingly, around 80% of 5-HT+ neurons in the ventral portion of the DR (DRv) and MnR express the vesicular glutamate transporter type 3 (Vglut3) and send axons to AMY and HIP. These neurons can release 5-HT and/or glutamate and then modulate the activation of AMY and HIP [93, 94, 97]. Generally, low frequency stimulation (<10Hz) induces glutamate release resulting in fast excitation of the targeted neuron while higher frequency stimulations (10-20Hz) induce 5-HT release suggesting that these neurons could rapidly switch their neurotransmitter output depending on activation [97]. A subgroup of DR 5-HT+/Vglut3+ neurons projecting to the nucleus accumbens (NAc) and orbitofrontal cortex (OPFc) to specifically receive inputs and integrate information from “reward encoding regions” such as the ventral pallidum. Conversely, another group of DR 5-HT+/Vglut3+ neurons specifically receives inputs from the “fear encoding regions” (periacqueducal grey (PAG) and LC) and project to the BA. This last subpopulation appears to potentiate fear via the 5-HT1A and 5-HT2A receptor pathways and to impair fear extinction [98]. Interestingly, in rats some DRv 5-HT+/Vglut3+ neurons are sensitive to CRH released by the AMY that induces a decrease of TPH2 in them and ameliorates stress-induced anhedonia [99]. The level of TPH2 regulation by CRH could be the signature of a resilience status [99]. In the MnR 5-HT+/Vglut3+ neurons appear to integrate selectively negative events and may play a central role in depression-related mood disorders [100]. Subgroups of MnR 5-HT neurons express the type 2 CRH receptor. These examples illustrate the complexity of the 5-HT neuron-driven behaviors. Possible co-transmission based on gene expression suggests that DR and MnR 5-HT+ neurons could potentially also co-release GABA, dynorphin, galanin, cholecystokinin (CCK), nitric oxide (NO), CRH and other neuropeptides for which a role remains to be established (Reviewed in [93]).
\nSerotoninergic axonal projections to the AMY mainly arise from 5HT+ DR neurons while only rare axons arise from MnR. The 5-HT+ axonal density is strong in BA, moderate in LA, and moderate to low in CE, intercalated nuclei and BNST [87, 89, 91]. 5-HT axons target both glutamatergic principal neurons (PN, not interneurons) bearing 5-HT2C receptors in LA and, 5-HT2A/1A receptors in BA and a variety of GABAergic interneurons [101]. GABAergic interneurons expressing PV bear 5-HT2A, receptors receive inputs from glutamatergic PN and project reciprocally on them and on somatostatin-expressing (SOM+) GABAergic neurons. 5-HT exerts most of its effects on PV+ GABAergic neurons that express the strongest levels of 5-HT2A receptors and facilitate GABAergic inhibition. Following inescapable stress 5-HT2A-receptor mediated facilitating actions are severely impaired. 5-HT2A receptor-mRNA is downregulated following the surge of 5-HT in the AMY leading to hyperactivity of PN neurons [102]. Neuropeptide Y-containing (NPY+) (5-HT2C+ and 5-HT1A+ receptor) and CCK+ and VIP+ (5-HT3A+receptor) also project on glutamatergic PN (Figure 2 in [15]. Within the BA and LA the role of 5-HT3A remains to be clarified. Glutamatergic principal neurons of LA and BA send numerous efferents to CE and to a lesser extent to BNST. These plastic efferent fields are sensitive to environmental conditions and in PTSD patients this could be responsible for the increased sensitivity of CE and BNST [103, 104]. The lateral part of the CE (CEL) receives major inputs from BA and LA but also from ventral HIP or sensory regions. CE is mainly populated by GABAergic interneurons. When avoidance of stressful stimulus is possible CRH+ GABAergic neurons are activated and SOM+ GABAergic projection neurons are inhibited [105]. Following fear conditioning, SOM+ GABAergic projection neurons disinhibiting the medial part of the CE (CEM) allowed a range of defensive behaviour as freezing [105, 106, 107] and fear recall [108]. Direct cross-talk between CRH+ and SOM+ neuronal populations allow the specific appropriate action [105].
\nThe amygdala complex is modulated by serotonin via various 5-HT receptor expressions. A, The major GABAergic neuron subtypes modulating the function of the amygdala complex are represented in the left panel. They could be subdivided into four main classes: the somatostatin-containing (SOM; orange), the 5-HT3A-expressing (5-HT3A; green), the parvalbumin-containing (PV; bleu) and the neuropeptide Y-containing (NPY; pink). The 5-HT3A-expressing GABAergic neurons could be further subdivided into three classes: the vasoactive intestinal peptide-containing (VIP), the cholecystokinin-containing (CCK) and the calretinin-containing (CR) GABAergic neurons. Their activities are modulated by serotoninergic axons arising from the dorsal raphe nucleus (violet arrows). B, In the amygdala complex, the lateral amygdala (LA) glutamatergic neurons (principal neurons, PN; black) that receive thalamic inputs stimulate glutamatergic neurons (principal neurons; PN) of the basal complex (BA; black). These neuronal populations are modulated by 5-HT2A/2C receptors and 5-HT1A autoreceptors. Glutamatergic BA neurons send outputs to the ventral hippocampus (vHPC) and to the ventromedial prefrontal cortex (vmPFC). LA and BA stimulate neurons of the central amygdala (CE). The central amygdala (CE) is mainly composed of GABAergic neurons. Lateral CE (CEL) contains GABAergic projection neurons that express somatostatin (SOM+) and are modulated by 5-HT2A receptors. These neurons send outputs to the medial CE (CEM) that drives the anxiogenic pathway. CEM modulates the periaqueducal gray (PAG) and brainstem to induce freezing behaviour. By contrast, CEL receives corticotropin-releasing factor inputs (CRF+; yellow) that suppresses anxiety-like behaviour and anxiogenic pathway. Cross-talk between CRF+ and CEL neurons are continuous (double headed arrow).
Interestingly, 5-HT2A receptors are expressed by SOM+ neurons of the CEL and the selective 5-HT2A receptor inactivation in CEL increases innate freezing behaviour but decreases learned freezing induced by predator odor. Innate freezing behaviour and risk assessment are processed by the dorsal PAG while learned freezing is processed by the ventral PAG. These data suggest that 5-HT2A receptor control innate freezing behaviour by the AMY-hypothalamus-dPAG pathway [109, 110]. As innate and acquired fears are controlled by antagonistic mechanisms, drugs that treat one type of fear could worsen the other one, leading to paradoxical results. Risperidon is largely used to treat various psychiatric disorders including PTSD. Although its main therapeutic target acts by antagonizing dopamine-D2 receptors, it is also targeting 5-HT2 and therefore should be used carefully.
\nThe activity of the bed nucleus of the stria terminalis (BNST) is correlated with fear mediated by uncertain threats [111]. It integrates fear, reward and stress-related circuits. BNST receives inputs from various limbic structures including BA and CE. The BNST displays a rich array of 5-HT receptors which define the three cell types I-III identified in this structure [112]. The 5-HT1A receptor is the most abundant in BNST and the global effect of increased 5-HT in the BNST is a hyperpolarization of type I BNST neurons [113, 114]. Such hyperpolarization is associated with suppression of anxiety [115]. By contrast, type III cells express 5-HT2C receptors and CRH and send outputs to the same hypothalamic and brainstem targets to which the CE projects and stimulate the anxiogenic pathway [116]. 5-HT2C receptor-mRNA splicing/editing that leads to overexpression of 5-HT2C receptors enhances anxiety and innate fear behaviour [117]. Specific 5-HT2C receptor antagonists are now considered as possible compounds to treat anxiety disorders including PTSD as they relieve anxiety symptoms in patients and are well tolerated [118]. Interestingly, high-frequency BLA stimulations in rat models of anxiety or PTSD reduce anxiety-like behaviour following exposure to predator odor. These results can be compared to those observed after deep brain stimulation in humans [119].
\nA dense serotoninergic innervation from the MnR is present in the hippocampus proper and has a powerful modulatory influence on hippocampal functions and memory formation [120]. In the CA1-CA3 hippocampal fields, stimulation of serotoninergic axons potentiates excitatory synapses and has positive effects on spatial memory processing in the dorsal hippocampus. Conversely, optogenetic silencing of CA1 5-HT terminals within the dorsal hippocampus inhibits spatial memory. Systemic modulation of 5-HT4 receptor function can impact memory formation. PTSD patients display memory deficits in encoding and retrieval as well as in extinction learning such as fear extinction. In these patients, the hippocampal volume is smaller [121]. This is a consequence of the damage caused by the continuous release of cortisol associated with an increase of glutamate release (Figure 3).
\nThe hippocampus and the medial prefrontal cortex are modulated by serotonin via various 5-HT receptors. A. The major GABAergic neuron subtypes modulating the function of the hippocampus and the medial prefrontal cortex are represented in the left panel. They could be subdivided into four main classes: the somatostatin-containing (SOM; orange), the 5-HT3A-expressing (5-HT3A; green), the parvalbumin-containing (PV; bleu) and the neuropeptide Y-containing (NPY; pink). The 5-HT3A-expressing GABAergic neurons could be further subdivided into three classes: the vasoactive intestinal peptide-containing (VIP), the cholecystokinin-containing (CCK) and the calretinin-containing (CR) GABAergic neurons. Their activities are modulated by serotoninergic axons arising from the dorsal (violet arrows) and median (MnR) raphe nuclei (purple arrows). B, The CA1-CA3 hippocampal neurons express 5-HT2A,4,7, receptors and 5-HT1A autoreceptors, they send axonal projections to the prefrontal cortex (mPFC), amygdala and the raphe. C, The prefrontal pyramidal glutamatergic neurons express 5-HT2A,2C,4 receptors and 5-HT1A autoreceptors. In addition 5-HT7 receptors are transiently expressed in layer 5-6 (L5-6) pyramidal neurons. The mPFC send axons to the hippocampus with which its activity is synchronized and to the amygdala and raphe nuclei. D, The dorsal (violet) and/or medial (purple) raphe nuclei send axons to the different structures mentioned above. A large number of raphe neurons located in the medial dorsal raphe (DR) and in the medial raphe (MnR) contain 5-HT and express the vesicular glutamate transporter type 3 (Vglut3; red dots in raphe). Some raphe neurons are sensitive to the corticotropin-releasing hormone (CRH; yellow).
MnR also sends axons to the ventral part of the hippocampus that is more specifically involved in anxiety-related disorders. Indeed, rats infused bilaterally with 5,7-dihydroxytryptamine (that induces a drastic reduction (80%) of 5-HT levels in the structure) in the ventral hippocampus spend less time in the open arm of an elevated plus maze. This suggests that reducing 5-HT level in the ventral hippocampus increases anxiety-like behavior [122]. In the same line of evidence, a rat strain selected for high levels of anxiety displayed reduced stress-induced 5-HT activation [123]. Increased anxiety-like behavior has been associated with decreased 5-HT1A receptor numbers in the ventral hippocampus [124] while reduced anxiety-like behavior has been reported to be associated with global overexpression of 5-HT1A receptors [125]. 5-HT2 receptors are expressed in both glutamatergic and GABAergic neurons of the hippocampus. 5-HT2 receptors modulate 5-HT-induced outward currents in hippocampal pyramidal neurons and facilitate GABAergic transmission [85]. The precise roles of hippocampal 5-HT2 receptors in the control of anxiety-like phenotype remains to be investigated.
\nThe modulation of 5-HT7 receptors appears promising for the treatment of PTSD. 5-HT7 receptors are expressed by CA3 neurons and activation of 5-HT7 receptors hyperpolarizes these neurons and induces freezing. By contrast, infusion of 5-HT7 antagonists in the ventral hippocampus decreases freezing behaviour induced by contextual fear conditioning [126, 127]. Since blockade of MnR 5-HT+/CRH2+ neurons reverse the effect mediated by 5-HT released in the ventral hippocampus, it has been speculated that 5-HT7+ CA3 neurons would receive specific 5-HT+/CRH2+ inputs [127]. 5-HT7 receptor antagonists are already used for the treatment of colonic intestinal symptoms and could be safely used for the treatment of fear-related disorders [128].
\n5-HT4 receptor antagonists appear to modulate stress induced defecation but not freezing suggesting that this role may engage different sub-circuits [127]. 5-HT4 receptor agonists may act rapidly and reduce immobility in forced swimming test, decrease sucrose intake following chronic mild stress and have been shown to display antidepressant potential. Drugs acting on 5-HT4 receptors should be carefully considered and used depending on the level/type of stress induced by the trauma [129].
\nThe serotoninergic system appears a potent regulator of the PFC circuitry acting through a variety of 5-HT receptors [85, 92, 130]. Throughout the rodent PFC, pyramidal neurons largely express 5-HT1A, 5-HT2A and 5-HT2c receptors. Some pyramidal neurons co-express 5-HT1A/5-HT2A receptors [131] whereas 5-HT2A and 5-HT2c receptors are expressed by overlapping populations [132]. The 5-HT2A receptor is more strongly expressed by layer 5 neurons [133, 134, 135]. 5-HT4 receptors are expressed by PFC glutamatergic neurons [136] and pyramidal neurons of deep layers express transiently (P2-P14) 5-HT7 receptors [137]. GABAergic interneurons express a large array of 5-HT receptors that mainly segregated in two subpopulations: 1/ the PV+ fast-spiking interneurons and the SOM+ interneurons both localized in deep cortical layers and expressing 5-HT1A and 5-HT2A receptors [130] and 2/the slow-spiking interneurons (VIP+, CR+) located in the superficial cortical layers and expressing 5-HT3A receptors [83, 84, 138]. This variety of 5-HT receptor expression allows 5-HT to finely tune the excitability of pyramidal neurons, and therefore control the mPFC top-down exerted on other structures, such as the AMY, the HIP and raphe nuclei.
\nThe global effect of 5-HT application in vitro or the stimulation of endogenous 5-HT release in vivo in PFC is inhibitory and mediated by 5-HT1A receptors. 5-HT1A receptor stimulation (via LY341495) appears to play antidepressant role as shown by the reduction of the immobility time in 24h forced swim test which is partially reversed by infusion of the 5-HT1A receptor antagonist WAY100635 in the mPFC [139]. Regulation of the GABAergic tone in the AMY (BLA) appears to be sensitive to mPFC top down-down control. 5-HT depletion in the mPFC increases expression of the immediate early gene c-fos in the BLA in the forced swimming test. It reduces GABA release induced by stress in the AMY [140, 141]. Moreover, unilateral 5-HT depletion in mPFC and infusion of an inhibitor of GABA synthesis into the contralateral BLA, selectively decrease immobility in the forced swimming test by inducing a “disconnection” between the PFC and the AMY [140].
\nThe 5-HT2A receptor is the major excitatory serotonin receptor in the brain. 5-HT2A receptors have been implicated in mediating specific aspects of stress-induced responses. Indeed, stressful events as those induced by a six week isolation in rat, induces 5-HT2A upregulation participating in anchoring the associative memory related to the stressful event [142, 143]. In humans, the density of 5-HT2A receptors in the mPFC was negatively associated with reduced threat-related right AMY reactivity [144].
\nmPFC and HIP form a functional neural networks as their activities are highly synchronized. Specific oscillatory activities, detectable by EEG, correlate with specific behaviors [85] and may provide means for regulating neural communications. Synchronous firing between different neuronal populations should more efficiently in driving the firing of downstream neurons. Such process is important for complex cognitive tasks that require coordination of long-range networks across the brain. Interestingly, in humans transcranial stimulation or deep-brain stimulation in mPFC can assist major treatment-resistant depression probably by stimulating the afore-mentioned pathway [145].
\nPFC and raphe nuclei form a functional loop. PFC is reciprocally connected to both the DR and MnR [146] and exerts a top-down control on 5-HT neurons. Descending excitatory fibers from the PFC exert complex functional regulation of 5-HT neuronal activity with an overall inhibitory effect mediated by 5-HT1A autoreceptors and feedforward inhibition [147, 148]. 5-HT2C receptors, the targets of antidepressant (mirtazapine, agomelatine) and antipsychotic drugs are expressed by GABAergic interneurons of the PFC and may function in a negative feedback loop involving reciprocal interactions between GABAergic and serotonergic neurons [149]. 5-HT4 and 5-HT7 receptors also exert a top-down control on DR and MnR 5-HT+ neurons. 5-HT4 receptor activation is associated with hypophagia induced by stress [150]. Selective activation of 5-HT4 receptors in the PFC has been shown to induce modifications of SERT (dowregulation) and 5-HT1A receptors and an increase in 5-HT release in the raphe [150]. 5-HT7 receptors are transiently co-expressed with SERT in layers 5-6 neurons of mPFC during the P2-P14 period in mice, and modulate the development of mPFC neurons [137]. While SERT inhibition (SSRI treatment) during the P2-P14 period induces an increase in the number of mPFC synaptic contacts on DR neurons, ablation of 5-HT7 (as observed in SERT-KO mice) induces a reduction of synaptic contacts in mPFC to DR [72, 137]. Therefore 5-HT7 receptor inhibition counteracts the developmental effect mediated by SERT inhibition. SSRI treatment at P2-P14 or 5-HT7 overexpression induces anxiety and depressive-like symptoms in adult mice. Such P2-P14 period is likely to correspond to the last trimester of pregnancy in humans [151]. During this period fetuses/babies (via the maternal milk) are highly impacted by maternal SSRI intake (see section 5). Since SERT-KO mice are not developing altered behavior, 5-HT7 receptor antagonists appear as good candidate for the treatment of mood disorder during pregnancy or post-partum [152, 153]).
\nInterestingly, the developmental maturation of the prefrontal cortex lasts far further into adolescence, up to the age of 20-24 years in humans [154]. Whether stress impacts the development apart the mature functions of mPFC is thus difficult to shape. Furthermore, the developmental expression of SERT in fetuses or infants is not known and much work has to be done to clarify the possible period of vulnerability to SSRI intake in humans (see [138] and section 5).
\nWhen reviewing the role of 5-HT in the predisposition to develop PTSD or to cope with stress, it is necessary to untangle what is due to developmental modifications of the neuronal circuits apart from what is specifically due to modifications occurring at mature stages. During development, environmental stimuli sculpt neuronal circuits by an experience-dependent axon/synaptic refinement and pruning over the course of different critical periods, specific for each structure/function (i.e. the prefrontal system maturing all along development [154]). These processes have been shown to be highly sensitive to the imbalance in 5-HT levels depending on numerous genetic/epigenetic modifications of genes encoding the various actors of different 5-HT systems [93, 138, 151].
\nAlthough more complex, the development of 5-HT neurons largely depends on two transcription factors Lmx1b and Pet-1 [93, 94, 155, 156]. In Pet-1 knockout (KO) mice only few 5-HT+ neurons are preserved [155]. They correspond to 5-HT+ neurons located in the hypothalamic paraventricular nucleus (PVH), the ventral PAG and the ventral medulla, all projecting to the AMY while other brain targets are deprived of 5-HT+ axons. In conflict models, these mice show decreased levels of anxiety but enhanced freezing in fear conditioning tests. This suggests that 5-HT neurons could mediate anxiogenic effects in unconditioned anxiety tasks mainly through the innervation of forebrain areas such as the medial PFC and HIP, which receive no 5-HT innervation in Pet-1KO mice. Conversely data also suggests in Pet-1KO, that 5-HT might inhibit fear responses through the remaining 5-HT innervation toward specific AMY and PAG subnuclei [94, 156]. Further studies are needed for a better understanding of the contradictory effects of 5-HT on fear/anxiety responses in this model. Alternatively, compensatory mechanisms may occur in Pet1-KO mice that remain to go into in depth.
\nIn the mouse, a single-nucleotide polymorphism (SNP) has been identified in the
In serotoninergic cell bodies and axons 5-HT is stored into vesicles preventing its degradation. Evidences that VMAT2 may play a role in regulating stress-related pathology was first discovered by reserpine treatment given to patients. Reserpine blocks VMATs function and induced depressive-like symptoms in humans. Reserpine’s effect appears due to a defective storage of both catecholamine and 5-HT [162]. Mice displaying an altered copy of the VMAT2 allele display exaggerated corticosterone levels in response to forced swim test but respond normally to classic tests measuring anxiety-like behavior. Together this suggests that VMAT2 might play a role in regulating “depressive-like” behavior [163]. Magnitude to the antidepressant-like response appears to depend on the
As discussed above, SSRIs are largely used for their anti-depressant and anti-anxiogenic effects in adults. However, despite the fact that they are largely used in pregnant women (2-13% of women [165]) suffering mood disorders, it has been clearly shown that they have paradoxical long-term effects on fetuses and infant development. When administered during perinatal periods SSRIs increased the risk to develop anxiety and depression in infancy. SSRIs cross the placenta, are detectable in breast milk and reach the developing brain where they disturb the development of neuronal circuitry. During gestation SSRIs induced a reduction of blood flow in the middle cerebral artery and reduced fetal head growth [166, 167]. SSRIs impair motor movements, speech perception at 6-10 months of age, increased irritability and altered psychomotor development in children [168, 169]. When given during pregnancy, they induce a two-fold increased predisposition to develop autism-spectrum disorder [170]. Such alterations appeared correlated with higher dosage of SSRIs [171].
\nThese various developmental roles are mainly related to the different developmental time windows in which SERT is expressed by a large array of glutamatergic neurons, increasing extracellular 5-HT levels and modulating the synaptic and axonal maturation of these neurons. Such a role has been first illustrated by pioneer studies analyzing the development of the somatosensory and visual system. In these systems, 5-HT excess acting via 5-HT1B receptors, reduced glutamate release and induced the maintenance of immature features by SERT+ axons [172, 173, 174, 175, 176, 177]. In the limbic system SERT expression has been described in the HIP, the AMY, the mPFC (for exhaustive list and time-window of expression see Table 1 in [173] and Figure 3 in [178]). However, in these regions, SERT+ neurons do not appear to express 5-HT1B receptors during development and are modulated by excess 5-HT via other pathways that remained to be identified.
\nSimilarly, genetic downregulation of the SERT causes depression-related behaviors of developmental origin. In humans, a lesser-expressing form of Slc6a4, the so-called short allele variant (Slc6a4s), has been associated with an increased risk of developing depression in response to early-life stress [179, 180]. This mutation also induces a decreased volume and activity of vmPFC, a structure actively implicated in the control of stress-coping response, which is hypoactive in depressive patients (review in [181]). Interestingly, in mice a subset of glutamatergic neurons located in the layer 5-6 of the IL cortex that transiently express SERT during early postnatal life (P2-P11) project to the DR. Conditional SERT ablation in those neurons leads to a 40% increase in the number of functional PFC synapses onto both 5-HT and GABA neurons of the DR, an effect that is reproduced by postnatal fluoxetine administration. Alteration of this neuronal population has been shown to mediate the depressive- and anxiety-like symptoms observed in adults previously subjected to early postnatal exposure to SSRIs. Thus, this neuronal population provides a top–down control of emotional deficits induced by exposure to SSRIs during early postnatal life, resulting in long-lasting effects on mood. Interestingly, 5-HT blockade during the P2-P11 period also impacts the development of prelimbic (PL) pyramidal neurons that neighbor IL neurons but in a reverse way. These neuronal populations which normally play a role in promoting fear extinction or inhibiting fear extinction respectively are permanently altered by SERT blockade leading to the emergence of affective and fear-related altered behaviours [72, 182].
\nLong life expression changes in SERT expression, such as those observed in mice knockout for SERT (SERT-KO) or overexpressing SERT (SERT-OE) result in altered development of limbic structures. SERT-KO mice display impaired recall of fear extinction compared to wild-type littermate controls. In these mice, BA and LA principal glutamatergic neurons display abnormal dendritic spine density [183]. Conversely, SERT-OE mice have lower extracellular 5-HT levels [184] and exhibit impaired fear learning [185]. Genetic manipulation of SERT during development induces compensatory mechanisms leading to modified levels of 5-HT1A [11] and 5-HT2A receptor expression [185, 186] in the AMY. Constitutive low levels of 5-HT2A receptors in BA and LA may result in a reduced GABAergic tone in this structure that would be hyperresponsive to traumatic reminders or even innocuous stimuli [102].
\nIt is to note that other risk alleles could interact within a context of SERT deficiency and further increase the risk for abnormal neural circuitry development. For instance, it has been observed in rodents that
MAOA blockade was one of the first treatments used in humans to relieve symptoms of depression. However they showed side effects since they increased anxiety-like behavior and caused resistance to chronic mild stress habituation [189]. MAOA-KO mice display increase 5-HT levels in the brain that normalized with age (by 6 months). These mice show exaggerated unconditioned and conditioned fear behavior as well as increase aggressive-like behavior [190]. Such increased outbursts of aggressive behavior were also observed in a Dutch family by men lacking MAOA gene (MAOA is located on the X chromosome [191]). More common variants located on the MAOA promoter leading to a low MAOA activity induce, in humans, various social and emotional alterations. They were associated with increased responses of the HIP and AMY to threatening faces and with a reduction of grey matter volume in anterior cingulate cortex, insula and HIP and increased orbitofrontal volumes [192, 193]. Interestingly, human carrier of a hyperactive MAOA form tends to be more prone to depressive-like behavior [194]. By contrast, human carriers of the hypoactive form of MAOA show higher subjective stress, lesser glucocorticoid responses and blunted HPA axis response to chronic stress reflecting HPA axis exhaustion [195]. However, such alterations probably of developmental origin, could not be attributed specifically to 5-HT increase but could also be due to the norepinephrine increase characterized in early developmental and adulthood of MAOA-KO mice [190]. Various interindividual DNA methylations were detected on the promoter core of MAOA in peripheral circulating white cells and appear to predict efficiently the MAOA brain endophenotype and the susceptibility to stressful events [196]. Interestingly, the levels of MAOA methylation return to normal during the process of cognitive therapy of patients undergoing panic disorders. This study suggests that modification of MAOA methylation is part of a process that mediates fear extinction [197, 198].
\n5-HT appeared early on the scale of evolution and is highly conserved across species. 5-HT modulates nearly all the functions that are needed to sustain life and is also implicated in the formation of brain circuits. Despite the fact that 5-HT was one of the first neurotransmitters/neurohormones discovered, the large number of receptors that mediate its role make it difficult to apprehend how 5-HT regulate these functions. Indeed, some 5-HT receptor expressions and time of expressions (they may be transiently expressed) are still to be determined in rodents and in humans. Even regions and times of SERT expression remains to be established in humans. The treatment of PTSD is complex depending on the delay from the stressful event and although SSRIs associated with various psychotherapies were initially largely prescribed, alternative pharmacological treatments are emerging. Some of them rely on 5-HT and modulate specific receptors, but a large array of pharmacological treatments currently used or clinically tested modulate other neurotransmitters, neurohormones or neuropeptides. They however all have a common goal: to decrease the strength of traumatic memories, to eliminate the pathological memories by reconsolidation blockade or even reducing the association between the traumatic event and the negative emotional valence. Anyway, the history of a patient and its genetic/epigenetic makeup he bears largely impact the way he will cope with a stressor. Regarding this last point it is clear that individual specificities of the 5-HT system will influence how people are coping with stress (Figure 4).
\nEtiology of Post-traumatic Stress Disorder and possible treatments. Risk or protective factors may impact the way people cope with a stressor. This includes the genetic makeup specific to a patient and its personal history. We point here the role of epigenetic modifications impacting the serotoninergic system, the status of the mother during gestation and lactation. In particular, inflammatory status of the patient or of its mother while pregnant could lead to 5-HT depletion (central or peripheral). Maternal serotonin reuptake inhibitors (SSRIs) intake induces increase 5-HT levels in the embryo, the fetus and in the maternal milk. Recently 5-H7 antagonists were suggested to be used instead of classical SSRIs as they may induce fewer side effects. After the trauma, there is a short intervention time during which the weight of a traumatic memory could be decreased by pharmacological tools. In addition to the norepinephrine receptor (NER) blockade, alternative therapeutics are currently tested or considered. When Post-Traumatic Stress Disorder is clearly installed pharmacological treatment in combination with psychotherapy could be used to both alleviate the symptom and decrease the strength of traumatic memories. Alternative treatments are emerging some of them target the serotoninergic system. Blue Blocks depict the patient history and the emergence of PTSD induced by the resurgence of the traumatic event. Green blocks review what is already clearly established. Violet blocks review what should be considered and the interrogation point indicates that the cited compound should be tested with caution. 5-HT, 5-hydroxytryptamin; 5-HTRs, 5-hydroxytryptamin receptor; Ago., agonist; Antago., antagonist; CCK, cholecystokinin; CRH, corticotropin releasing hormone; DA, dopamine; GABA, gamma aminobutyric acid; MAOs, monoamine oxidase; MDMA, 3,4-Methylenedioxymethamphetamine; NE, norepinephrine; NER, norepinephrine receptor; NMDA, n-methyl-D-aspartate; NPY, neuropeptide Y; SERT, serotonin transporter; SSRIs, serotonin reuptake inhibitors; SP, substance P; TPH2, tryptophan hydroxylase 2; TPH1, tryptophan hydroxylase 1; VMAT2, vesicular.
TV was founded by the inserm and “The Fondation de France” grant No 00089602. TV and CV warmly thank Dr Pierre Gressens for constant support. TV wish to thank Drs Guilan Vodjdani and Sylvie Berard and, Oriane Bergiers and Renald Buzenet, two master students in the lab and H. Langzam for fruitful discussions.
\n\n 5-hydroxytryptamin 5hydroxyindolacetic acid aminoacid decarboxylase adrenocorticotropic hormone amygdala complex basal nucleus of amygdala brain blood barrier basolateral nucleus of amygdala bed nucleus of the stria terminalis cyclic adenosin monophosphate hippocampal fields cholecystokinin central nucleus of amygdala lateral part of the CE medial part of the CE central nervous system catéchol-O-méthyltransferase cortisol/corticosterone calretinin corticotrophin releasing hormone/factor dorsal raphe nuclei ventral dorsal raphe gamma aminobutyric acid glucocorticoid receptors hippocampal formation hypothalamic-pituitary-adrenal axis indoleamine 2,3-dioxygenase infralimbic cortex knockout lateral nucleus of the amygdala locus coeruleus monoamine oxidase A monoamine oxidase B median raphe nucleus nucleus accumbens nitric oxide neuropeptide Y orbitoprefrontal cortex over expression periacqueductal grey prefrontal cortex prelimbic cortex principal glutamatergic neurons post-traumatic stress disorder parvalbumin paraventricular nucleus of the hypothalamus serotonin transporter single-nucleotide polymorphism somatostatin serotonin reuptake inhibitor tyrosine Hydroxylase tryptophan hydroxylase tryptophan hydroxylase type1 tryptophan hydroxylase type 2 vesicular glutamate transporter 3 vasoactive intestinal polypeptide vesicular monoamine transporter 2 ventromedial prefrontal cortex ventral tegmental area
Multiple sclerosis (MS) is a demyelinating disorder with an underlying neuroinflammatory disease process affecting approximately 2.5 million people worldwide [1]. Traditionally, the disease has a greater prevalence in locations which are geographically north of the equator. In a study from 2015, North America and Europe had an average prevalence of greater than 100/100,000 individuals, whereas East Asia and Sub-Saharan Africa had rates of 2/100,000 individuals [2].
\nTo better understand this disparity, an umbrella systemic review looked at the possible environmental risk factors involved in the development of multiple sclerosis [3]. An analysis of 44 potential risk factors was filtered down to 3 which were found to be profoundly significant: anti-Epstein-Barr Virus Nuclear Antigen IgG seropositivity, infectious mononucleosis, and smoking [3]. The hypothesis behind anti-EBVNA IgG suggests that late adolescence exposure to EBV leads to infectious mononucleosis with significantly elevated IgG titers when compared to individuals who were exposed at a younger age [4, 5]. These titers in turn correlate to an increased risk of developing multiple sclerosis. One study done on this, “high-hygiene” population found that individuals of the same age who were not infected with EBV had a 10-fold lower risk of developing multiple sclerosis when compared to their EBV infected counterparts [4]. The pathology linking EBV titers to the initiation of multiple sclerosis are not yet clear, however it may increase the risk for an autoimmune type response as was seen with Systemic Lupus Erythematous and EBV [4, 6].
\nSeveral studies have shown a direct correlation between cigarette smoking and incidence of multiple sclerosis [4, 7, 8, 9, 10]. There is some variability in the literature between gender and age groups. One study suggests cigarette smoking at a younger age (<26.4 years) is associated with a 50% increased risk that was alleviated in individuals who were older [8]. A Canadian study comparing gender and smoking history and found that 71.5% males diagnosed with multiple sclerosis had previously smoked compared to 63.6% of females [10]. Smoking has previously been defined in several pathologies including cancer, asthma, atherosclerosis and heart disease, but within multiple sclerosis, the mechanism is still not understood.
\nGenetic risk factors have come to the forefront of current research as some have been linked with modulation of the immune response. Initial studies linked loci of the Major Histocompatibility Complex (MHC) and Human Leukocyte Antigen (HLA) as contributing risk in the development and progression of multiple sclerosis [4, 11, 12, 13, 14]. In particular, HLA-
In 2001, the McDonald criteria were created to streamline the diagnosis of multiple sclerosis even with its heterogeneous clinical presentation. The initial criteria introduced the utility of magnetic resonance imaging (MRI) and integration of multiple clinical symptoms while removing “clinically definite” and “possible multiple sclerosis” as alternatives [17]. Since 2001, 3 additional revisions have been made to the initial McDonald criteria: 2005, 2010 and 2017 [18, 19, 20, 21]. Diagnosis of multiple sclerosis is now approached based on dissemination of time (temporal) and space. Dissemination in space is defined by either clinical presentation or MRI. Clinically, an individual must have symptoms which are distinct to different anatomical locations of the central nervous system. Usually, individuals present with optic neuritis or ocular symptoms and later acquire gait disturbances or peripheral weakness [18, 22]. On MRI, dissemination in space requires T2 evident lesions located in at least two distinct zones such as periventricular, infratentorial, juxtacortical or within the spinal cord [18, 22]. Dissemination in time requires the presence of a gadolinium-enhancing lesion on MRI, indicating an acute or active lesion, along with a non-enhancing lesion [18, 22]. The presence of a new lesion alone can meet the criteria if it is performed on a follow up scan. Essentially, dissemination in time seeks to distinguish multiple sclerosis symptomatology both typical and atypical from other neurological disorders which may share certain characteristics. As of McDonald 2010, CSF analysis is not required in order to make a definitive diagnosis [19, 20, 21, 22]. Analysis of CSF typically presents with mildly elevated white blood cell count, protein, and IgG oligoclonal bands which are not typically seen in serum analysis [22]. IgG oligoclonal bands can be found in 90% of multiple sclerosis patients, but it may have a greater role in distinguishing individuals with clinically isolated syndrome (CIS) [20]. Some studies demonstrated that CSF oligoclonal bands increase the specificity of MR imaging in adults with CIS and pediatrics with radiologically isolated syndrome (RIS) [23, 24]. Beyond the diagnosis of multiple sclerosis, CSF analysis may help distinguish other immune mediated neurological and non-neurological pathologies.
\nThe disease course of multiple sclerosis is usually defined into four clinical subtypes: clinically isolated syndrome (CIS), relapsing-remitting multiple sclerosis, secondary progressive multiple sclerosis, and primary progressive multiple sclerosis. A majority of patients have a disease course defined by stages of relapses and remission which may later translate into the secondary progressive form [25]. Clinically, relapses are defined as distinct episodes of neurological dysfunction which can present as a wide array of symptoms including sensory defects of the limbs, visual loss, motor defects, gait disturbances, vertigo, heat sensitivity (Uhthoff phenomenon), Lhermitte sign and fatigue [22, 26]. However, multiple sclerosis can present atypically in younger individuals, making it difficult to diagnosis properly. The initial episodes are followed by periods of remission where the patient will fully or partially regain normal function and be deemed neurologically stable [27]. In the long term, as some individuals transition from the relapsing-remitting form to secondary progressive, relapses no longer occur, yet patients will experience worsening neurological function [27]. After 10 years of disease, 50% of individuals with relapsing-remitting multiple sclerosis will convert to secondary-progressive, whereas after 25 years of the disorder, more than 90% of the individuals have secondary progressive multiple sclerosis [14].
\nPrior to establishing criteria for dissemination in time and space, individuals may present with clinically isolated syndrome (CIS) or radiologically isolated syndrome (RIS). Clinically isolated syndrome is defined as a clinical episode resembling a multiple sclerosis attack, after which there is full or partial recovery of neurological function [14, 20, 27]. Studies have shown that individuals with CIS may have an increased rate of conversion to multiple sclerosis especially with the presence of CSF oligoclonal bands and gadolinium enhancing lesions on MRI [14, 18, 20]. Incidental findings of cerebral and spinal cord plaques without a clinical phenotype are defined as radiologically isolated syndrome (RIS). In a 5-year study of 451 patients with RIS, 34% of individuals developed a clinical event for which 9.6% were defined as primary progressive multiple sclerosis [28]. Interestingly, this study was able to strongly correlate the presence of cervical or thoracic spinal cord lesions with the first clinical event [28]. With this increase risk of progression to multiple sclerosis, the utility of disease-modifying therapies and longitudinal monitoring of CIS and RIS has become a priority for clinicians.
\nThe direct cause of multiple sclerosis still eludes the scientific community; however, several hypotheses have emerged which have been utilized to develop disease-modifying therapies (DMTs) and alter the course of disease. Traditionally, multiple sclerosis has been considered a demyelinating disease of the white matter tracts leading to peripheral symptomatology with an underlying autoimmune cause. Recently, demyelination located in the cerebral cortex and deep gray matter has emerged as a marker of progressing neurological disability [13, 29, 30]. Damage seen to the CNS with infiltration of immune cells suggests the role of peripheral immune response leading to damage of the blood brain barrier prior to established demyelination. Peripheral inflammation in this case may be a result of a foreign pathogen (virus), autoimmune activation, or a combination of multiple events. Malpass [31] characterized the term “outside-in” based on evidence of cortical inflammation originating in the subarachnoid space in multiple sclerosis patients which transitioned into the white matter [32]. This further strengthens the argument for modulation of the peripheral inflammatory response which is facilitating early multiple sclerosis disease through activation of CD4 T lymphocytes. Once within the CNS, regional activation of microglia, astrocytes and macrophages occurs through expression of cytokines and chemokines from infiltration of T lymphocytes [13, 29, 30, 33]. Activation of specific subsets of CD4 lymphocytes dictates which cytokines are released. Pro-inflammatory cytokines are expressed after direct activation of Th1 and Th17 cells, whereas anti-inflammatory cytokines are a product of Th2 and T-regulatory cells [34, 35, 36]. Histopathology of the CNS white matter plaques has shown an abundance of macrophages, CD8, CD4 T lymphocytes, and B lymphocytes [13, 29, 30, 35]. Over time, the prolonged inflammation and infiltration of T and B lymphocytes leads to a disruption of the axonal-glial interaction which results in an increase in gray matter atrophy and axonal loss with marked demyelination [13, 29]. During the remission phase following each flare, there is some evidence to suggest a possible role for regulatory T cells with the induction of Foxp3 [37]. It is possible that during remission, a baseline level of inflammation is present; however, the expression of specific phenotypes of T lymphocytes shifts toward anti-inflammatory/regulatory rather than pro-inflammatory mechanisms. Based on these observations, vitamin D has emerged as a potential homeopathic regulator of immune cell function [2, 3, 38].
\nCurrently, there is no definitive treatment for multiple sclerosis. Most approved therapies are focused on controlling peripheral inflammation and preventing migration across the blood brain barrier thereby reducing the incidence of acute flares [13, 30, 39, 40]. A majority of these therapies are administered orally, as an injection or through an infusion. With both invasive and non-invasive methods, side effects include increases in liver enzymes, injection site reactions, nausea, diarrhea, and most importantly, progressive multifocal leukoencephalopathy (PML) [39]. The primary therapies prescribed at our institution are Copaxone®, Gilenya®, and Tecfidera®. Copaxone®, glatiramer acetate is an immunomodulator that is FDA approved to reduce the frequency of relapses. Gilenya®, fingolimod, is also an immunomodulator that targets reduction in the number of relapses more than progression of disease. Tecfidera®, dimethyl fumarate, is a combination of fumaric acid esters that was originally approved for oral treatment of psoriasis. Because of the inconsistent or incomplete outcomes from treatment, as well as the evolving nature of the disorder, other biotherapies have been used as adjuvants.
\nOne alternative biotherapeutic is the use of low doses of naltrexone (LDN), an opioid receptor antagonist. LDN is often used as an adjuvant to disease-modifying therapy to target fatigue associated with either the disorder or the medication. LDN has a strong profile of safety and tolerability [41, 42, 43, 44]. Pilot studies utilizing LDN demonstrated that MS patients had an improvement in peripheral spasticity and mental health composite scores without inducing any side effects [42, 45]. In a retrospective analysis which compared LDN patients with LDN plus Copaxone® patients, there was no significant difference between the groups with respect to MRI, complete blood count, liver enzymes and the 25-foot walk test [44].
\nA number of published studies, clinical trials and anecdotal stories have supported the use of LDN as a beneficial therapy for multiple sclerosis [41, 42, 43, 44, 45, 46, 47, 48]. The mechanism of action for this general antagonist is to block the interaction of Opioid Growth Factor (OGF) (chemically termed [Met5]-enkephalin) from interacting at the nuclear-associated receptor OGFr. In addition to being a neurotransmitter, OGF is an inhibitory growth factor that suppresses proliferation of cells, including T and B cells associated with autoimmune disorders. Naltrexone was initially developed to treat opioid use disorder and alcoholism at a dosing of 50 mg where it acts as an opioid receptor antagonist for mu, delta, and kappa opiate receptors. At a dosage less than 5 mg, LDN acts as a biotherapeutic and modulates the activity of endogenous enkephalins and endorphins [49, 50]. In the multiple sclerosis patient population, endogenous [Met5]-enkephalin (i.e., OGF) is reduced when compared to non-multiple sclerosis patients [51]. It is hypothesized that the reduction in serum levels of this inhibitory growth factor are unable to control the increase in T cell proliferation that occurs with immune-related flares. These T cells are the source of other pro-inflammatory cytokines that exacerbate the symptomatology of multiple sclerosis. The decreased serum levels of OGF appear to be compensated by low dosages of naltrexone (LDN).
\nAnimal studies have been used to study both the mechanisms of LDN, as well as to establish the role of LDN as a biotherapy in mice with experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. In these studies, mice were immunized with antigens against myelin proteins—either myelin oligodendrocyte glycoprotein 35–55 or proteolipid peptides 139–151. The key component in the mechanistic pathway is the duration of opioid receptor blockade. This work is detailed in animal studies [51, 52, 53, 54, 55, 56, 57]. LDN produces an intermittent blockade of OGFr preventing OGF from binding and thereby increasing cellular replication, similar to what is seen with high doses of Naltrexone (HDN) through a prolonged blockade of OGFr [49]. Conversely, after the blockade has subsided, within 4–6 h, there is over proliferation of endogenous OGF and OGFr and a resulting exaggerated expression of p16 and p21 leading to promotion of cellular senescence [49].
\nA newly discovered pathway involves the antagonism of Toll-like receptor 4 (TLR4) by LDN as means to reduce neuroinflammation or persistent pain [58, 59]. Specifically, activation of Toll-like receptor 4 (TLR4) initiates the release of inflammatory cytokines: interleukin 1 (IL-1), tumor necrosis factor α (TNFα), nitric oxide (NO), and interferon β (IFNβ) [48, 60]. Currently, the relationship of the Toll-like receptor pathway to pro-inflammatory cytokine activation is not completely understood.
\nSeveral studies have been conducted to evaluate multiple sclerosis patients who are prescribed LDN. The use of enkephalins, particularly OGF, has been demonstrated to be safe and tolerable in Phase I and Phase II studies of pancreatic cancer [61, 62]. LDN is widely used for treatment of other autoimmune disorders including Crohn’s disease [63] and fibromyalgia [64].
\nClinical trials using LDN for multiple sclerosis were conducted more than a decade ago, and most likely because it is widely used with no side-effects, government agencies are reluctant to support new trials. Three clinical trials have suggested that LDN increased the quality of life of patients with relapse-remitting or secondary progressive multiple sclerosis, without serious adverse effects [42, 43, 45]. Two retrospective studies examining charts of patients prescribed LDN alone, as well as in combination with the disease-modifying therapy Copaxone®, revealed no exacerbation of the disease or any substantial side effect for patients in either cohort [44]. In this study, the average length of disease was 14 years, with an average of 3 years on LDN alone. Clinical laboratory data revealed that patients on LDN alone had no significant differences in their blood chemistry, nutrition or liver data from patients on disease-modifying therapies.
\nHowever, these studies did not measure serum enkephalins, endorphins, or cytokines in an effort to gain more information on the mechanism of action for this biotherapeutic. A small study obtained stored serum from relapsing-remitting multiple sclerosis subjects and reported that enkephalin (i.e., OGF) levels were depressed relative to controls [51]. In the few individuals on LDN alone, serum OGF levels were elevated 2-fold in comparison to multiple sclerosis subjects on Copaxone® alone, suggesting that LDN may be effective at restoring serum enkephalin. Given this information, studies on both the mouse model of EAE and multiple sclerosis have been pursued to evaluate select cytokines that may be dysregulated in multiple sclerosis and possibly modulated by LDN (and enkephalin levels) and restored to normal levels.
\nA retrospective clinical study was designed to examine serum levels of cytokines and endogenous peptides, including [Met5]-enkephalin.
\nPatients were identified through the Institute of Personalized Medicine at the Pennsylvania State University College of Medicine and had a clinically definitive diagnosis of relapsing–remitting multiple sclerosis [17, 18, 21, 36]. Selected individuals were between 18 and 70 years of age, of which 17 were males and 36 were females. Cohorts were established based on the disease-modifying therapy each of these patients was receiving. The five groups included multiple sclerosis patients receiving dimethyl fumarate, glatiramer acetate, low-dose naltrexone, or no disease-modifying therapy and a control group of non-multiple sclerosis patients. The 13 non-multiple sclerosis patients were recruited from the Neuroscience Institute and were age and gender matched to the study population. All patients were de-identified to the study team.
\nBlood was collected and stored in non-heparinized ethylenediaminetetraacetic acid (EDTA) tubes to prevent formation of a clot [65, 66]. Whole blood was centrifuged at 4°C for 10 min at 2500 rpm [65, 66]. Serum was aliquoted and stored long term at −80°C in 200 μL vials to prevent repeated freeze and thaw cycles.
\nSerum was analyzed using commercially produced sandwich or competitive enzyme labeled immunosorbent assay (ELISA). Opioid growth factor (MBS990622), β-endorphin (MBS770600), IL17A (MBS00565) and IL17 (MBS772095) ELISA kits were manufactured by MyBioSource (San Diego, CA); whereas the TNFα ELISA kit (EK0525) was purchased from BosterBio (Pleasanton, CA). Assays were completed following the manufacturer’s recommendations; all samples and standards were run in duplicate and averaged for the data analyses. Chemiluminescence was measured using a BioTek microplate spectrophotometer and Gen5 software at 450 nm. To ensure redundancy and reproducibility, duplicate samples were run on multiple ELISA kits from the same manufacturer.
\nData analysis was performed using GraphPad Prism 8.0 software. Parametric data were analyzed using one-way analysis of variance (ANOVA) with post-hoc comparisons made using Newman-Keuls. Correlations were determined using Pearson’s Correlation Coefficient (R). Significance was determined with a p value less than 0.05.
\nA cohort of 53 patients was analyzed in this study, 40 of whom were individuals with an established diagnosis of relapsing-remitting (RR) multiple sclerosis and 13 who did not have multiple sclerosis. Patients with multiple sclerosis who received no disease-modifying therapy were designated as controls along with the 13 individuals with no diagnosis of multiple sclerosis. Within the control population, 17 were females and 7 males, whereas the study population had 19 females and 10 males. The age distribution between the cohorts of patients on treatment ranged between 25 and 69 years of age while the control cohort ranged in age from 25 to 78 years. Length of disease in the multiple sclerosis patient group was similar between the no-drug, dimethyl fumarate and LDN group which had mean lengths of 14.3, 10.4 and 16.5 years, respectively.
\nSerum OGF levels differed substantially between multiple sclerosis patients who declined therapy and control subjects considered non-multiple sclerosis (Figure 1A). OGF levels were more than three-fold higher in non-multiple sclerosis cohort relative to the no-drug cohort (93 ± 26 pg/ml). Because there is no diagnosis provided for the no-drug volunteers, it is difficult to more fully assess these data. Mean serum levels for RR-multiple sclerosis subjects prescribed disease-modifying therapy were comparable to serum values for the no-drug cohort, and significantly less than serum values for the non-multiple sclerosis cohort (Figure 1B). RR-multiple sclerosis patients receiving dimethyl fumarate had serum OGF values of 125 ± 22 pg/ml whereas those individuals receiving glatiramer acetate had serum levels of 136 ± 30 pg/ml. RR-multiple sclerosis subjects receiving LDN had mean OGF serum levels of 217 ± 29 mg/ml; these values did not differ from the non-multiple sclerosis cohort. Correlations between serum OGF levels and age or length of disease for cohorts of no drug, DMTs, or LDN are presented in Figure 2A and B, respectively. The association between age and serum OGF had an overall significance, with dimethyl fumarate subjects revealing a corresponding decrease in OGF serum values with increasing age (p = 0.03). Regarding the length of disease, RR-multiple sclerosis subjects taking LDN had comparable OGF serum values irrespective of having disease for 2 months or 33 years (Figure 2B). RR-multiple sclerosis subjects not taking any drugs (no-drug cohort) also displayed a biphasic response, suggesting that length of disease does not impact OGF serum. Analyses of OGF serum values by gender indicated that females had a pattern similar to that in Figure 1B. A majority of the males in this study received dimethyl fumarate and had serum OGF levels that ranged from 25 to 200 pg/ml; the small number of male subjects in the other cohorts prevented data analyses.
\nScatterplots of serum OGF levels (pg/ml) in (A) control subjects who were either non-multiple sclerosis subjects or (B) RR-MS patients who were not receiving any therapy (no drug) or RR-multiple sclerosis patients receiving dimethyl fumarate, glatiramer acetate, or low dose naltrexone (LDN). One-way ANOVA or t-tests were used to show the differences between groups. Significantly different from non-multiple sclerosis values at p < 0.01 (**).
Expression levels of serum OGF (pg/ml) measured by ELISA as a function of the age (years) of subject (A) or the length of disease (years) (B). Correlations were determined by Pearson’s Correlation Coefficient (R) tests. P values less than 0.05 were considered significant.
Serum β-endorphin levels were also measured in three cohorts of RR-multiple sclerosis subjects and non-multiple sclerosis subjects. Levels of serum β-endorphin ranged between ~1 ng/ml (no-drug and dimethyl fumarate cohorts) to the mean of 2.3 ng/ml (non-multiple sclerosis cohorts); individual samples ranged as high as 4 ng/ml in the non-multiple sclerosis cohort. Despite the variation, significant two-fold increases were recorded for non-multiple sclerosis and glatiramer acetate cohorts relative to no drug and dimethyl fumarate RR-multiple sclerosis individuals. Associations between age and β-endorphin revealed that endorphin levels were relatively stable within the population of RR-multiple sclerosis subjects on DMT.
\nWith regard to serum levels of inflammatory cytokines, expression levels of two cytokines in serum are presented in Figure 3. Serum levels of IL-17 (A) and TNFα (B) were measured in RR-multiple sclerosis subjects on DMTs, LDN, or no-drug, as well as non-multiple sclerosis controls. Mean IL-17A (not shown) concentrations ranged from 27 ± 3 pg/ml (dimethyl fumarate) to 39 ± 10 pg/ml (glatiramer acetate group). Only one sample of blood from RR-multiple sclerosis patients on LDN was assayed; serum IL-17A value was 46 pg/ml. No differences in serum levels were noted between any therapeutic treatment and controls. IL-17 levels ranged from the mean 0.12 ng/ml recorded for non-multiple sclerosis cohort to 0.92 ± 0.35 ng/ml for the dimethyl fumarate group (Figure 3A); levels of the IL-17 cytokine recorded for these subjects differed significantly from glatiramer acetate and no-drug cohorts. RR-multiple sclerosis patients had a mean IL-17 cytokine level of near 0, whereas some individuals using dimethyl fumarate had more than 3 pg/ml IL-17 levels.
\nScatterplots of serum cytokines IL-17 (A) and TNFα (B) measured by ELISA tests (pg/ml) in RR-multiple sclerosis patients receiving DMTs or no drug; controls include volunteer non-multiple sclerosis subjects. Data was analyzed using one-way ANOVA with subject comparisons made by Newman-Keuls tests. Significantly different at p < 0.05 (*) and p < 0.01 (**).
Non-multiple sclerosis and RR-multiple sclerosis patients not taking any DMT had comparable TNFα values (16 ± 10 and 22 ± 3 pg/ml, respectively) (Figure 3B). RR-multiple sclerosis cohorts on DMTs had TNFα serum values that were at least 6-fold higher and differed significantly from the non-multiple sclerosis levels. Correlation analyses indicated that OGF (Figure 4A) and IL-17A (Figure 4B) were positively associated (R = 0.82), whereas TNFα values did not correlate (R = 0.20) with OGF serum values.
\nAssociations of cytokine expression between IL-17A (pg/ml) and OGF (pg/ml) (A) or TNFα (pg/ml) and OGF (B) for RR-multiple sclerosis subjects receiving a DMT. Data were analyzed by Pearson’s Correlation Coefficient (R) tests. P values less than 0.05 were considered significant.
Cohorts of RR-multiple sclerosis patients on disease-modifying therapy, as well as a group of individuals diagnosed with RR-multiple sclerosis and taking LDN only were compared with control volunteers. in an assessment of peripheral serum levels of two endogenous neuropeptides—OGF (chemically termed methionine enkephalin) and β-endorphin, as well as 3 cytokines that are known to be involved in RR-multiple sclerosis, specifically IL-17, IL-17A, and TNFα [67, 68, 69, 70, 71]. Inclusion criteria restricted our analyses to RR-MS subjects to those receiving glatiramer acetate or dimethyl fumarate. A few RR-multiple sclerosis subjects in this study were only prescribed LDN as an off-label product.
\nThe restricted access to blood samples and corresponding patient data in this retrospective study limited the findings, as did inclusion of RR-multiple sclerosis patients on no drug. No rationale was reported in the REDCap database to explain why the RR-multiple sclerosis patients had denied therapy. It is conjured that some multiple sclerosis patients who have stabilized over a long period of time request to be removed from therapy.
\nThe focus of this study was to determine the relationship between serum expression levels of endogenous neuropeptides, specifically OGF, and a select group of pro-inflammatory cytokines. OGF levels in the serum of RR-multiple sclerosis subjects declined with age and were not associated with the length of disease. In general, the OGF levels of RR-multiple sclerosis patients using DMTs, or those on no therapy, were substantially lower than RR-multiple sclerosis subjects on LDN. This relationship between OGF and RR-multiple sclerosis has been reported previously [51], suggesting that the biotherapeutic LDN treatment is producing enkephalins. Clinical studies have reported that LDN treatment resulted in perceived increased quality of life [42, 43] and stabilization of disease symptomatology [44]. A second neuropeptide, β-endorphin, is known as the “feel-good” hormone and has been reported to increase during exercise and pregnancy [72] and to increase during multiple sclerosis remission [73]. In this study, β-endorphin levels were comparable in all subjects suggesting that these RR-multiple sclerosis patients had stabilized endorphins. Based on the scatter gram plots of individual expression levels of endorphin, some of the individuals in the glatiramer acetate group may have been in remission. Moreover, whereas OGF levels fluctuate with RR-multiple sclerosis and different therapies, β-endorphin does not appear to be altered by DMTs in RR-multiple sclerosis.
\nThe proinflammatory cytokine IL-17 may be a prime indicator of RR-multiple sclerosis progression [69, 71]. The IL-17 family of cytokines is produced by CD4+ T-helper cells known as Th17 cells. At least 7 polymorphisms have been identified, with IL-17A and IL-17F most frequently associated with neutrophils activation in autoimmunity [67, 69]. IL-17A has been identified in the CNS following migration of Th17 cells in response to a pro-inflammatory event [74]. Clinical studies have reported that IL-17A may be responsible for breakdown of the blood-brain barrier facilitating the entrance of other inflammatory cytokines into the CNS [71]. IL-17A has been shown in preclinical studies to accelerate glial activation leading to neuroinflammation and neurodegeneration [68]. Thus, it would be expected that IL-17A levels may be lowest in RR-multiple sclerosis individuals who are in remission or most responsive to therapy [67]. Moreover, recent preclinical studies have reported that both IL-17A and IL-17F increase pro-inflammatory cytokine IL-6 secretion [70].
\nIn the present study, TNFα, a proinflammatory marker has been shown to increase in RR-multiple sclerosis [75, 76] and to be consistently elevated regardless of the status of disease type (i.e., clinically isolated syndrome, primary progressive, or relapsing-remitting), with serum levels 40–50% higher in multiple sclerosis subjects relative to controls. Preclinical studies have reported an association between TNFα and impaired memory in mice with EAE [77] and implicated astrocyte signaling as the downstream target of overexpression of the cytokine. Despite studies whereby TNFα knockdown mice had more severe EAE [69] and therapeutic administration of the cytokine protected against the disease [74], this cytokine is reported to be a major contributor to cognitive deficits related to late stages of multiple sclerosis. In the present study, age, gender, number of relapses, or length of disease had no effect of TNFα levels, but in general, the expression levels of this cytokine were elevated in RR-multiple sclerosis subjects relative to cohorts of RR-multiple sclerosis patients presumably in remission or non-multiple sclerosis.
\nLDN is an off-label therapeutic used in substantially lower dosages than prescribed for drug overdose or alcohol use (3 vs. 50 mg). Its use is increasing worldwide [78, 79] and is consistently reported to be well-tolerated over extended periods of time [46]. Small clinical trials have reported few, if any, side effects [42, 43]. In this study, OGF serum levels appear to be correlated with IL-17A. Alternatively, whereas β-endorphin has been associated with the propensity to avoid alcohol or opioids, it was not related to RR-multiple sclerosis. The serum levels of cytokines IL-17A and TNFα did not appear to be discriminating biomarkers at least with the current population of RR-multiple sclerosis subjects. Perhaps with additional study, and possibly other DMTs, these cytokines will be able to discern progression of disease.
\nIn summary, the preclinical and clinical data illustrate that enkephalin levels (i.e., OGF) are decreased in animals with EAE and humans with relapsing remitting multiple sclerosis. LDN as a biotherapy is associated with elevating enkephalins and from all aspects, appears to reduce symptomatology of multiple sclerosis. LDN therapy to upregulate the body’s own production of enkephalins has been shown by a number of clinical trials to be a safe adjuvant, or primary, treatment for RR-multiple sclerosis. LDN continues to be associated with stabilizing multiple sclerosis and does not appear to interfere with other disease-modifying therapies. Whether enkephalin levels directly or indirectly alter the therapeutic pathways is unclear at this time. Moreover, it is difficult to determine at this point whether specific disease-modifying therapies are more advantageous for manipulating enkephalin levels. However, it is evident that restored serum enkephalin expression is associated with reduced inflammatory cytokines and better patient outcome. Moving forward, studies will be conducted to determine the mechanistic role of OGF in modulating both pro and anti-inflammatory cytokines. Collectively the data from published studies as well as the new data presented in this report demonstrate that the biotherapeutic LDN and resulting enkephalin (specifically OGF) levels play a role in disease progression of multiple sclerosis. By integrating animal model work and patient serum analysis, future studies will try and understand the role of OGF during initiation of disease and definitive diagnosis of disease. The efficacy of LDN alone needs to be evaluated in prospective, randomized, controlled studies, but unfortunately this design is not forthcoming as most physicians will prescribe the off-label drug based on its safety record.
\nThis research was supported in part by a generous gift from The Paul K. and Anna E. Shockley Family Foundation, and private donations to the Penn State LDN Fund.
\nThe authors acknowledge the support of Indira Purushothaman from the McLaughlin and Zagon lab as well as Syndi Reed and Trang Doan from the Institute of Personalized Medicine at Penn State College of Medicine.
\nAt the time of preparation of this manuscript, PJM, ISZ, and CLP had no personal or financial conflicts or disclosures, and GAT was on the speaker bureau for Biogen, but had no equity interest in the product (Tecfidera®).
\nAt IntechOpen, we not only specialize in the publication of Book Chapters as part of our Edited Volumes, but also the publication and dissemination of longer manuscripts, known as Long Form Monographs. Monographs allow Authors to focus on presenting a single subject or a specific aspect of that subject and publish their research in detail.
\n\nEven if you have an area of research that does not at first sight fit within a previously defined IntechOpen project, we can still offer support and help you in publishing your individual research. Publishing your IntechOpen book in the form of a Long Form Monograph is a viable alternative.
",metaTitle:"Publish a Whole Book",metaDescription:"At IntechOpen, we not only specialize in the publication of book chapters as part of our Edited Volumes, but also the publication and dissemination of long form manuscripts, known as monographs. Monographs allow authors to focus on presenting a single subject or a specific aspect of that subject and publish their research at length.\n\nPerhaps you have an area of research that does not fit within a previously defined IntechOpen project, but rather need help in publishing your individual research? Publishing your IntechOpen book in the form of a long form monograph is a great alternative.",metaKeywords:null,canonicalURL:"/page/publish-a-whole-book",contentRaw:'[{"type":"htmlEditorComponent","content":"MONOGRAPH - LONG FORM MANUSCRIPT
\\n\\nFORMATS
\\n\\nCOST
\\n\\n10,000 GBP Monograph - Long Form
\\n\\nThe final price includes project management, editorial and peer-review services, technical editing, language copyediting, cover design, book layout, book promotion and ISBN assignment.
\\n\\n*The price does not include Value-Added Tax (VAT). Residents of European Union countries need to add VAT based on the specific rate applied in their country of residence. Institutions and companies registered as VAT taxable entities in their own EU member state will not pay VAT by providing us with their VAT registration number. This is made possible by the EU reverse charge method.
\\n\\nOptional Services
\\n\\nIntechOpen has collaborated with Enago, through its sister brand, Ulatus, which is one of the world’s leading providers of book translation services. The services are designed to convey the essence of your work to readers from across the globe in a language they understand. Enago’s expert translators incorporate cultural nuances in translations to make the content relevant for local audiences while retaining the original meaning and style. Enago translators are equipped to handle all complex and multiple overlapping themes encompassed in a single book and their high degree of linguistic and subject expertise enables them to deliver a superior quality output.
\\n\\nIntechOpen Authors that wish to use this service will receive a 20% discount on all translation services. To find out more information or obtain a quote, please visit: https://www.enago.com/intech.
\\n\\nFUNDING
\\n\\nWe feel that financial barriers should never prevent researchers from publishing their work. Please consult our Open Access Funding page to explore funding opportunities and learn more about how you can finance your IntechOpen publication.
\\n\\nBENEFITS
\\n\\nPUBLISHING PROCESS STEPS
\\n\\nFor a complete overview of all publishing process steps and descriptions, go to How Open Access Publishing Works.
\\n\\nSEND YOUR PROPOSAL
\\n\\nIf you are interested in publishing your book with IntechOpen, please submit your book proposal by completing the Publishing Proposal Form.
\\n\\nNot sure if this is the right option for you? Please refer back to the main Publish with IntechOpen page or feel free to contact us directly at book.department@intechopen.com.
\\n"}]'},components:[{type:"htmlEditorComponent",content:'MONOGRAPH - LONG FORM MANUSCRIPT
\n\nFORMATS
\n\nCOST
\n\n10,000 GBP Monograph - Long Form
\n\nThe final price includes project management, editorial and peer-review services, technical editing, language copyediting, cover design, book layout, book promotion and ISBN assignment.
\n\n*The price does not include Value-Added Tax (VAT). Residents of European Union countries need to add VAT based on the specific rate applied in their country of residence. Institutions and companies registered as VAT taxable entities in their own EU member state will not pay VAT by providing us with their VAT registration number. This is made possible by the EU reverse charge method.
\n\nOptional Services
\n\nIntechOpen has collaborated with Enago, through its sister brand, Ulatus, which is one of the world’s leading providers of book translation services. The services are designed to convey the essence of your work to readers from across the globe in a language they understand. Enago’s expert translators incorporate cultural nuances in translations to make the content relevant for local audiences while retaining the original meaning and style. Enago translators are equipped to handle all complex and multiple overlapping themes encompassed in a single book and their high degree of linguistic and subject expertise enables them to deliver a superior quality output.
\n\nIntechOpen Authors that wish to use this service will receive a 20% discount on all translation services. To find out more information or obtain a quote, please visit: https://www.enago.com/intech.
\n\nFUNDING
\n\nWe feel that financial barriers should never prevent researchers from publishing their work. Please consult our Open Access Funding page to explore funding opportunities and learn more about how you can finance your IntechOpen publication.
\n\nBENEFITS
\n\nPUBLISHING PROCESS STEPS
\n\nFor a complete overview of all publishing process steps and descriptions, go to How Open Access Publishing Works.
\n\nSEND YOUR PROPOSAL
\n\nIf you are interested in publishing your book with IntechOpen, please submit your book proposal by completing the Publishing Proposal Form.
\n\nNot sure if this is the right option for you? Please refer back to the main Publish with IntechOpen page or feel free to contact us directly at book.department@intechopen.com.
\n'}]},successStories:{items:[]},authorsAndEditors:{filterParams:{},profiles:[{id:"396",title:"Dr.",name:"Vedran",middleName:null,surname:"Kordic",slug:"vedran-kordic",fullName:"Vedran Kordic",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/396/images/7281_n.png",biography:"After obtaining his Master's degree in Mechanical Engineering he continued his education at the Vienna University of Technology where he obtained his PhD degree in 2004. He worked as a researcher at the Automation and Control Institute, Faculty of Electrical Engineering, Vienna University of Technology until 2008. His studies in robotics lead him not only to a PhD degree but also inspired him to co-found and build the International Journal of Advanced Robotic Systems - world's first Open Access journal in the field of robotics.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"441",title:"Ph.D.",name:"Jaekyu",middleName:null,surname:"Park",slug:"jaekyu-park",fullName:"Jaekyu Park",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/441/images/1881_n.jpg",biography:null,institutionString:null,institution:{name:"LG Corporation (South Korea)",country:{name:"Korea, South"}}},{id:"465",title:"Dr",name:"Christian",middleName:null,surname:"Martens",slug:"christian-martens",fullName:"Christian Martens",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"479",title:"Dr.",name:"Valentina",middleName:null,surname:"Colla",slug:"valentina-colla",fullName:"Valentina Colla",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/479/images/358_n.jpg",biography:null,institutionString:null,institution:{name:"Sant'Anna School of Advanced Studies",country:{name:"Italy"}}},{id:"494",title:"PhD",name:"Loris",middleName:null,surname:"Nanni",slug:"loris-nanni",fullName:"Loris Nanni",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/494/images/system/494.jpg",biography:"Loris Nanni received his Master Degree cum laude on June-2002 from the University of Bologna, and the April 26th 2006 he received his Ph.D. in Computer Engineering at DEIS, University of Bologna. On September, 29th 2006 he has won a post PhD fellowship from the university of Bologna (from October 2006 to October 2008), at the competitive examination he was ranked first in the industrial engineering area. He extensively served as referee for several international journals. He is author/coauthor of more than 100 research papers. He has been involved in some projects supported by MURST and European Community. His research interests include pattern recognition, bioinformatics, and biometric systems (fingerprint classification and recognition, signature verification, face recognition).",institutionString:null,institution:null},{id:"496",title:"Dr.",name:"Carlos",middleName:null,surname:"Leon",slug:"carlos-leon",fullName:"Carlos Leon",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Seville",country:{name:"Spain"}}},{id:"512",title:"Dr.",name:"Dayang",middleName:null,surname:"Jawawi",slug:"dayang-jawawi",fullName:"Dayang Jawawi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Technology Malaysia",country:{name:"Malaysia"}}},{id:"528",title:"Dr.",name:"Kresimir",middleName:null,surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/528/images/system/528.jpg",biography:"K. Delac received his B.Sc.E.E. degree in 2003 and is currentlypursuing a Ph.D. degree at the University of Zagreb, Faculty of Electrical Engineering andComputing. His current research interests are digital image analysis, pattern recognition andbiometrics.",institutionString:null,institution:{name:"University of Zagreb",country:{name:"Croatia"}}},{id:"557",title:"Dr.",name:"Andon",middleName:"Venelinov",surname:"Topalov",slug:"andon-topalov",fullName:"Andon Topalov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/557/images/1927_n.jpg",biography:"Dr. Andon V. Topalov received the MSc degree in Control Engineering from the Faculty of Information Systems, Technologies, and Automation at Moscow State University of Civil Engineering (MGGU) in 1979. He then received his PhD degree in Control Engineering from the Department of Automation and Remote Control at Moscow State Mining University (MGSU), Moscow, in 1984. From 1985 to 1986, he was a Research Fellow in the Research Institute for Electronic Equipment, ZZU AD, Plovdiv, Bulgaria. In 1986, he joined the Department of Control Systems, Technical University of Sofia at the Plovdiv campus, where he is presently a Full Professor. He has held long-term visiting Professor/Scholar positions at various institutions in South Korea, Turkey, Mexico, Greece, Belgium, UK, and Germany. And he has coauthored one book and authored or coauthored more than 80 research papers in conference proceedings and journals. His current research interests are in the fields of intelligent control and robotics.",institutionString:null,institution:{name:"Technical University of Sofia",country:{name:"Bulgaria"}}},{id:"585",title:"Prof.",name:"Munir",middleName:null,surname:"Merdan",slug:"munir-merdan",fullName:"Munir Merdan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/585/images/system/585.jpg",biography:"Munir Merdan received the M.Sc. degree in mechanical engineering from the Technical University of Sarajevo, Bosnia and Herzegovina, in 2001, and the Ph.D. degree in electrical engineering from the Vienna University of Technology, Vienna, Austria, in 2009.Since 2005, he has been at the Automation and Control Institute, Vienna University of Technology, where he is currently a Senior Researcher. His research interests include the application of agent technology for achieving agile control in the manufacturing environment.",institutionString:null,institution:null},{id:"605",title:"Prof",name:"Dil",middleName:null,surname:"Hussain",slug:"dil-hussain",fullName:"Dil Hussain",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/605/images/system/605.jpg",biography:"Dr. Dil Muhammad Akbar Hussain is a professor of Electronics Engineering & Computer Science at the Department of Energy Technology, Aalborg University Denmark. Professor Akbar has a Master degree in Digital Electronics from Govt. College University, Lahore Pakistan and a P-hD degree in Control Engineering from the School of Engineering and Applied Sciences, University of Sussex United Kingdom. Aalborg University has Two Satellite Campuses, one in Copenhagen (Aalborg University Copenhagen) and the other in Esbjerg (Aalborg University Esbjerg).\n· He is a member of prestigious IEEE (Institute of Electrical and Electronics Engineers), and IAENG (International Association of Engineers) organizations. \n· He is the chief Editor of the Journal of Software Engineering.\n· He is the member of the Editorial Board of International Journal of Computer Science and Software Technology (IJCSST) and International Journal of Computer Engineering and Information Technology. \n· He is also the Editor of Communication in Computer and Information Science CCIS-20 by Springer.\n· Reviewer For Many Conferences\nHe is the lead person in making collaboration agreements between Aalborg University and many universities of Pakistan, for which the MOU’s (Memorandum of Understanding) have been signed.\nProfessor Akbar is working in Academia since 1990, he started his career as a Lab demonstrator/TA at the University of Sussex. After finishing his P. hD degree in 1992, he served in the Industry as a Scientific Officer and continued his academic career as a visiting scholar for a number of educational institutions. In 1996 he joined National University of Science & Technology Pakistan (NUST) as an Associate Professor; NUST is one of the top few universities in Pakistan. In 1999 he joined an International Company Lineo Inc, Canada as Manager Compiler Group, where he headed the group for developing Compiler Tool Chain and Porting of Operating Systems for the BLACKfin processor. The processor development was a joint venture by Intel and Analog Devices. In 2002 Lineo Inc., was taken over by another company, so he joined Aalborg University Denmark as an Assistant Professor.\nProfessor Akbar has truly a multi-disciplined career and he continued his legacy and making progress in many areas of his interests both in teaching and research. He has contributed in stochastic estimation of control area especially, in the Multiple Target Tracking and Interactive Multiple Model (IMM) research, Ball & Beam Control Problem, Robotics, Levitation Control. He has contributed in developing Algorithms for Fingerprint Matching, Computer Vision and Face Recognition. He has been supervising Pattern Recognition, Formal Languages and Distributed Processing projects for several years. He has reviewed many books on Management, Computer Science. Currently, he is an active and permanent reviewer for many international conferences and symposia and the program committee member for many international conferences.\nIn teaching he has taught the core computer science subjects like, Digital Design, Real Time Embedded System Programming, Operating Systems, Software Engineering, Data Structures, Databases, Compiler Construction. In the Engineering side, Digital Signal Processing, Computer Architecture, Electronics Devices, Digital Filtering and Engineering Management.\nApart from his Academic Interest and activities he loves sport especially, Cricket, Football, Snooker and Squash. He plays cricket for Esbjerg city in the second division team as an opener wicket keeper batsman. He is a very good player of squash but has not played squash since his arrival in Denmark.",institutionString:null,institution:null},{id:"611",title:"Prof.",name:"T",middleName:null,surname:"Nagarajan",slug:"t-nagarajan",fullName:"T Nagarajan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universiti Teknologi Petronas",country:{name:"Malaysia"}}}],filtersByRegion:[{group:"region",caption:"North America",value:1,count:6601},{group:"region",caption:"Middle and South America",value:2,count:5906},{group:"region",caption:"Africa",value:3,count:2400},{group:"region",caption:"Asia",value:4,count:12541},{group:"region",caption:"Australia and Oceania",value:5,count:1008},{group:"region",caption:"Europe",value:6,count:17561}],offset:12,limit:12,total:132763},chapterEmbeded:{data:{}},editorApplication:{success:null,errors:{}},ofsBooks:{filterParams:{topicId:"23"},books:[{type:"book",id:"11433",title:"Human Migration in the Last Three Centuries",subtitle:null,isOpenForSubmission:!0,hash:"9836df9e82aa9f82e3852a60204909a8",slug:null,bookSignature:"Dr. Ingrid Muenstermann",coverURL:"https://cdn.intechopen.com/books/images_new/11433.jpg",editedByType:null,editors:[{id:"77112",title:"Dr.",name:"Ingrid",surname:"Muenstermann",slug:"ingrid-muenstermann",fullName:"Ingrid Muenstermann"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"11437",title:"Social Media - Risks and Opportunities",subtitle:null,isOpenForSubmission:!0,hash:"000e31f2e2f7295805e9a3864158ad63",slug:null,bookSignature:"Dr. Shafizan Mohamed and Dr. Shazleen Mohamed",coverURL:"https://cdn.intechopen.com/books/images_new/11437.jpg",editedByType:null,editors:[{id:"302450",title:"Dr.",name:"Shafizan",surname:"Mohamed",slug:"shafizan-mohamed",fullName:"Shafizan Mohamed"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"11438",title:"Fake News in the Era of Pandemics",subtitle:null,isOpenForSubmission:!0,hash:"bc9e4cab86c76f35cd70b39086d9b69e",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/11438.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"11472",title:"21st Century Slavery",subtitle:null,isOpenForSubmission:!0,hash:"b341f3fc3411ced881e43ce007a892b8",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/11472.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"11473",title:"Social Inequality",subtitle:null,isOpenForSubmission:!0,hash:"20307129f7fb39aa443d5449acb6a784",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/11473.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"11474",title:"Quality of Life Interventions - Magnitude of Effect and Transferability",subtitle:null,isOpenForSubmission:!0,hash:"5a6bcdaf5ee144d043bcdab893ff9e1c",slug:null,bookSignature:"Ph.D. Sage Arbor",coverURL:"https://cdn.intechopen.com/books/images_new/11474.jpg",editedByType:null,editors:[{id:"245319",title:"Ph.D.",name:"Sage",surname:"Arbor",slug:"sage-arbor",fullName:"Sage Arbor"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"11479",title:"Social Aspects of Ageing - Selected Challenges, Analyses, and Solutions",subtitle:null,isOpenForSubmission:!0,hash:"dbf515446deb32a56696801cd224984d",slug:null,bookSignature:"Ph.D. Andrzej Klimczuk",coverURL:"https://cdn.intechopen.com/books/images_new/11479.jpg",editedByType:null,editors:[{id:"320017",title:"Ph.D.",name:"Andrzej",surname:"Klimczuk",slug:"andrzej-klimczuk",fullName:"Andrzej Klimczuk"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"11480",title:"Second Language Acquisition - Learning Theories and Recent Approaches",subtitle:null,isOpenForSubmission:!0,hash:"353e6f5278b4862f1f610fe7f1842125",slug:null,bookSignature:"Assistant Prof. Tabassum Maqbool",coverURL:"https://cdn.intechopen.com/books/images_new/11480.jpg",editedByType:null,editors:[{id:"450261",title:"Assistant Prof.",name:"Tabassum",surname:"Maqbool",slug:"tabassum-maqbool",fullName:"Tabassum Maqbool"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"11769",title:"Multiculturalism and Interculturalism",subtitle:null,isOpenForSubmission:!0,hash:"6c4bda24f278d74f943f2155f13f4d73",slug:null,bookSignature:"Dr. Muhammad Mohiuddin, Dr. Tareque Aziz and Dr. Sreenivasan Jayashree",coverURL:"https://cdn.intechopen.com/books/images_new/11769.jpg",editedByType:null,editors:[{id:"418514",title:"Dr.",name:"Muhammad",surname:"Mohiuddin",slug:"muhammad-mohiuddin",fullName:"Muhammad Mohiuddin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"11770",title:"Feminism",subtitle:null,isOpenForSubmission:!0,hash:"008be465c708a6fde48c8468757a40af",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/11770.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"11771",title:"Photography",subtitle:null,isOpenForSubmission:!0,hash:"466454ffeb31a0953c5120379ffece18",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/11771.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"11772",title:"Corruption - New Insights",subtitle:null,isOpenForSubmission:!0,hash:"9cda6d2feaa52a6d523da74f2e2d7ffb",slug:null,bookSignature:"Dr. Josiane Fahed-Sreih",coverURL:"https://cdn.intechopen.com/books/images_new/11772.jpg",editedByType:null,editors:[{id:"103784",title:"Dr.",name:"Josiane",surname:"Fahed-Sreih",slug:"josiane-fahed-sreih",fullName:"Josiane Fahed-Sreih"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],filtersByTopic:[{group:"topic",caption:"Agricultural and Biological Sciences",value:5,count:42},{group:"topic",caption:"Biochemistry, Genetics and Molecular Biology",value:6,count:12},{group:"topic",caption:"Business, Management and Economics",value:7,count:5},{group:"topic",caption:"Chemistry",value:8,count:24},{group:"topic",caption:"Computer and Information Science",value:9,count:19},{group:"topic",caption:"Earth and Planetary Sciences",value:10,count:17},{group:"topic",caption:"Engineering",value:11,count:62},{group:"topic",caption:"Environmental Sciences",value:12,count:9},{group:"topic",caption:"Immunology and Microbiology",value:13,count:10},{group:"topic",caption:"Materials Science",value:14,count:29},{group:"topic",caption:"Mathematics",value:15,count:11},{group:"topic",caption:"Medicine",value:16,count:123},{group:"topic",caption:"Nanotechnology and Nanomaterials",value:17,count:9},{group:"topic",caption:"Neuroscience",value:18,count:3},{group:"topic",caption:"Pharmacology, Toxicology and Pharmaceutical Science",value:19,count:6},{group:"topic",caption:"Physics",value:20,count:12},{group:"topic",caption:"Psychology",value:21,count:9},{group:"topic",caption:"Robotics",value:22,count:4},{group:"topic",caption:"Social Sciences",value:23,count:9},{group:"topic",caption:"Veterinary Medicine and Science",value:25,count:3}],offset:12,limit:12,total:41},popularBooks:{featuredBooks:[{type:"book",id:"9974",title:"E-Learning and Digital Education in the Twenty-First Century",subtitle:null,isOpenForSubmission:!1,hash:"88b58d66e975df20425fc1dfd22d53aa",slug:"e-learning-and-digital-education-in-the-twenty-first-century",bookSignature:"M. Mahruf C. Shohel",coverURL:"https://cdn.intechopen.com/books/images_new/9974.jpg",editors:[{id:"94099",title:"Dr.",name:"M. Mahruf C.",middleName:null,surname:"Shohel",slug:"m.-mahruf-c.-shohel",fullName:"M. Mahruf C. Shohel"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"11001",title:"Density Functional Theory",subtitle:"Recent Advances, New Perspectives and Applications",isOpenForSubmission:!1,hash:"82d53383af78ab41eb982086c02fb2bb",slug:"density-functional-theory-recent-advances-new-perspectives-and-applications",bookSignature:"Daniel Glossman-Mitnik",coverURL:"https://cdn.intechopen.com/books/images_new/11001.jpg",editors:[{id:"198499",title:"Dr.",name:"Daniel",middleName:null,surname:"Glossman-Mitnik",slug:"daniel-glossman-mitnik",fullName:"Daniel Glossman-Mitnik"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10251",title:"Plankton Communities",subtitle:null,isOpenForSubmission:!1,hash:"e11e441ca2d2d5f631b1b4704505cfb6",slug:"plankton-communities",bookSignature:"Leonel Pereira and Ana Marta Gonçalves",coverURL:"https://cdn.intechopen.com/books/images_new/10251.jpg",editors:[{id:"279788",title:"Dr.",name:"Leonel",middleName:null,surname:"Pereira",slug:"leonel-pereira",fullName:"Leonel Pereira"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10830",title:"Animal Feed Science and Nutrition",subtitle:"Production, Health and Environment",isOpenForSubmission:!1,hash:"79944fc8fbbaa329aed6fde388154832",slug:"animal-feed-science-and-nutrition-production-health-and-environment",bookSignature:"Amlan Kumar Patra",coverURL:"https://cdn.intechopen.com/books/images_new/10830.jpg",editors:[{id:"310962",title:"Dr.",name:"Amlan",middleName:"Kumar",surname:"Patra",slug:"amlan-patra",fullName:"Amlan Patra"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10356",title:"Natural Medicinal Plants",subtitle:null,isOpenForSubmission:!1,hash:"943e56ccaaf19ff696d25aa638ae37d6",slug:"natural-medicinal-plants",bookSignature:"Hany A. El-Shemy",coverURL:"https://cdn.intechopen.com/books/images_new/10356.jpg",editors:[{id:"54719",title:"Prof.",name:"Hany",middleName:null,surname:"El-Shemy",slug:"hany-el-shemy",fullName:"Hany El-Shemy"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"11752",title:"Natural Drugs from Plants",subtitle:null,isOpenForSubmission:!1,hash:"a0a83c0822608ef7592bf16a5ed0ada4",slug:"natural-drugs-from-plants",bookSignature:"Hany A. El-Shemy",coverURL:"https://cdn.intechopen.com/books/images_new/11752.jpg",editors:[{id:"54719",title:"Prof.",name:"Hany",middleName:null,surname:"El-Shemy",slug:"hany-el-shemy",fullName:"Hany El-Shemy"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10853",title:"Recent Advances in Polynomials",subtitle:null,isOpenForSubmission:!1,hash:"9e8671bae09ccaa8b8e276c639a737fc",slug:"recent-advances-in-polynomials",bookSignature:"Kamal Shah",coverURL:"https://cdn.intechopen.com/books/images_new/10853.jpg",editors:[{id:"231748",title:"Dr.",name:"Kamal",middleName:null,surname:"Shah",slug:"kamal-shah",fullName:"Kamal Shah"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10676",title:"Recent Applications in Graph Theory",subtitle:null,isOpenForSubmission:!1,hash:"900c60742d224080732bd16bd25ccba8",slug:"recent-applications-in-graph-theory",bookSignature:"Harun Pirim",coverURL:"https://cdn.intechopen.com/books/images_new/10676.jpg",editors:[{id:"146092",title:"Dr.",name:"Harun",middleName:null,surname:"Pirim",slug:"harun-pirim",fullName:"Harun Pirim"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10903",title:"Genetically Modified Plants and Beyond",subtitle:null,isOpenForSubmission:!1,hash:"4d7ed4faab99c92cd4d676dc86501df9",slug:"genetically-modified-plants-and-beyond",bookSignature:"Idah Sithole Niang",coverURL:"https://cdn.intechopen.com/books/images_new/10903.jpg",editors:[{id:"90172",title:"Prof.",name:"Idah",middleName:null,surname:"Sithole-Niang",slug:"idah-sithole-niang",fullName:"Idah Sithole-Niang"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10904",title:"Fusarium",subtitle:"An Overview of the Genus",isOpenForSubmission:!1,hash:"49d9063e43f94bd1517d65fbc58b93c3",slug:"fusarium-an-overview-of-the-genus",bookSignature:"Seyed Mahyar Mirmajlessi",coverURL:"https://cdn.intechopen.com/books/images_new/10904.jpg",editors:[{id:"100573",title:"Dr.",name:"Seyed Mahyar",middleName:null,surname:"Mirmajlessi",slug:"seyed-mahyar-mirmajlessi",fullName:"Seyed Mahyar Mirmajlessi"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10871",title:"Computed-Tomography (CT) Scan",subtitle:null,isOpenForSubmission:!1,hash:"966d8cf74fa27eea1b9cbc9a6ee94993",slug:"computed-tomography-ct-scan",bookSignature:"Reda R. Gharieb",coverURL:"https://cdn.intechopen.com/books/images_new/10871.jpg",editors:[{id:"225387",title:"Prof.",name:"Reda R.",middleName:"R.",surname:"Gharieb",slug:"reda-r.-gharieb",fullName:"Reda R. Gharieb"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"11196",title:"New Updates in E-Learning",subtitle:null,isOpenForSubmission:!1,hash:"6afaadf68e2a0a4b370ac5ceb5ca89c6",slug:"new-updates-in-e-learning",bookSignature:"Eduard Babulak",coverURL:"https://cdn.intechopen.com/books/images_new/11196.jpg",editors:[{id:"10086",title:"Prof.",name:"Eduard",middleName:null,surname:"Babulak",slug:"eduard-babulak",fullName:"Eduard Babulak"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}}],offset:12,limit:12,total:4383},hotBookTopics:{hotBooks:[],offset:0,limit:12,total:null},publish:{},publishingProposal:{success:null,errors:{}},books:{featuredBooks:[{type:"book",id:"9974",title:"E-Learning and Digital Education in the Twenty-First Century",subtitle:null,isOpenForSubmission:!1,hash:"88b58d66e975df20425fc1dfd22d53aa",slug:"e-learning-and-digital-education-in-the-twenty-first-century",bookSignature:"M. Mahruf C. Shohel",coverURL:"https://cdn.intechopen.com/books/images_new/9974.jpg",publishedDate:"May 18th 2022",numberOfDownloads:3340,editors:[{id:"94099",title:"Dr.",name:"M. Mahruf C.",middleName:null,surname:"Shohel",slug:"m.-mahruf-c.-shohel",fullName:"M. Mahruf C. Shohel"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"11001",title:"Density Functional Theory",subtitle:"Recent Advances, New Perspectives and Applications",isOpenForSubmission:!1,hash:"82d53383af78ab41eb982086c02fb2bb",slug:"density-functional-theory-recent-advances-new-perspectives-and-applications",bookSignature:"Daniel Glossman-Mitnik",coverURL:"https://cdn.intechopen.com/books/images_new/11001.jpg",publishedDate:"May 18th 2022",numberOfDownloads:1845,editors:[{id:"198499",title:"Dr.",name:"Daniel",middleName:null,surname:"Glossman-Mitnik",slug:"daniel-glossman-mitnik",fullName:"Daniel Glossman-Mitnik"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10251",title:"Plankton Communities",subtitle:null,isOpenForSubmission:!1,hash:"e11e441ca2d2d5f631b1b4704505cfb6",slug:"plankton-communities",bookSignature:"Leonel Pereira and Ana Marta Gonçalves",coverURL:"https://cdn.intechopen.com/books/images_new/10251.jpg",publishedDate:"May 18th 2022",numberOfDownloads:1096,editors:[{id:"279788",title:"Dr.",name:"Leonel",middleName:null,surname:"Pereira",slug:"leonel-pereira",fullName:"Leonel Pereira"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10830",title:"Animal Feed Science and Nutrition",subtitle:"Production, Health and Environment",isOpenForSubmission:!1,hash:"79944fc8fbbaa329aed6fde388154832",slug:"animal-feed-science-and-nutrition-production-health-and-environment",bookSignature:"Amlan Kumar Patra",coverURL:"https://cdn.intechopen.com/books/images_new/10830.jpg",publishedDate:"May 18th 2022",numberOfDownloads:995,editors:[{id:"310962",title:"Dr.",name:"Amlan",middleName:"Kumar",surname:"Patra",slug:"amlan-patra",fullName:"Amlan Patra"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10356",title:"Natural Medicinal Plants",subtitle:null,isOpenForSubmission:!1,hash:"943e56ccaaf19ff696d25aa638ae37d6",slug:"natural-medicinal-plants",bookSignature:"Hany A. El-Shemy",coverURL:"https://cdn.intechopen.com/books/images_new/10356.jpg",publishedDate:"May 11th 2022",numberOfDownloads:3791,editors:[{id:"54719",title:"Prof.",name:"Hany",middleName:null,surname:"El-Shemy",slug:"hany-el-shemy",fullName:"Hany El-Shemy"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"11752",title:"Natural Drugs from Plants",subtitle:null,isOpenForSubmission:!1,hash:"a0a83c0822608ef7592bf16a5ed0ada4",slug:"natural-drugs-from-plants",bookSignature:"Hany A. El-Shemy",coverURL:"https://cdn.intechopen.com/books/images_new/11752.jpg",publishedDate:"May 11th 2022",numberOfDownloads:2982,editors:[{id:"54719",title:"Prof.",name:"Hany",middleName:null,surname:"El-Shemy",slug:"hany-el-shemy",fullName:"Hany El-Shemy"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10853",title:"Recent Advances in Polynomials",subtitle:null,isOpenForSubmission:!1,hash:"9e8671bae09ccaa8b8e276c639a737fc",slug:"recent-advances-in-polynomials",bookSignature:"Kamal Shah",coverURL:"https://cdn.intechopen.com/books/images_new/10853.jpg",publishedDate:"May 18th 2022",numberOfDownloads:559,editors:[{id:"231748",title:"Dr.",name:"Kamal",middleName:null,surname:"Shah",slug:"kamal-shah",fullName:"Kamal Shah"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10676",title:"Recent Applications in Graph Theory",subtitle:null,isOpenForSubmission:!1,hash:"900c60742d224080732bd16bd25ccba8",slug:"recent-applications-in-graph-theory",bookSignature:"Harun Pirim",coverURL:"https://cdn.intechopen.com/books/images_new/10676.jpg",publishedDate:"May 18th 2022",numberOfDownloads:546,editors:[{id:"146092",title:"Dr.",name:"Harun",middleName:null,surname:"Pirim",slug:"harun-pirim",fullName:"Harun Pirim"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10903",title:"Genetically Modified Plants and Beyond",subtitle:null,isOpenForSubmission:!1,hash:"4d7ed4faab99c92cd4d676dc86501df9",slug:"genetically-modified-plants-and-beyond",bookSignature:"Idah Sithole Niang",coverURL:"https://cdn.intechopen.com/books/images_new/10903.jpg",publishedDate:"May 18th 2022",numberOfDownloads:539,editors:[{id:"90172",title:"Prof.",name:"Idah",middleName:null,surname:"Sithole-Niang",slug:"idah-sithole-niang",fullName:"Idah Sithole-Niang"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10904",title:"Fusarium",subtitle:"An Overview of the Genus",isOpenForSubmission:!1,hash:"49d9063e43f94bd1517d65fbc58b93c3",slug:"fusarium-an-overview-of-the-genus",bookSignature:"Seyed Mahyar Mirmajlessi",coverURL:"https://cdn.intechopen.com/books/images_new/10904.jpg",publishedDate:"May 18th 2022",numberOfDownloads:535,editors:[{id:"100573",title:"Dr.",name:"Seyed Mahyar",middleName:null,surname:"Mirmajlessi",slug:"seyed-mahyar-mirmajlessi",fullName:"Seyed Mahyar Mirmajlessi"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}}],latestBooks:[{type:"book",id:"10251",title:"Plankton Communities",subtitle:null,isOpenForSubmission:!1,hash:"e11e441ca2d2d5f631b1b4704505cfb6",slug:"plankton-communities",bookSignature:"Leonel Pereira and Ana Marta Gonçalves",coverURL:"https://cdn.intechopen.com/books/images_new/10251.jpg",editedByType:"Edited by",publishedDate:"May 18th 2022",editors:[{id:"279788",title:"Dr.",name:"Leonel",middleName:null,surname:"Pereira",slug:"leonel-pereira",fullName:"Leonel Pereira"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10830",title:"Animal Feed Science and Nutrition",subtitle:"Production, Health and Environment",isOpenForSubmission:!1,hash:"79944fc8fbbaa329aed6fde388154832",slug:"animal-feed-science-and-nutrition-production-health-and-environment",bookSignature:"Amlan Kumar Patra",coverURL:"https://cdn.intechopen.com/books/images_new/10830.jpg",editedByType:"Edited by",publishedDate:"May 18th 2022",editors:[{id:"310962",title:"Dr.",name:"Amlan",middleName:"Kumar",surname:"Patra",slug:"amlan-patra",fullName:"Amlan Patra"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10853",title:"Recent Advances in Polynomials",subtitle:null,isOpenForSubmission:!1,hash:"9e8671bae09ccaa8b8e276c639a737fc",slug:"recent-advances-in-polynomials",bookSignature:"Kamal Shah",coverURL:"https://cdn.intechopen.com/books/images_new/10853.jpg",editedByType:"Edited by",publishedDate:"May 18th 2022",editors:[{id:"231748",title:"Dr.",name:"Kamal",middleName:null,surname:"Shah",slug:"kamal-shah",fullName:"Kamal Shah"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10871",title:"Computed-Tomography (CT) Scan",subtitle:null,isOpenForSubmission:!1,hash:"966d8cf74fa27eea1b9cbc9a6ee94993",slug:"computed-tomography-ct-scan",bookSignature:"Reda R. Gharieb",coverURL:"https://cdn.intechopen.com/books/images_new/10871.jpg",editedByType:"Edited by",publishedDate:"May 18th 2022",editors:[{id:"225387",title:"Prof.",name:"Reda R.",middleName:"R.",surname:"Gharieb",slug:"reda-r.-gharieb",fullName:"Reda R. Gharieb"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10903",title:"Genetically Modified Plants and Beyond",subtitle:null,isOpenForSubmission:!1,hash:"4d7ed4faab99c92cd4d676dc86501df9",slug:"genetically-modified-plants-and-beyond",bookSignature:"Idah Sithole Niang",coverURL:"https://cdn.intechopen.com/books/images_new/10903.jpg",editedByType:"Edited by",publishedDate:"May 18th 2022",editors:[{id:"90172",title:"Prof.",name:"Idah",middleName:null,surname:"Sithole-Niang",slug:"idah-sithole-niang",fullName:"Idah Sithole-Niang"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10904",title:"Fusarium",subtitle:"An Overview of the Genus",isOpenForSubmission:!1,hash:"49d9063e43f94bd1517d65fbc58b93c3",slug:"fusarium-an-overview-of-the-genus",bookSignature:"Seyed Mahyar Mirmajlessi",coverURL:"https://cdn.intechopen.com/books/images_new/10904.jpg",editedByType:"Edited by",publishedDate:"May 18th 2022",editors:[{id:"100573",title:"Dr.",name:"Seyed Mahyar",middleName:null,surname:"Mirmajlessi",slug:"seyed-mahyar-mirmajlessi",fullName:"Seyed Mahyar Mirmajlessi"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10654",title:"Brain-Computer Interface",subtitle:null,isOpenForSubmission:!1,hash:"a5308884068cc53ed31c6baba756857f",slug:"brain-computer-interface",bookSignature:"Vahid Asadpour",coverURL:"https://cdn.intechopen.com/books/images_new/10654.jpg",editedByType:"Edited by",publishedDate:"May 18th 2022",editors:[{id:"165328",title:"Dr.",name:"Vahid",middleName:null,surname:"Asadpour",slug:"vahid-asadpour",fullName:"Vahid Asadpour"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10676",title:"Recent Applications in Graph Theory",subtitle:null,isOpenForSubmission:!1,hash:"900c60742d224080732bd16bd25ccba8",slug:"recent-applications-in-graph-theory",bookSignature:"Harun Pirim",coverURL:"https://cdn.intechopen.com/books/images_new/10676.jpg",editedByType:"Edited by",publishedDate:"May 18th 2022",editors:[{id:"146092",title:"Dr.",name:"Harun",middleName:null,surname:"Pirim",slug:"harun-pirim",fullName:"Harun Pirim"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"11196",title:"New Updates in E-Learning",subtitle:null,isOpenForSubmission:!1,hash:"6afaadf68e2a0a4b370ac5ceb5ca89c6",slug:"new-updates-in-e-learning",bookSignature:"Eduard Babulak",coverURL:"https://cdn.intechopen.com/books/images_new/11196.jpg",editedByType:"Edited by",publishedDate:"May 18th 2022",editors:[{id:"10086",title:"Prof.",name:"Eduard",middleName:null,surname:"Babulak",slug:"eduard-babulak",fullName:"Eduard Babulak"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9974",title:"E-Learning and Digital Education in the Twenty-First Century",subtitle:null,isOpenForSubmission:!1,hash:"88b58d66e975df20425fc1dfd22d53aa",slug:"e-learning-and-digital-education-in-the-twenty-first-century",bookSignature:"M. Mahruf C. Shohel",coverURL:"https://cdn.intechopen.com/books/images_new/9974.jpg",editedByType:"Edited by",publishedDate:"May 18th 2022",editors:[{id:"94099",title:"Dr.",name:"M. Mahruf C.",middleName:null,surname:"Shohel",slug:"m.-mahruf-c.-shohel",fullName:"M. Mahruf C. Shohel"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},subject:{topic:{id:"1317",title:"Public Health",slug:"social-sciences-education-public-health",parent:{id:"265",title:"Education",slug:"social-sciences-education"},numberOfBooks:2,numberOfSeries:0,numberOfAuthorsAndEditors:14,numberOfWosCitations:1,numberOfCrossrefCitations:12,numberOfDimensionsCitations:17,videoUrl:null,fallbackUrl:null,description:null},booksByTopicFilter:{topicId:"1317",sort:"-publishedDate",limit:12,offset:0},booksByTopicCollection:[{type:"book",id:"10191",title:"Health and Academic Achievement",subtitle:"New Findings",isOpenForSubmission:!1,hash:"7ee3f57e3911318305ac5c2eef39f8ab",slug:"health-and-academic-achievement-new-findings",bookSignature:"Blandina Bernal-Morales",coverURL:"https://cdn.intechopen.com/books/images_new/10191.jpg",editedByType:"Edited by",editors:[{id:"174721",title:"Dr.",name:"Blandina",middleName:null,surname:"Bernal-Morales",slug:"blandina-bernal-morales",fullName:"Blandina Bernal-Morales"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8645",title:"Contemporary Topics in Graduate Medical Education",subtitle:null,isOpenForSubmission:!1,hash:"76d224ba3c158c43fda8141a61ababd6",slug:"contemporary-topics-in-graduate-medical-education",bookSignature:"Stanislaw P. Stawicki, Michael S. Firstenberg, James P. Orlando and Thomas J. Papadimos",coverURL:"https://cdn.intechopen.com/books/images_new/8645.jpg",editedByType:"Edited by",editors:[{id:"181694",title:"Dr.",name:"Stanislaw P.",middleName:null,surname:"Stawicki",slug:"stanislaw-p.-stawicki",fullName:"Stanislaw P. Stawicki"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],booksByTopicTotal:2,seriesByTopicCollection:[],seriesByTopicTotal:0,mostCitedChapters:[{id:"66759",doi:"10.5772/intechopen.84235",title:"Resident Autonomy",slug:"resident-autonomy",totalDownloads:900,totalCrossrefCites:3,totalDimensionsCites:5,abstract:"Autonomy in medical training is required to develop independent and competent physicians. The way in which this incremental level of independence is granted to a trainee must be thoughtful and deliberate to ensure appropriate supervision and patient safety. Theories that support the role of autonomy will be introduced and discussed in this chapter. Ethical considerations that describe the implications of balancing the necessary independence for trainees and an attending physician’s responsibility to the patient and the patient’s safety will also be considered. The level of autonomy that is granted is the responsibility of both the attending physician and trainee so that it is not only appropriate but also well-earned. There are multiple tools that may be used to objectively measure one’s competence and necessary level of autonomy based on performance that will be discussed within this chapter. Finally we will demonstrate that encouraging and striking the balance of supervision and autonomy may be done safely with appropriate patient outcomes and trainee development into independent physicians. These outcomes will help to encourage autonomy amongst medical trainees, no matter one’s specialty, to train and develop competent, independent physicians of the future.",book:{id:"8645",slug:"contemporary-topics-in-graduate-medical-education",title:"Contemporary Topics in Graduate Medical Education",fullTitle:"Contemporary Topics in Graduate Medical Education"},signatures:"Amanda Cooper and Steven Allen",authors:null},{id:"64635",doi:"10.5772/intechopen.82343",title:"Wellness in Residency: A Paradigm Shift",slug:"wellness-in-residency-a-paradigm-shift",totalDownloads:811,totalCrossrefCites:2,totalDimensionsCites:3,abstract:"There has been a cultural shift in the state of residency training over the past two decades. While the traditional view of trainees heavily emphasized the service component of residency, training programs are gaining an increasing awareness of the trainees’ well-being as crucial to their functioning, the success of the training program, and ultimately, to the care of patients. To this end, work-hour limitations have been imposed universally. Additionally, some programs have established interventions that allow residents to lead balanced lives with emphasis on time away from work, sleep, and outside activities. A paradigm shift recognizing the importance of wellness in residency may reduce the risk of physician burnout in the long term.",book:{id:"8645",slug:"contemporary-topics-in-graduate-medical-education",title:"Contemporary Topics in Graduate Medical Education",fullTitle:"Contemporary Topics in Graduate Medical Education"},signatures:"Roderick M. Quiros and Elspeth Black",authors:null},{id:"73295",doi:"10.5772/intechopen.93886",title:"The Social Isolation Triggered by COVID-19: Effects on Mental Health and Education in Mexico",slug:"the-social-isolation-triggered-by-covid-19-effects-on-mental-health-and-education-in-mexico",totalDownloads:740,totalCrossrefCites:1,totalDimensionsCites:3,abstract:"Public health in Mexico was on alert since the World Health Organization declared a pandemic of COVID-19. This disease represents a challenge not only for the health system but also for the education system, which implement emerging measures such as online education. In Mexico online education has several limitations associated with computer and internet access, which affect the academic achievement of the students. Additionally, the main measures against the pandemic are social isolation, but this measure can generate stress and affect the academic achievement and mental health of the population. The present review was based on Mexican scientific and journalistic sources, and a thesaurus system such as Medical Subject Headings (MeSH) terms to find original articles to social isolation, mental health, and academic achievement. The contribution of this chapter is to describe the effects that social isolation has caused on mental health and scholar challenges in the Mexican student population.",book:{id:"10191",slug:"health-and-academic-achievement-new-findings",title:"Health and Academic Achievement",fullTitle:"Health and Academic Achievement - New Findings"},signatures:"Ana Karen Limón-Vázquez, Gabriel Guillén-Ruiz and Emma Virginia Herrera-Huerta",authors:[{id:"218681",title:"Dr.",name:"Gabriel",middleName:null,surname:"Guillén-Ruiz",slug:"gabriel-guillen-ruiz",fullName:"Gabriel Guillén-Ruiz"},{id:"306437",title:"Dr.",name:"Emma Virgina",middleName:null,surname:"Herrera-Huerta",slug:"emma-virgina-herrera-huerta",fullName:"Emma Virgina Herrera-Huerta"},{id:"306438",title:"MSc.",name:"Ana Karen",middleName:null,surname:"Limón-Vázquez",slug:"ana-karen-limon-vazquez",fullName:"Ana Karen Limón-Vázquez"}]},{id:"63925",doi:"10.5772/intechopen.81532",title:"Curriculum Development: Foundations and Modern Advances in Graduate Medical Education",slug:"curriculum-development-foundations-and-modern-advances-in-graduate-medical-education",totalDownloads:2291,totalCrossrefCites:2,totalDimensionsCites:2,abstract:"Curriculum development has undergone many transitions since the inception of medical education in the United States in the 1800’s. In this chapter, we briefly review the history of curriculum development in medical education. We discuss the landmark models of curriculum development including the concept of a curriculum map and Harden’s SPICES model of educational strategy, detail the six steps of Kern’s foundational framework, and provide an overview of the PRISMS strategy. We address the importance of adult learning theory and the advancing understanding of education for the millennial generation, including implementation of the flipped classroom model of education. Finally, we turn our focus on contemporary applications of curriculum design, including the application of simulation to medical education, the rise of massive open online courses (MOOC), and the implementation of free open access medical education (FOAM) within undergraduate and graduate medical curricula.",book:{id:"8645",slug:"contemporary-topics-in-graduate-medical-education",title:"Contemporary Topics in Graduate Medical Education",fullTitle:"Contemporary Topics in Graduate Medical Education"},signatures:"Simiao Li-Sauerwine and Andrew King",authors:null},{id:"64979",doi:"10.5772/intechopen.82618",title:"Teaching Balanced Patient Care Using Principles of Reductionism and Holism: The Example of Chronic Low Back Pain",slug:"teaching-balanced-patient-care-using-principles-of-reductionism-and-holism-the-example-of-chronic-lo",totalDownloads:997,totalCrossrefCites:2,totalDimensionsCites:2,abstract:"This chapter explores how integrating holistic and reductionistic approaches to care may better optimize value based care. First, we define the terms ‘Holistic,’ ‘Reductionistic’ and ‘Integrative’. Then we explore their scope in the arenas of teaching and patient care, with the advantages, disadvantages and pitfalls of each approach. We review how these styles are embedded in and interact with the cultures of medicine and western societies at large. As an example of a balanced care approach, we focus on the example of chronic low back pain (CLBP), an increasingly common and expensive medical problem. We present practical examples of teaching and practicing these different styles, Holism and Reductionism, illustrating when each may be appropriate to optimize value of patient care. Study questions are included. A list of further readings and resources is included for the interested reader.",book:{id:"8645",slug:"contemporary-topics-in-graduate-medical-education",title:"Contemporary Topics in Graduate Medical Education",fullTitle:"Contemporary Topics in Graduate Medical Education"},signatures:"Alan Remde, Stephen DeTurk and Thomas Wojda",authors:null}],mostDownloadedChaptersLast30Days:[{id:"74883",title:"Relation between Student Mental Health and Academic Achievement Revisited: A Meta-Analysis",slug:"relation-between-student-mental-health-and-academic-achievement-revisited-a-meta-analysis",totalDownloads:947,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"In the present research, the relationship between mental health and academic achievement in adolescents was investigated. The research adopted meta-analysis model to investigate the relationship between these two phenomena. In the meta-analysis, 13 independent studies were included, and their data were combined to display effect sizes. According to the result of the research, it was indicated that there was a positive relationship between mental health and academic achievement. Also, it was revealed that there was no significant relationship within sub-group variation in the relationship between mental health and academic achievement in terms of year of publication, publication type, community, and sample size, but not the setting.",book:{id:"10191",slug:"health-and-academic-achievement-new-findings",title:"Health and Academic Achievement",fullTitle:"Health and Academic Achievement - New Findings"},signatures:"Gokhan Bas",authors:[{id:"324308",title:"Associate Prof.",name:"Gokhan",middleName:null,surname:"Bas",slug:"gokhan-bas",fullName:"Gokhan Bas"}]},{id:"66601",title:"Leadership in Graduate Medical Education",slug:"leadership-in-graduate-medical-education",totalDownloads:821,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Graduate medical education (GME) is a very complex endeavor within an even more complex healthcare system. This chapter examines many questions that need to be considered and the role of the key individual with oversight of the GME, the designated institutional official (DIO). Topics examined are the leadership theories, practices and strategies for the DIO, dealing with change when the DIO starts, using authority versus power, effective problem-solving and decision-making, adaptive leadership style, the historical function of the DIO, as well as the many tools available to the DIO including networking. The chapter concludes with several pearls of wisdom to positively help the DIO meet the many challenges of this very important role in GME.",book:{id:"8645",slug:"contemporary-topics-in-graduate-medical-education",title:"Contemporary Topics in Graduate Medical Education",fullTitle:"Contemporary Topics in Graduate Medical Education"},signatures:"Jay M. Yanoff",authors:null},{id:"63925",title:"Curriculum Development: Foundations and Modern Advances in Graduate Medical Education",slug:"curriculum-development-foundations-and-modern-advances-in-graduate-medical-education",totalDownloads:2287,totalCrossrefCites:2,totalDimensionsCites:2,abstract:"Curriculum development has undergone many transitions since the inception of medical education in the United States in the 1800’s. In this chapter, we briefly review the history of curriculum development in medical education. We discuss the landmark models of curriculum development including the concept of a curriculum map and Harden’s SPICES model of educational strategy, detail the six steps of Kern’s foundational framework, and provide an overview of the PRISMS strategy. We address the importance of adult learning theory and the advancing understanding of education for the millennial generation, including implementation of the flipped classroom model of education. Finally, we turn our focus on contemporary applications of curriculum design, including the application of simulation to medical education, the rise of massive open online courses (MOOC), and the implementation of free open access medical education (FOAM) within undergraduate and graduate medical curricula.",book:{id:"8645",slug:"contemporary-topics-in-graduate-medical-education",title:"Contemporary Topics in Graduate Medical Education",fullTitle:"Contemporary Topics in Graduate Medical Education"},signatures:"Simiao Li-Sauerwine and Andrew King",authors:null},{id:"64979",title:"Teaching Balanced Patient Care Using Principles of Reductionism and Holism: The Example of Chronic Low Back Pain",slug:"teaching-balanced-patient-care-using-principles-of-reductionism-and-holism-the-example-of-chronic-lo",totalDownloads:995,totalCrossrefCites:2,totalDimensionsCites:2,abstract:"This chapter explores how integrating holistic and reductionistic approaches to care may better optimize value based care. First, we define the terms ‘Holistic,’ ‘Reductionistic’ and ‘Integrative’. Then we explore their scope in the arenas of teaching and patient care, with the advantages, disadvantages and pitfalls of each approach. We review how these styles are embedded in and interact with the cultures of medicine and western societies at large. As an example of a balanced care approach, we focus on the example of chronic low back pain (CLBP), an increasingly common and expensive medical problem. We present practical examples of teaching and practicing these different styles, Holism and Reductionism, illustrating when each may be appropriate to optimize value of patient care. Study questions are included. A list of further readings and resources is included for the interested reader.",book:{id:"8645",slug:"contemporary-topics-in-graduate-medical-education",title:"Contemporary Topics in Graduate Medical Education",fullTitle:"Contemporary Topics in Graduate Medical Education"},signatures:"Alan Remde, Stephen DeTurk and Thomas Wojda",authors:null},{id:"66801",title:"Physician Burnout",slug:"physician-burnout",totalDownloads:879,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"Burnout is pervasive among physicians and is rapidly becoming a pandemic in healthcare. It is characterized by increasing demands without adequate support and hallmarked by depersonalization, emotional exhaustion, and a reduced sense of personal accomplishment. It is essential to address burnout, as it can lead to decreased productivity, increased healthcare costs, medical errors, workforce attrition, depression, and even suicide. Many factors contribute to burnout, and it occurs at all stages of medicine: it can begin during medical school, intensify during the years of graduate medical education (GME) or residency training, and persist as residents become staff physicians. It affects both sexes, but may impact female physicians disproportionately. Impact can also vary among specialties. Recognizing the problem and intervening with unified physician and organization-directed solutions centered on well-being, efficient practice models, and goal prioritization may help to reduce the prevalence and effects of burnout.",book:{id:"8645",slug:"contemporary-topics-in-graduate-medical-education",title:"Contemporary Topics in Graduate Medical Education",fullTitle:"Contemporary Topics in Graduate Medical Education"},signatures:"Bess Connors, Charlotte Horne, Valery Vilchez and Sofya Asfaw",authors:null}],onlineFirstChaptersFilter:{topicId:"1317",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:87,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:98,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:27,numberOfPublishedChapters:287,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:9,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:139,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:0,numberOfUpcomingTopics:2,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!1},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:107,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:10,numberOfPublishedChapters:103,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:12,numberOfOpenTopics:2,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:0,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!1},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:10,numberOfOpenTopics:4,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}},{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}}]},series:{item:{id:"22",title:"Business, Management and Economics",doi:"10.5772/intechopen.100359",issn:"2753-894X",scope:"\r\n\tThis series will provide a comprehensive overview of recent research trends in business and management, economics, and marketing. Topics will include asset liability management, financial consequences of the financial crisis and covid-19, financial accounting, mergers and acquisitions, management accounting, SMEs, financial markets, corporate finance and governance, managerial technology and innovation, resource management and sustainable development, social entrepreneurship, corporate responsibility, ethics and accountability, microeconomics, labour economics, macroeconomics, public economics, financial economics, econometrics, direct marketing, creative marketing, internet marketing, market planning and forecasting, brand management, market segmentation and targeting and other topics under business and management. This book series will focus on various aspects of business and management whose in-depth understanding is critical for business and company management to function effectively during this uncertain time of financial crisis, Covid-19 pandemic, and military activity in Europe.
",coverUrl:"https://cdn.intechopen.com/series/covers/22.jpg",latestPublicationDate:"May 18th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:1,editor:{id:"356540",title:"Prof.",name:"Taufiq",middleName:null,surname:"Choudhry",slug:"taufiq-choudhry",fullName:"Taufiq Choudhry",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000036X2hvQAC/Profile_Picture_2022-03-14T08:58:03.jpg",biography:"Prof. Choudhry holds a BSc degree in Economics from the University of Iowa, as well as a Masters and Ph.D. in Applied Economics from Clemson University, USA. In January 2006, he became a Professor of Finance at the University of Southampton Business School. He was previously a Professor of Finance at the University of Bradford Management School. He has over 80 articles published in international finance and economics journals. His research interests and specialties include financial econometrics, financial economics, international economics and finance, housing markets, financial markets, among others.",institutionString:null,institution:{name:"University of Southampton",institutionURL:null,country:{name:"United Kingdom"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:3,paginationItems:[{id:"86",title:"Business and Management",coverUrl:"https://cdn.intechopen.com/series_topics/covers/86.jpg",isOpenForSubmission:!0,editor:{id:"128342",title:"Prof.",name:"Vito",middleName:null,surname:"Bobek",slug:"vito-bobek",fullName:"Vito Bobek",profilePictureURL:"https://mts.intechopen.com/storage/users/128342/images/system/128342.jpg",biography:"Dr. Vito Bobek works as an international management professor at the University of Applied Sciences FH Joanneum, Graz, Austria. He has published more than 400 works in his academic career and visited twenty-two universities worldwide as a visiting professor. Dr. Bobek is a member of the editorial boards of six international journals and a member of the Strategic Council of the Minister of Foreign Affairs of the Republic of Slovenia. He has a long history in academia, consulting, and entrepreneurship. His own consulting firm, Palemid, has managed twenty significant projects, such as Cooperation Program Interreg V-A (Slovenia-Austria) and Capacity Building for the Serbian Chamber of Enforcement Agents. He has also participated in many international projects in Italy, Germany, Great Britain, the United States, Spain, Turkey, France, Romania, Croatia, Montenegro, Malaysia, and China. Dr. Bobek is also a co-founder of the Academy of Regional Management in Slovenia.",institutionString:"Universities of Applied Sciences FH Joanneum, Austria",institution:null},editorTwo:{id:"293992",title:"Dr.",name:"Tatjana",middleName:null,surname:"Horvat",slug:"tatjana-horvat",fullName:"Tatjana Horvat",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002hXb0hQAC/Profile_Picture_1642419002203",biography:"Tatjana Horvat works as a professor for accountant and auditing at the University of Primorska, Slovenia. She is a Certified State Internal Auditor (licensed by Ministry of Finance RS) and Certified Internal Auditor for Business Sector and Certified accountant (licensed by Slovenian Institute of Auditors). At the Ministry of Justice of Slovenia, she is a member of examination boards for court expert candidates and judicial appraisers in the following areas: economy/finance, valuation of companies, banking, and forensic investigation of economic operations/accounting. At the leading business newspaper Finance in Slovenia (Swedish ownership), she is the editor and head of the area for business, finance, tax-related articles, and educational programs.",institutionString:null,institution:{name:"University of Primorska",institutionURL:null,country:{name:"Slovenia"}}},editorThree:null},{id:"87",title:"Economics",coverUrl:"https://cdn.intechopen.com/series_topics/covers/87.jpg",isOpenForSubmission:!0,editor:{id:"327730",title:"Prof.",name:"Jaime",middleName:null,surname:"Ortiz",slug:"jaime-ortiz",fullName:"Jaime Ortiz",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00002zaOKZQA2/Profile_Picture_1642145584421",biography:"Dr. Jaime Ortiz holds degrees from Chile, the Netherlands, and the United States. He has held tenured faculty, distinguished professorship, and executive leadership appointments in several universities around the world. Dr. Ortiz has previously worked for international organizations and non-government entities in economic and business matters, and he has university-wide globalization engagement in more than thirty-six countries. He has advised, among others, the United Nations Development Program, Inter-American Development Bank, Organization of American States, Pre-investment Organization of Latin America and the Caribbean, Technical Cooperation of the Suisse Government, and the World Bank. Dr. Ortiz is the author, co-author, or editor of books, book chapters, textbooks, research monographs and technical reports, and refereed journal articles. He is listed in Who’s Who in the World, Who’s Who in America, Who’s Who in Finance and Business, Who’s Who in Business Higher Education, Who’s Who in American Education, and Who’s Who Directory of Economists. Dr. Ortiz has been a Fulbright Scholar and an MSI Leadership Fellow with the W.K. Kellogg Foundation. His teaching interests revolve around global economies and markets while his research focuses on topics related to development and growth, global business decisions, and the economics of technical innovation.",institutionString:null,institution:{name:"University of Houston",institutionURL:null,country:{name:"United States of America"}}},editorTwo:null,editorThree:null},{id:"88",title:"Marketing",coverUrl:"https://cdn.intechopen.com/series_topics/covers/88.jpg",isOpenForSubmission:!1,editor:null,editorTwo:null,editorThree:null}]},overviewPageOFChapters:{paginationCount:1,paginationItems:[{id:"81831",title:"Deep Network Model and Regression Analysis using OLS Method for Predicting Lung Vital Capacity",doi:"10.5772/intechopen.104737",signatures:"Harun Sümbül",slug:"deep-network-model-and-regression-analysis-using-ols-method-for-predicting-lung-vital-capacity",totalDownloads:2,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Decision Science - Recent Advances and Applications",coverURL:"https://cdn.intechopen.com/books/images_new/11604.jpg",subseries:{id:"86",title:"Business and Management"}}}]},overviewPagePublishedBooks:{paginationCount:1,paginationItems:[{type:"book",id:"11392",title:"Leadership in a Changing World",subtitle:"A Multidimensional Perspective",coverURL:"https://cdn.intechopen.com/books/images_new/11392.jpg",slug:"leadership-in-a-changing-world-a-multidimensional-perspective",publishedDate:"May 11th 2022",editedByType:"Edited by",bookSignature:"Muhammad Mohiuddin, Bilal Khalid, Md. Samim Al Azad and Slimane Ed-dafali",hash:"86a6d33cf601587e591064ce92effc02",volumeInSeries:1,fullTitle:"Leadership in a Changing World - A Multidimensional Perspective",editors:[{id:"418514",title:"Dr.",name:"Muhammad",middleName:null,surname:"Mohiuddin",slug:"muhammad-mohiuddin",fullName:"Muhammad Mohiuddin",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000038UqSfQAK/Profile_Picture_2022-05-13T10:39:03.jpg",biography:"Dr. Muhammad Mohiuddin is an Associate Professor of International Business at Laval University, Canada. He has taught at Thompson Rivers University, Canada; University of Paris-Est, France; Osnabruck University of Applied Science, Germany; and Shanghai Institute of Technology and Tianjin University of Technology, China. He has published research in Research Policy, Applied Economics, Review of Economic Philosophy, Strategic Change, International Journal of Logistics, Sustainability, Journal of Environmental Management, Journal of Global Information Management, Journal of Cleaner Production, M@N@GEMENT, and more. He is a member of CEDIMES Institut (France), Academy of International Business (AIB), Strategic Management Society (SMS), Academy of Management (AOM), Administrative Science Association of Canada (ASAC), and Canadian council of small business and entrepreneurship (CCSBE). He is currently the director of the Research Group on Contemporary Asia (GERAC) at Laval University. He is also co-managing editor of Transnational Corporations Review and a guest editor for Electronic Commerce Research and Journal of Internet Technology.",institutionString:"Université Laval",institution:{name:"Université Laval",institutionURL:null,country:{name:"Canada"}}}]}]},openForSubmissionBooks:{paginationCount:5,paginationItems:[{id:"11576",title:"Malaria - Recent Advances, and New Perspectives",coverURL:"https://cdn.intechopen.com/books/images_new/11576.jpg",hash:"5a01644fb0b4ce24c2f947913d154abe",secondStepPassed:!0,currentStepOfPublishingProcess:3,submissionDeadline:"April 26th 2022",isOpenForSubmission:!0,editors:[{id:"76041",title:"Prof.",name:"Pier Paolo",surname:"Piccaluga",slug:"pier-paolo-piccaluga",fullName:"Pier Paolo Piccaluga"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null},{id:"11577",title:"Tick-Borne Diseases - A Review and an Update of Knowledge on Infections in Human and Animal Population",coverURL:"https://cdn.intechopen.com/books/images_new/11577.jpg",hash:"3d72ae651ee2a04b2368bf798a3183ca",secondStepPassed:!0,currentStepOfPublishingProcess:3,submissionDeadline:"April 29th 2022",isOpenForSubmission:!0,editors:[{id:"51521",title:"Prof.",name:"Elisa",surname:"Pieragostini",slug:"elisa-pieragostini",fullName:"Elisa Pieragostini"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null},{id:"11570",title:"Influenza - New Approaches",coverURL:"https://cdn.intechopen.com/books/images_new/11570.jpg",hash:"157b379b9d7a4bf5e2cc7a742f155a44",secondStepPassed:!0,currentStepOfPublishingProcess:3,submissionDeadline:"May 10th 2022",isOpenForSubmission:!0,editors:[{id:"139889",title:"Dr.",name:"Seyyed Shamsadin",surname:"Athari",slug:"seyyed-shamsadin-athari",fullName:"Seyyed Shamsadin Athari"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null},{id:"11569",title:"Bacterial Sexually Transmitted Infections - New Findings, Diagnosis, Treatment, and Prevention",coverURL:"https://cdn.intechopen.com/books/images_new/11569.jpg",hash:"069d6142ecb0d46d14920102d48c0e9d",secondStepPassed:!1,currentStepOfPublishingProcess:2,submissionDeadline:"May 31st 2022",isOpenForSubmission:!0,editors:[{id:"189561",title:"Dr.",name:"Mihaela Laura",surname:"Vica",slug:"mihaela-laura-vica",fullName:"Mihaela Laura Vica"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null},{id:"11568",title:"Staphylococcal Infections - Recent Advances and Perspectives",coverURL:"https://cdn.intechopen.com/books/images_new/11568.jpg",hash:"92c881664d1921c7f2d0fee34b78cd08",secondStepPassed:!1,currentStepOfPublishingProcess:2,submissionDeadline:"June 1st 2022",isOpenForSubmission:!0,editors:[{id:"59719",title:"Dr.",name:"Jaime",surname:"Bustos-Martínez",slug:"jaime-bustos-martinez",fullName:"Jaime Bustos-Martínez"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null}]},onlineFirstChapters:{paginationCount:49,paginationItems:[{id:"80495",title:"Iron in Cell Metabolism and Disease",doi:"10.5772/intechopen.101908",signatures:"Eeka Prabhakar",slug:"iron-in-cell-metabolism-and-disease",totalDownloads:4,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Iron Metabolism - Iron a Double‐Edged Sword",coverURL:"https://cdn.intechopen.com/books/images_new/10842.jpg",subseries:{id:"17",title:"Metabolism"}}},{id:"81799",title:"Cross Talk of Purinergic and Immune Signaling: Implication in Inflammatory and Pathogenic Diseases",doi:"10.5772/intechopen.104978",signatures:"Richa Rai",slug:"cross-talk-of-purinergic-and-immune-signaling-implication-in-inflammatory-and-pathogenic-diseases",totalDownloads:10,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Purinergic System",coverURL:"https://cdn.intechopen.com/books/images_new/10801.jpg",subseries:{id:"17",title:"Metabolism"}}},{id:"81764",title:"Involvement of the Purinergic System in Cell Death in Models of Retinopathies",doi:"10.5772/intechopen.103935",signatures:"Douglas Penaforte Cruz, Marinna Garcia Repossi and Lucianne Fragel Madeira",slug:"involvement-of-the-purinergic-system-in-cell-death-in-models-of-retinopathies",totalDownloads:5,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Purinergic System",coverURL:"https://cdn.intechopen.com/books/images_new/10801.jpg",subseries:{id:"17",title:"Metabolism"}}},{id:"81756",title:"Alteration of Cytokines Level and Oxidative Stress Parameters in COVID-19",doi:"10.5772/intechopen.104950",signatures:"Marija Petrusevska, Emilija Atanasovska, Dragica Zendelovska, Aleksandar Eftimov and Katerina Spasovska",slug:"alteration-of-cytokines-level-and-oxidative-stress-parameters-in-covid-19",totalDownloads:10,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Chemokines Updates",coverURL:"https://cdn.intechopen.com/books/images_new/11672.jpg",subseries:{id:"18",title:"Proteomics"}}},{id:"81681",title:"Immunomodulatory Effects of a M2-Conditioned Medium (PRS® CK STORM): Theory on the Possible Complex Mechanism of Action through Anti-Inflammatory Modulation of the TLR System and the Purinergic System",doi:"10.5772/intechopen.104486",signatures:"Juan Pedro Lapuente",slug:"immunomodulatory-effects-of-a-m2-conditioned-medium-prs-ck-storm-theory-on-the-possible-complex-mech",totalDownloads:5,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Purinergic System",coverURL:"https://cdn.intechopen.com/books/images_new/10801.jpg",subseries:{id:"17",title:"Metabolism"}}},{id:"81647",title:"Diabetes and Epigenetics",doi:"10.5772/intechopen.104653",signatures:"Rasha A. Alhazzaa, Thomas Heinbockel and Antonei B. Csoka",slug:"diabetes-and-epigenetics",totalDownloads:12,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Epigenetics to Optogenetics - A New Paradigm in the Study of Biology",coverURL:"https://cdn.intechopen.com/books/images_new/9672.jpg",subseries:{id:"14",title:"Cell and Molecular Biology"}}},{id:"81580",title:"Graft-Versus-Host Disease: Pathogenesis and Treatment",doi:"10.5772/intechopen.104450",signatures:"Shin Mukai",slug:"graft-versus-host-disease-pathogenesis-and-treatment",totalDownloads:15,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Purinergic System",coverURL:"https://cdn.intechopen.com/books/images_new/10801.jpg",subseries:{id:"17",title:"Metabolism"}}},{id:"81533",title:"Prenylation of Natural Products: An Overview",doi:"10.5772/intechopen.104636",signatures:"Kantharaju Kamanna and Aravind Kamath",slug:"prenylation-of-natural-products-an-overview",totalDownloads:20,totalCrossrefCites:0,totalDimensionsCites:0,authors:[{name:"Kantharaju",surname:"Kamanna"}],book:{title:"Modifications of Biomolecules",coverURL:"https://cdn.intechopen.com/books/images_new/11098.jpg",subseries:null}},{id:"81067",title:"Encapsulation of Essential Oils and Their Use in Food Applications",doi:"10.5772/intechopen.103147",signatures:"Hamdy A. Shaaban and Amr Farouk",slug:"encapsulation-of-essential-oils-and-their-use-in-food-applications",totalDownloads:49,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Essential Oils - Advances in Extractions and Biological Applications",coverURL:"https://cdn.intechopen.com/books/images_new/11332.jpg",subseries:{id:"15",title:"Chemical Biology"}}},{id:"81099",title:"SK Channels and Heart Disease",doi:"10.5772/intechopen.104115",signatures:"Katherine Zhong, Shawn Kant, Frank Sellke and Jun Feng",slug:"sk-channels-and-heart-disease",totalDownloads:17,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Ion Channels - From Basic Properties to Medical Treatment",coverURL:"https://cdn.intechopen.com/books/images_new/10838.jpg",subseries:{id:"14",title:"Cell and Molecular Biology"}}}]},subseriesFiltersForOFChapters:[{caption:"Proteomics",value:18,count:3,group:"subseries"},{caption:"Metabolism",value:17,count:9,group:"subseries"},{caption:"Cell and Molecular Biology",value:14,count:17,group:"subseries"},{caption:"Chemical Biology",value:15,count:19,group:"subseries"}],publishedBooks:{paginationCount:27,paginationItems:[{type:"book",id:"10803",title:"Reactive Oxygen Species",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/10803.jpg",slug:"reactive-oxygen-species",publishedDate:"April 28th 2022",editedByType:"Edited by",bookSignature:"Rizwan Ahmad",hash:"176adcf090fdd1f93cb8ce3146e79ca1",volumeInSeries:28,fullTitle:"Reactive Oxygen Species",editors:[{id:"40482",title:null,name:"Rizwan",middleName:null,surname:"Ahmad",slug:"rizwan-ahmad",fullName:"Rizwan Ahmad",profilePictureURL:"https://mts.intechopen.com/storage/users/40482/images/system/40482.jpeg",institutionString:"Imam Abdulrahman Bin Faisal University",institution:{name:"Imam Abdulrahman Bin Faisal University",institutionURL:null,country:{name:"Saudi Arabia"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null},{type:"book",id:"9008",title:"Vitamin K",subtitle:"Recent Topics on the Biology and Chemistry",coverURL:"https://cdn.intechopen.com/books/images_new/9008.jpg",slug:"vitamin-k-recent-topics-on-the-biology-and-chemistry",publishedDate:"March 23rd 2022",editedByType:"Edited by",bookSignature:"Hiroyuki Kagechika and Hitoshi Shirakawa",hash:"8b43add5389ba85743e0a9491e4b9943",volumeInSeries:27,fullTitle:"Vitamin K - Recent Topics on the Biology and Chemistry",editors:[{id:"180528",title:"Dr.",name:"Hiroyuki",middleName:null,surname:"Kagechika",slug:"hiroyuki-kagechika",fullName:"Hiroyuki Kagechika",profilePictureURL:"https://mts.intechopen.com/storage/users/180528/images/system/180528.jpg",institutionString:"Tokyo Medical and Dental University",institution:{name:"Tokyo Medical and Dental University",institutionURL:null,country:{name:"Japan"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null},{type:"book",id:"10799",title:"Phenolic Compounds",subtitle:"Chemistry, Synthesis, Diversity, Non-Conventional Industrial, Pharmaceutical and Therapeutic Applications",coverURL:"https://cdn.intechopen.com/books/images_new/10799.jpg",slug:"phenolic-compounds-chemistry-synthesis-diversity-non-conventional-industrial-pharmaceutical-and-therapeutic-applications",publishedDate:"February 23rd 2022",editedByType:"Edited by",bookSignature:"Farid A. Badria",hash:"339199f254d2987ef3167eef74fb8a38",volumeInSeries:26,fullTitle:"Phenolic Compounds - Chemistry, Synthesis, Diversity, Non-Conventional Industrial, Pharmaceutical and Therapeutic Applications",editors:[{id:"41865",title:"Prof.",name:"Farid A.",middleName:null,surname:"Badria",slug:"farid-a.-badria",fullName:"Farid A. Badria",profilePictureURL:"https://mts.intechopen.com/storage/users/41865/images/system/41865.jpg",institutionString:"Mansoura University",institution:{name:"Mansoura University",institutionURL:null,country:{name:"Egypt"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null},{type:"book",id:"9659",title:"Fibroblasts",subtitle:"Advances in Inflammation, Autoimmunity and Cancer",coverURL:"https://cdn.intechopen.com/books/images_new/9659.jpg",slug:"fibroblasts-advances-in-inflammation-autoimmunity-and-cancer",publishedDate:"December 22nd 2021",editedByType:"Edited by",bookSignature:"Mojca Frank Bertoncelj and Katja Lakota",hash:"926fa6446f6befbd363fc74971a56de2",volumeInSeries:25,fullTitle:"Fibroblasts - Advances in Inflammation, Autoimmunity and Cancer",editors:[{id:"328755",title:"Ph.D.",name:"Mojca",middleName:null,surname:"Frank Bertoncelj",slug:"mojca-frank-bertoncelj",fullName:"Mojca Frank Bertoncelj",profilePictureURL:"https://mts.intechopen.com/storage/users/328755/images/system/328755.jpg",institutionString:"BioMed X Institute",institution:{name:"University Hospital of Zurich",institutionURL:null,country:{name:"Switzerland"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null},{type:"book",id:"8977",title:"Protein Kinases",subtitle:"Promising Targets for Anticancer Drug Research",coverURL:"https://cdn.intechopen.com/books/images_new/8977.jpg",slug:"protein-kinases-promising-targets-for-anticancer-drug-research",publishedDate:"December 8th 2021",editedByType:"Edited by",bookSignature:"Rajesh Kumar Singh",hash:"6d200cc031706a565b554fdb1c478901",volumeInSeries:24,fullTitle:"Protein Kinases - Promising Targets for Anticancer Drug Research",editors:[{id:"329385",title:"Dr.",name:"Rajesh K.",middleName:"Kumar",surname:"Singh",slug:"rajesh-k.-singh",fullName:"Rajesh K. Singh",profilePictureURL:"https://mts.intechopen.com/storage/users/329385/images/system/329385.png",institutionString:"Punjab Technical University",institution:{name:"Punjab Technical University",institutionURL:null,country:{name:"India"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null},{type:"book",id:"8018",title:"Extracellular Matrix",subtitle:"Developments and Therapeutics",coverURL:"https://cdn.intechopen.com/books/images_new/8018.jpg",slug:"extracellular-matrix-developments-and-therapeutics",publishedDate:"October 27th 2021",editedByType:"Edited by",bookSignature:"Rama Sashank Madhurapantula, Joseph Orgel P.R.O. and Zvi Loewy",hash:"c85e82851e80b40282ff9be99ddf2046",volumeInSeries:23,fullTitle:"Extracellular Matrix - Developments and Therapeutics",editors:[{id:"212416",title:"Dr.",name:"Rama Sashank",middleName:null,surname:"Madhurapantula",slug:"rama-sashank-madhurapantula",fullName:"Rama Sashank Madhurapantula",profilePictureURL:"https://mts.intechopen.com/storage/users/212416/images/system/212416.jpg",institutionString:"Illinois Institute of Technology",institution:{name:"Illinois Institute of Technology",institutionURL:null,country:{name:"United States of America"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null},{type:"book",id:"9759",title:"Vitamin E in Health and Disease",subtitle:"Interactions, Diseases and Health Aspects",coverURL:"https://cdn.intechopen.com/books/images_new/9759.jpg",slug:"vitamin-e-in-health-and-disease-interactions-diseases-and-health-aspects",publishedDate:"October 6th 2021",editedByType:"Edited by",bookSignature:"Pınar Erkekoglu and Júlia Scherer Santos",hash:"6c3ddcc13626110de289b57f2516ac8f",volumeInSeries:22,fullTitle:"Vitamin E in Health and Disease - Interactions, Diseases and Health Aspects",editors:[{id:"109978",title:"Prof.",name:"Pınar",middleName:null,surname:"Erkekoğlu",slug:"pinar-erkekoglu",fullName:"Pınar Erkekoğlu",profilePictureURL:"https://mts.intechopen.com/storage/users/109978/images/system/109978.jpg",institutionString:"Hacettepe University",institution:{name:"Hacettepe University",institutionURL:null,country:{name:"Turkey"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null},{type:"book",id:"9753",title:"Terpenes and Terpenoids",subtitle:"Recent Advances",coverURL:"https://cdn.intechopen.com/books/images_new/9753.jpg",slug:"terpenes-and-terpenoids-recent-advances",publishedDate:"July 28th 2021",editedByType:"Edited by",bookSignature:"Shagufta Perveen and Areej Mohammad Al-Taweel",hash:"575689df13c78bf0e6c1be40804cd010",volumeInSeries:21,fullTitle:"Terpenes and Terpenoids - Recent Advances",editors:[{id:"192992",title:"Prof.",name:"Shagufta",middleName:null,surname:"Perveen",slug:"shagufta-perveen",fullName:"Shagufta Perveen",profilePictureURL:"https://mts.intechopen.com/storage/users/192992/images/system/192992.png",institutionString:"King Saud University",institution:{name:"King Saud University",institutionURL:null,country:{name:"Saudi Arabia"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null},{type:"book",id:"9403",title:"Human Microbiome",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/9403.jpg",slug:"human-microbiome",publishedDate:"June 16th 2021",editedByType:"Edited by",bookSignature:"Natalia V. Beloborodova and Andrey V. Grechko",hash:"c31366ba82585ba3ac91d21eb1cf0a4d",volumeInSeries:20,fullTitle:"Human Microbiome",editors:[{id:"199461",title:"Prof.",name:"Natalia V.",middleName:null,surname:"Beloborodova",slug:"natalia-v.-beloborodova",fullName:"Natalia V. Beloborodova",profilePictureURL:"https://mts.intechopen.com/storage/users/199461/images/system/199461.jpg",institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null},{type:"book",id:"9731",title:"Oxidoreductase",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/9731.jpg",slug:"oxidoreductase",publishedDate:"February 17th 2021",editedByType:"Edited by",bookSignature:"Mahmoud Ahmed Mansour",hash:"852e6f862c85fc3adecdbaf822e64e6e",volumeInSeries:19,fullTitle:"Oxidoreductase",editors:[{id:"224662",title:"Prof.",name:"Mahmoud Ahmed",middleName:null,surname:"Mansour",slug:"mahmoud-ahmed-mansour",fullName:"Mahmoud Ahmed Mansour",profilePictureURL:"https://mts.intechopen.com/storage/users/224662/images/system/224662.jpg",institutionString:"King Saud bin Abdulaziz University for Health Sciences",institution:{name:"King Saud bin Abdulaziz University for Health Sciences",institutionURL:null,country:{name:"Saudi Arabia"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null},{type:"book",id:"9742",title:"Ubiquitin",subtitle:"Proteasome Pathway",coverURL:"https://cdn.intechopen.com/books/images_new/9742.jpg",slug:"ubiquitin-proteasome-pathway",publishedDate:"December 9th 2020",editedByType:"Edited by",bookSignature:"Xianquan Zhan",hash:"af6880d3a5571da1377ac8f6373b9e82",volumeInSeries:18,fullTitle:"Ubiquitin - Proteasome Pathway",editors:[{id:"223233",title:"Prof.",name:"Xianquan",middleName:null,surname:"Zhan",slug:"xianquan-zhan",fullName:"Xianquan Zhan",profilePictureURL:"https://mts.intechopen.com/storage/users/223233/images/system/223233.png",institutionString:"Shandong First Medical University",institution:{name:"Affiliated Hospital of Shandong Academy of Medical Sciences",institutionURL:null,country:{name:"China"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null},{type:"book",id:"9002",title:"Glutathione System and Oxidative Stress in Health and Disease",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/9002.jpg",slug:"glutathione-system-and-oxidative-stress-in-health-and-disease",publishedDate:"August 26th 2020",editedByType:"Edited by",bookSignature:"Margarete Dulce Bagatini",hash:"127defed0a50ad5ed92338dc96e1e10e",volumeInSeries:17,fullTitle:"Glutathione System and Oxidative Stress in Health and Disease",editors:[{id:"217850",title:"Dr.",name:"Margarete Dulce",middleName:null,surname:"Bagatini",slug:"margarete-dulce-bagatini",fullName:"Margarete Dulce Bagatini",profilePictureURL:"https://mts.intechopen.com/storage/users/217850/images/system/217850.jpeg",institutionString:"Universidade Federal da Fronteira Sul",institution:{name:"Universidade Federal da Fronteira Sul",institutionURL:null,country:{name:"Brazil"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null}]},subseriesFiltersForPublishedBooks:[{group:"subseries",caption:"Proteomics",value:18,count:3},{group:"subseries",caption:"Metabolism",value:17,count:6},{group:"subseries",caption:"Cell and Molecular Biology",value:14,count:8},{group:"subseries",caption:"Chemical Biology",value:15,count:10}],publicationYearFilters:[{group:"publicationYear",caption:"2022",value:2022,count:3},{group:"publicationYear",caption:"2021",value:2021,count:7},{group:"publicationYear",caption:"2020",value:2020,count:12},{group:"publicationYear",caption:"2019",value:2019,count:3},{group:"publicationYear",caption:"2018",value:2018,count:2}],authors:{paginationCount:33,paginationItems:[{id:"424419",title:"Dr.",name:"Matthew",middleName:"Ayorinde",surname:"Ayorinde Adebayo",slug:"matthew-ayorinde-adebayo",fullName:"Matthew Ayorinde Adebayo",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/424419/images/17356_n.jpg",biography:null,institutionString:null,institution:null},{id:"354033",title:"Dr.",name:"Ahmed",middleName:null,surname:"Nasri",slug:"ahmed-nasri",fullName:"Ahmed Nasri",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Carthage",country:{name:"Tunisia"}}},{id:"435702",title:"Dr.",name:"Amel",middleName:null,surname:"Hannachi",slug:"amel-hannachi",fullName:"Amel Hannachi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Carthage",country:{name:"Tunisia"}}},{id:"420857",title:"Prof.",name:"Ezzeddine",middleName:null,surname:"Mahmoudi",slug:"ezzeddine-mahmoudi",fullName:"Ezzeddine Mahmoudi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Carthage",country:{name:"Tunisia"}}},{id:"420856",title:"Prof.",name:"Hamouda",middleName:null,surname:"Beyrem",slug:"hamouda-beyrem",fullName:"Hamouda Beyrem",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Carthage",country:{name:"Tunisia"}}},{id:"435703",title:"Dr.",name:"Hary",middleName:null,surname:"Demey",slug:"hary-demey",fullName:"Hary Demey",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Polytechnic University of Cartagena",country:{name:"Spain"}}},{id:"425026",title:"Mr.",name:"Kholofelo",middleName:null,surname:"Clifford Malematja",slug:"kholofelo-clifford-malematja",fullName:"Kholofelo Clifford Malematja",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Tshwane University of Technology",country:{name:"South Africa"}}},{id:"435701",title:"Dr.",name:"Mohamed",middleName:null,surname:"Allouche",slug:"mohamed-allouche",fullName:"Mohamed Allouche",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Carthage",country:{name:"Tunisia"}}},{id:"420855",title:"Prof.",name:"Patricia",middleName:null,surname:"Aïssa",slug:"patricia-aissa",fullName:"Patricia Aïssa",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Carthage",country:{name:"Tunisia"}}},{id:"435699",title:"Dr.",name:"Takoua",middleName:null,surname:"Mhadhbi",slug:"takoua-mhadhbi",fullName:"Takoua Mhadhbi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Carthage",country:{name:"Tunisia"}}},{id:"442300",title:"Prof.",name:"Véronique",middleName:null,surname:"Perrier",slug:"veronique-perrier",fullName:"Véronique Perrier",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Montpellier",country:{name:"France"}}},{id:"445179",title:"Mr.",name:"Aman",middleName:null,surname:"Jaiswal",slug:"aman-jaiswal",fullName:"Aman Jaiswal",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Indian Institute of Science Education and Research Mohali",country:{name:"India"}}},{id:"445178",title:"Mr.",name:"Dhiraj",middleName:null,surname:"Dutta",slug:"dhiraj-dutta",fullName:"Dhiraj Dutta",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Defence Research Laboratory",country:{name:"India"}}},{id:"445180",title:"Dr.",name:"Rama",middleName:null,surname:"Dubey",slug:"rama-dubey",fullName:"Rama Dubey",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Defence Research Laboratory",country:{name:"India"}}},{id:"424992",title:"Dr.",name:"Mohamed",middleName:null,surname:"Helal",slug:"mohamed-helal",fullName:"Mohamed Helal",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"National Institute of Oceanography and Fisheries",country:{name:"Egypt"}}},{id:"428329",title:"Mr.",name:"Collet",middleName:null,surname:"Maswanganyi",slug:"collet-maswanganyi",fullName:"Collet Maswanganyi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Limpopo",country:{name:"South Africa"}}},{id:"428546",title:"MSc.",name:"Ndivhuwo",middleName:null,surname:"Shumbula",slug:"ndivhuwo-shumbula",fullName:"Ndivhuwo Shumbula",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"352155",title:"Dr.",name:"Poslet",middleName:"Morgan",surname:"Shumbula",slug:"poslet-shumbula",fullName:"Poslet Shumbula",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Limpopo",country:{name:"South Africa"}}},{id:"435064",title:"Dr.",name:"Mohammadtaghi",middleName:null,surname:"Vakili",slug:"mohammadtaghi-vakili",fullName:"Mohammadtaghi Vakili",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Yangtze Normal University",country:{name:"China"}}},{id:"437268",title:"Dr.",name:"Linda Lunga",middleName:null,surname:"Sibali",slug:"linda-lunga-sibali",fullName:"Linda Lunga Sibali",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"437269",title:"Dr.",name:"Peter P.",middleName:null,surname:"Ndibewu",slug:"peter-p.-ndibewu",fullName:"Peter P. Ndibewu",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"424106",title:"Ph.D. Student",name:"Siyabonga",middleName:null,surname:"Aubrey Mhlongo",slug:"siyabonga-aubrey-mhlongo",fullName:"Siyabonga Aubrey Mhlongo",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"424233",title:"Ph.D. Student",name:"Ifeoluwa Oluwafunmilayo",middleName:null,surname:"Daramola",slug:"ifeoluwa-oluwafunmilayo-daramola",fullName:"Ifeoluwa Oluwafunmilayo Daramola",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"446429",title:"Dr.",name:"Dev Vrat",middleName:null,surname:"Kamboj",slug:"dev-vrat-kamboj",fullName:"Dev Vrat Kamboj",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"425585",title:"Dr.",name:"NISHA",middleName:null,surname:"GAUR",slug:"nisha-gaur",fullName:"NISHA GAUR",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"226635",title:"Prof.",name:"Amany",middleName:null,surname:"El-Sikaily",slug:"amany-el-sikaily",fullName:"Amany El-Sikaily",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"435668",title:"Dr.",name:"Sara",middleName:null,surname:"Ghanem",slug:"sara-ghanem",fullName:"Sara Ghanem",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"426808",title:"Associate Prof.",name:"Yesim",middleName:null,surname:"Gucbilmez",slug:"yesim-gucbilmez",fullName:"Yesim Gucbilmez",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"423291",title:"Assistant Prof.",name:"Giovanni",middleName:null,surname:"Cagnetta",slug:"giovanni-cagnetta",fullName:"Giovanni Cagnetta",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null}]}},subseries:{item:{id:"28",type:"subseries",title:"Animal Reproductive Biology and Technology",keywords:"Animal Reproduction, Artificial Insemination, Embryos, Cryopreservation, Conservation, Breeding, Epigenetics",scope:"The advances of knowledge on animal reproductive biology and technologies revolutionized livestock production. Artificial insemination, for example, was the first technology applied on a large scale, initially in dairy cattle and afterward applied to other species. Nowadays, embryo production and transfer are used commercially along with other technologies to modulate epigenetic regulation. Gene editing is also emerging as an innovative tool. This topic will discuss the potential use of these techniques, novel strategies, and lines of research in progress in the fields mentioned above.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/28.jpg",hasOnlineFirst:!0,hasPublishedBooks:!0,annualVolume:11417,editor:{id:"177225",title:"Prof.",name:"Rosa Maria Lino Neto",middleName:null,surname:"Pereira",slug:"rosa-maria-lino-neto-pereira",fullName:"Rosa Maria Lino Neto Pereira",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bS9wkQAC/Profile_Picture_1624519982291",biography:"Rosa Maria Lino Neto Pereira (DVM, MsC, PhD and) is currently a researcher at the Genetic Resources and Biotechnology Unit of the National Institute of Agrarian and Veterinarian Research (INIAV, Portugal). She is the head of the Reproduction and Embryology Laboratories and was lecturer of Reproduction and Reproductive Biotechnologies at Veterinary Medicine Faculty. She has over 25 years of experience working in reproductive biology and biotechnology areas with a special emphasis on embryo and gamete cryopreservation, for research and animal genetic resources conservation, leading research projects with several peer-reviewed papers. Rosa Pereira is member of the ERFP-FAO Ex situ Working Group and of the Management Commission of the Portuguese Animal Germplasm Bank.",institutionString:"The National Institute for Agricultural and Veterinary Research. Portugal",institution:null},editorTwo:null,editorThree:null,series:{id:"13",title:"Veterinary Medicine and Science",doi:"10.5772/intechopen.73681",issn:"2632-0517"},editorialBoard:[{id:"90066",title:"Dr.",name:"Alexandre",middleName:"Rodrigues",surname:"Silva",slug:"alexandre-silva",fullName:"Alexandre Silva",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRt8pQAC/Profile_Picture_1622531020756",institutionString:null,institution:{name:"Universidade Federal Rural do Semi-Árido",institutionURL:null,country:{name:"Brazil"}}},{id:"176987",title:"Ph.D.",name:"María-José",middleName:"Carrascosa",surname:"Argente",slug:"maria-jose-argente",fullName:"María-José Argente",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bS9vOQAS/Profile_Picture_1630330499537",institutionString:null,institution:{name:"Miguel Hernandez University",institutionURL:null,country:{name:"Spain"}}},{id:"321396",title:"Prof.",name:"Muhammad Subhan",middleName:null,surname:"Qureshi",slug:"muhammad-subhan-qureshi",fullName:"Muhammad Subhan Qureshi",profilePictureURL:"https://mts.intechopen.com/storage/users/321396/images/system/321396.jpg",institutionString:null,institution:{name:"University of Agriculture",institutionURL:null,country:{name:"Pakistan"}}},{id:"183723",title:"Dr.",name:"Xiaojun",middleName:null,surname:"Liu",slug:"xiaojun-liu",fullName:"Xiaojun Liu",profilePictureURL:"https://mts.intechopen.com/storage/users/183723/images/system/183723.jpg",institutionString:null,institution:null}]},onlineFirstChapters:{paginationCount:1,paginationItems:[{id:"81813",title:"Schistosomiasis: Discovery of New Molecules for Disease Treatment and Vaccine Development",doi:"10.5772/intechopen.104738",signatures:"Andressa Barban do Patrocinio",slug:"schistosomiasis-discovery-of-new-molecules-for-disease-treatment-and-vaccine-development",totalDownloads:4,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"New Horizons for Schistosomiasis Research",coverURL:"https://cdn.intechopen.com/books/images_new/10829.jpg",subseries:{id:"5",title:"Parasitic Infectious Diseases"}}}]},publishedBooks:{paginationCount:0,paginationItems:[]},testimonialsList:[{id:"8",text:"I work with IntechOpen for a number of reasons: their professionalism, their mission in support of Open Access publishing, and the quality of their peer-reviewed publications, but also because they believe in equality.",author:{id:"202192",name:"Catrin",surname:"Rutland",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/202192/images/system/202192.png",slug:"catrin-rutland",institution:{id:"134",name:"University of Nottingham",country:{id:null,name:"United Kingdom"}}}},{id:"18",text:"It was great publishing with IntechOpen, the process was straightforward and I had support all along.",author:{id:"71579",name:"Berend",surname:"Olivier",institutionString:"Utrecht University",profilePictureURL:"https://mts.intechopen.com/storage/users/71579/images/system/71579.png",slug:"berend-olivier",institution:{id:"253",name:"Utrecht University",country:{id:null,name:"Netherlands"}}}},{id:"27",text:"The opportunity to work with a prestigious publisher allows for the possibility to collaborate with more research groups interested in animal nutrition, leading to the development of new feeding strategies and food valuation while being more sustainable with the environment, allowing more readers to learn about the subject.",author:{id:"175967",name:"Manuel",surname:"Gonzalez Ronquillo",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/175967/images/system/175967.png",slug:"manuel-gonzalez-ronquillo",institution:{id:"6221",name:"Universidad Autónoma del Estado de México",country:{id:null,name:"Mexico"}}}}]},submityourwork:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:87,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:98,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:27,numberOfPublishedChapters:287,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:9,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:139,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:0,numberOfUpcomingTopics:2,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!1},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:107,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:10,numberOfPublishedChapters:103,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:12,numberOfOpenTopics:2,numberOfUpcomingTopics:1,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:0,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!1},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:10,numberOfOpenTopics:4,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],subseriesList:[{id:"4",title:"Fungal Infectious Diseases",scope:"Fungi are ubiquitous and there are almost no non-pathogenic fungi. Fungal infectious illness prevalence and prognosis are determined by the exposure between fungi and host, host immunological state, fungal virulence, and early and accurate diagnosis and treatment. \r\nPatients with both congenital and acquired immunodeficiency are more likely to be infected with opportunistic mycosis. Fungal infectious disease outbreaks are common during the post- disaster rebuilding era, which is characterised by high population density, migration, and poor health and medical conditions.\r\nSystemic or local fungal infection is mainly associated with the fungi directly inhaled or inoculated in the environment during the disaster. The most common fungal infection pathways are human to human (anthropophilic), animal to human (zoophilic), and environment to human (soilophile). Diseases are common as a result of widespread exposure to pathogenic fungus dispersed into the environment. \r\nFungi that are both common and emerging are intertwined. In Southeast Asia, for example, Talaromyces marneffei is an important pathogenic thermally dimorphic fungus that causes systemic mycosis. Widespread fungal infections with complicated and variable clinical manifestations, such as Candida auris infection resistant to several antifungal medicines, Covid-19 associated with Trichoderma, and terbinafine resistant dermatophytosis in India, are among the most serious disorders. \r\nInappropriate local or systemic use of glucocorticoids, as well as their immunosuppressive effects, may lead to changes in fungal infection spectrum and clinical characteristics. Hematogenous candidiasis is a worrisome issue that affects people all over the world, particularly ICU patients. CARD9 deficiency and fungal infection have been major issues in recent years. Invasive aspergillosis is associated with a significant death rate. Special attention should be given to endemic fungal infections, identification of important clinical fungal infections advanced in yeasts, filamentous fungal infections, skin mycobiome and fungal genomes, and immunity to fungal infections.\r\nIn addition, endemic fungal diseases or uncommon fungal infections caused by Mucor irregularis, dermatophytosis, Malassezia, cryptococcosis, chromoblastomycosis, coccidiosis, blastomycosis, histoplasmosis, sporotrichosis, and other fungi, should be monitored. \r\nThis topic includes the research progress on the etiology and pathogenesis of fungal infections, new methods of isolation and identification, rapid detection, drug sensitivity testing, new antifungal drugs, schemes and case series reports. It will provide significant opportunities and support for scientists, clinical doctors, mycologists, antifungal drug researchers, public health practitioners, and epidemiologists from all over the world to share new research, ideas and solutions to promote the development and progress of medical mycology.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/4.jpg",keywords:"Emerging Fungal Pathogens, Invasive Infections, Epidemiology, Cell Membrane, Fungal Virulence, Diagnosis, Treatment"},{id:"5",title:"Parasitic Infectious Diseases",scope:"Parasitic diseases have evolved alongside their human hosts. In many cases, these diseases have adapted so well that they have developed efficient resilience methods in the human host and can live in the host for years. Others, particularly some blood parasites, can cause very acute diseases and are responsible for millions of deaths yearly. Many parasitic diseases are classified as neglected tropical diseases because they have received minimal funding over recent years and, in many cases, are under-reported despite the critical role they play in morbidity and mortality among human and animal hosts. The current topic, Parasitic Infectious Diseases, in the Infectious Diseases Series aims to publish studies on the systematics, epidemiology, molecular biology, genomics, pathogenesis, genetics, and clinical significance of parasitic diseases from blood borne to intestinal parasites as well as zoonotic parasites. We hope to cover all aspects of parasitic diseases to provide current and relevant research data on these very important diseases. In the current atmosphere of the Coronavirus pandemic, communities around the world, particularly those in different underdeveloped areas, are faced with the growing challenges of the high burden of parasitic diseases. At the same time, they are faced with the Covid-19 pandemic leading to what some authors have called potential syndemics that might worsen the outcome of such infections. Therefore, it is important to conduct studies that examine parasitic infections in the context of the coronavirus pandemic for the benefit of all communities to help foster more informed decisions for the betterment of human and animal health.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/5.jpg",keywords:"Blood Borne Parasites, Intestinal Parasites, Protozoa, Helminths, Arthropods, Water Born Parasites, Epidemiology, Molecular Biology, Systematics, Genomics, Proteomics, Ecology"},{id:"6",title:"Viral Infectious Diseases",scope:"The Viral Infectious Diseases Book Series aims to provide a comprehensive overview of recent research trends and discoveries in various viral infectious diseases emerging around the globe. The emergence of any viral disease is hard to anticipate, which often contributes to death. A viral disease can be defined as an infectious disease that has recently appeared within a population or exists in nature with the rapid expansion of incident or geographic range. This series will focus on various crucial factors related to emerging viral infectious diseases, including epidemiology, pathogenesis, host immune response, clinical manifestations, diagnosis, treatment, and clinical recommendations for managing viral infectious diseases, highlighting the recent issues with future directions for effective therapeutic strategies.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/6.jpg",keywords:"Novel Viruses, Virus Transmission, Virus Evolution, Molecular Virology, Control and Prevention, Virus-host Interaction"}],annualVolumeBook:{},thematicCollection:[],selectedSeries:null,selectedSubseries:null},seriesLanding:{item:{id:"11",title:"Biochemistry",doi:"10.5772/intechopen.72877",issn:"2632-0983",scope:"Biochemistry, the study of chemical transformations occurring within living organisms, impacts all areas of life sciences, from molecular crystallography and genetics to ecology, medicine, and population biology. Biochemistry examines macromolecules - proteins, nucleic acids, carbohydrates, and lipids – and their building blocks, structures, functions, and interactions. Much of biochemistry is devoted to enzymes, proteins that catalyze chemical reactions, enzyme structures, mechanisms of action and their roles within cells. Biochemistry also studies small signaling molecules, coenzymes, inhibitors, vitamins, and hormones, which play roles in life processes. Biochemical experimentation, besides coopting classical chemistry methods, e.g., chromatography, adopted new techniques, e.g., X-ray diffraction, electron microscopy, NMR, radioisotopes, and developed sophisticated microbial genetic tools, e.g., auxotroph mutants and their revertants, fermentation, etc. More recently, biochemistry embraced the ‘big data’ omics systems. Initial biochemical studies have been exclusively analytic: dissecting, purifying, and examining individual components of a biological system; in the apt words of Efraim Racker (1913 –1991), “Don’t waste clean thinking on dirty enzymes.” Today, however, biochemistry is becoming more agglomerative and comprehensive, setting out to integrate and describe entirely particular biological systems. The ‘big data’ metabolomics can define the complement of small molecules, e.g., in a soil or biofilm sample; proteomics can distinguish all the comprising proteins, e.g., serum; metagenomics can identify all the genes in a complex environment, e.g., the bovine rumen. This Biochemistry Series will address the current research on biomolecules and the emerging trends with great promise.",coverUrl:"https://cdn.intechopen.com/series/covers/11.jpg",latestPublicationDate:"May 18th, 2022",hasOnlineFirst:!0,numberOfOpenTopics:4,numberOfPublishedChapters:287,numberOfPublishedBooks:27,editor:{id:"31610",title:"Dr.",name:"Miroslav",middleName:null,surname:"Blumenberg",fullName:"Miroslav Blumenberg",profilePictureURL:"https://mts.intechopen.com/storage/users/31610/images/system/31610.jpg",biography:"Miroslav Blumenberg, Ph.D., was born in Subotica and received his BSc in Belgrade, Yugoslavia. He completed his Ph.D. at MIT in Organic Chemistry; he followed up his Ph.D. with two postdoctoral study periods at Stanford University. Since 1983, he has been a faculty member of the RO Perelman Department of Dermatology, NYU School of Medicine, where he is codirector of a training grant in cutaneous biology. Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. He has published more than 100 peer-reviewed research articles and graduated numerous Ph.D. and postdoctoral students.",institutionString:null,institution:{name:"New York University Langone Medical Center",institutionURL:null,country:{name:"United States of America"}}},subseries:[{id:"14",title:"Cell and Molecular Biology",keywords:"Omics (Transcriptomics; Proteomics; Metabolomics), Molecular Biology, Cell Biology, Signal Transduction and Regulation, Cell Growth and Differentiation, Apoptosis, Necroptosis, Ferroptosis, Autophagy, Cell Cycle, Macromolecules and Complexes, Gene Expression",scope:"The Cell and Molecular Biology topic within the IntechOpen Biochemistry Series aims to rapidly publish contributions on all aspects of cell and molecular biology, including aspects related to biochemical and genetic research (not only in humans but all living beings). We encourage the submission of manuscripts that provide novel and mechanistic insights that report significant advances in the fields. Topics include, but are not limited to: Advanced techniques of cellular and molecular biology (Molecular methodologies, imaging techniques, and bioinformatics); Biological activities at the molecular level; Biological processes of cell functions, cell division, senescence, maintenance, and cell death; Biomolecules interactions; Cancer; Cell biology; Chemical biology; Computational biology; Cytochemistry; Developmental biology; Disease mechanisms and therapeutics; DNA, and RNA metabolism; Gene functions, genetics, and genomics; Genetics; Immunology; Medical microbiology; Molecular biology; Molecular genetics; Molecular processes of cell and organelle dynamics; Neuroscience; Protein biosynthesis, degradation, and functions; Regulation of molecular interactions in a cell; Signalling networks and system biology; Structural biology; Virology and microbiology.",annualVolume:11410,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/14.jpg",editor:{id:"165627",title:"Dr.",name:"Rosa María",middleName:null,surname:"Martínez-Espinosa",fullName:"Rosa María Martínez-Espinosa",profilePictureURL:"https://mts.intechopen.com/storage/users/165627/images/system/165627.jpeg",institutionString:null,institution:{name:"University of Alicante",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"79367",title:"Dr.",name:"Ana Isabel",middleName:null,surname:"Flores",fullName:"Ana Isabel Flores",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRpIOQA0/Profile_Picture_1632418099564",institutionString:null,institution:{name:"Hospital Universitario 12 De Octubre",institutionURL:null,country:{name:"Spain"}}},{id:"328234",title:"Ph.D.",name:"Christian",middleName:null,surname:"Palavecino",fullName:"Christian Palavecino",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000030DhEhQAK/Profile_Picture_1628835318625",institutionString:null,institution:{name:"Central University of Chile",institutionURL:null,country:{name:"Chile"}}},{id:"186585",title:"Dr.",name:"Francisco Javier",middleName:null,surname:"Martin-Romero",fullName:"Francisco Javier Martin-Romero",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSB3HQAW/Profile_Picture_1631258137641",institutionString:null,institution:{name:"University of Extremadura",institutionURL:null,country:{name:"Spain"}}}]},{id:"15",title:"Chemical Biology",keywords:"Phenolic Compounds, Essential Oils, Modification of Biomolecules, Glycobiology, Combinatorial Chemistry, Therapeutic peptides, Enzyme Inhibitors",scope:"Chemical biology spans the fields of chemistry and biology involving the application of biological and chemical molecules and techniques. In recent years, the application of chemistry to biological molecules has gained significant interest in medicinal and pharmacological studies. This topic will be devoted to understanding the interplay between biomolecules and chemical compounds, their structure and function, and their potential applications in related fields. Being a part of the biochemistry discipline, the ideas and concepts that have emerged from Chemical Biology have affected other related areas. This topic will closely deal with all emerging trends in this discipline.",annualVolume:11411,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/15.jpg",editor:{id:"441442",title:"Dr.",name:"Şükrü",middleName:null,surname:"Beydemir",fullName:"Şükrü Beydemir",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003GsUoIQAV/Profile_Picture_1634557147521",institutionString:null,institution:{name:"Anadolu University",institutionURL:null,country:{name:"Turkey"}}},editorTwo:{id:"13652",title:"Prof.",name:"Deniz",middleName:null,surname:"Ekinci",fullName:"Deniz Ekinci",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYLT1QAO/Profile_Picture_1634557223079",institutionString:null,institution:{name:"Ondokuz Mayıs University",institutionURL:null,country:{name:"Turkey"}}},editorThree:null,editorialBoard:[{id:"241413",title:"Dr.",name:"Azhar",middleName:null,surname:"Rasul",fullName:"Azhar Rasul",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRT1oQAG/Profile_Picture_1635251978933",institutionString:null,institution:{name:"Government College University, Faisalabad",institutionURL:null,country:{name:"Pakistan"}}},{id:"178316",title:"Ph.D.",name:"Sergey",middleName:null,surname:"Sedykh",fullName:"Sergey Sedykh",profilePictureURL:"https://mts.intechopen.com/storage/users/178316/images/system/178316.jfif",institutionString:null,institution:{name:"Novosibirsk State University",institutionURL:null,country:{name:"Russia"}}}]},{id:"17",title:"Metabolism",keywords:"Biomolecules Metabolism, Energy Metabolism, Metabolic Pathways, Key Metabolic Enzymes, Metabolic Adaptation",scope:"Metabolism is frequently defined in biochemistry textbooks as the overall process that allows living systems to acquire and use the free energy they need for their vital functions or the chemical processes that occur within a living organism to maintain life. Behind these definitions are hidden all the aspects of normal and pathological functioning of all processes that the topic ‘Metabolism’ will cover within the Biochemistry Series. Thus all studies on metabolism will be considered for publication.",annualVolume:11413,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/17.jpg",editor:{id:"138626",title:"Dr.",name:"Yannis",middleName:null,surname:"Karamanos",fullName:"Yannis Karamanos",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002g6Jv2QAE/Profile_Picture_1629356660984",institutionString:null,institution:{name:"Artois University",institutionURL:null,country:{name:"France"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"243049",title:"Dr.",name:"Anca",middleName:null,surname:"Pantea Stoian",fullName:"Anca Pantea Stoian",profilePictureURL:"https://mts.intechopen.com/storage/users/243049/images/system/243049.jpg",institutionString:null,institution:{name:"Carol Davila University of Medicine and Pharmacy",institutionURL:null,country:{name:"Romania"}}},{id:"203824",title:"Dr.",name:"Attilio",middleName:null,surname:"Rigotti",fullName:"Attilio Rigotti",profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institutionString:null,institution:{name:"Pontifical Catholic University of Chile",institutionURL:null,country:{name:"Chile"}}},{id:"300470",title:"Dr.",name:"Yanfei (Jacob)",middleName:null,surname:"Qi",fullName:"Yanfei (Jacob) Qi",profilePictureURL:"https://mts.intechopen.com/storage/users/300470/images/system/300470.jpg",institutionString:null,institution:{name:"Centenary Institute of Cancer Medicine and Cell Biology",institutionURL:null,country:{name:"Australia"}}}]},{id:"18",title:"Proteomics",keywords:"Mono- and Two-Dimensional Gel Electrophoresis (1-and 2-DE), Liquid Chromatography (LC), Mass Spectrometry/Tandem Mass Spectrometry (MS; MS/MS), Proteins",scope:"With the recognition that the human genome cannot provide answers to the etiology of a disorder, changes in the proteins expressed by a genome became a focus in research. Thus proteomics, an area of research that detects all protein forms expressed in an organism, including splice isoforms and post-translational modifications, is more suitable than genomics for a comprehensive understanding of the biochemical processes that govern life. The most common proteomics applications are currently in the clinical field for the identification, in a variety of biological matrices, of biomarkers for diagnosis and therapeutic intervention of disorders. From the comparison of proteomic profiles of control and disease or different physiological states, which may emerge, changes in protein expression can provide new insights into the roles played by some proteins in human pathologies. Understanding how proteins function and interact with each other is another goal of proteomics that makes this approach even more intriguing. Specialized technology and expertise are required to assess the proteome of any biological sample. Currently, proteomics relies mainly on mass spectrometry (MS) combined with electrophoretic (1 or 2-DE-MS) and/or chromatographic techniques (LC-MS/MS). MS is an excellent tool that has gained popularity in proteomics because of its ability to gather a complex body of information such as cataloging protein expression, identifying protein modification sites, and defining protein interactions. The Proteomics topic aims to attract contributions on all aspects of MS-based proteomics that, by pushing the boundaries of MS capabilities, may address biological problems that have not been resolved yet.",annualVolume:11414,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/18.jpg",editor:{id:"200689",title:"Prof.",name:"Paolo",middleName:null,surname:"Iadarola",fullName:"Paolo Iadarola",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSCl8QAG/Profile_Picture_1623568118342",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorTwo:{id:"201414",title:"Dr.",name:"Simona",middleName:null,surname:"Viglio",fullName:"Simona Viglio",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRKDHQA4/Profile_Picture_1630402531487",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorThree:null,editorialBoard:[{id:"72288",title:"Dr.",name:"Arli Aditya",middleName:null,surname:"Parikesit",fullName:"Arli Aditya Parikesit",profilePictureURL:"https://mts.intechopen.com/storage/users/72288/images/system/72288.jpg",institutionString:null,institution:{name:"Indonesia International Institute for Life Sciences",institutionURL:null,country:{name:"Indonesia"}}},{id:"40928",title:"Dr.",name:"Cesar",middleName:null,surname:"Lopez-Camarillo",fullName:"Cesar Lopez-Camarillo",profilePictureURL:"https://mts.intechopen.com/storage/users/40928/images/3884_n.png",institutionString:null,institution:{name:"Universidad Autónoma de la Ciudad de México",institutionURL:null,country:{name:"Mexico"}}},{id:"81926",title:"Dr.",name:"Shymaa",middleName:null,surname:"Enany",fullName:"Shymaa Enany",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRqB9QAK/Profile_Picture_1626163237970",institutionString:null,institution:{name:"Suez Canal University",institutionURL:null,country:{name:"Egypt"}}}]}]}},libraryRecommendation:{success:null,errors:{},institutions:[]},route:{name:"profile.detail",path:"/profiles/275221",hash:"",query:{},params:{id:"275221"},fullPath:"/profiles/275221",meta:{},from:{name:null,path:"/",hash:"",query:{},params:{},fullPath:"/",meta:{}}}},function(){var e;(e=document.currentScript||document.scripts[document.scripts.length-1]).parentNode.removeChild(e)}()