Experimental and theoretical structural parameter of the 5-nirofuran-2-aldoxime.
\\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:"9535",leadTitle:null,fullTitle:"Education in Childhood",title:"Education in Childhood",subtitle:null,reviewType:"peer-reviewed",abstract:"This book reviews literature and research linked to early childhood education and care (ECEC). This educational level is fundamental for acquiring key competencies for school entry and establishing the physical, cognitive, and emotional bases for lifelong learning. Preschool education should promote student autonomy as the ability of a child to act on their own free will because it is a critical part of learning for all children. When a child has autonomy, it helps build confidence for responding to the demands of the family, self-esteem values linked to collaboration tasks, and independence in selecting reasonable choices.",isbn:"978-1-83969-015-0",printIsbn:"978-1-83969-014-3",pdfIsbn:"978-1-83969-016-7",doi:"10.5772/intechopen.87330",price:119,priceEur:129,priceUsd:155,slug:"education-in-childhood",numberOfPages:148,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"edc0b902fe67ee1b6fab1df4992cb55d",bookSignature:"Olga María Alegre de la Rosa, Luis Miguel Villar Angulo and Carla Giambrone",publishedDate:"December 15th 2021",coverURL:"https://cdn.intechopen.com/books/images_new/9535.jpg",numberOfDownloads:1599,numberOfWosCitations:0,numberOfCrossrefCitations:1,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:2,numberOfDimensionsCitationsByBook:0,hasAltmetrics:0,numberOfTotalCitations:3,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"October 5th 2020",dateEndSecondStepPublish:"November 2nd 2020",dateEndThirdStepPublish:"January 1st 2021",dateEndFourthStepPublish:"March 22nd 2021",dateEndFifthStepPublish:"May 21st 2021",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"338767",title:"Prof.",name:"Olga María",middleName:null,surname:"Alegre de la Rosa",slug:"olga-maria-alegre-de-la-rosa",fullName:"Olga María Alegre de la Rosa",profilePictureURL:"https://mts.intechopen.com/storage/users/338767/images/system/338767.jpg",biography:"Olga María Alegre de la Rosa has a Ph.D. in Psychology and a Ph.D. in Information Sciences. She is the director of the University Study Centre for Education in Diversity. She has several national and international publications to her credit. She leads competitive research projects and supervises theses related to the field of quality and inclusion at different levels of the education system. Dr. de la Rosa has co-directed the International Journal of University Teaching and Faculty Development.",institutionString:"University of La Laguna",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"University of La Laguna",institutionURL:null,country:{name:"Spain"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:{id:"338765",title:"Prof.",name:"Luis Miguel",middleName:null,surname:"Villar Angulo",slug:"luis-miguel-villar-angulo",fullName:"Luis Miguel Villar Angulo",profilePictureURL:"https://mts.intechopen.com/storage/users/338765/images/system/338765.png",biography:"Luis Miguel Villar Angulo has a Ph.D. in Educational Sciences. He has national and international publications in the field of teacher training, quality, evaluation, and professional development. He has led competitive research projects and supervised theses on teaching and teacher education. Dr. Angulo co-directed the International Journal of University Teaching and Faculty Development. He is chair of quality assessment and accreditation committees for degrees and universities.",institutionString:"University of Seville",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"University of Seville",institutionURL:null,country:{name:"Spain"}}},coeditorTwo:{id:"267499",title:"Ph.D.",name:"Carla",middleName:null,surname:"Giambrone",slug:"carla-giambrone",fullName:"Carla Giambrone",profilePictureURL:"https://mts.intechopen.com/storage/users/267499/images/system/267499.png",biography:"Dr. Carla A. Giambrone is a successful 30+ year CFO/entrepreneur turned psychologist who has followed her passion for creating safe and nurturing educational programs to help people grow and flourish. Specializing in physiological integration and somatic therapies, her work entails creating new pathways to well-being and encourages embodied growth and recovery. \n\nA creative therapist and researcher, Dr. Giambrone provides a deep conceptual understanding that promotes sustainable and positive trajectories for her clients and patients. A sought-after speaker, she regularly presents to research communities, boards, schools, and non-profits on topics ranging from employee engagement to increased capacity for change. \n\nShe is passionate about creating a dynamic community and continues to lend her executive expertise to boards that promote her passions for creativity and education. Her research lines focus on well-being through yoga, promoting biometric specificity for physical activity prescription, and educational best practices throughout the lifespan.",institutionString:"University at Buffalo, State University of New York",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"University at Buffalo, State University of New York",institutionURL:null,country:{name:"United States of America"}}},coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"265",title:"Education",slug:"social-sciences-education"}],chapters:[{id:"76723",title:"Early Childhood Education",doi:"10.5772/intechopen.97771",slug:"early-childhood-education",totalDownloads:215,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"The relevance of early childhood education and care (ECEC) is widely acknowledged in many countries, the number of ECEC settings is expanding correspondingly. This trend reflects the tremendous learning potential during early childhood. Right from birth and during early childhood a variety of learning processes are initiated that foster agency, self-regulation and development. Even the newborn is an active learner, a competent interaction partner and a problem-solver. In line with a deeper understanding of the mechanisms, principles and conditions of learning, early childhood education relies on pedagogical concepts, approaches and didactic methods that promote early learning and development. ECEC settings for young children stimulate exploration and action in everyday situations, embedded in social relations and interactions with peers and with a skilled and reliable pedagogical professional. The expansion and professionalization of the ECEC sector requires establishing a research infrastructure as well as implementing different research approaches at the micro-, meso- and macro-level of the system of early childhood education.",signatures:"Bernhard Kalicki and Anke Koenig",downloadPdfUrl:"/chapter/pdf-download/76723",previewPdfUrl:"/chapter/pdf-preview/76723",authors:[{id:"337837",title:"Prof.",name:"Bernhard",surname:"Kalicki",slug:"bernhard-kalicki",fullName:"Bernhard Kalicki"},{id:"337845",title:"Prof.",name:"Anke",surname:"Koenig",slug:"anke-koenig",fullName:"Anke Koenig"}],corrections:null},{id:"77529",title:"Contemporary Challenges for Education in Early Childhood",doi:"10.5772/intechopen.98903",slug:"contemporary-challenges-for-education-in-early-childhood",totalDownloads:230,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Over the past two centuries the Age of Modernity has dominated intellectual thought and related actions predominantly in the English-speaking world. It is now becoming increasingly recognized by academics and powerful organizations both nationally and internationally that the consequence of this mode of thinking has generated immense problems for the contemporary world. The level of social and economic inequalities that continue to increase has now become the concern of many, particularly those who identify with the thinking and ideas associated with the emerging Age of Post-Modernity. The challenge to Education is profound not least so in how young children’s awareness, knowledge and understanding about the society in which they live is transmitted, often unwittingly, initially in families and subsequently in kindergartens and schools. This paper first addresses the main social constructions of childhood that can be identified in democratic countries and then links these constructions to the three dominant ideologies that exert axiomatic influence on the education process in different countries. Emerging from this brief analysis the paper identifies three fundamental and important challenges to those with responsibility and influence on young children’s education be they in governments, educational institutions or families.",signatures:"John Eric Wilkinson",downloadPdfUrl:"/chapter/pdf-download/77529",previewPdfUrl:"/chapter/pdf-preview/77529",authors:[{id:"338161",title:"Dr.",name:"John",surname:"Wilkinson",slug:"john-wilkinson",fullName:"John Wilkinson"}],corrections:null},{id:"77523",title:"Learning through Play - Improving Academic Performance through Play",doi:"10.5772/intechopen.97740",slug:"learning-through-play-improving-academic-performance-through-play",totalDownloads:131,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The education in the early period provides the cognitive development of the child. Globally world organizations are thriving hard to increase the literacy percentage of the children, as education forms the base for the economic improvement of the country. Depending upon educational skills the individual will be placed in the appropriate job. Education in childhood is focused much on the past few decades. Learning through play is a traditional concept of developing the cognition level. At present, an educational scenario also focuses on Game-based pedagogy for teaching and learning. To some extent, this method will reduce school dropouts in developing countries. The children are more attracted to video games and the learning becomes easy for them. In this digital era, blooming technology is the milestone in the educational sector. The grandma’s game is now transforming into the digitalized version. Designing video games by keeping the concepts of traditional games will enhance the learning outcome of the students, especially in early education. Structured, goal-oriented, educational outcome-based video games are necessary to improve the growth and development of the children.",signatures:"K. Madhumathi and P. Senthil Selvam",downloadPdfUrl:"/chapter/pdf-download/77523",previewPdfUrl:"/chapter/pdf-preview/77523",authors:[{id:"331985",title:"Prof.",name:"P. Senthil",surname:"Selvam",slug:"p.-senthil-selvam",fullName:"P. Senthil Selvam"},{id:"344993",title:"Dr.",name:"K.",surname:"Madhumathi",slug:"k.-madhumathi",fullName:"K. Madhumathi"}],corrections:null},{id:"77698",title:"Enhancing Self-Regulation and Metacognition in Online Learning",doi:"10.5772/intechopen.99104",slug:"enhancing-self-regulation-and-metacognition-in-online-learning",totalDownloads:149,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Nowadays, online education is in the limelight. During the COVID-19 pandemic, K-12 students endured an abrupt transition from everyday learning in classrooms to online education. In the process, the concept that learning only occurs if students are physically present in a classroom has changed drastically. As the spaces and interactions are different, teachers need formal training, flexibility, and willingness to provide efficient online education that adjusts to the new and fluctuating realities. Simultaneously, students need to enhance self-regulation and metacognition and be the leaders of their education process and results. It is pivotal that teachers keep in mind that close relationships with students and families and personalized support are critically important to fostering ties, developing knowledge, and preventing school dropout. Consequently, curricula must respond to students’ singularities, socioeconomic conditions, contexts, resources, and interests. This chapter advocates that teachers should support students to work on the development of self-regulation, metacognition, collaborative technology-mediated tasks, and problem-solving in online environments. These are tools that help students to be autonomous, engage with their learning process, learn, create knowledge, decide accurately, improve their creativity, and increase intrinsic motivation skills.",signatures:"Adriana Carolina Torres Escobar",downloadPdfUrl:"/chapter/pdf-download/77698",previewPdfUrl:"/chapter/pdf-preview/77698",authors:[{id:"345447",title:"M.A.",name:"Adriana Carolina",surname:"Torres Escobar",slug:"adriana-carolina-torres-escobar",fullName:"Adriana Carolina Torres Escobar"}],corrections:null},{id:"76881",title:"Effects of the Peace Education Program on the Social and Emotional Behaviour for Pre-School in the Sultanate of Oman",doi:"10.5772/intechopen.97795",slug:"effects-of-the-peace-education-program-on-the-social-and-emotional-behaviour-for-pre-school-in-the-s",totalDownloads:228,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The education of peace has become a prominent pre-requisite for societies to survive in this competitive globalised system. As a result of the tremendous technological development, especially in communications and the intermingling of interests among members of societies, and the codification of many issues of common concern among nations, it is very necessary to set foundations for peaceful co-existence among human beings. Johnson and Johnson, stated that students should be equipped with core values such as respect for the efforts and ideas of others, an inclusive relationship with people, skills for compassion and peaceful conflict resolution. Furthermore, the present chapter provided a study of peace education program (PEP) for pre-school children aged (4–6) years in Oman. Where the program contains (28) training sessions are offered within (15) weeks at the rate of one hour per session. The researcher used a scale of two images, the behaviour of the children was measured before and after the experiment, where the researcher adopted the quasi experimental method, the sample consisted of (40) children in the experimental group and (40) children in the control group. In addition, the results of the study were in favour of the experimental group, where an improvement in their behaviour was observed after being enrolled in the program.",signatures:"Mahfouda Rashid Al Mushaiqri, Zahari Bin Ishak and Wail Muin Ismail",downloadPdfUrl:"/chapter/pdf-download/76881",previewPdfUrl:"/chapter/pdf-preview/76881",authors:[{id:"335463",title:"Ph.D. Student",name:"Mahfouda",surname:"Rashid Al Mushaiqri",slug:"mahfouda-rashid-al-mushaiqri",fullName:"Mahfouda Rashid Al Mushaiqri"},{id:"335464",title:"Prof.",name:"Zahari",surname:"Bin Ishak",slug:"zahari-bin-ishak",fullName:"Zahari Bin Ishak"},{id:"343719",title:"Dr.",name:"Wail",surname:"Muin Ismail",slug:"wail-muin-ismail",fullName:"Wail Muin Ismail"}],corrections:null},{id:"78009",title:"Teachers’ Time for Planning, Assessment and Development Connected to Staff Well-Being in Early Childhood Education",doi:"10.5772/intechopen.99103",slug:"teachers-time-for-planning-assessment-and-development-connected-to-staff-well-being-in-early-childho",totalDownloads:127,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The planning, assessment and development (PAD) of pedagogy carried out by early childhood education (ECE) teachers is an important quality factor in ECE. In Finland, the working hours reserved for PAD tasks for ECE teachers were increased from 8 to 13% in 2018. The purpose of this study was to investigate ECE teachers’ and centre directors’ perceptions of the impact of increased PAD hours on the well-being of ECE staff. Based on the mixed-methods approach, 325 ECE teachers and 107 ECE centre directors participated in the study. The results of the study indicated that, apart from the atmosphere in the work community, the impact of working hours on the well-being at work was positive. In particular, the reform has increased the well-being of teachers at work. The increased PAD hours have had only a minor impact on the well-being of all staff.",signatures:"Johanna Heikka, Sanni Kahila, Harri Pitkäniemi and Eeva Hujala",downloadPdfUrl:"/chapter/pdf-download/78009",previewPdfUrl:"/chapter/pdf-preview/78009",authors:[{id:"335579",title:"Dr.",name:"Johanna",surname:"Heikka",slug:"johanna-heikka",fullName:"Johanna Heikka"},{id:"335942",title:"Prof.",name:"Eeva",surname:"Hujala",slug:"eeva-hujala",fullName:"Eeva Hujala"},{id:"335944",title:"Mrs.",name:"Sanni",surname:"Kahila",slug:"sanni-kahila",fullName:"Sanni Kahila"},{id:"335945",title:"Dr.",name:"Harri",surname:"Pitkäniemi",slug:"harri-pitkaniemi",fullName:"Harri Pitkäniemi"}],corrections:null},{id:"78141",title:"Inclusion in Early Childhood Development Settings: A Reality or an Oasis",doi:"10.5772/intechopen.99105",slug:"inclusion-in-early-childhood-development-settings-a-reality-or-an-oasis",totalDownloads:236,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Inclusive education within the Early Childhood Development settings has been identified as the most equitable practice for children with disabilities and is based on acknowledging it as a fundamental human right and a foundation for life-long learning for all children. Based on the concept of human rights, inclusion has been viewed as an ambiguous and imaginable consequence of excessive promise, which does not refer to early childhood; hence, practitioners have challenges in its applicability. This chapter aims to unravel the mysteries behind inclusion in early childhood, exploring the realities of what works and what does not work to inform policy making mechanism. Literature from renowned published work that focuses extensively on various countries across continents is reviewed. Local recently published and unpublished studies that scrutinise the association between practitioner qualification and quality of the ECD centres; those that have explored the success and challenges of inclusion in ECD will be examined. It is envisaged that this chapter would come up with best practices in the implementation and assessment of inclusive education in the ECD settings that will benefit children with disabilities, their parents or caregivers, and stakeholders.",signatures:"Joyce Mathwasa and Lwazi Sibanda",downloadPdfUrl:"/chapter/pdf-download/78141",previewPdfUrl:"/chapter/pdf-preview/78141",authors:[{id:"310698",title:"Dr.",name:"Joyce",surname:"Mathwasa",slug:"joyce-mathwasa",fullName:"Joyce Mathwasa"},{id:"345905",title:"Dr.",name:"Lwazi",surname:"Sibanda",slug:"lwazi-sibanda",fullName:"Lwazi Sibanda"}],corrections:null},{id:"77288",title:"Bringing Out the Best",doi:"10.5772/intechopen.98646",slug:"bringing-out-the-best",totalDownloads:113,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Bringing Out the Best (BOB) is an early intervention program that provides short term, free, family-centered, and community-based services that target children in early childhood (ages 0–5). A priority goal of the program is to increase the number of children that are healthy and ready to succeed as they enter school. Through trainings and technical assistance for educators and administrators, trainings and consultation for families, and screenings and individual interventions for children, specialists, families and teachers collaboratively develop individualized plans for increasing a child’s success in the classroom and at home. BOB is in its 15th year of operation under the Center for Youth, Family, and Community Partnerships at UNC Greensboro and has served over 2400 participants to date. With BOB’s aim to increase the number of healthy children ready to succeed as they enter school, this chapter will emphasize that although elementary students may not be entering physical classrooms this year, the attendance for childcare centers has maintained if not increased; therefore, social and emotional learning are even more essential to the early care curriculum. This chapter will describe the previous processes in place at BOB as well as measures taken to reinvent those services during the COVID-19 pandemic.",signatures:"Brittany S. Hewett",downloadPdfUrl:"/chapter/pdf-download/77288",previewPdfUrl:"/chapter/pdf-preview/77288",authors:[{id:"336641",title:"Dr.",name:"Brittany S.",surname:"Hewett",slug:"brittany-s.-hewett",fullName:"Brittany S. Hewett"}],corrections:null},{id:"76665",title:"Preschoolers Learning by Playing with Technology",doi:"10.5772/intechopen.97791",slug:"preschoolers-learning-by-playing-with-technology",totalDownloads:183,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"In an evolving world, where both adults and children continuously have to adapt to different and unexpected situations, the need to develop strong problem-solving skills from early years is evident. In addition, recent events such as COVID-19 that have led schools to close have highlighted the parent’s role in supporting learning. Technology should be considered a useful tool for communication and learning, both in-home and in preschool. A possible approach to enhance problem-solving skills is to play with technological devices together. This chapter results from a series of considerations on playful programming-based home learning experiences with tactile elements for preschool children. The text presents a qualitative analysis of children’s learning of problem-solving skills enhanced by this activity as well as mathematics and language. The children use the device as part of their free play. In the state of this play, the children in our examples show happiness and a form of flow that can remind of what is found in mindfulness. The findings are discussed in light of related theories on play and problem-solving. 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Reports of theoretical bases of MEP and the development of efficient computational methods state that MEP has become an important reactivity index in studies of a large variety of molecular interactions [1]. The usefulness of this theoretical approach in studies and interpretation of chemical, biochemical, and related phenomena is well documented [2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18].
Chemometrics is a discipline that collects mathematical, statistical, information theory, and computer science tools to deal with complex chemical data [19, 20, 21, 22]. PR techniques were introduced in the chemistry, at the beginning of the 1970s, to analyze various types of spectroscopic data. Since then, PR became part of chemometrics and has been an excellent tool to aid in the interpretation of chemical data to obtain relevant information in different application sectors of chemical science [19, 20]. PR techniques are especially useful for the classification of objects into discrete classes on the basis of measured features. A set of characteristic features of an object is considered as an abstract pattern that contains information about a not directly measured property of the object [19].
The MEP and PR techniques have been used as independent strategies in the study of active compounds and lead to the proposal of new molecules for synthesis and biological testing. The joint applications of these powerful tools were described carefully, to unravel the structure-activity relationship of bioactive compounds, consequently proposing new molecules. Therefore, a more intense exploration of its potentials is needed in order to design biologically active compounds.
The design of molecules with a desired property is one of the objectives of chemoinformatics. In this chapter, we present a study of the application of MEP and PR techniques to design nitrofuran compounds with potential activity against
According to the literature, MEP [1, 3] has been a tool of quantum chemistry used by researchers for several decades to study and understand the relationships between structure and activity of molecules. Among the papers that point out the importance of this tool in the matter, and consequently in the planning of bioactive compounds, we can mention those reported by Bernardinelli et al. [23] and by Jefford et al. [24].
Another tool, in the form of a set of techniques has been used emphatically over the years in the understanding of the structure-activity relationship of molecules is Chemometrics [25, 26, 27]. This set of techniques has also enables the planning of new biologically active compounds, and most of the developed research is focused on the construction of QSAR (quantitative structure-activity relationship) models.
The combination of MEP and chemometrics as tools for designing new bioactive compounds has almost always been focused on the elaboration of quantitative models, for example, the CoMFA methodology [28]. This methodology was developed in the late 1980s by Cramer et al. [29]. Its application is richly extensive and recently it has been used in several studies of structure–activity relationships of bioactive compounds. Chatbar et al. conducted a study of triazine morpholino derivatives as mTOR inhibitors for the treatment of breast cancer [30]. Pourbasheer et al. performed 3D-QSAR and 2D-QSAR analyses on the series of compounds hepatitis C virus NS5B polymerase inhibitors [31]. Cramer applied the CoMFA methodology for a large majority of 116 biological targets and obtained acceptable 3D-QSAR models [32]. Cramer et al. introduced in the literature a novel alignment methodology for training or test set structures in 3D-QSAR [33]. Dong et al. performed QSAR analyses of aromatic heterocycle thiosemicarbazone analogues for finding novel tyrosinase inhibitors [34]. Dong et al. built 3D-QSAR models of dabigatran analogues as thrombin inhibitors [35]. Ding et al. performed 3D-QSAR models of 6-aryl-5-cyano-pyrimidine derivatives to explore the structure requirements of LSD1 inhibitors [36].
Applications of MEP to investigate the key features of compounds that are necessary for their biological activities and thus proposing new derivatives as well as the construction of chemometric models as indicative of the most promising among the new derivatives for syntheses and biological assays were reported by us in literature [37, 38, 39, 40, 41, 42, 43]. Pinheiro et al. stated the use of MEP and partial least squares regression (PLS) method in the design of new artemisinin derivatives with activities against
The MEP is also suitable for analyzing processes based on the “recognition” of one molecule by another as in drug-receptor and enzyme-substrate interactions, because it is through their potentials that the two species first “see” each other [2, 3, 44, 45, 46].
MEP for the electronic density is a very useful property for understanding the site of electrophilic attack and nucleophilic reactions as well as the hydrogen bonding interactions [46]. The MEP at a given point (x, y, z) in the vicinity of a molecule is defined in terms of the interaction energy between the electrical charge generated from the molecule’s electrons and nuclei and a positive charge test (a proton) located at
where K is the number of nuclei with charges
In this section, we will make a brief presentation of the PR techniques used in this chapter. A deeper and detailed description of these matters can be found elsewhere [47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66].
When computing large multivariate data, it is mandatory to find and reduce unknown data trends using exploratory tools. The main idea of the PCA technique is to reduce the dimensionality of a data set consisting of large numbers of interrelated variables while retaining the variation present in the data set as much as possible. This can be achieved by transforming them into a new set of variables, the PCs, which are uncorrelated and ordered so that the first few retain most of the variation present in all of the original variables. As the final result, the PCA technique performs the selection of a small number of variables (molecular properties) considered better related to the dependent property or feature [67], in this study, the biological activity against
This technique has become, together with PCA, another important tool in pattern recognition [67]. The purpose of using it is to display the data in such a way as to emphasize its natural clusters and patterns in a two-dimensional space. The results are presented as dendrograms. In HCA technique, the distances between objects or variables are calculated and computed through the similarity index which ranges from zero, that is, no similarity and large distance among objects, to one, for identical objects.
The KNN technique [67] classifies the objects based on distance comparison among them. The multivariate Euclidean distances between every pair of objects with known class membership are calculated. The closest K objects are used to build the model. The optimal K is determined by cross-validation applied to the training set objects. The classification of a test object is determined based on the multivariate distance of this object with respect to the K objects in the training set. In this technique no assumption is made about the size and shape of the training set classes.
This technique separates objects from distinct populations and allocates new objects into populations previously defined. It uses a stepwise procedure in which, at each step, the most powerful variable is entered into the discriminant function. The SDA technique is anchored in the F-test for the significance of variables and at each step selects a variable based on its significance, and, after several steps, the most significant variables are extracted from the set in question [20, 68].
This SIMCA technique develops principal component models for each training set category. Its main objective is the reliable classification of new samples. When a prediction is made with the SIMCA technique, new samples insufficiently close to the PC space of a class are considered nonmembers. Furthermore, the technique requires that each training sample be pre-assigned to one of
For the present chapter, we performed molecular calculations on an AMD PHENOM 955 X4 2.2 GHz processor with 4 Gb of RAM with the Gaussian 98 program package [69]. The MEP was computed from the electronic density, and the maps were displayed using the MOLEKEL software [70], while the PR models were carried out on a PC Pentium machine with the Pirouette program [71].
Figure 1 shows the 2D structure of the 5-nitrofuran-2-aldoxim molecule [72] used in the selection of method/basis set (see Section 3.1.3.1). In Figures 2 and 3 the 2D structures of the nitrofuran compounds from the training [73, 74, 75] and prediction sets are displayed, respectively. In this work, the nitrofuran molecules were defined as more active against
2D molecular structure for 5-nitrofuran-2-aldoxime.
2D molecular structure for nitrofurans (training set).
2D molecular structures for nitrofurans for the prediction set.
In general, the structure–activity relationship shows that for the compounds
The molecular descriptors were obtained for the most stable conformation of each compound. These descriptors were computed to give information about the influence of electronic, steric, hydrophilic, and hydrophobic features on the antitrypanosomal activity of the studied nitrofurans. The atomic charges in this work were derived from the electrostatic potential obtained with HF/6-31G method/basis set as implemented in the Gaussian program package. The electrostatic potential is obtained through the calculation of a set of punctual atomic charges so that it represents the possible best quantum molecular electrostatic potential for a set of points defined around the molecule [76, 77]. The charges derived from electrostatic potential present the advantage of being, in general, physically more satisfactory than the charges of Mülliken [78], especially with regard to biological activity.
The quantum–chemical descriptors employed and obtained with the Gaussian 98 program package [69] were total energy of molecules (TE), highest occupied molecular orbital (HOMO) energy, one level below to highest occupied molecular orbital (HOMO–1) energy; lowest unoccupied molecular orbital (LUMO) energy, one level about lowest unoccupied molecular orbital (LUMO+1) energy, HOMO energy–LUMO energy (gap energy), total dipole moment (μ), Mulliken’s electronegativity (χ), atomic charges on the Nth atom (QN), molecular hardness (HD), and molecular softness (MS).
The physicochemical descriptors obtained with ChemPlus module [79] were total surface area (TSA), molecular volume (VOL), molecular refractivity (MR), and molecule hydration energy (MHE).
Molecular holistic (MH) descriptors were included with the purpose of representing different sources of chemical information in terms of molecular size, symmetry, and distribution of atoms in molecules. Also, we include topologic indices, connectivity indices, geometric descriptors, 3D-MoRSE descriptors, and Moriguchi octanol–water partition coefficient (MlogP). These descriptors were calculated with the Dragon software [80].
In the calculations with the nitrofuran compounds (Figure 1), quantum–chemical approaches were used [81, 82, 83, 84, 85, 86, 87]. We use Becke’s three-parameter hybrid methods [81], the Lee-Yang-Parr (LYP) correlation functional [82], B3LYP and Becke’s 1988 functional (BLYP) [83], Hartree-Fock (HF) method [84], Austin model 1 (AM1) method [85], Parametric Method Number 3 (PM3) [86], and standard basis sets [87] available in the Gaussian program package. In 5-nitrofuran-2-aldoxim, geometry optimization was carried out by B3LYP/6-21G, B3LYP/6-21G*, B3LYP/6-31G, B3LYP/6-31-G*, BLYP/6-21G, BLYP/6-21G*, BLYP/6-31G, BLYP/6-31G*, HF/6-21G, HF/6-21G*, HF/6-31G, and HF/6-31G* approaches [81, 82, 83, 84] and basis sets [87] and AM1 and PM3 approaches [85, 86] . The calculations were performed to find the approach and basis set that would present the best compromise between computational time and accuracy of the information relative to the experimental data. The experimental structure of 5-nitrofuran-2-aldoxim molecule was retrieved from the Cambridge Structural Database CSD [72]. PCA and HCA techniques were used to compare the computed structures with different methods/basis sets of quantum chemistry with the experimental structure of 5-nitrofuran-2-aldoxim molecule to identify the appropriate method and the basis set for further calculations. The analyzes were carried out on an auto-scaled data matrix with dimension 26 × 5, where each row was associate 26 computed and 1 experimental geometry, and each column represented one of 5 geometrical parameters of the 5-nitrofuran-2-aldoxim molecule (bond lengths and bond angles). In order to compute all structures and perform calculations to obtain the molecular properties, the HF/6-31G method has selected (see Results and discussion section); the initial geometries of the nitrofurans (Figures 2 and 3) were built with the optimized geometry of the 5-nitrofuran-2-aldoxim molecule selected by PCA and HCA techniques. A conformational analysis for each compound was carried out with the MM+ algorithm [79], and the lowest energy conformation was submitted to a conformational search with the Gaussian program.
The advantage in using the PCA and HCA techniques in this step was that all structural information are considered simultaneously and it takes into account the correlations among them. Table 1 shows the theoretical and experimental structural information (bond lengths and bond angles) of the geometry of the 5-nitrofuran-2-aldoxim molecule. It was used with the aim to select using PCA and HCA techniques, which quantum–chemical approach and basis set give results closest to the experimental data [72].
Approaches/basis set | |||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Geometric parameters | B3LYP/6-21G | B3LYP/6-21G* | B3LYP/6-31G | B3LYP/6-31G* | BLYP/6-21G | BLYP/6-21G* | BLYP/6-31G | BLYP/6-31G* | HF/6-21G | HF/6-21G* | HF/6-31G | HF/6-31G* | AM1 | PM3 | Exp [72] |
Bond length (Å) | |||||||||||||||
C2C3 | 1.42 | 1.42 | 1.42 | 1.42 | 1.43 | 1.47 | 1.43 | 1.42 | 1.43 | 1.43 | 1.43 | 1.43 | 1.43 | 1.43 | 1.41 |
C4C5 | 1.36 | 1.36 | 1.37 | 1.37 | 1.38 | 1.38 | 1.39 | 1.38 | 1.34 | 1.39 | 1.34 | 1.34 | 1.40 | 1.39 | 1.34 |
C1C2 | 1.38 | 1.38 | 1.38 | 1.38 | 1.39 | 1.39 | 1.40 | 1.39 | 1.35 | 1.35 | 1.35 | 1.35 | 1.33 | 1.38 | 1.36 |
C1O1 | 1.40 | 1.37 | 1.39 | 1.36 | 1.42 | 1.39 | 1.42 | 1.38 | 1.37 | 1.39 | 1.37 | 1.33 | 1.34 | 1.37 | 1.37 |
C4O1 | 1.38 | 1.35 | 1.38 | 1.35 | 1.41 | 1.37 | 1.40 | 1.37 | 1.36 | 1.37 | 1.35 | 1.33 | 1.40 | 1.38 | 1.35 |
C4N1 | 1.41 | 1.43 | 1.41 | 1.43 | 1.43 | 1.44 | 1.43 | 1.49 | 1.40 | 1.43 | 1.40 | 1.42 | 1.45 | 1.48 | 1.42 |
N1O2 | 1.41 | 1.43 | 1.41 | 1.43 | 1.43 | 1.44 | 1.43 | 1.48 | 1.40 | 1.43 | 1.41 | 1.42 | 1.46 | 1.47 | 1.42 |
N1O3 | 1.28 | 1.23 | 1.26 | 1.23 | 1.31 | 1.25 | 1.29 | 1.25 | 1.24 | 1.19 | 1.22 | 1.19 | 1.19 | 1.21 | 1.22 |
C1C5 | 1;29 | 1.23 | 1.27 | 1.23 | 1.32 | 1.26 | 1.30 | 1.26 | 1.26 | 1.20 | 1.23 | 1.20 | 1.20 | 1.22 | 1.22 |
C5N2 | 1.43 | 1.44 | 1.43 | 1.44 | 1.44 | 1.45 | 1.44 | 1.45 | 1.45 | 1.46 | 1.45 | 1.46 | 1.45 | 1.45 | 1.45 |
N2O4 | 1.29 | 1.28 | 1.29 | 1.28 | 1.32 | 1.31 | 1.31 | 1.30 | 1.26 | 1.25 | 1.26 | 1.25 | 1.31 | 1.29 | 1.27 |
O4H1 | 1.47 | 1.40 | 1.44 | 1.39 | 1.50 | 1.42 | 1.47 | 1.41 | 1.44 | 1.37 | 1.40 | 1.36 | 1.31 | 1.39 | 1.38 |
Bond angle (°) | |||||||||||||||
C1O1C4 | 105.3 | 105.6 | 106.0 | 106.1 | 104.7 | 105.3 | 105.5 | 105.8 | 105.4 | 106.3 | 105.8 | 106.9 | 105.3 | 106.3 | 104.5 |
O1C1C2 | 109.5 | 110.2 | 109.2 | 110.1 | 109.5 | 110.0 | 109.2 | 109.9 | 109.1 | 109.6 | 110.7 | 109.4 | 105.2 | 106.0 | 104.8 |
O1C1C5 | 119.3 | 118.7 | 119.8 | 119.5 | 119.2 | 118.8 | 119.7 | 119.6 | 119.5 | 119.4 | 118.5 | 119.8 | 110.6 | 110.7 | 110.2 |
C5C1C2 | 131.2 | 131.0 | 130.9 | 130.4 | 131.3 | 131.1 | 131.1 | 130.5 | 131.3 | 130.9 | 130.6 | 130.9 | 119.5 | 120.4 | 114.1 |
C5N2O2 | 121.2 | 120.6 | 121.8 | 121.3 | 121.2 | 120.7 | 121.9 | 121.4 | 122.0 | 120.9 | 120.1 | 121.7 | 129.7 | 128.8 | 135.6 |
C1O1C4 | 107.9 | 110.0 | 109.5 | 110.6 | 107.1 | 109.2 | 108.5 | 109.8 | 108.8 | 109.6 | 111.2 | 111.4 | 122.8 | 120.4 | 127.8 |
N2O4H1 | 100.7 | 100.8 | 103.6 | 102.7 | 99.3 | 99.8 | 102.0 | 101.6 | 102.4 | 103.7 | 102.1 | 106.9 | 115.2 | 116.7 | 112.2 |
C1C2C3 | 107.5 | 106.6 | 107.5 | 106.6 | 107.7 | 106.8 | 107.7 | 106.9 | 107.8 | 106.9 | 106.0 | 106.9 | 104.2 | 101.6 | 106 |
O1C4C3 | 111.5 | 112.3 | 111.2 | 112.0 | 111.5 | 112.2 | 111.2 | 111.9 | 111.1 | 111.4 | 112.8 | 111.1 | 105.9 | 106.0 | 105.1 |
C3C4N1 | 130.2 | 129.9 | 130.6 | 130.2 | 130.1 | 130.0 | 130.9 | 130.5 | 130.9 | 130.3 | 129.5 | 130.4 | 111.1 | 110.6 | 113.2 |
O1C4N1 | 118.4 | 117.8 | 118.1 | 117.6 | 118.3 | 117.7 | 117.9 | 117.5 | 117.8 | 118.2 | 117.5 | 118.4 | 131.4 | 131.4 | 129.8 |
C4N1O2 | 115.0 | 114.9 | 115.8 | 115.6 | 114.6 | 114.6 | 115.9 | 115.5 | 115.7 | 115.4 | 115.0 | 116.0 | 117.4 | 117.8 | 116.9 |
C4N1O3 | 117.7 | 117.2 | 118.9 | 118.1 | 117.6 | 117.2 | 115.6 | 118.2 | 118.9 | 118.1 | 117.2 | 119.2 | 117.3 | 117.5 | 116.3 |
O2N1O3 | 127.3 | 127.9 | 125.3 | 126.2 | 127.7 | 128.1 | 118.8 | 126.2 | 125.2 | 126.4 | 127.6 | 126.4 | 119.6 | 120.1 | 118.8 |
Experimental and theoretical structural parameter of the 5-nirofuran-2-aldoxime.
*Refers to the base sets cited in the corresponding references.
The first two principal components explain 86.02% of the original information as follows: PC1 = 58.01% and PC2 = 28.02%. The PC1 versus PC2 scores plot is shown in Figure 4, from which it can be seen that the methods are discriminated into two classes according to PC2. The semiempirical approaches (AM1 and PM3) are at the top of the graph, while the other theoretical (HF, BLYP, and B3LYP) approaches and experimental data are at the bottom. Moreover, it can be seen that the HF/6-31G approach/basis set is the closest to the experimental data, indicating that they should be used in the development of this work.
Score plots of the two first PCs, PC1 and PC2, for the separation of the approaches basis sets into classes: semiempirical and semiempirical not.
Also, to investigate the most appropriate approach and basis set for further calculations, we used HCA. Figure 5 shows the dendrogram obtained with complete linkage method; from this figure, we conclude that the theoretical approaches are distributed in a similar way as in PCA, i.e., HCA confirmed the PCA results. Moreover, we can observe that the HF/6-31G approach/basis set is closer to the experimental data therefore being the most suitable to carry out this work.
Dendrogram obtained with HCA technique for the separation of the approach basis set into two classes: semiempirical and semiempirical not.
Figure 6 shows the MEP maps for the nitrofurans in the training set. The analysis of these maps reveals that the most active compounds, in general, have the following characteristics:
MEP maps (kcal/mol) for nitrofurans (training set).
(i) Compounds with an unsaturation and presenting O atom neighboring the carbonyl in the carbonic chain present greater electron density in the proximities of the furan ring with the decrease of the chain size. In these compounds (
(ii) Compounds with double unsaturation, containing O atom neighboring the carbonyl, raising the carbon chain, increase the electron density in the atoms of the nitro group, extending through the O atom of the furan ring to the O atoms of the ester group following the unsaturated chain. In these compounds (
(iii) Compound with an unsaturation, N atom neighboring the carbonyl in the carbonic chain and bulky substituents, has higher electron density in the vicinity of the furan ring and in the N and O atoms of the amide group. In this compound (
From the above discussion, as a rule, to plan more active nitrofurans, we can assume we resort to one of the basic structures of the most active compounds and introduce groups of atoms or substituents electron donors enhancing the key structural features that are necessary for their activities.
To perform the chemometric modeling, all variables were auto-scaled as pre-processing so that they could be standardized and so they could have the same importance regarding the scale. Furthermore, given a large quantity of multivariate data available, it was necessary to reduce the number of variables. Thus if any two descriptors had a high Pearson correlation coefficient (r ˃ 0.8), one of the two was excluded from the matrix at random, since theoretically they describe the same property [88]; they also have a high correlation with antitrypanosomal activity, and only one of them is enough to be used as independent variable in a predictive model.
Four molecular descriptors were selected for PCA model. The molecular descriptors (QN1, gap energy, Mor05u, and MlogP), in vitro
Nitrofurans | QN1 | Gap energy (kcal/mol) | Mor05u | MlogP | % in vitro | Activityc |
---|---|---|---|---|---|---|
1− | 0.201 | 220.9 | −3.966 | 1.135 | 30 | LA |
2− | 0.201 | 220.9 | −2.938 | 1.708 | 20 | LA |
3− | 0.165 | 220.9 | −2.723 | 0.181 | 32 | LA |
4+ | 0.165 | 226.5 | −6.869 | 1.980 | 92.7 | MA |
5+ | 0.165 | 225.3 | −7.439 | 3.155 | 83.7 | MA |
6+ | 0.169 | 229.7 | −0.016 | 1.708 | 96.2 | MA |
7+ | 0.164 | 208.3 | −7.439 | 1.889 | 81.9 | MA |
8− | 0.164 | 205.2 | −4.854 | 0.334 | 26.7 | LA |
9− | 0.166 | 215.9 | −3.292 | 0.478 | 58 | LA |
10+ | 0.166 | 215.9 | −7.470 | 2.146 | 90 | MA |
11+ | 0.164 | 208.3 | −5.674 | 1.354 | 87.4 | MA |
12+ | 0.164 | 208.3 | −8.435 | 3.307 | 92.3 | MA |
13− | 0.167 | 195.2 | −4.338 | 0.751 | 12 | LA |
14− | 0.161 | 203.3 | −2.872 | 0.501 | 3 | LA |
15− | 0.167 | 208.3 | −4.217 | 0.411 | 30 | LA |
16− | 0.167 | 225.3 | −2.373 | 0.609 | 20 | LA |
17− | 0.167 | 225.9 | −4.054 | 1.063 | 6 | LA |
18+ | 0.167 | 225.3 | −6.339 | 2.001 | 75 | MA |
19− | 0.166 | 225.3 | −4.145 | 0.398 | 31 | LA |
20− | 0.167 | 226.5 | −4.786 | 0.667 | 35 | LA |
21− | 0.167 | 225.3 | −3.398 | 1.157 | 23 | LA |
22− | 0.166 | 218.4 | −3.876 | 0.802 | 14 | LA |
23+ | 0.166 | 224.6 | −6.314 | 3.014 | 90.5 | MA |
Gap energy | −0.171 | |||||
Mor05u | 0.27 | −0.006 | ||||
MlogP | 0.026 | −0.184 | −0.785 |
Values for the four most important descriptors which classify the studied nitrofuran compounds, in vitro
aInhibitor concentration of 5 μM. bGrowth inhibition ≥ 75, more active (MA)c, and growth inhibition < 75, less active (LA)c.
Score plots of the two first PCs, PC1 and PC2, responsible for the separation of the 23 nitrofurans (training set) into two classes: (+) more active and (−) less active against
Loading vector plots of the first PCs, PC1 and PC2, for four variables responsible for the separation of the 23 nitrofurans (training set) into two classes: (+) more active and (−) less active against
Table 3 shows the loading vectors for PC1, PC2, and PC3. According to this table, PC1 can be expressed through the following equation:
Variable | PC1 | PC2 | PC3 |
---|---|---|---|
QN1 | 0.20 | 0.66 | 0.69 |
Gap energy | 0.06 | −0.70 | 0.70 |
Mor05u | 0.71 | 0.11 | −0.10 |
MlogP | −0.68 | 0.26 | 0.17 |
Variables matrix for the first three principal components.
From this equation, more active nitrofurans, in general, can be obtained when we have lower values for the QN1 combined with lower values for Gap energy and Mor05u and higher values for MlogP.
The results of the HCA model are displayed in the dendrogram in Figure 9 and are similar to those of PCA model. The nitrofurans are fairly well grouped according to their activity. From this figure, the two clusters (+ and −) mirror the same two classes displayed by PCA model (Figure 7).
Dendrogram obtained with HCA technique for the separation of the nitrofurans into two classes: (+) more active and (−) less active against
Table 4 shows the results for the KNN models obtained with the KNN technique and constructed with one (1NN) to four (4NN) nearest neighbors. To all models the percentage of correct information was 100%. We used the model 4NN because the greater the number of the nearest neighbors, the better the reliability of the KNN technique, and the same was used for validation of the training set from Figure 2.
Category | Number of compounds | Compounds incorrectly classified | |||
---|---|---|---|---|---|
1NN | 2NN | 3NN | 4NN | ||
Class:more active | 9 | 0 | 0 | 0 | 0 |
Class: less active | 14 | 0 | 0 | 0 | 0 |
Total | 23 | 0 | 0 | 0 | 0 |
% Correct information | 100 | 100 | 100 | 100 |
Classification obtained with the KKN technique.
In the construction of the SDA model, the discrimination functions for groups more active and less active, respectively, are given below:
Group MA (more active):
Group LA (less active):
Also, through the discrimination functions, Eqs. (3) and (4), and of the value of each descriptor for the nitrofurans, we obtain the classification matrix by using all compounds from the training set (Table 5). The classification error was 0.00% resulting in a satisfactory separation of more active and less active compounds. From SDA model, the allocation rule was derived when the activity against
True group | |||
---|---|---|---|
Classification group or class | Number of compounds | More active | Less active |
Group (Class): more active | 9 | 9 | 0 |
Group (Class): less active | 14 | 0 | 14 |
Total | 23 | 9 | 14 |
% Correct information | — | 100 | 100 |
Classification matrix obtained using SDA technique.
In order to check the reliability of the model, the “leave-one-out technique” was employed. One nitrofuran compound is excluded from the data set, and the remaining compounds are used in building the classification functions.
Subsequently, the removed analogue is classified according the generated classification functions. In the further step, the omitted compound is included, and a new nitrofuran is removed, and the procedure goes on until the last compound is removed. In Table 6 the results obtained with the cross-validation model are summarized.
True group | |||
---|---|---|---|
Classification group or class | Number of compounds | More active | Less active |
Group (class): more active | 9 | 9 | 0 |
Group (class): less active | 14 | 0 | 14 |
Total | 23 | 9 | 14 |
% correct information | — | 100 | 100 |
Classification matrix obtained by using SDA technique with cross-validation technique.
The SIMCA model were built with the same descriptors as PCA, HCA, KNN, and SDA models and used two (2) PCs in the modeling of the two classes: more active nitrofurans (
Category | Number of compounds | Correct classification |
---|---|---|
Class: more active | 9 | 9 |
Class: less active | 14 | 14 |
TOTAL | 23 | |
% correct information | 100 |
Classification obtained by using SIMCA technique.
As QN1, gap energy, Mor05u, and MlogP properties were selected in the chemometric modeling as the most important characteristics to describe the antitrypanosomal activity, some considerations about them may be relevant to the understanding of the behavior of more active nitrofurans. According to classical chemical theory, chemical interactions can be classified in two categories: electrostatic (polar) or orbital (covalent). Electrical charges in the molecule are indubitably the impelling cause of electrostatic interactions. It has been demonstrated that local electron densities or charges are important in many chemical reactions, physicochemical properties, and ligand–receptor interactions [89, 90]. Thus, charge-based parameters have been widely employed as chemical reactivity indices or as measures of weak intermolecular interactions. Many quantum–chemical descriptors are derived from the partial charge distribution in a molecule or from the electron densities on particular atoms [91]. From Table 2, we can observe that, in general, QN1 for more active analogues must present lower values than the less active ones. This is an indication that biological processes can occur through electrostatic interactions between the more active nitrofurans and an eventual biological receptor.
Gap energy is an important stability index. A large gap energy implies high stability for the molecule in the sense of its lower reactivity in chemical reactions. It is an approximation of the lowest excitation energy of the molecule and can be used for the definition of absolute and activation hardness [89, 90]. In Table 2, we can observe that, in general, the more active nitrofurans present lower gap energy than the less active ones. This indicates that the more active nitrofurans have a great probability of interacting with the biological receptor through a charge transfer mechanism.
Mor05u is a 3D-MoRSE descriptor based on the idea of obtaining information from 3D atomic coordinates through the transformed used in electrons diffraction studies [91] and is strictly related to the stereochemistry of the compounds [92]. According to Table 2, the more active nitrofurans present lower values of Mor5u. This may be, in general, an indication of the importance of the stereochemical properties of the more active nitrofurans in a possible mechanism of action of its own.
MlogP is an important hydrophobic descriptor in diverse biochemical, pharmacological, and toxicological processes involved in drug absorption [93]. As identified in Table 2, the more active reported nitrofurans exhibit the higher MlogP values. This is an indication that in processes involving nitrofurans and a biological receptor, hydrophobic interactions may be important in the mechanism of action of these compounds.
Knowing the performance of the RP models constructed for the 23 studied nitrofurans, we decided to apply them to a series of eight compounds (Figure 3) designed to maintain the key structural features that are necessary for their biological activities evidenced by the MEP maps of the compounds of the training set. The basic nucleus of these compounds corresponds to that of the most active nitrofurans with double unsaturation, containing vicinal O atom to carbonyl (see compounds
The results obtained of the application of the PR models (PCA, HCA, KNN, SDA, and SIMCA) and the descriptors for the compounds of the prediction set are summarized in Tables 8 and 9, respectively. In Table 8, the compounds
Nitrofuran | PCA model | HCA model | KNN model | SDA model | SIMCA model |
---|---|---|---|---|---|
24 | MA | MA | MA | LA | MA |
25 | MA | MA | MA | MA | MA |
26 | LA | LA | MA | LA | LA |
27 | MA | MA | MA | LA | MA |
28 | MA | MA | MA | LA | MA |
29 | MA | MA | MA | MA | 0 |
30 | MA | MA | MA | MA | MA |
31 | MA | MA | LA | LA | 0 |
Results of application of chemometric models for the nitrofurans of the prediction set.
Nitrofuran | QN1 | Gap energy (kcal/mol) | Mor05u | MLogP |
---|---|---|---|---|
24 | 0.165 | 205.2 | −6.352 | 3.155 |
25 | 0.165 | 203.3 | −7.332 | 2.250 |
26 | 0.165 | 204.6 | −5.835 | 1.146 |
27 | 0.169 | 203.9 | −6.164 | 2.508 |
28 | 0.166 | 203.9 | −7.146 | 1.875 |
29 | 0.164 | 229.7 | −8.201 | 3.854 |
30 | 0.164 | 229.7 | −6.421 | 3.373 |
31 | 0.164 | 223.4 | −5.525 | 2.167 |
Values for descriptors for the prediction set.
Figure 10 shows the MEP maps for the most active nitrofurans in the validation set (
MEP maps (kcal/mol) for most promising nitrofurans in the prediction set against
The negative MEP region of compounds
MEP and chemometric techniques in the last decades have become efficient tools in the study of the structure–activity relationships of bioactive molecules. The use of such tools has occurred through the inherent principles of each or combining their potentials to more efficiently unravel information about the structure–activity relationships of pharmacologically interesting compounds. This chapter is circumscribed in this second possibility. MEP maps were constructed for 23 nitrofurans with activity against
PR models (PCA, HCA, KNN, SDA, and SIMCA) were constructed and demonstrated that 23 nitrofurans can be classified into two classes or groups: more active and less active according to their degrees of activity against
The results of the application of PR models on the validation set evidenced two nitrofurans (
We gratefully acknowledge the financial support of the Brazilian agencies: Conselho Nacional de Desenvolvimento Científico e Tecnológico and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior. The authors would like to thank the Virtual Computational Chemistry Laboratory (VCCLAB–Munich) and the Swiss Center for Scientific Computing for the use of the DRAGON and MOLEKEL software, respectively. We employed computing facilities at the Laboratório de Química Teórica e Computacional (LQTC)–Universidade Federal do Pará.
Clotting is a physiological property of the body to form clots and thus minimize blood loss at the site of injury. Normal blood flow is kept in balance by factors that promote clotting and by antithrombotic factors. A hypercoagulable state, which may be complicated by the development of thromboembolism, is a consequence of hyperactivity of clotting promoters or anticoagulant deficiency. But the interaction between the two facets is much more complex than this, as thrombosis can be influenced by the qualitative and quantitative properties of factors, for example, their secretion, accumulation, or degradation [1].
What Virchow described in 1856 as the triad of conditions that must be met to develop venous thrombosis is accepted nowadays as hypercoagulability, vascular stasis and vascular trauma underlie the pathophysiological mechanism that explains this situation. Arterial thrombosis, on the other hand, results from the rupture of an atherosclerotic plaque, which pierces the vascular endothelium, resulting in the formation of platelet-rich thrombus around it [1].
Thrombophilia is a hypercoagulable or prothrombotic state, which is defined as an abnormality of blood clotting, thus increasing the risk of thrombosis. It can be classified into different categories, depending on its mechanism of action, how it occurs, whether it is an acquired or an inborn disease. [Genetic vs. acquired; primary vs. secondary; permanent vs. transient; low risk vs. high risk].
The known possible causes of thrombophilia are listed in Table 1 [3].
Primary (genetic) | Secondary (acquired) |
---|---|
Factor V mutation (G1691A mutation; factor V Leiden) | Prolonged bed rest or immobilization |
Prothrombin mutation (G20210A) | Myocardial infarction |
5,10-Methylene tetrahydrofolate reductase (hyperhomocysteinemia) | Atrial fibrillation |
Increased levels of factor VIII, IX, XI, or fibrinogen | Tissue injury (surgery, fracture, burn) |
Antithrombin III deficiency | Cancer |
Protein C deficiency | Prosthetic cardiac valves |
Protein S deficiency | Disseminated intravascular coagulation |
Fibrinolysis defect | Heparin-induced thrombocytopenia |
Homozygous homocystinuria (deficiency of cystathionine B-synthase) | Antiphospholipid syndrome |
Cardiomyopathy | |
Nephrotic syndrome | |
Hyperestrogenic states (pregnancy and postpartum) | |
Oral contraceptive use | |
Sickle cell anemia | |
Smoking | |
Infection (Covid 19) |
Thrombophilia causes, Robbins and Cotran pathologic basis of disease (ninth edition.) [2].
Type 1 or major thrombophilias are a group of rare diseases that include antithrombin deficiency, protein C deficiency, or protein S deficiency, which together occur in less than 1% of the population but account for up to 7% of patients with thrombosis [4].
Type 2 thrombophilias or minor thrombophilias are much more common, the most important example being the factor V Leiden mutation, which can be identified in 5% of the European-born population and 30–50% of patients referred for thrombophilia testing.
The prothrombin mutation affects 1–4% of the general population but is found in up to 15% of patients tested for thrombophilia. Both types of mutations are much more common in Caucasians and almost never found in patients of Asian or African descent [4].
Hereditary thrombophilias are those in which a genetic mutation inherited from one or both parents leads to a condition in which the function of certain proteins of the clotting system is impaired. The condition can be expressed as a deficiency or loss of function, best exemplified by mutations in the antithrombin, protein C, or protein S genes, or as a gain of function, such as mutations in factor V Leiden and prothrombin 20,210 A/G. Other conditions, although less common, are the presence of abnormal levels of clotting factors, elevated homocysteine, or defects in the fibrinolytic pathway. Nowadays, we have reached a point where gene factors can be identified in up to 30% of patients with thrombophilia [5, 6].
Acquired thrombophilia is a hypercoagulable status composed of the association of a divergent group of clinical conditions, which include malignancy, pregnancy, prolonged bed rest, postoperative, nephrotic syndrome, or lifestyle risk factors, such as smoking or obesity. But the most important example is an antiphospholipid syndrome which is also included in the guidelines and should be tested for each time thrombophilia is suspected [5].
Although hypercoagulability disorders are classified as either inherited or acquired, thrombosis develops due to the interaction of both genetic and environmental factors, which has led to the development of the multiple-hit hypothesis, thus providing a possible explanation for the differences observed between subjects carrying the same gene mutation [6].
In an article by R H Thomas, the CALMSHAPES mnemonic was proposed to more easily recall the different etiologies of the hypercoagulable state, which are as follows:.
Protein C deficiency
Antiphospholipid syndrome
Factor V Leiden mutation
Malignancy
Protein S deficiency
Hyperhomocysteinemia
Antithrombin III deficiency
Prothrombin G2021A mutation
Factor eight excesses
Sticky platelet syndrome [6]
Venous thromboembolism is the main and most common complication of a hypercoagulable condition, with a huge impact on any national health system. Available data from the United States estimates that venous thromboembolism is responsible for more than half a million hospitalizations annually, with an estimated cost of treatment per patient of more than $56,000, totaling an estimated $5–$20 billion. The different mechanisms of occurrence of a hypercoagulable state have different penetration in the general population, with different risk rates for complications, such as venous thromboembolism, as shown in Table 2.
Syndrome | % in the general population | % in patients with venous thromboembolism | Relative risk of thromboembolism |
---|---|---|---|
Factor V Leiden (G1691A) | 0.05–4.8 | 18.8 | 4 |
Factor V Leiden (A1691A) | 0.02 | 1.5 | 80 |
Prothrombin G20210A | 0.06–2.7 | 7.1 | 2.8 |
Low protein C levels | 0.2–0.4 | 3.7 | 6.5 |
Low protein S levels | 0.16–0.1 | 2.3 | 5.0 |
Low antithrombin levels | 0.02 | 1.9 | 20 |
Hyperhomocysteinemia | 5–7 | 10 | 2.95 |
High factor VIII levels | 11 | 25 | 4.8 |
High factor IX levels | 10 | 20 | 2.8 |
High factor XI levels | 10 | 19 | 2.2 |
Lipoprotein (a) | 7 | 20 | 3.2 |
Antiphospholipid antibody | 0–7 | 5–15 | 5.5 |
Prevalence of different thrombophilias and the risk of developing venous thromboembolism [3].
Factor V Leiden is an autosomal dominant transmissible gene abnormality that shows incomplete penetrance; therefore, the disease will not be developed by all carriers of the mutation. In terms of pathophysiological mechanism, factor V Leiden is also known as factor V Arg506Gln and as factor V R506Q, due to a single mutation of the factor V gene in which guanine replaces arginine at nucleotide 1691. Consequently, just one amino acid change, replacing arginine with glutamine, suppresses the binding site to the activated proteolytic protein C of factors V and Va [7, 8]. With the malformed binding site, the natural anticoagulant protein C can no longer bind and cleave factor V and Va to inactivate it, therefore factor V concentration increases and disrupts the pro−/anticoagulant balance, leading to an increased risk of thrombosis [7]. The result of the so-called activated protein C resistance phenotype is blamed in up to 95% of cases as a consequence of a factor V mutation, which has resulted in a 7-fold increase in the relative risk of developing deep vein thrombosis in patients [8].
Prothrombin G20210A is a specific genetic mutation of nucleotide 20210A of the second factor of the coagulation cascade (factor II—prothrombin) and consists of a change of guanine to adenine, with a higher concentration of prothrombin found in mutation carriers [9]. Although several attempts have been made to explain why this happens, the exact mechanism of how the mutation leads to increased protein production, thereby increasing the overall risk of thrombosis, is not yet fully understood [10]. Caucasians have a higher risk of developing this condition, but the risk of thrombosis is minimal for heterozygotes in whom no other risk factors are identified. However, in the presence of other secondary risk factors, such as prolonged bed rest or pregnancy, the risk is greatly increased. Homozygous carriers face an increased risk of thrombosis by 2 to 3 folds [11].
Protein C and its activated form are vitamin K-dependent zymogens with an important role in the regulation of anticoagulation by inactivating coagulation factors Va and VIIIa [12].
Protein C deficiency is a rare abnormality that alters the activity of protein C, a consequence of which is the loss of activated protein C function and, consequently, its inability to control coagulation [13].
Mutations in the PROC gene are responsible for the development of congenital protein C deficiency and are transmitted in an autosomal dominant manner, affecting heterozygous carriers much less than homozygous carriers. To date, more than 160 PROC mutations have been identified, which can affect protein C concentration (type I) or result in the production of an altered protein with reduced activity and ineffective anticoagulant function (type II) [13].
Protein C is activated by interactions with thrombin after the latter has attached to thrombomodulin expressed on the endothelial cell surface. Activated protein C then proceeds to reduce clotting by cleaving and inactivating clotting factors Va and VIIIa. Low concentrations or structural alterations of protein C disturb the coagulation balance, favoring the development of a hypercoagulable state [13].
Protein S is a vitamin K-dependent glycoprotein synthesized by the liver with an important role in coagulation, where it acts as a cofactor for protein C to inactivate coagulation factors Va and VIIIa and also as a cofactor for tissue factor pathway inhibitory protein, leading to inactivation of factor Xa and tissue factor/factor VII. In the human body, protein S exists in two forms—one free and one bound to the complementary protein C4b [13, 14].
Protein S deficiency is an unusual condition caused by quantitative or qualitative abnormalities following point mutations in the PROS1 gene. Mutations are transmitted in an autosomal dominant manner with incomplete penetrance. Homozygous individuals have a higher risk of thrombosis than heterozygous individuals, of whom only an estimated 50% develop venous thromboembolism, the other half remaining asymptomatic. More than 200 genetic mutations have been identified, causing a range of defects, which can be classified into three types—type I is characterized by low levels of total S protein and free S protein, type II total S protein concentrations are normal but with low activity, while type III has normal levels of total S protein but low levels of free S protein [13].
A quantitative or qualitative deficiency of protein S will have great implications in the regulation of coagulation, as the natural anticoagulant mechanisms will be less effective in inactivating coagulation factors Va, VIIIa, and VIIa, thus favoring a thrombosis-prone state.
Antiphospholipid syndrome is an autoimmune-generated hypercoagulable state caused by the presence of antiphospholipid antibodies and is the most common cause of acquired thrombophilia. It is characterized by the presence of at least one of three antiphospholipid antibodies, which are lupus anticoagulant, anticardiolipin antibodies, or antibeta2 glycoprotein antibodies, in addition to one or more clinical manifestations of thrombosis [15, 16].
The condition can be classified into a primary antiphospholipid syndrome, which occurs without a concurrent autoimmune disease, and a secondary antiphospholipid syndrome, in the presence of another autoimmune condition, the most prominent example being systemic lupus erythematosus [15].
Two profile risks for thrombosis have been identified in terms of the type and titer of antibodies present:
A high-risk profile involves one of the following: Thromboembolism risk profile:
the presence of lupus anticoagulant at 2 different measurements taken at least 12 weeks apart;
any combination of 2 of the 3 defining antibodies;
identification of all 3 antiphospholipid antibodies;
the persistence of high antiphospholipid antibody titers;
A low-risk profile requires transient isolation of anticardiolipin antibodies or antibeta2 glycoprotein antibodies at low-to-medium titers [16].
The mechanisms involved in the generation of hypercoagulability require further investigation, as the few proposed mechanisms cannot exclusively explain this condition. Antiphospholipid antibodies are thought to interfere with platelet and endothelial cell membranes, proteins in the coagulation cascade or inhibit protein C.
The types, isotypes, and titers of antibodies found to correlate directly with the risk of thrombosis risk increases with higher titers, the presence of IgG antibodies, or the identification of lupus anticoagulant [15].
Thromboembolic complications in cancer patients are the second leading cause of mortality, presenting in various forms from venous or arterial thrombosis to disseminated intravascular coagulation. Venous thromboembolism is a significant cause of morbidity and mortality, with pulmonary embolism being three times more common than in a person who has developed venous thrombosis but does not have cancer [17, 18].
Other rarer thrombotic complications are also seen more frequently in patients with cancer, such as disseminated intravascular coagulation and thrombotic microangiopathy. Disseminated intravascular coagulation is a condition in which the coagulation cascade is activated systemically, resulting on the one hand in the formation of fibrin deposits that move to different organs blocking microcirculation, and on the other hand consuming clotting factors and platelets, which can lead to life-threatening bleeding [17, 19].
It has long been observed that patients with cancer and thromboembolic disease are strongly associated, but despite this, the mechanisms leading to the hypercoagulable state are numerous, complex, and not yet fully understood. Tumor-specific factors are also thought to play a role, because of the variable risk of thrombosis for different cancers. Returning to Virchow’s triad, all three conditions for thrombosis can occur simultaneously in a cancer patient, the best example being venous stasis following venous compression by a tumor [17, 18].
Various cancer therapies can also contribute to a prothrombotic state, with many reports suggesting an association between chemotherapy and arterial thrombosis. The most implicated agents are platinum-based therapeutics (cisplatin) and those that interfere with vascular endothelial growth factor, either to inhibit it directly (bevacizumab) or to inhibit its receptor tyrosine kinase (sorafenib) [20].
The hypercoagulable state observed during pregnancy is the result of physiological, hormonal, and physical changes that affect women during pregnancy and in the peri- and post-natal periods.
As a result of hormonal changes, levels of certain clotting factors are increased, such as those of factors VII, VIII, X, von Willebrand factor, and fibrinogen. Meanwhile, during the second and third trimesters, resistance to activated protein C has been observed, as well as decreased activity of protein S. The number of studies has also reported decreased activity of the fibrinolytic pathway, due to an increase in its inhibitors, such as plasminogen activator inhibitor 1 and 2 and activable fibrinolytic inhibitor. All of these changes contribute to a tilting of the coagulation balance toward a prothrombotic state [21, 22].
Physical changes that promote thrombosis include prolonged bed rest in the peripartum period and mechanical compression of the pelvic veins by the gravid uterus, leading to decreased venous return from the lower extremities, consecutive stasis, and the development of venous thrombosis [21].
Heparin-induced thrombocytopenia (HIT) is a condition mediated by the immune system through the development of heparin-dependent antibodies that have activated platelets, thereby increasing the risk of both venous and arterial thrombosis [15, 23].
IgG antibodies are directed against the antigenic complex formed by the binding of platelet factor 4 to heparin on the surface of platelets. This, in turn, activates surrounding platelets, leading to thrombin generation and the procoagulant state with the characteristic clinical manifestations of thrombocytopenia and thrombosis [23].
The diagnosis is confirmed by a decrease in platelets below 150,000/mL or by 50% from baseline in the presence of IgG HIT antibodies. The condition usually develops between 5 and 14 days after the start of heparin treatment, but may also develop within the first 24 hours in the case of previously administered heparin treatment. The risk is higher in surgical patients, especially following orthopedic and cardiac surgery, and is related to the period of exposure to heparin. Although heparin-induced thrombocytopenia is usually the result of treatment with unfractionated heparin, the occurrence of this condition has also been observed after administration of LMWH due to cross-reactivity between the two classes [15].
COVID-19 infection with severe acute respiratory syndrome coronavirus 2 has been shown to lead to a prothrombotic state, with variably reported incidences ranging from 11 to 70%, conditional on case severity and other predisposing factors.
The pathogen is thought to injure the vascular endothelium by attaching spike protein to the angiotensin-converting enzyme 2 receptors, thereby altering the properties of the endothelium into a thrombogenic surface, favoring platelet adhesion, hypercoagulability, and the development of micro or macrothrombosis at this level [11, 24].
Anticoagulant drugs are the first line of treatment for the prevention and treatment of thrombosis. This includes unfractionated heparin, low molecular weight heparin, fondaparinux, vitamin K antagonists (warfarin), and direct oral anticoagulants, which have a better safety profile than warfarin and have been shown to be equally effective, gradually replacing older agents [25].
The use of anticoagulants for primary prophylaxis has selected indications, such as for transient risk factors (prolonged hospitalization, postoperative status, certain orthopedic conditions) or may be considered for patients with high-risk hereditary thrombophilia, although for the latter there are not a large number of studies to support this indication [11, 26].
A patient who has developed a deep vein thrombosis and/or pulmonary embolism, whether provoked or unprovoked, should begin treatment with a direct oral anticoagulant for 3–6 months, according to the 2020 guidelines developed by the American Society of Hematology. It is also recommended that patients who have developed an unprovoked episode of deep vein thrombosis and/or pulmonary embolism or in whom a chronic risk factor can be identified should continue to receive secondary prophylaxis with either a standard or low-dose direct oral anticoagulant [10, 27].
For the purpose of secondary prophylaxis of various low-risk thrombophilias, the most recent studies recommend the use of direct oral anticoagulants instead of vitamin K antagonists, as the former possess a similar efficacy profile but with a better safety profile in terms of minor or major bleeding events. In high-risk thrombophilia, there is little data available to support the use of direct oral anticoagulants. A recent study testing the use of Rivaroxaban for secondary prophylaxis of high-risk antiphospholipid syndrome showed no additional benefit over traditional treatment, but an increased risk of bleeding [28, 29].
In patients carrying the factor V Leiden mutation, no benefit of long-term anticoagulation has been shown in asymptomatic patients with no history of thrombosis. Although, short-term anticoagulation may be beneficial when other transient risk factors are identified. It is also recommended that women with or without a history of venous thromboembolism refrain from using estrogen-containing contraception and hormone replacement therapy [30].
Following an unprovoked venous thromboembolism event, the evidence favors long-term anticoagulation over short-term anticoagulation as secondary prophylaxis, although the duration has not been established but may be extended indefinitely if the risk of bleeding permits [31].
As a therapeutic agent, any direct oral anticoagulant can be used, as this is in line with the latest guidelines for the management of thromboembolism and the conclusion of several studies [29].
Carriers of heterozygous mutations, in the absence of other risk factors, do not require anticoagulation as primary prophylaxis [32].
After a first episode of deep vein thrombosis and/or pulmonary embolism associated with a reversible risk factor, it is recommended that the patient undergo anticoagulation therapy for at least 3 months, which may continue throughout life in case of recurrence [10, 32].
The initial treatment of venous thromboembolism is direct oral anticoagulation, although not all patient groups are suitable for this therapy, such as patients with antiphospholipid syndrome or extreme bodyweight. LMWH should be given before dabigatran and edoxaban [10, 32].
If treatment with direct oral anticoagulants is not possible, it is recommended to start warfarin therapy concomitantly with LMWH or fondaparinux for at least 5 days, monitoring INR, which should be in the range of 2.0–3.0 [33].
The conclusion from the analysis of patients with factor C and S deficiency is limited by the lack of sufficient data to make specific recommendations, but it is safe to approach these patients from the point of view of venous thromboembolism management [10, 29].
Treatment of the first episode of venous thromboembolism should consist of unfractionated or LMWH for at least 5 days followed by vitamin k antagonists or DOAC for at least 3–6 months. In the presence of other clotting disorders or risk factors for thrombosis, or if the first episode was life-threatening or occurred in multiple sites, anticoagulation may be prolonged indefinitely [13].
Primary prophylaxis with anticoagulant medication has not been shown to be beneficial for asymptomatic patients with no other risk factors, regardless of risk profile. Instead, some authors suggest daily administration of a low dose of aspirin, but this measure is not widely accepted. If other risk factors for thrombosis are associated, such as hospitalization, surgery, or concomitant autoimmune disease, prophylaxis is recommended, on a case-by-case basis [16, 34].
Secondary prophylaxis is recommended for patients with definite antiphospholipid syndrome and consists of lifelong vitamin K antagonist medication with a target INR of 2–3. In case of relapse or episodes of arterial thrombosis, the target INR should be >3. Combination with aspirin is not supported by data and is subject to controversy [16, 35].
The use of DOAC in patients with the definite antiphospholipid syndrome is not recommended, following the results of several studies that found direct oral anticoagulation to have a lower efficacy and safety profile than traditional vitamin K antagonist therapy [36].
Primary thromboprophylaxis of ambulatory cancer patients should be decided according to the individual risk of bleeding, the type of cancer, or the stage of the disease [37]. For hospitalized patients without acute venous thromboembolism or a history of venous thromboembolism, the American Society of Hematology recommends thromboprophylaxis with low molecular weight heparin, but only for the duration of the hospital stay. If during hospitalization a patient has undergone surgery or if a patient is receiving outpatient systemic chemotherapy and is at high risk of thrombosis, continued administration of LMWH has been shown to be beneficial. Oral anticoagulation, in the form of vitamin K antagonists or DOAC, is not included in current guidelines because there is insufficient data on its efficacy [38].
For a patient with active cancer who develops venous thromboembolism, initial treatment can be with either LMWH or DOAC, the latter being the medication of choice. It is recommended to continue treatment for at least 3–6 months, which may be extended as a secondary prophylactic measure in patients with active cancer and/or recurrence of venous thromboembolism. Direct oral anticoagulation remains the first choice of treatment in this case as well [38].
In a cancer patient with visceral or splanchnic venous thrombosis, according to the guidelines, treatment should consist of short-term anticoagulation (3–6 months) or clinical observation [38].
Despite the prothrombotic status of physiological changes occurring during pregnancy, prophylactic anticoagulation of asymptomatic patients with no history of venous thromboembolism should be judged on a case-by-case basis [21, 39].
Anticoagulation for a venous thromboembolism event should be with LMWH if occurring before the 36th week of pregnancy and should be switched to unfractionated heparin afterward to minimize complications of epidural anesthesia. Vitamin K antagonists are not recommended after the first trimester as they are known to cause “warfarin embryopathy.” Direct oral anticoagulation is also not approved for administration during pregnancy [21, 40].
Following an episode of venous thromboembolism, anticoagulation should be continued for 3–6 months, or 4–6 weeks postpartum, with either low molecular dose heparin or unfractionated heparin [21].
Patients with antiphospholipid syndrome and a history of thrombotic complications during previous pregnancies may benefit from prophylactic anticoagulation during pregnancy and for an additional 6 weeks postpartum [34].
Anticoagulation management of patients with Covid-19 depends on the severity of the disease. The administration of unfractionated heparin to patients hospitalized in an uncritical state has been observed to reduce the need for intensive care maneuvers, such as specific organ support or intubation, and also reduces the death rate. On the other hand, the condition of critically ill patients has not been improved by heparin treatment, and heparin treatment actually increases the rate of complications and is subsequently not recommended.[41].
After discharge, patients with high thrombotic risk and a low bleeding risk could benefit from low-dose rivaroxaban treatment for an optimal duration to be determined [41].
A hypercoagulable state increases the patient’s risk of developing arterial or venous thrombosis with subsequent complications. Venous thromboembolism is much more common, places a greater financial burden on health systems and therefore more data are available for its management.
Venous thromboembolism is now considered a multifaceted condition, usually resulting from the interaction of inherited and acquired risk factors, with different penetration in the general population and also with distinct risk profiles.
In terms of treatment, primary anticoagulant prophylaxis is recommended only for selected cases, while most patients require no treatment other than minimization of modifiable risk factors.
For the treatment of a first thrombotic event, secondary prophylaxis or relapse, anticoagulation is recommended. Although most episodes of a first thrombosis episode, especially when transient risk factors are identified, require short-term anticoagulation (3–6 months), there are cases where long-term (>6 months) or even indefinite anticoagulation may be given.
When choosing appropriate therapy, a large number of factors must be weighed, such as patient education, preference, and compliance for certain drugs, their availability for long-term follow-up, the financial burden of some therapies, or quality of life, for example when choosing between parenteral and oral treatment.
For patients with venous thromboembolism, the modern approved and guideline-supported treatment is DOAC, with superior efficacy and safety, and quality of life profiles compared to traditional vitamin K antagonist therapy. However, a limitation of DOAC is for the treatment of patients with high-risk antiphospholipid syndrome, where, in a recent study, DOAC showed no efficacy benefit but a higher risk compared to warfarin treatment.
Even though DOAC is finding an increasing number of indications, further research is needed to fully understand what is the best drug choice for each patient, for each condition, for the dose needed, for the duration of treatment, and for follow-up.
In conclusion, hypercoagulable conditions develop as a result of numerous individual or coexisting genetic or acquired risk factors that may be present and induce a higher risk for the patient to develop thrombotic complications. To prevent them, asymptomatic patients may have to undergo anticoagulant treatment in selected cases. For initial treatment and prevention of relapses, the modern and most recommended treatment is with direct anticoagulants, except for patients with high-risk antiphospholipid syndrome.
"Open access contributes to scientific excellence and integrity. It opens up research results to wider analysis. It allows research results to be reused for new discoveries. And it enables the multi-disciplinary research that is needed to solve global 21st century problems. Open access connects science with society. It allows the public to engage with research. To go behind the headlines. And look at the scientific evidence. And it enables policy makers to draw on innovative solutions to societal challenges".
\n\nCarlos Moedas, the European Commissioner for Research Science and Innovation at the STM Annual Frankfurt Conference, October 2016.
",metaTitle:"About Open Access",metaDescription:"Open access contributes to scientific excellence and integrity. It opens up research results to wider analysis. It allows research results to be reused for new discoveries. And it enables the multi-disciplinary research that is needed to solve global 21st century problems. Open access connects science with society. It allows the public to engage with research. To go behind the headlines. And look at the scientific evidence. And it enables policy makers to draw on innovative solutions to societal challenges.\n\nCarlos Moedas, the European Commissioner for Research Science and Innovation at the STM Annual Frankfurt Conference, October 2016.",metaKeywords:null,canonicalURL:"about-open-access",contentRaw:'[{"type":"htmlEditorComponent","content":"The Open Access publishing movement started in the early 2000s when academic leaders from around the world participated in the formation of the Budapest Initiative. They developed recommendations for an Open Access publishing process, “which has worked for the past decade to provide the public with unrestricted, free access to scholarly research—much of which is publicly funded. Making the research publicly available to everyone—free of charge and without most copyright and licensing restrictions—will accelerate scientific research efforts and allow authors to reach a larger number of readers” (reference: http://www.budapestopenaccessinitiative.org)
\\n\\nIntechOpen’s co-founders, both scientists themselves, created the company while undertaking research in robotics at Vienna University. Their goal was to spread research freely “for scientists, by scientists’ to the rest of the world via the Open Access publishing model. The company soon became a signatory of the Budapest Initiative, which currently has more than 1000 supporting organizations worldwide, ranging from universities to funders.
\\n\\nAt IntechOpen today, we are still as committed to working with organizations and people who care about scientific discovery, to putting the academic needs of the scientific community first, and to providing an Open Access environment where scientists can maximize their contribution to scientific advancement. By opening up access to the world’s scientific research articles and book chapters, we aim to facilitate greater opportunity for collaboration, scientific discovery and progress. We subscribe wholeheartedly to the Open Access definition:
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\\n\\nOAI-PMH
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\\n\\nLicense
\\n\\nBook chapters published in edited volumes are distributed under the Creative Commons Attribution 3.0 Unported License (CC BY 3.0). IntechOpen upholds a very flexible Copyright Policy. There is no copyright transfer to the publisher and Authors retain exclusive copyright to their work. All Monographs/Compacts are distributed under the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). Read more
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\\n\\nAll scientific works are Peer Reviewed prior to publishing. Read more
\\n\\nOA Publishing Fees
\\n\\nThe Open Access publishing model employed by IntechOpen eliminates subscription charges and pay-per-view fees, enabling readers to access research at no cost. In order to sustain operations and keep our publications freely accessible we levy an Open Access Publishing Fee for manuscripts, which helps us cover the costs of editorial work and the production of books. Read more
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\\n\\nIntechOpen is committed to ensuring the long-term preservation and the availability of all scholarly research we publish. We employ a variety of means to enable us to deliver on our commitments to the scientific community. Apart from preservation by the Croatian National Library (for publications prior to April 18, 2018) and the British Library (for publications after April 18, 2018), our entire catalogue is preserved in the CLOCKSS archive.
\\n\\nOpen Science is transparent and accessible knowledge that is shared and developed through collaborative networks.
\\n\\nOpen Science is about increased rigour, accountability, and reproducibility for research. It is based on the principles of inclusion, fairness, equity, and sharing, and ultimately seeks to change the way research is done, who is involved and how it is valued. It aims to make research more open to participation, review/refutation, improvement and (re)use for the world to benefit.
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The Open Access publishing movement started in the early 2000s when academic leaders from around the world participated in the formation of the Budapest Initiative. They developed recommendations for an Open Access publishing process, “which has worked for the past decade to provide the public with unrestricted, free access to scholarly research—much of which is publicly funded. Making the research publicly available to everyone—free of charge and without most copyright and licensing restrictions—will accelerate scientific research efforts and allow authors to reach a larger number of readers” (reference: http://www.budapestopenaccessinitiative.org)
\n\nIntechOpen’s co-founders, both scientists themselves, created the company while undertaking research in robotics at Vienna University. Their goal was to spread research freely “for scientists, by scientists’ to the rest of the world via the Open Access publishing model. The company soon became a signatory of the Budapest Initiative, which currently has more than 1000 supporting organizations worldwide, ranging from universities to funders.
\n\nAt IntechOpen today, we are still as committed to working with organizations and people who care about scientific discovery, to putting the academic needs of the scientific community first, and to providing an Open Access environment where scientists can maximize their contribution to scientific advancement. By opening up access to the world’s scientific research articles and book chapters, we aim to facilitate greater opportunity for collaboration, scientific discovery and progress. We subscribe wholeheartedly to the Open Access definition:
\n\n“By “open access” to [peer-reviewed research literature], we mean its free availability on the public internet, permitting any users to read, download, copy, distribute, print, search, or link to the full texts of these articles, crawl them for indexing, pass them as data to software, or use them for any other lawful purpose, without financial, legal, or technical barriers other than those inseparable from gaining access to the internet itself. The only constraint on reproduction and distribution, and the only role for copyright in this domain, should be to give authors control over the integrity of their work and the right to be properly acknowledged and cited” (reference: http://www.budapestopenaccessinitiative.org)
\n\nOAI-PMH
\n\nAs a firm believer in the wider dissemination of knowledge, IntechOpen supports the Open Access Initiative Protocol for Metadata Harvesting (OAI-PMH Version 2.0). Read more
\n\nLicense
\n\nBook chapters published in edited volumes are distributed under the Creative Commons Attribution 3.0 Unported License (CC BY 3.0). IntechOpen upholds a very flexible Copyright Policy. There is no copyright transfer to the publisher and Authors retain exclusive copyright to their work. All Monographs/Compacts are distributed under the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). Read more
\n\nPeer Review Policies
\n\nAll scientific works are Peer Reviewed prior to publishing. Read more
\n\nOA Publishing Fees
\n\nThe Open Access publishing model employed by IntechOpen eliminates subscription charges and pay-per-view fees, enabling readers to access research at no cost. In order to sustain operations and keep our publications freely accessible we levy an Open Access Publishing Fee for manuscripts, which helps us cover the costs of editorial work and the production of books. Read more
\n\nDigital Archiving Policy
\n\nIntechOpen is committed to ensuring the long-term preservation and the availability of all scholarly research we publish. We employ a variety of means to enable us to deliver on our commitments to the scientific community. Apart from preservation by the Croatian National Library (for publications prior to April 18, 2018) and the British Library (for publications after April 18, 2018), our entire catalogue is preserved in the CLOCKSS archive.
\n\nOpen Science is transparent and accessible knowledge that is shared and developed through collaborative networks.
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\n\nOpen Science refers to doing traditional science with more transparency involved at various stages, for example by openly sharing code and data. It implies a growing set of practices - within different disciplines - aiming at:
\n\nWe aim at improving the quality and availability of scholarly communication by promoting and practicing:
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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. 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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. 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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. 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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. 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Her research interests include archaea metabolism, enzymes purification and characterization, gene regulation, carotenoids and bioplastics production, antioxidant\ncompounds, waste water treatments, and brines bioremediation.\nRosa María’s other roles include editorial board member for several journals related\nto biochemistry, reviewer for more than 60 journals (biochemistry, molecular biology, biotechnology, chemistry and microbiology) and president of several organizing committees in international meetings related to the N-cycle or respiratory processes.",institutionString:null,institution:{name:"University of Alicante",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"15",title:"Chemical Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/15.jpg",isOpenForSubmission:!0,editor:{id:"441442",title:"Dr.",name:"Şükrü",middleName:null,surname:"Beydemir",slug:"sukru-beydemir",fullName:"Şükrü Beydemir",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003GsUoIQAV/Profile_Picture_1634557147521",biography:"Dr. Şükrü Beydemir obtained a BSc in Chemistry in 1995 from Yüzüncü Yıl University, MSc in Biochemistry in 1998, and PhD in Biochemistry in 2002 from Atatürk University, Turkey. 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