Risk factors for increased mortality in PPCM.
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These books synthesize perspectives of renowned scientists from the world’s most prestigious institutions - from Fukushima Renewable Energy Institute in Japan to Stanford University in the United States, including Columbia University (US), University of Sidney (AU), University of Miami (USA), Cardiff University (UK), and many others.
\\n\\nThis collaboration embodied the true essence of Open Access by simplifying the approach to OA publishing for Academic editors and authors who contributed their research and allowed the new research to be made available free and open to anyone anywhere in the world.
\\n\\nTo celebrate the 50 books published, we have gathered them at one location - just one click away, so that you can easily browse the subjects of your interest, download the content directly, share it or read online.
\\n\\n\\n\\n\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'
IntechOpen and Knowledge Unlatched formed a partnership to support researchers working in engineering sciences by enabling an easier approach to publishing Open Access content. Using the Knowledge Unlatched crowdfunding model to raise the publishing costs through libraries around the world, Open Access Publishing Fee (OAPF) was not required from the authors.
\n\nInitially, the partnership supported engineering research, but it soon grew to include physical and life sciences, attracting more researchers to the advantages of Open Access publishing.
\n\n\n\nThese books synthesize perspectives of renowned scientists from the world’s most prestigious institutions - from Fukushima Renewable Energy Institute in Japan to Stanford University in the United States, including Columbia University (US), University of Sidney (AU), University of Miami (USA), Cardiff University (UK), and many others.
\n\nThis collaboration embodied the true essence of Open Access by simplifying the approach to OA publishing for Academic editors and authors who contributed their research and allowed the new research to be made available free and open to anyone anywhere in the world.
\n\nTo celebrate the 50 books published, we have gathered them at one location - just one click away, so that you can easily browse the subjects of your interest, download the content directly, share it or read online.
\n\n\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:"2277",leadTitle:null,fullTitle:"Applications of Virtual Reality",title:"Applications of Virtual Reality",subtitle:null,reviewType:"peer-reviewed",abstract:"Information Technology is growing rapidly. With the birth of high-resolution graphics, high-speed computing and user interaction devices Virtual Reality has emerged as a major new technology in the mid 90es, last century. \nVirtual Reality technology is currently used in a broad range of applications. The best known are games, movies, simulations, therapy. From a manufacturing standpoint, there are some attractive applications including training, education, collaborative work and learning. \nThis book provides an up-to-date discussion of the current research in Virtual Reality and its applications. It describes the current Virtual Reality state-of-the-art and points out many areas where there is still work to be done. We have chosen certain areas to cover in this book, which we believe will have potential significant impact on Virtual Reality and its applications. \nThis book provides a definitive resource for wide variety of people including academicians, designers, developers, educators, engineers, practitioners, researchers, and graduate students.",isbn:null,printIsbn:"978-953-51-0583-1",pdfIsbn:"978-953-51-5688-8",doi:"10.5772/2667",price:119,priceEur:129,priceUsd:155,slug:"applications-of-virtual-reality",numberOfPages:224,isOpenForSubmission:!1,isInWos:1,isInBkci:!1,hash:"1984848a9c90105b49dc6d3662c189e9",bookSignature:"Cecilia Sik Lanyi",publishedDate:"May 2nd 2012",coverURL:"https://cdn.intechopen.com/books/images_new/2277.jpg",numberOfDownloads:28953,numberOfWosCitations:23,numberOfCrossrefCitations:14,numberOfCrossrefCitationsByBook:1,numberOfDimensionsCitations:20,numberOfDimensionsCitationsByBook:3,hasAltmetrics:0,numberOfTotalCitations:57,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"May 5th 2011",dateEndSecondStepPublish:"June 2nd 2011",dateEndThirdStepPublish:"October 7th 2011",dateEndFourthStepPublish:"November 6th 2011",dateEndFifthStepPublish:"March 5th 2012",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6,7",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"106377",title:"Dr.",name:"Cecília",middleName:null,surname:"Sik Lányi",slug:"cecilia-sik-lanyi",fullName:"Cecília Sik Lányi",profilePictureURL:"https://mts.intechopen.com/storage/users/106377/images/2769_n.jpg",biography:'Dr. Cecília Sik Lányi studied Mathematics and Computer Science (B.S. and M.S.) at the József Attila University (1981 and 1984). She became a Teacher of Mathematics at the Berzsenyi Dániel Teacher Training College in 1988. Dr. Lányi obtained the Dr. Univ. degree at the University of Veszprém, Hungary in Physical-chemistry (1993), and the Ph.D. degree at the University of Veszprém, Hungary in Computer Science (2000). She has worked as a software engineer and as an associate professor for program languages at the University of Pannonia.\nCurrently, she is focused on virtual reality and its application, user interface design, computer graphics for informatics engineering students and using multimedia in the education for teacher training courses. Ph.D. and Masters’ supervision has an emphasis on multimedia/ virtual reality for the rehabilitation of children with disabilities and patients with mental health issues. She has supervised altogether 180 BSc and MSc thesis works from 1997. Her students received numerous awards.\nDr. Lányi received several awards, the most important ones are: “Master teacher” award of the Hungarian Ministry of Education (2001), the \\"Kalmar\\" award from the John von Neumann Computer Society (2016), the “Hungarian Higher Education Plague” of the Ministry of Human Capacities (2016), the “Diamond-Award from the Association for the Advancement of Assistive Technology in Europe (2015), which is a personal recognition, granted for outstanding work in advancing assistive technology in Europe and the “King Salman Award for Disability Research” of the King Salman Center for Disability Research (2018).\nShe was the secretariat manager of EDeAN in 2009 and the representative of Hungary in IFIP Technical Committee 13: Human-Computer Interaction (TC13) in the period of 2008-2018. She has published more than 400 refereed articles and conference papers and worked as a guest editor for many renowned journals.',institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"3",institution:{name:"University of Pannonia",institutionURL:null,country:{name:"Hungary"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"573",title:"Virtual Computer System",slug:"virtual-computer-system"}],chapters:[{id:"36536",title:"Virtual Design of Piston Production Line",doi:"10.5772/36247",slug:"changing-skills-in-changing-environments-skills-needed-in-virtual-construction-teams",totalDownloads:5902,totalCrossrefCites:7,totalDimensionsCites:10,hasAltmetrics:0,abstract:null,signatures:"Zhou Jun, Li Puhong, Zhang Yanliang, Deng Jianxin and Liu Zhanqiang",downloadPdfUrl:"/chapter/pdf-download/36536",previewPdfUrl:"/chapter/pdf-preview/36536",authors:[{id:"107626",title:"Prof.",name:"Zhou",surname:"Jun",slug:"zhou-jun",fullName:"Zhou Jun"},{id:"115896",title:"Ms.",name:"Li",surname:"Puhong",slug:"li-puhong",fullName:"Li Puhong"},{id:"115897",title:"Prof.",name:"Deng",surname:"Jianxin",slug:"deng-jianxin",fullName:"Deng Jianxin"},{id:"138604",title:"Mr.",name:"Zhang",surname:"Yanliang",slug:"zhang-yanliang",fullName:"Zhang Yanliang"},{id:"138605",title:"Prof.",name:"Liu",surname:"Zhanqiang",slug:"liu-zhanqiang",fullName:"Liu Zhanqiang"}],corrections:null},{id:"36537",title:"Changing Skills in Changing Environments: Skills Needed in Virtual Construction Teams",doi:"10.5772/36893",slug:"human-visual-field-and-navigational-strategies",totalDownloads:2770,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:null,signatures:"Willy Sher, Sue Sherratt, Anthony Williams and Rod Gameson",downloadPdfUrl:"/chapter/pdf-download/36537",previewPdfUrl:"/chapter/pdf-preview/36537",authors:[{id:"110321",title:"Mr.",name:"Willy",surname:"Sher",slug:"willy-sher",fullName:"Willy Sher"},{id:"112448",title:"Dr.",name:"Sue",surname:"Sherratt",slug:"sue-sherratt",fullName:"Sue Sherratt"},{id:"112450",title:"Dr.",name:"Anthony",surname:"Williams",slug:"anthony-williams",fullName:"Anthony Williams"},{id:"112451",title:"Dr.",name:"Rod",surname:"Gameson",slug:"rod-gameson",fullName:"Rod Gameson"}],corrections:null},{id:"36538",title:"Virtual Garment Creation",doi:"10.5772/35928",slug:"virtual-worlds-as-an-extended-classroom",totalDownloads:6677,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:null,signatures:"Ausma Viļumsone and Inga Dāboliņa",downloadPdfUrl:"/chapter/pdf-download/36538",previewPdfUrl:"/chapter/pdf-preview/36538",authors:[{id:"106393",title:"Prof.",name:"Ausma",surname:"Vilumsone",slug:"ausma-vilumsone",fullName:"Ausma Vilumsone"},{id:"136196",title:"Dr.",name:"Inga",surname:"Dabolina",slug:"inga-dabolina",fullName:"Inga Dabolina"}],corrections:null},{id:"36539",title:"Human Visual Field and Navigational Strategies",doi:"10.5772/36837",slug:"3d-multi-user-learning-environment-management-an-exploratory-study-on-student-engagement-with-the-le",totalDownloads:1843,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:null,signatures:"J. 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Is food also medicine? Are products that intend to cure diseases medicinal products and not food? Do we know the combination of foods or food components with functional properties that can help promote the well-being or reduce the risk of chronic diseases? In general terms, all foods are functional because they provide the nutrients necessary for a healthy diet. So what are the components that functional foods have beyond their nutrition value? What is the definition of functional foods? What scientific research is needed to validate health claims for functional foods? This book will provide answers to all of these questions. It is important for scientists to have the opportunities to study the relationship between a food type or a food active component and the improved state of health or reduction of diseases. The communication of health benefits to consumers is of critical importance so that they have the knowledge to make informed choices about the foods they eat and enjoy.',isbn:"978-1-83881-150-1",printIsbn:"978-1-83881-149-5",pdfIsbn:"978-1-83881-151-8",doi:"10.5772/intechopen.73983",price:119,priceEur:129,priceUsd:155,slug:"functional-foods",numberOfPages:132,isOpenForSubmission:!1,isSalesforceBook:!1,hash:"8023d990ea5254d039f9c438b66899c6",bookSignature:"Vasiliki Lagouri",publishedDate:"October 23rd 2019",coverURL:"https://cdn.intechopen.com/books/images_new/7183.jpg",keywords:null,numberOfDownloads:10046,numberOfWosCitations:12,numberOfCrossrefCitations:16,numberOfDimensionsCitations:39,numberOfTotalCitations:67,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"March 28th 2018",dateEndSecondStepPublish:"May 2nd 2018",dateEndThirdStepPublish:"July 1st 2018",dateEndFourthStepPublish:"September 19th 2018",dateEndFifthStepPublish:"November 18th 2018",remainingDaysToSecondStep:"4 years",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:"Edited by",kuFlag:!1,biosketch:null,coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"232589",title:"Dr.",name:"Vasiliki",middleName:null,surname:"Lagouri",slug:"vasiliki-lagouri",fullName:"Vasiliki Lagouri",profilePictureURL:"https://mts.intechopen.com/storage/users/232589/images/system/232589.jpeg",biography:"Vasiliki Lagouri BA MSc PhD received her three degrees from Aristotle University of Thessaloniki and National and Kapodistrian University of Athens, Greece. She has research and academic experience (1992-2019) at the Chemistry Department of Aristotle University of Thessaloniki, Food Technology Department in Technological Educational Institute of Thessaloniki, Post doc positions in the Department of Organic Chemistry, Faculty of Chemistry and Department of Pharmacognosy and Chemistry of Natural Products, Faculty of Pharmacy, School of Health Sciences at National and Kapodistrian University of Athens. Her current position is Project Manager in National Hellenic Research Foundation (NHRF), Institute of Chemical Biology (ICB). \r\nShe has over 30 of publications in International Journals, Conference Proceedings and 3 Book authorships and editorships in food chemistry, natural antioxidants, and olive oil and olives as functional foods (number of citations more than 400). She has research experience on experimental designs and applications of different methods to study the chemistry of natural sources, the isolation, identification and quantification of biologically active polar and non-polar compounds. She offered her services as a reviewer for the Journals: International Journal of Food properties, Journal of the Science of Food and Agriculture, Central European Journal of Chemistry, Separation Science and Technology, Natural Products Research, Nutrients, Molecules. She is a member of the American Chemical Society, Society Free-Radical Research-Europe (SFRR-E), Oxygen Club of California (OCC), ISEKI-Food Association: European Association for Integrating Food Science and Engineering Knowledge Into the Food Chain and the Greek Chemist’s Union and she is included in Who’s Who of America.",institutionString:"National Hellenic Research Foundation",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"National Hellenic Research Foundation",institutionURL:null,country:{name:"Greece"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"323",title:"Food and Nutrition",slug:"food-and-nutrition"}],chapters:[{id:"64524",title:"Introductory Chapter: Functional Foods",slug:"introductory-chapter-functional-foods",totalDownloads:1020,totalCrossrefCites:2,authors:[{id:"232589",title:"Dr.",name:"Vasiliki",surname:"Lagouri",slug:"vasiliki-lagouri",fullName:"Vasiliki Lagouri"}]},{id:"63575",title:"Olive Oil: Antioxidant Compounds and Their Potential Effects over Health",slug:"olive-oil-antioxidant-compounds-and-their-potential-effects-over-health",totalDownloads:2153,totalCrossrefCites:2,authors:[{id:"248097",title:"Ph.D.",name:"Seray",surname:"Kabaran",slug:"seray-kabaran",fullName:"Seray Kabaran"}]},{id:"64324",title:"Olive Oil Phenols",slug:"olive-oil-phenols",totalDownloads:1399,totalCrossrefCites:4,authors:[{id:"258502",title:"Ph.D.",name:"Christos",surname:"Papanikolaou",slug:"christos-papanikolaou",fullName:"Christos Papanikolaou"},{id:"267135",title:"Prof.",name:"Prokopios",surname:"Magiatis",slug:"prokopios-magiatis",fullName:"Prokopios Magiatis"},{id:"267136",title:"Dr.",name:"Eleni",surname:"Melliou",slug:"eleni-melliou",fullName:"Eleni Melliou"}]},{id:"63677",title:"Functional Properties of Snack Bars",slug:"functional-properties-of-snack-bars",totalDownloads:2133,totalCrossrefCites:2,authors:[{id:"252951",title:"Dr.",name:"Daniela",surname:"Istrati",slug:"daniela-istrati",fullName:"Daniela Istrati"},{id:"253109",title:"Associate Prof.",name:"Oana",surname:"Constantin",slug:"oana-constantin",fullName:"Oana Constantin"}]},{id:"63516",title:"Fermented Functional Beverages",slug:"fermented-functional-beverages",totalDownloads:1207,totalCrossrefCites:1,authors:[{id:"252951",title:"Dr.",name:"Daniela",surname:"Istrati",slug:"daniela-istrati",fullName:"Daniela Istrati"},{id:"252503",title:"Prof.",name:"Camelia",surname:"Vizireanu",slug:"camelia-vizireanu",fullName:"Camelia Vizireanu"},{id:"253118",title:"Dr.",name:"Eugenia",surname:"Pricop",slug:"eugenia-pricop",fullName:"Eugenia Pricop"},{id:"253119",title:"Dr.",name:"Alina",surname:"Profir",slug:"alina-profir",fullName:"Alina Profir"}]},{id:"65354",title:"Fish as an Important Functional Food for Quality Life",slug:"fish-as-an-important-functional-food-for-quality-life",totalDownloads:1243,totalCrossrefCites:5,authors:[{id:"253367",title:"Dr.",name:"Dr",surname:"Hei",slug:"dr-hei",fullName:"Dr Hei"},{id:"258615",title:"Prof.",name:"Ch",surname:"Sarojnalini",slug:"ch-sarojnalini",fullName:"Ch Sarojnalini"}]},{id:"64935",title:"Instant Controlled Pressure-Drop DIC as a Strategic Technology for Different Types of Natural Functional Foods",slug:"instant-controlled-pressure-drop-dic-as-a-strategic-technology-for-different-types-of-natural-functi",totalDownloads:892,totalCrossrefCites:0,authors:[{id:"22910",title:"Prof.",name:"Abdul Karim Salim",surname:"Allaf",slug:"abdul-karim-salim-allaf",fullName:"Abdul Karim Salim Allaf"},{id:"22911",title:"Ms.",name:"Tamara",surname:"Allaf",slug:"tamara-allaf",fullName:"Tamara Allaf"},{id:"24143",title:"Ms.",name:"Colette",surname:"Besombes",slug:"colette-besombes",fullName:"Colette Besombes"},{id:"258593",title:"Dr.",name:"Sabah",surname:"Mounir",slug:"sabah-mounir",fullName:"Sabah Mounir"},{id:"258680",title:"Dr.",name:"Carmen",surname:"Tellez-Perez",slug:"carmen-tellez-perez",fullName:"Carmen Tellez-Perez"},{id:"258758",title:"Dr.",name:"Maritza",surname:"Alonzo-Macías",slug:"maritza-alonzo-macias",fullName:"Maritza Alonzo-Macías"},{id:"268755",title:"Dr.",name:"Ezzeddine",surname:"Amami",slug:"ezzeddine-amami",fullName:"Ezzeddine Amami"}]}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"220812",firstName:"Lada",lastName:"Bozic",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/220812/images/6021_n.jpg",email:"lada@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. 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Peripartum cardiomyopathy (PPCM) is the heart muscle weakness that begins during the late pregnancy and extending into 5 months in puerperium without any other known etiology. PPCM is a dilated cardiomyopathy and involves systolic dysfunction, decreased left ventricular ejection fraction (EF), and congestive heart failure. There is an increased risk of atrial and ventricular arrhythmias and thromboembolism. PPCM is a diagnosis of exclusion, patients have no prior history of heart disease, and there are no other known possible causes of heart failure (HF). Echocardiogram is essentially used for both diagnosis and monitoring purposes in the progress of PPCM. Although initially described in the 18th century, it was recognized as distinct clinical in 1930, and Demakis et al. described and defined PPCM [1]. PPCM was initially termed as pregnancy-associated cardiomyopathy, toxic postpartum heart failure, Meadows’ syndrome, postpartum myocarditis, and Zaria syndrome.
\nThere are varieties of definitions for PPCM; the more simplified one is by the working group on peripartum cardiomyopathy from the European Society of Cardiology in 2010. It avoids under diagnosis by adopting a broader definition. It contains the following characteristics:
The development of heart failure in last month of pregnancy or up to 5 months in postpartum period
Absence of another known or identifiable cause for heart failure
Systolic dysfunction of left ventricle (LV) and LV ejection fraction of less than 0.45 with or without LV dilatation [2]
PPCM constitutes less than 1% of all cardiovascular events related to pregnancy. It is more common in Africa, 1:300 pregnancies. This may be due to the consumption of kanwa, a tradition, for 40 postpartum days. Kanwa is a dry salt and causes hypervolemia and hypertension. Ninety percent of PPCM occurs within 2 months of delivery [3]. In a recently concluded study about the incidence of PPCM from 43 countries, affecting females from all ethnicity and all continents, the incidence widely differs depending on geographic location. PPCM was common in Nigeria (1100), Haiti (1300), South Africa (11,000), Canada (12,400), and Denmark (110,149) and was lowest in Japan (1,20,000 live births). There are case reports from other countries [4]. Hence the information is not complete as many countries are not having a registry. The higher incidence in Nigeria may be related to abovementioned postpartum high salt intake or may be a genetic factor superimposing the geographic and dietary variabilities [5].
\nThe following are the risk factors for PCCM, even though the etiology of PPCM is still not clear.
Age over 30 years, pregnancy with multiple fetuses [6].
Multiparty, African descent [7].
Maternal cocaine abuse [8].
Long-term tocolytic therapy [9].
History of preeclampsia, eclampsia, or peripartum hypertension, the hypertensive disorders of pregnancy are significant predispose for PPCM, and the preeclampsia patient is four times more susceptible for developing PPCM [10].
In the pathology of peripartum cardiomyopathy, the macroscopic view is a pale myocardium, dilated heart often with intramural thrombus in the ventricles. There will be endocardial thickening and pericardial effusion. The myocardial cellular hypertrophy and myofibril degeneration with areas of fibrosis with interstitial edema are the nonspecific findings. In a small group of patients, there are features of myocarditis with the presence of inflammatory cell infiltration of myocardium, focal necrosis, variable hypertrophy, and fibrosis of the myocardium [11].
\nAlthough PPCM is a separate clinical entity, the exact etiology of PPCM is still not known. Following hypothesis had been proposed for the etiology.
\nThe familial clustering of PPCM is well known; it could be due to genetic or environmental factors. Ancestry with African genomics may be a risk factor and explains the higher prevalence of PPCM in Haiti, Africa, and black women in other countries. The guanine nucleotide-binding protein beta-3 (GNB3) subunit has a polymorphism called C825T. This polymorphism is associated with an increased risk of hypertension, low plasma renin, and cardiac remodeling. GNB3 has a prevalence of 50% in black individuals compared with 10% in white individuals [12].
\nFirst time Melvin et al. proposed myocarditis as a cause for PPCM. Myocarditis could be viral or autoimmune. With pregnancy there is increased in susceptibility to both. In another study, endomyocardial biopsies in five patients showed features of myocarditis. The reason for lesser positive biopsy report among the studies may be related to small sample size and timing of biopsy with relation to the onset of symptoms. The incidence of inflammation is greater in patients who are biopsied soon after presentation [13, 14]. The proinflammatory-inflammatory cytokines may play a role in the pathogenesis and progression of PPCM, as the cytokines that are elevated in PPCM compared with controls include tumor necrosis factor (TNF)-alpha and interleukin-6 [15].
\nThe entrance of fetal cells into the maternal circulation remains in the circulation without rejection due to weak immunogenic paternal haplotype of chorionic cell. If these cells lodge into the cardiac tissue, immune response may be triggered. The raised titres of immunoglobulins and other autoantibodies in patients with PPCM are suggestive of abnormal immune response, whereas other studies found no significant difference in levels of immunoglobulins and other autoantibodies in PPCM and control group of patients [12, 16].
\nThe hyperdynamic circulation during pregnancy causes remodeling and transient hypertrophy of the left ventricle. The exaggerated reduction in left ventricular systolic function with stress of gestational hypertension may contribute to heart failure in PPCM patients. In pregnancy 40–50% increase in blood volume and cardiac output occurs which results in transient LV hypertrophy. The hemodynamic stress of gestational hypertension, may contribute to the development of PPCM and heart failure, with an angiogenic imbalance may better explain the association between preeclampsia and PPCM [17].
\nHuman and animal studies suggest that PPCM is caused by systemic angiogenic imbalance. Animals that lack cardiac PGC-1α, a regulator of proangiogenic factors such as VEGF, develop severe PPCM. These data may also explain why preeclampsia and multiple gestations are risk factors for PPCM. During late gestation, the human placenta secretes VEGF inhibitors such as soluble fms-like tyrosine kinase 1 (sFlt1), which damages the vasculature, with higher levels seen with multiple gestations or preeclampsia. Preeclampsia and multiple gestations are risk factors for PPCM as in these patients subclinical cardiac dysfunction correlates with sFlt1 levels [18].
\nAlteration in prolactin processing is involved in the pathogenesis of peripartum cardiomyopathy; animal with a knockout in the cardiac tissue-specific signal transduction and activator of transcription 3 (STAT3) developed PPCM. Reduction in STAT3 leads to increased cleavage of prolactin into an anti-angiogenic and proapoptotic 16 kDa isoform by cathepsin D. The 16 kDa prolactin fragment (16K PRL) causes endothelial damage leading to myocardial dysfunction; 16K PRL induces microRNA-146a expression in endothelial cells, which leads to most of the anti-angiogenic effects of 16K PRL. Females with PPCM have elevated levels of microRNA-146a compared with healthy postpartum women or women with other cardiomyopathies (Figure 1) [20].
\nSummary of etiopathogenesis of PPCM (from [
PPCM is common in first postpartum month; it is also rare before 36 weeks of gestation (Figure 2). The common presentations of PPCM are dyspnea, cough, orthopnea, and paroxysmal nocturnal dyspnea, which may be confused with the physiological changes of pregnancy. Initial diagnosis may be delayed since symptoms such as nonspecific fatigue, shortness of breath, and pedal edema are similar to those observed in normal pregnancy The patient may have arrhythmia and even cardiac arrest rarely [4]; PPCM can present with thromboembolic manifestations; patients with left ventricular ejection fraction (LVEF) < 35% are at risk for developing left ventricular thrombus. PPCM is manifested after 38 weeks of pregnancy, whereas pregnant patients with chronic heart disease develop sign and symptoms of heart failure in the second trimester of pregnancy due to stress of hemodynamic overload.
\nPregnancy and occurrence of PPCM [
Signs and symptoms are variable and similar to that in other forms of systolic HF due to cardiomyopathy. Signs include an elevated jugular venous pressure, displaced apical impulse, a third heart sound, and a murmur of mitral regurgitation. Signs and symptoms of systemic or pulmonary thromboembolism may be present. Various studies have reported varying rates of thromboembolism, and further data are required to quantify the risk of this complication. Patients with PPCM left ventricular thrombus were identified by echocardiography in 16 of 100 patients with PPCM (with mean LVEF of 26%) in a case series [2, 21].
\nAs mentioned initially diagnosis of PPCM based on three clinical criteria, development of heart failure in last month of pregnancy or in the initial 5 months following delivery with the absence of another identifiable cause of HF and left ventricular (LV) systolic dysfunction with an left ventricular ejection fraction (LVEF) of < 45%. The last criteria will exclude patients with accelerated hypertension, diastolic dysfunction, systemic infection, pulmonary embolism, or preeclampsia or amniotic fluid embolus. Chest X-ray, electrocardiogram (ECG), and echocardiogram should be performed in patients who are clinically suspected of having PPCM.
\nStudies showed brain natriuretic peptide (BNP) levels, cardiac magnetic resonance (CMR) imaging, cardiac catheterization, and endomyocardial biopsy (EMB) will be helpful in these patients. Bacterial cultures and viral titers are usually not indicated, as these tests are nonspecific and without proven value in patients with myocarditis. The novel markers, plasma concentrations of proangiogenic and anti-angiogenic factors, placenta growth factor, and fms-like tyrosine kinase 1 receptor, have been proposed to be used to distinguish patients with PPCM [22].
\nIt is not specific in PPCM patients and may show sinus tachycardia rarely arrhythmias and nonspecific ST segment and T wave changes. PR and QRS intervals may be prolonged. An ECG is helpful in identifying conditions in the differential diagnosis such as myocardial infarction and pulmonary embolism [1].
\nPlasma BNP or pro-BNP (proBNP) measurement is helpful in the evaluation and diagnosis of patients with heart failure. Patients with PPCM have increased BNP and NT-proBNP levels, higher than seen in healthy women during pregnancy or postpartum.
\nCommonly it will show enlargement of the cardiac silhouette with pulmonary congestion and/or interstitial edema and pleural effusions. However, a chest radiograph is not necessary to make a diagnosis of HF or PPCM and exposes the patient to ionizing radiation.
\nEchocardiogram is essential in the diagnosis of PPCM; it reveals a global reduction in LV systolic function with LVEF of < 45%. Left ventricle is commonly but not always dilated. Assessment of right ventricular systolic pressures can be performed (Figure 3). Echo may show presence of left atrial thrombus, dilated right ventricle, abnormal ventricular wall motion, mitral and tricuspid regurgitation, and pericardial effusion.
\nFour chamber view of PPCM A: Echocardiographic four chamber view of PPCM. B: Echocardiogrhic Mitral regurgitation view of PPCM.
If echocardiography is technically suboptimal, CMR can help. It helps in assessing LV function and LV volumes. Experience with CMR in PPCM is limited and its role is still being evaluated.
\nIt may be helpful in critically ill patients, requiring a complete assessment or ongoing evaluation of their hemodynamic state.
\nIt is required in selected patients in whom it is necessary to evaluate coronary artery disease as a potential cause for the cardiomyopathy. The coronary angiography exposes the patient to ionizing radiation and it is commonly not required in patients with suspected PPCM.
\nEMB is recommended in clinical scenarios in which a biopsy is anticipated to yield a diagnosis of a specific condition with treatment implications. These scenarios include heart failure with hemodynamic compromise of less than 2 weeks duration or heart failure of less than 3 months duration if associated with heart block, new ventricular arrhythmias, or refractory heart failure. EMB is not recommended for the routine evaluation of heart failure, as there are no pathognomonic findings in PPCM. The risk of a serious acute complication is less than 1% using flexible bioptomes.
\nPPCM should be differentiated from other forms of cardiomyopathy (Figure 4), heart failure, pulmonary thromboembolism, severe eclampsia, and pneumonia. From history, in physical examination and investigations, one must exclude myocardial infarction, idiopathic dilated cardiomyopathy, and valvular heart disease [9].
\nFour chamber echocardiographic view showing thrombus in PPCM.
The therapeutic approach of PPCM is the same as for other types of HF with left ventricular systolic dysfunction. Precautions should be taken to ensure the safety of the mother and the unborn or breastfeeding child; these patients may need antiarrhythmic drugs, anticoagulation therapy, mechanical support, and the use of investigational medications (bromocriptine).
\nThe cornerstone in the management of PPCM is to reduce preload and after load and increase the cardiac contractility. Heart failure during pregnancy may be acute or acute on chronic. The pregnant patient with known cardiac disease can present in stable condition during early stages of pregnancy. Careful physical examination should be done. Their management is mainly adjustment of their medication and monitoring for cardiac failure. The initial New York Heart Association functional class status should be documented. Serial ECG and echocardiogram should be performed.
\nPatients presenting heart failure during pregnancy or the peripartum period require a detail history and physical examination and the evaluation of severity of decompensation. An ECG may reveal deteriorating left ventricular functions, arrhythmia, LVH, or arterial abnormality. The therapeutic approach in these patients includes optimizing hemodynamics, reducing after load, optimizing preload, and cardiac contractility. These can be achieved by treatment of pulmonary congestion, control of hyper-/hypotension, treatment of cardiac arrhythmia, and prevention of thromboembolic events.
\nArrhythmias are common in patients hospitalized for PPCM. The occurrence of arterial and ventricular arrhythmias is variable. In one of the studies, 18.7% PPCM patients had an arrhythmia, and ventricular tachycardia was in 4.2% with cardiac arrest in 2.2%. In smaller studies, the reported incidence of ventricular tachycardia was 20 and 25%. The atrial fibrillation was reported to occur in 3.1–11.9% of patients with PPCM [23].
\nVentricular arrhythmias should be treated aggressively in PPCM patients. Class III antiarrythmic medications are the best option. Intravenous medications are needed in PPCM patients admitted to the intensive care therapy unit. Therapy with inotropes such as dobutamine, adrenaline, and milrinone should be directed by invasive cardiac monitoring. While interpreting the invasive hemodynamic monitoring, one should take into account the normal changes that occur during pregnancy. Digoxin is safe to use in pregnancy. Diuretics can be used if salt restriction is not sufficient. Beta-blocker improves left ventricular function in patients of PPCM, but ACE inhibitors are the drugs of choice in postpartum PPCM [24].
\nThe anticoagulation in PPCM is a must as pregnancy itself is a hypercoagulable state, in addition to PPCM, dilatation of heart, and turbulent flow of blood. For pregnant patients requiring anticoagulation, decisions and choosing anticoagulation therapy are challenging due to the risk of bleeding in all stages of pregnancy and the potential teratogenic effects of warfarin in the first trimester, dosage of various agents, and management during labor and delivery. PPCM patients receiving bromocriptine have an increased risk of thromboembolic events; hence, it is suggested to start anticoagulation therapy in patients with PPCM treated with bromocriptine. There is no clear data, but expert suggests anticoagulation for patients with PPCM with acute cardiac thrombus or evidence of systemic embolism. Before delivery unfraction or low-molecular-weight heparin is the choice, whereas in postpartum period warfarin is used.
\nThe decisions to use implantable cardioverter defibrillator (ICD) or cardiac resynchronization therapy in PPCM patients should be taken after a detailed natural history and the potential of recovery of ventricular function. All these therapies should be deferred at least for 3 months and possibly for 6 months of presentation as 20–60% of PPCM patients have complete recovery of left ventricular ejection functions to normal by 6 months to 5 years [25].
\nMechanical circulatory support (MCS) is considered early for PPCM patients who are hemodynamically unstable and unresponsive to medical therapy with maximal inotropic support. A device can be implanted in the acute phase either to work as a bridge-to-recovery and subsequent weaning when the ventricular function improves, or it can be a bridge-to-bridge for implantation of a longer durable device. The bridge-to-transplantation is rarely required as the initial approach as a high proportion of PPCM patients will have recovery of ventricular function. Hence initially a temporary device should be used if required in these patients.
\nSeverely reduced LVEF alone should not be an indication for the use of aggressive therapies (MCS and cardiac transplantation) in PPCM patients. If MCS is indicated, various devices can be used including intra-aortic balloon counterpulsation (IABP), venoarterial extracorporeal membrane oxygenation (ECMO), and LV assist device (LVAD). The choice of device will depend on the hemodynamic status of the patient and local availability and expertise. Venoarterial ECMO has been associated with an increase in prolactin levels, which may be detrimental in PPCM patients [26].
\nLoyaga-Rendon et al. reported that the PPCM patients who received durable mechanical circulatory support had better survival rate than that of females without PPCM with a survival rate of 83% in PPCM. These may be related to PPCM patients who were younger and had fewer comorbidities. The rates of myocardial function recovery were poor, 6% in the PPCM group and 2% in without PPCM [27].
\nAccording to the older literature, the transplantation was performed in up to one-third of PPCM patients, whereas the contemporary reports demonstrate that transplantation rates vary from 4 to 23% of patients [28]. Hence PPCM patients with significant LV systolic dysfunction should be managed at a tertiary center with transplant facilities.
\nIn a large study, it is found that the long-term survival in transplanted PPCM patients was worse compared with all others undergoing transplantation. PPCM patient who received a cardiac transplant had higher mortality, higher incidence of rejection, poorer graft survival, and higher retransplantation rates. Younger patient age, higher allosensitization, higher pretransplant acuity, and increased rejection rates are all important factors for poorer outcomes in these PPCM patients [28].
\nFurther multicenter trial would be valuable to establish if these devices are beneficial; in a single smaller study, it was found to be useful.
\nFollowing therapies are not recommended for PPCM patients as its efficacy and safety have not been established.
\nThe use of bromocriptine therapy in PPCM patients is controversial. The preliminary data have shown a benefit of bromocriptine in PPCM patients, but further studies are needed to establish safety and efficacy; it is suggested not to routinely use bromocriptine in PPCM patients. Its use is based upon experimental animal studies of prevention of PPCM by prolactin blockade with bromocriptine. Smaller and observational reports showed the beneficial response to bromocriptine therapy in patients with PPCM [29].
\nA multicenter study showed that the rate of full recovery (LVEF ≥ 50%) was not significantly higher in the 8-week group compared with the 1-week group. The patients in this trial had better outcomes than observed in prior series, but a placebo control group was not included in the study [30]. One should start anticoagulation in PPCM patients treated with bromocriptine, as the risk of thromboembolic complications.
\nThe advantage of immunosuppressive therapy has been found to be useful in PPCM patients with biopsy-proven myocarditis, but its efficacy is unclear, and empiric immunosuppression in the absence of evidence of a responsive form of myocarditis is not recommended [31]. These medications have significant side effects.
\nThis therapy is tried in patients with myocarditis or newly onset dilated cardiomyopathy with no clear evidence of clinical benefit, and the efficacy of this approach has not been confirmed in any type of myocarditis.
\nIn PPCM patient the risks and benefits of early delivery should be considered and discussed. The 2010 European Society of Cardiology working group statement advised that early delivery is not required if the maternal and fetal conditions are stable. But the patient-related factors, gestational age, cervical status, fetal status, and the potential cardiovascular impact of continuing pregnancy must be considered in timing delivery. The decisions regarding timing and mode of delivery should be based on combined multidisciplinary meeting. In PPCM patients with advanced heart failure, prompt delivery of fetus is indicated for maternal cardiovascular indications and hemodynamic instability. The elective cesarean delivery is preferred for PPCM patients with advanced heart failure requiring inotropic therapy or mechanical circulatory support [12].
\nAccording to the expert group, breastfeeding is to be avoided because of the potential effects of prolactin subfragments, but in a study where PPCM patients chose to breastfeed, none had adverse maternal effects, and that rate of recovery of left ventricular function was significantly higher in lactating women, and accordingly given the benefits of breastfeeding, it is recommended that women who are stable should continue breastfeeding as long as it is compatible with their heart failure medications [32].
\nThe most common complication is thromboembolism. A premature delivery rate of 25% has been reported in cases with PPCM. PPCM cases had increased incidence of cesarean section up to 40% [33].
\nThe overall reported mortality rate in PPCM is better than other cardiomyopathy (Figure 5) patients approximately 10% in 2 years and 11–29% in 3 years [15]. Cardiac transplantation rates of less than 1–2% per year [15]. The mortality in PPCM patient is commonly caused by progressive pump failure, sudden death, or thromboembolic events. The following factors have been shown to increase the mortality in PPCCM patients (Table 1).
\nComparative mortality of cardiomyopathies [
Worse New York Heart Association functional class | \n
Left ventricular ejection fraction (LVEF) ≤ 25% | \n
Black race | \n
Multiparity | \n
Age more than 35 years [35] | \n
Risk factors for increased mortality in PPCM.
PPCM is associated with a significant morbidity including brain injury, cardiopulmonary arrest, fulminant pulmonary edema, thromboembolic complications, an-d defibrillator or pacemaker implantation [36].
\nLower section cesarean delivery was performed in 40% of patients, largely for obstetric indications. Preterm birth was noted in 25 and 5.9% of infants were small for date [37].
\nIn patients who have recovered or not recovered from left ventricular failure due to PPCM, there is a high risk of PPCM in subsequent pregnancy. Termination of pregnancy may not prevent relapse.
\nIn patients who have recovered from left ventricular failure due to PPCM, there is a high risk of PPCM in subsequent pregnancy, and so the best way to avoid PPCM is avoid subsequent pregnancy. The literature suggests that the patient or her partner undergo a sterilization procedure or the patient use a highly effective non-estrogen method of contraception. Though the risk of recurrence appears to be less in PPCM patient with recovered LV function and LVEF > 25%, still these patients should receive counseling, including the option of avoidance of subsequent pregnancy due to the risk of relapse of PPCM, heart failure, and death. There is not much evidence on the safety of contraceptives in PPCM patients; it is advised that the estrogen-progestin contraceptives should be avoided in PPCM patients with persistent LV dysfunction because of their potential to increase the risk of thromboembolism [38].
\nPPCM is a rare but potentially life-threatening disease of pregnancy. PPCM is common in postpartum period. PPCM patient has various risk factor including hypertensive disorders of pregnancy. PPCM patients may present with shortness of breath, arrhythmias, pulmonary edema, and thromboembolic signs and symptoms. Echocardiography will essentially diagnose the PPCM, and it also helps in differential diagnosis. The management of PPCM patients is the management of heart failure with special consideration of fetus. Therapy may involve the use of mechanical devices or even cardiac transplant, but the anticoagulation and antiarrhythmic medication plays an important role in the management. The medical management with bromocriptine, immunosuppression, and immunoglobulin is controversial. Commonly the left ventricular function recovers, but in PCCM the maternal mortality is around 10%, and there is increased incidence of cesarean section. In subsequent pregnancy in patient with PCCM, heart failure may be more severe and may cause death. Family counseling is essential in these patients.
\nThe mechanistic process to establish centromeric chromatin of budding yeast and its structures have been actively studied [1, 2, 3]. In contrast to most eukaryotic centromeres that span megabases of DNA, in the budding yeast,
In
Early studies showed that Scm3 is required for G2/M progression and Cse4 localization at centromeres. Scm3 contains 2 essential protein domains: a Leu-rich nuclear export signals and a heptad repeat domain that is widely conserved in fungi [5, 6, 7, 8, 9, 10, 11]. Localization of Cse4 to centromeres and the assembly activity is dependent on an evolutionarily conserved central core motif in Scm3 [13]. Camahort et al. showed that Scm3 is required throughout the whole cell cycle as well as the loading period for Cse4 [5, 14]. Consistent with these findings, Xiao et al. showed that Scm3 has an N-terminal nonspecific DNA binding domain for AT-rich DNA and a central histone chaperone domain (Cse4/H4 binding domain, CBD) that promotes specific loading of Cse4/H4 [15]. Moreover, Xiao et al. demonstrated that Scm3-GFP is enriched at centromeres in all cell cycle phases in live cells, and their results of ChIP analysis showed that Scm3 occupies centromere DNA throughout the cell cycle, even when Cse4 and H4 are temporarily dislodged in the S phase, suggesting Scm3 is a critical factor for recruitment of Cse4/H4 as well as maintenance of an H2A/H2B-deficient centromeric nucleosome [15]. Luconi et al. showed that Scm3 signals are present at centromeres when metaphase begins, and enriched in anaphase [14, 16] as observed for Scm3 in fission yeast
Currently, the structure of budding yeast centromeric CENP-ACse4-containing nucleosomes remains controversial among different research groups as in other species [17]. Dechassa et al. performed structural analysis and showed that the substitution of H3 with Cse4 results in octameric nucleosomes that organize DNA in a left-handed superhelix [18]. Cse4-nucleosomes exhibit an open conformation with weakly bound terminal DNA segments and do not preferentially form nucleosomes on its cognate centromeric DNA. The Cse4-specific octameric nucleosomes do not contain Scm3 as a stably bound component. Cho et al. reported the structure of a complex formed by an N-terminal fragment of Scm3 with the histone-fold domains of Cse4, and H4, which were all purified from the budding yeast
Mechanistic scheme for
Recently, the importance of centromeric long non-coding RNA (cenRNA) for centromere integrity has been suggested in various species [35, 36, 37] including budding yeast [38, 39, 40]. Ling et al. reported that all the budding yeast centromere express long noncoding RNAs (cenRNAs), especially in S phase and induction of cenRNAs coincides with Cse4 loading time and is dependent on DNA replication [38]. The cenRNA is tightly regulated and repressed by the kinetochore protein Cbf1 and histone H2A variant H2A.ZHtz1, and de-repressed during the S phase of the cell cycle, suggesting that an appropriate level of cenRNAs is essential for point centromere activity [38]. Interestingly, when they knocked down all cenRNAs from the endogenous chromosomes, but not the cenRNA from the circular minichromosome, they still observed an increase in minichromosome loss, suggesting that cenRNA functions in trans to regulate centromere activity. Chen et al. independently demonstrated that budding yeast cenRNA is negatively regulated by Cbf1 and binding of the Pif1 DNA helicase to the centromeres, which happens in mid–late S phase, occurred at about the same time as Cbf1 loss from the centromere [40]. These data suggest that Pif1 may facilitate this loss by its known ability to displace proteins from DNA. Ling et al. further showed that budding yeast cenRNAs are cryptic unstable transcripts (CUTs) that can be degraded by the nuclear RNA decay pathway suggesting that cenRNA can serve important cellular functions when it exists at the right time with the right level [39]. Together, these results in budding yeast indicate that the regulation of cenRNA is an essential factor for centromere structure and function.
CENP-A (CenH3) proteolysis has also been reported in senescent human cells [41] or upon infection with herpes simplex virus 1 [42]. However, little had been known about the actual mechanisms that regulate CENP-A (CenH3) proteolysis. Collins et al. initially reported that the levels of the budding yeast CenH3, Cse4, are regulated by ubiquitin-proteasome-mediated proteolysis in 2004 [43]. They isolated a dominant lethal mutant,
lo | CENP-A homolog | E3 ligase (ubiquitylation or sumoylation) | Function | Preceding PTMs before ubiquitylation or sumoylation | Other proposed factor relevant to E3 function |
---|---|---|---|---|---|
Cse4 | Psh1 (ubiquitylation) | Proteasomal degradation to remove non-centromeric CENP-A | P134 isomerization by Fpr3 | Scm3, Snf2, Doa1, Fpr3, Spt16. Phosphorylation of Psh1 by Cka2, Pat1, Histone H4-R36, Gene dosage of histone H4 (HHF1 and HHF2), CAF-1, Hir2, Cdc7, Ubp8 (deubiquitylation, SAGA-DUB), Cse4 MIMAS motif | |
Slx5/8 (vertebrate RNF4)(ubiquitylation) | Proteasomal degradation to remove non-centromeric CENP-A (Slx5-mediated Cse4 proteolysis could be independent of Psh1) | K65 sumoylation by Siz1/2 | K65 sumoylation by Siz1/2 | ||
Siz1/2 (sumoylation) | Proteasomal degradation to remove non-centromeric CENP-A | N.D. | N.D. (The effect of SUMO-proteases Ulp2/SENP6, on CenH3 was not confirmed.) | ||
Ubr1, Rcy1 (ubiquitylation) | Proteasomal degradation of Cse4 | N.D. | N.D. | ||
Met30/Cdc4 (ubiquitylation) | Proteasomal degradation of Cse4 (Met30/Cdc4-mediated Cse4 proteolysis could be independent of Psh1) | N.D. | N.D. |
E3 ligase for budding yeast (
Hewawasam et al. performed TAP purification of Psh1 and identified Cse4 as well as several other kinetochore proteins by multidimensional protein identification technology analysis [22]. They described that Psh1 consists of three main domains: (i) a RING finger, (ii) a zinc finger, and (iii) a highly acidic domain [22, 23]. They performed co-immunoprecipitation using whole-cell extracts and showed that the RING finger of Psh1 is important to interact with Cse4. They also performed a pulse-chase assay and demonstrated that both RING and zinc fingers are critical for efficient control of Cse4 levels. They demonstrated the specificity of the ubiquitylation activity of Psh1 toward Cse4 in vitro and identified the sites of ubiquitylation. Mutation of these lysine sites prevents ubiquitylation of Cse4 by Psh1 in vitro and stabilizes Cse4 in vivo. Elimination of the Cse4-specific chaperone Scm3 destabilizes Cse4, and the addition of Scm3 to the Psh1-Cse4 ubiquitylation reaction prevents Cse4 ubiquitylation. Meanwhile, the deletion of Psh1 stabilizes Cse4. These data suggest that Scm3 and Psh1 might compete for binding to Cse4. Cse4 that is not associated with Scm3 may be targeted by Psh1 for proteolysis, but Cse4 in a complex with Scm3 may be protected [23] (Figure 1, right) (see also next chapter, section 4.2). Cse4 overexpression is toxic without Psh1, and Cse4 is found at ectopic locations. Therefore, they suggested that the E3 activity of Psh1 prevents the mislocalization of Cse4 (Figure 1, left).
Ranjitkar et al. also identified Psh1 by mass spectrometry analysis after purification of 3xFLAG-Cse416R that is not ubiquitylated in vivo [45]. They demonstrated that Cse4 overexpression causes growth defects on
However, the new findings of E3 ligase, Psh1, by these two groups left these open questions and stimulated other researchers to study the Psh1-mediated ubiquitylation and degradation of Cse4 as well as CENP-A homologs of other species.
Why does deletion of
No Psh1 ortholog in other eukaryotes is yet identified. Because the RING and zinc fingers are highly conserved motifs in many proteins from yeast to human, it is difficult to verify such an ortholog. It is also unclear whether the ubiquitin–proteasome pathway that controls CENP-A proteolysis is conserved among different species.
Can Psh1 be the unique E3 ligase in yeast? Is it possible to identify other E3 ligases that ubiquitylate Cse4 in the same or different function? Is the function of the Cse4 ubiquitylation restricted only to proteolysis?
Are any other post-translational modifications of Cse4 involved in upstream or downstream functions of Cse4 ubiquitylation?
What is the genome-wide misincorporation pattern of Cse4? How does the pattern change in the presence and absence of Psh1? Does Cse4 misincorporation affect promotor function and transcriptional regulation?
What is the molecular mechanism for the selective recognition and ubiquitylation of Cse4 by Psh1? Are other components required for such activities, or are other PTMs of Cse4 involved?
What are the deubiquitylase and deubiquitylation mechanisms of Cse4?
In the following sections, answers to some of these questions are further described.
Gkikopoulos et al. had identified DNA sequences to which the
The aforementioned groups had shown interactions of Psh1 with the C-terminus CATD of Cse4 and ubiquitylation of Cse4 at its C-terminus in vitro [22, 45]. Further, Au et al. demonstrated a role for ubiquitination of the N-terminus of Cse4 in regulating Cse4 proteolysis [47]. They initiated their studies with a mutant
Ohkuni et al. reported that the proline isomerase Fpr3 regulates Cse4 proteolysis [32] (Figure 1 and Table 1).
Deyter et al. identified a role for the conserved chromatin-modifying complex FACT (facilitates chromatin transcription/transactions) in preventing Cse4 mislocalization to euchromatin by mediating its proteolysis [58]. They initially found that Psh1 cannot efficiently ubiquitylate Cse4 nucleosomes in vitro, suggesting that additional factors must facilitate Cse4 removal from chromatin in vivo. The Spt16 subunit (Figure 1b and Table 1) of the FACT complex binds to Psh1, and this interaction between Psh1 and Spt16 is critical for both Cse4 ubiquitylation and its exclusion from euchromatin. Therefore, a Psh1 mutant that cannot associate with FACT has reduced interaction with Cse4 in vivo. Collectively, they proposed a previously unknown mechanism to maintain centromere identity and genomic stability through the FACT-mediated degradation of ectopically localized Cse4.
Hewawasam et al. reported that Psh1 is phosphorylated by the Cka2 subunit of casein kinase 2 (CK2) to promote its E3 activity for Cse4 [29] (Figure 1a and Table 1). They first showed that the deletion of
Mishra et al. showed that a kinetochore protein, Pat1 (Figure 1, right and Table 1), protects
One interesting question is if Cse4 misincorporation affects promotor function and transcriptional regulation. Hildebrand et al. addressed the genome-wide misincorporation pattern of Cse4 in the presence and absence of Psh1, performing chromatin immunoprecipitation analysis followed by high throughput sequencing [59]. They found that ectopic Cse4 mislocalized to intergenic regions of the genome. Mislocalized Cse4 is enriched at promoters that contain histone H2A. ZHtz1 nucleosomes flanking nucleosome-depleted regions (NDRs), however, Cse4 mislocalization does not depend on H2A.ZHtz1. Instead, the chromatin remodeling inositol-requiring 80 (INO80) complex (INO80-C), which removes H2A.ZHtz1 from nucleosomes, contributes to the ectopic deposition of Cse4 [59] (Figure 1, left). However, the functional relationship of INO80-C with other factors (e.g., CAF-1 complex) for Cse4 ectopic deposition remains to be elucidated (Figure 1, left). Together, this transcriptional profiling revealed that mislocalized Cse4 significantly disturbs transcription in the absence of Psh1, suggesting that regulating centromeric nucleosome localization is important for ensuring accurate promoter function and transcriptional regulation.
Because Cse4 proline residues though the Fpr3 regulation influence its degradation as reported by Ohkuni et al. [32] (see also Section 1.2.3), Deyter et al. hypothesized that additional features of the Cse4 nucleosome might be important for Cse4 proteolysis [31]. They initially asked whether histone H4 residues are important for Cse4 degradation, since Cse4 binds with high affinity to histone H4 before and after deposition on DNA, and they determined that Cse4 protein levels are stabilized in H4-R36A mutant cells and Cse4 is enriched in the euchromatin. Consistent with those data, they also demonstrated that H4-R36 is important for the interaction between Cse4 and Psh1 (Figure 1 and Table 1). They also analyzed Psh1 localization in WT vs. H4- R36A cells at the 5′, 3′, and coding regions of two highly transcribed genes,
This group previously had discovered that overexpressed Cse4 is mislocalized to nucleosomes in both tandem and divergent intergenic regions in the absence of Psh1, as shown earlier [59]. Therefore, they tested whether this is also true in the H4-R36A mutant cells by performing ChIP-qPCR. Cse4 mislocalization was negatively correlated with Psh1 enrichment in H4-R36A cells. Taken together, these data revealed H4-R36 is a key residue for efficient Cse4 degradation, likely by facilitating the interaction between Psh1 and Cse4.
Eisenstatt et al. further utilized a genome-wide screen (SGA) to identify factors that facilitate the mislocalization of overexpressed Cse4 by characterizing suppressors of the
One question is how this H4 dosage balance affects the function of H4-R36 (see also Section 1.5.1). Deyter et al. reported that H4-R36 is a key residue for efficient Cse4 degradation, likely by facilitating the interaction between Psh1 and Cse4 [31]. This group also found that a basic residue at H4-R36, but not PTM (e.g., methylation) of the amino acid, is required to prevent sensitivity to Cse4 overexpression [31]. Then how is it possible that reduced dosage of H4 leads to sumoylation and reduced mislocalization of overexpressed Cse4? Eisenstatt et al. showed that deletion of either histone H4 allele resulted in reduced levels of sumoylated Cse4 and concluded that physiologic levels of histone H4 are required for Cse4 sumoylation [27] (see also Section 1.4). However, the level of sumoylation loss caused by the deletion of either histone H4 allele (in
The mechanism by which other histones’ PTMs and dosages are involved in the incorporation of CENP-A/CenH3 is highly interesting, but at the same time, it suggests many questions. A further question raised is whether H4 dosage affects heterotypic CENP-A-H3.3 nucleosomes (see also Section 1.6) or H3 dosage among species including humans? Results in both budding and fission yeast suggest that the balance among histones H3,H4 and CENP-A is important for centromeric chromatin assembly [60, 61]. In fission yeast, increasing cellular histone H3 levels relative to Cnp1 promotes accumulation of H3 and loss of Cnp1 from the central domain and leads to defects in kinetochore function, however, there does not appear to be an efficient mechanism for the active exclusion of histone H3 from the centromeric nucleosomes [60, 62]. If H4 dosage affects heterotypic CENP-A-H3.3 nucleosomes or H3 dosage, is there an indirect pathway through which H4 dosage affects CENP-A incorporation into chromatin through H3? The inter-regulation among different histones, including CENP-A/CenH3 for high(macro) and low(micro) order chromatin structures, must be intricate. However, this could make it difficult to elucidate the mechanisms of incorporation, maintenance, and inheritance of CENP-A/CenH3.
In fission yeast and human studies, Mis18 (human Mis18α and Mis18β homolog) and Mis16 (human RbAp46 and RbAp48 homolog) are required for loading of newly synthesized Cnp1/CENP-A into centromeric chromatin [63, 64] (see also next chapter, sections 2.1, 3.1, and 4.1). Mis16 and Mis18 are also required for the maintenance of the hypoacetylation of histone H4 specifically within the central domain of the centromere [64], and Mis16 homologs are components of several histone chaperone complexes [65]. Moreover, acetylation of histone H4 lysine 5 and 12 (H4K5ac and H4K12ac) within the pre-nucleosomal CENP-A-H4-HJURP complex mediated by the RbAp46/48-Hat1 complex is required for CENP-A deposition into centromeres in chicken and humans [66], consistent with the Hat1 role shown in
It is known that sumoylation is involved in multiple intercellular pathways, and a subset of polysumoylation-mediated polyubiquitylation processes lead to proteasome-mediated degradation [70, 71]. Such machineries of SUMO-dependent ubiquitylation and degradation of CENP-A are interesting and important issues. Recent research has revealed new insights about the sumoylation of Cse4.
Ohkuni et al. reported the first evidence that Cse4 is sumoylated by E3 ligases Siz1 and Siz2 in vivo and in vitro [28] (Figure 1 and Table 1). Siz1 is the founding member of the Siz/PIAS (protein inhibitor of activated STAT) RING family of SUMO E3 ligases, and both Siz1 and Siz2 are normally bound to chromatin via their SAP domains [72]. The Siz/PIAS RING family is involved in the sumoylation of the septin protein group and several chromatin proteins including core histones and the replication clamp PCNA (proliferating cell nuclear antigen) [70, 72]. They showed that ubiquitylation of Cse4 by the small ubiquitin-related modifier (SUMO)-targeted ubiquitin ligase (STUbL), Slx5, is important for proteolysis of Cse4 and prevents mislocalization of Cse4 to euchromatin under normal physiologic conditions (Figure 1b and Table 1). Sumoylated Cse4 proteins are accumulated and protein stability of Cse4 is increased in
Further, Ohkuni et al. identified lysine 65 (K65) in Cse4 as a site that regulates sumoylation and ubiquitin-mediated proteolysis of Cse4 through Slx5 [52] (Figure 1b). The abundance of sumoylated and ubiquitinated Cse4 in vivo is reduced in budding yeast strains expressing cse4 K65R. They also showed that the interaction of cse4 K65R with Slx5 is significantly reduced, and stability and mislocalization of cse4 K65R are increased under normal physiologic conditions. The stability of cse4 K65R in
In humans, depletion of the human Slx5 homolog ring finger protein 4 (RNF4) contributes to sumoylation-dependent degradation of the CCAN protein CENP-I, while SENP6 (a member of a large family of Sentrin-specific protease enzymes that belongs to the yeast Ulp2 group) stabilizes CENP-I by antagonizing RNF4 [73]. However, depletion of SENP6 in HeLa cells leads to the loss of the CENP-H/I/K complex from the centromeres, but not an apparent reduction in centromeric CENP-A/B/C levels recognized by CREST sera [73]. Recent analyses by some groups also indicated that CENP-A was not a direct substrate of SENP6 [74, 75]. Differences among species of roles of sumoylation in the regulation of CENP-A stability are described later (see also next chapter, section [4]).
C-terminal sumoylation of Cse4 also contributes to the deposition of Cse4 into chromatin. Ohkuni et al. identified sumoylation sites lysine (K) 215/216 in the C-terminus of Cse4 and showed that sumoylation of Cse4 K215/216 facilitates its genome-wide deposition into chromatin when overexpressed [21] (Figure 1). Their results showed reduced levels of sumoylation of mutant Cse4 K215/216R/A [K changed to arginine (R) or alanine (A)] and reduced interaction of mutant Cse4 K215/216R/A with Scm3 and CAF-1 (Figure 1 and Table 1) (see also Section 1.5.3) when compared to wild-type Cse4. Consistently, levels of Cse4 K215/216R/A in the chromatin fraction and localization to centromeric and noncentromeric regions were reduced. In addition, GAL-cse4 K215/216R does not exhibit synthetic dosage lethality (SDL) in these strains—unlike
Further questions remain about the SUMO E3 ligase of Cse4 C-terminal K215/216 sumoylation. Sumoylation of Cse4 is barely detectable in a
Samel et al. reported that the absence of the E3 ubiquitin ligase Ubr2, as well as its adaptor protein Mub1, suppresses the synthetic growth defects (or lethality) caused by the absence of Cse4-R37 methylation in
However, the relationship between Ubr2 and Psh1, and E3 activity of Ubr2 on Cse4 is still not clear, although the absence of both E3s suppressed the synthetic growth defects (or lethality) shown in their study. The authors stated that most likely increased levels of kinetochore proteins other than Dsn1 in
In addition to the aforementioned report of Slx5 by Ohkuni et al. [28], Cheng et al. demonstrated that 4 ubiquitin ligases (i.e., Ubr1, Slx5, Psh1, and Rcy1) (Figure 1c and Table 1) contribute in parallel to the Cse4 proteolysis and turnover in budding yeast cells [33]. Cse4 overexpression generates cellular toxicity and cell cycle delay in budding yeast cells lacking
On the other hand, Cheng et al. also noted the lack of clarity about how this different E3s collaborate [33]. Their finding also generated these questions:
How do these E3s specifically recognize Cse4?
How do they work with other cellular cues and pathways (e.g., casein kinase 2, Siz1- and Siz2-mediated sumoylation, SWI/SNF remodeling enzymes, the FACT complex, and the proline isomerase Fpr3)?
What is the functional role and mechanism of each degradation pathway?
Further study is required to address these intricate E3 networks of Cse4 as well as other kinetochore proteins. In addition, the ubiquitin ligase(s) involved in human CENP-A degradation still remains unclear, although the CUL4A complex was identified as an E3 ligase that is required for CENP-A deposition at the centromere [79] (see also next chapter, section [4.2]). As Cheng et al. noted, while Psh1 does not seem to have a mammalian counterpart, Ubr1 (human UBR1), Slx5 (human RNF4) and Rcy1 (human EXOC5) are known to have human homologs. It is highly interesting to test CENP-A turnover in mammalian cells deficient for these homologs and also to determine if the human homologs of these E3s are altered in CENP-A-related cancer cells. Analogous questions are also raised in Section 1.6.2.
Hewawasam et al. reported that chromatin assembly factor-1 (CAF-1) (Figure 1 and Table 1) controls Cse4 deposition in budding yeast (see also Section 1.4.2). CAF-1 is an evolutionarily conserved histone H3/H4 chaperone; its subunits were shown to interact with CenH3 in flies and human cells. Previously, it had been reported that subunits of CAF-1 are required for building functional kinetochores [80], for recruitment of CenH3/Cnp1 and Scm3 to centromeres in fission yeast,
Some questions remain about the relationships among Cse4, Psh1, Scm3, and CAF-1. The first question is about the role of CAF- 1 in Psh1-mediated proteolysis of Cse4: How does CAF-1 function in the process of Cse4 ubiquitylation by Psh1? Hewawasam et al. observed more ubiquitylation of Cse4 in the presence of CAF-1 compared with the absence of CAF-1 in vitro, suggesting CAF-1 can promote ubiquitylation of free Cse4, opposite to the effect of Scm3 that protects Cse4 from ubiquitylation by Psh1 in vitro [22]. They also tested CAF-1 interaction with Psh1, but their co-immunoprecipitation experiment in whole-cell extracts did not show any interactions. Thus, they speculated that soluble Cse4 bound to CAF-1 may expose ubiquitylation sites on Cse4, promoting ubiquitylation by Psh1.
The second question is whether CAF-1 could assemble Cse4 at centromere as Scm3. If so, do the roles of the two proteins simply overlap, or does each protein have a unique role in the process of Cse4 assembly at centromere? To test this question, Hewawasam et al. used the Scm3on/off strain, which can be toggled by galactose, along with copper-inducible Cse4 overexpression, so that Cse4 protein levels can be controlled by the concentration of copper [26]. Their results suggest that when Scm3 is absent and Cse4 levels are high, CAF1 may be a primary chaperone targeting Cse4 to the centromere (Figure 1, center). Meanwhile, in the fission yeast
The third question is how CAF-1 can be responsible for the mislocalization of Cse4/CENP-A in cancer development. The human CAF-1 subunit p60 was one of the overexpressed chaperones in CENP-A-overexpressing breast cancer cells [82], and ectopic CENP-A nucleosomes from colorectal cancer cells keep a subpopulation of structurally distinct hybrid (chimeric) nucleosomes containing both CENP-A and H3.3 [82, 83]. Misregulation of Scm3/HJURP causes chromosome instability in both yeast and humans [84], and many previous reports suggested the functional relevance of Scm3/HJURP with the development of a wide spectrum of cancers (e.g., colon, lung, liver, breast, pancreatic, brain cancer) [85, 86, 87, 88, 89, 90, 91, 92, 93, 94]. As aforementioned, CAF-1 may cooperate with Psh1 and Scm3 to regulate proteolysis of Cse4, in the way that CAF-1 association with free Cse4 may promote ubiquitylation and proteolysis. If so, how do these two chaperons (CAF-1 and Scm3/HJURP) cooperate together in genomic stability and anti-cancer development? Further in-depth study is required to elucidate the collaboration among Psh1, Scm3, and CAF-1 in genomic stability and anti-cancer development.
Deletion for genes encoding the replication-independent histone chaperone HIR complex (HIR1, HIR2, HIR3, HPC2) and a Cse4-specific E3 ubiquitin ligase, PSH1, showed the highest SDL using a genome-wide synthetic genetic array (SGA) to identify gene deletions that exhibit SDL when Cse4 is overexpressed [30]. Thus, Ciftci-Yilmaz et al. performed functional analysis for Hir2 (Figure 1 and Table 1) in proteolysis of Cse4 that prevents mislocalization of Cse4 to noncentromeric regions for genome stability. They demonstrated the interaction of Hir2 with Cse4 in vivo, and defects in Cse4 proteolysis and stabilization of chromatin-bound Cse4 appear in
Analogous questions can be raised regarding CAF-1, especially about the functional relationships among different Cse4 chaperone proteins (e.g., Scm3, CAF-1, and Hir2) and their roles in cancer development. In the Psh1-mediated proteolysis of free Cse4 using whole-cell lysates, CAF-1 and Hir2 promote proteolysis and Scm3 inhibits it [22, 26, 30]. CAF-1 and Hir2 could be involved in the proteolysis of noncentromeric Cse4, but Scm3 in the anti-proteolysis of the centromeric Cse4. However, CAF-1 may promote centromeric localization of overexpressed Cse4 only under conditions when Scm3 is depleted (
Studying the real-time 3D structure of free CENP-A/CenH3 after post-translational modification and before incorporation into chromatin could be a key future direction. In budding yeast, Ohkuni et al. proposed that structural change in Cse4 caused by the proline isomerase Fpr3 might be important for the interaction between Cse4 and the E3 ubiquitin ligase Psh1 [32] (see also Section 1.2.3).
Au et al. identified two Skp1, Cullin, F-box (SCF) ubiquitin ligases with the evolutionarily conserved F-box proteins Met30 and Cdc4 (Figure 1c and Table 1) as essential genes required for Cse4 homeostasis through a genome-wide SGA screen [34]. They showed that Met30 and Cdc4 interact through the Met30-WD40 domain, and these two proteins cooperatively regulate proteolysis of endogenous Cse4 and prevent its mislocalization for faithful chromosome segregation (Figure 1). The interaction of Met30 with Cdc4 is independent of the Met30-D domain, which is essential for their homodimerization and ubiquitination of other substrates. Ubiquitin affinity pull-down assays showed that both Cdc4 and Met30 specifically target Cse4 for its ubiquitination. They suggest that Met30 is necessary for the interaction between Cdc4 and Cse4, and its defective interaction leads to stabilization and mislocalization of Cse4, which in turn promotes to CIN. They also provided the first direct link between Cse4 mislocalization and defects in kinetochore structure measured by the sensitivity against the restriction enzyme
Further studies are also required to address analogous questions as in Section 1.5.2: How does the Met30/Cdc4-pathway work with other cellular cues and multiple E3 pathways, including Psh1-dependent and independent proteolysis? Are the human homologs of these E3s (e.g., human FBXO24, TRAF7, etc.) altered in CENP-A-related cancer cells?
Eisenstatt et al. identified five alleles of CDC7 and DBF4 that encode the Dbf4-dependent kinase complex, which regulates DNA replication initiation in their SGA [95]. They found that cdc7–7 strains show defects in ubiquitin-mediated proteolysis of Cse4 and mislocalization of Cse4 [95]. Mutation of MCM5 (mcm5-bob1) bypasses the requirement of Cdc7 for replication initiation and rescues replication defects in a cdc7-7 strain. They demonstrated that mcm5-bob1 does not rescue the SDL and defects in proteolysis of overexpressed Cse4 (
Recently, Eisenstatt et al. further utilized SGA to identify factors that facilitate the mislocalization of overexpressed Cse4 by characterizing suppressors of the
Compared to the ubiquitylation mechanism of Cse4, there are relatively few studies on the deubiquitylation mechanism of Cse4. We should also consider how the deubiquitylation affects the localization and the function of Cse4 at both centromere and ectopic sites along chromosomes.
Canzonetta et al. investigated the role of Ubp8-driven deubiquitylation of the Cse4 in budding yeast [96]. Ubp8 is a component of the SAGA (Spt-Ada-Gcn5-acetyltransferase) complex, a multicomponent regulator of acetylation. The SAGA complex is also involved in deubiquitylation through its deubiquitylation (DUB) module, and one example of its activity is upon histone H2B [97, 98]. Canzonetta et al. demonstrated that the deubiquitylation process was inhibited and a short ubiquitin oligomer on Cse4 was accumulated by the loss of Ubp8. Such defective deubiquitylation caused by Ubp8 loss leads to chromosome instability and Cse4 protein degradation, and induces ectopic localization of the Cse4 outside the centromere.
Interestingly, there was a report suggesting that Psh1 is also involved in proper plasmid segregation [99]. Metzger et al. initially sought to assess the involvement of the ubiquitin-proteasome system in the turnover of mitochondrial proteins in budding yeast [99]. Then, they found that deletion of a specific ubiquitin ligase (E3), Psh1p, increases the level of a temperature-sensitive mitochondrial protein, mia40-4pHA, when it is expressed from a centromere-containing (
Zhou et al. first solved the structure of the Cse4-binding domain (CBD) of Scm3 in complex with Cse4 and H4 in a single chain model using nuclear magnetic spectroscopy [12]. They suggested that four Cse4-specific residues in the N-terminal region of helix 2 (MIMAS motif; Table 1) are sufficient for specific recognition by conserved and functionally important residues in the N-terminal helix of Scm3 through the formation of a hydrophobic cluster.
Scm3 (CBD) also induces major conformational changes and sterically occludes DNA-binding sites in the structure of Cse4 and H4. Furthermore, Zhou et al. showed that Psh1 uses a CBD (residues 1–211) to interact with Cse4-H4 instead of H3-H4, yielding a dissociation constant (Kd) of 27 nM in their isothermal titration calorimetric experiments [100]. They are in vitro pull-down assays revealed that Psh1 interacts with Cse4-specific residues in the L1 loop and α2 helix for Cse4 binding and ubiquitination. They also mapped the Psh1-binding region of Cse4-H4 and identified a wide range of Cse4 specific residues required for the Psh1-mediated Cse4 recognition and ubiquitination. Consistent with the previous reports of the inhibitory effect of Scm3 on Cse4 ubiquitylation [22], their data showed that the histone chaperone Scm3 prevents Cse4 ubiquitination by abrogating Psh1-Cse4 binding. Their results suggest that Scm3 interacts with the Cse4 MMAS motif (a particular Cse4 region containing residues M181/M184/ A189/S190 reported previously [12]) to prevent Psh1 from binding to Cse4. Elimination of the Psh1-binding residues outside of the Cse4 MMAS motif promotes the inhibitory effect of Scm3. Thus, the MMAS motif plays a central role in the activation or inhibition of Cse4 ubiquitination as well as yeast cell growth. Taken together, they elucidated a novel Cse4 binding mode distinct from those of known CenH3 chaperones and the mechanism by which Scm3 competes with Psh1 for Cse4 binding.
The budding yeast is a powerful organism for centromere-kinetochore research in many aspects. For example, the centromere sequence size of the budding yeast is small and the sequences can be easily mutated to identify the important functional regions [1]. Techniques such as ChIP are also possible, which cannot be easily performed on highly repetitive centromeres in other organisms. Moreover, the centromere can be shifted to other genomic regions, allowing the construction of artificial chromosomes and plasmids as well as tools such as conditional centromeres. As a result, the most common species studied and reported in the past for E3 ligase of CenH3 (Cse4) is budding yeast at present. However, many questions described in this chapter are unanswered even in the budding yeast model. Especially, little has been studied on how each of such multiple E3 ligases of budding yeast selectively recognizes Cse4 substrate and functions specifically. Currently, 4 types of E3 ligases for ubiquitylation and one type of E3 ligases for sumoylation (Slx5/8) have been reported (Table 1). In particular, the functions of the 4 types of E3 ligases for ubiquitylation including Psh1 are common, all of which are related to ectopic degradation and/or quality control of soluble or chromatin-bound Cse4, and the functional differences are not clear. It is neither clear why E3 ligases with overlapping functions exist in one species. The simple interpretation is that at least such a number (4–5) of E3 ligases of Cse4 is required as a backup system, so that it can be complemented if one of the E3 functions is defective. As we described the compensatory system of CENP- A PTM (see also the next chapter, Conclusion), compensatory systems and resilience of CENP-ACse4 could be expected as future directions to study the spatiotemporal regulation of E3 ligase of CENP-ACse4.
No neocentromere has been found in budding yeast. As a simple reason, it seems that there is no or little possibility of ectopic centromere formation, because the kinetochore formation of budding yeast depends on centromeric DNA elements. However, in terms of considering centromeric evolution, it is interesting to question why budding yeast has maintained point centromere which relies on DNA elements, and other species have evolved to regional centromere which allows the system to generate neocentromere? There is also no clear answer as to whether simply introducing centromeric DNA elements into ectopic loci causes neocentromere or it is still eliminated by the specific E3 activity in budding yeast. The building and establishment of artificial chromosomes are facilitated by studying the mechanisms of formation and maintenance of neocentromeres, and these topics of other species are described in the next chapter.
The regulation of budding yeast cenRNA is an essential factor for centromere structure and function as other eukaryotes, but we have little understanding of the causality or feedback between cenRNA transcription and overall transcriptional change after chromosome mis-segregation and CIN. In addition, little is known about the effects of these cenRNAs on the E3 ligase of CENP-A, including how these transcriptional changes and regulation are related to the function of E3 ligase. Although, it is essential to study specific physiological functions of each E3 ligase, the physiological phenotype of budding yeast is limited (e.g., growth, cell death, etc.), thus naturally there is a limit in the discussion of the results in the budding yeast model. Thus, studies of an E3 ligase in CENP-A in higher eukaryotes, mammals, or humans are essential for translational research and informing future therapy, and these topics are described in the next chapter.
We thank past and current researchers at Model Animal Research Center, School of Medicine, Nanjing University, Greehey Children’s Cancer Research Institute at UT Health Science Center San Antonio, The Research Institute at Nationwide Children’s Hospital, and St. Jude Children’s Research Hospital for their helpful discussions. Y.N. was supported by Jiangsu Province “Double-First-Class” Construction Fund, Jiangsu Province Natural Science Fund (BK20191252), Jiangsu Province 16th Six Big Talent Peaks Fund (TD-SWYY-001), Jiangsu Province “Foreign Expert Hundred Talents Program” Fund (BX2019082), and National Natural Science Foundation in China (31970665). KK was supported by the National Science Foundation under Grant No.1949653 (KK) and a Mays Cancer Center Pilot Award CCSG P30 CA054174.
The authors declare no conflict of interest.
Authors are listed below with their open access chapters linked via author name:
",metaTitle:"IntechOpen authors on the Global Highly Cited Researchers 2018 list",metaDescription:null,metaKeywords:null,canonicalURL:null,contentRaw:'[{"type":"htmlEditorComponent","content":"New for 2018 (alphabetically by surname).
\\n\\n\\n\\n\\n\\n\\n\\n\\n\\nJocelyn Chanussot (chapter to be published soon...)
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\\n\\nAbdul Latif Ahmad 2016-18
\\n\\nKhalil Amine 2017, 2018
\\n\\nEwan Birney 2015-18
\\n\\nFrede Blaabjerg 2015-18
\\n\\nGang Chen 2016-18
\\n\\nJunhong Chen 2017, 2018
\\n\\nZhigang Chen 2016, 2018
\\n\\nMyung-Haing Cho 2016, 2018
\\n\\nMark Connors 2015-18
\\n\\nCyrus Cooper 2017, 2018
\\n\\nLiming Dai 2015-18
\\n\\nWeihua Deng 2017, 2018
\\n\\nVincenzo Fogliano 2017, 2018
\\n\\nRon de Graaf 2014-18
\\n\\nHarald Haas 2017, 2018
\\n\\nFrancisco Herrera 2017, 2018
\\n\\nJaakko Kangasjärvi 2015-18
\\n\\nHamid Reza Karimi 2016-18
\\n\\nJunji Kido 2014-18
\\n\\nJose Luiszamorano 2015-18
\\n\\nYiqi Luo 2016-18
\\n\\nJoachim Maier 2014-18
\\n\\nAndrea Natale 2017, 2018
\\n\\nAlberto Mantovani 2014-18
\\n\\nMarjan Mernik 2017, 2018
\\n\\nSandra Orchard 2014, 2016-18
\\n\\nMohamed Oukka 2016-18
\\n\\nBiswajeet Pradhan 2016-18
\\n\\nDirk Raes 2017, 2018
\\n\\nUlrike Ravens-Sieberer 2016-18
\\n\\nYexiang Tong 2017, 2018
\\n\\nJim Van Os 2015-18
\\n\\nLong Wang 2017, 2018
\\n\\nFei Wei 2016-18
\\n\\nIoannis Xenarios 2017, 2018
\\n\\nQi Xie 2016-18
\\n\\nXin-She Yang 2017, 2018
\\n\\nYulong Yin 2015, 2017, 2018
\\n"}]'},components:[{type:"htmlEditorComponent",content:'New for 2018 (alphabetically by surname).
\n\n\n\n\n\n\n\n\n\nJocelyn Chanussot (chapter to be published soon...)
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nYuekun Lai
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nPrevious years (alphabetically by surname)
\n\nAbdul Latif Ahmad 2016-18
\n\nKhalil Amine 2017, 2018
\n\nEwan Birney 2015-18
\n\nFrede Blaabjerg 2015-18
\n\nGang Chen 2016-18
\n\nJunhong Chen 2017, 2018
\n\nZhigang Chen 2016, 2018
\n\nMyung-Haing Cho 2016, 2018
\n\nMark Connors 2015-18
\n\nCyrus Cooper 2017, 2018
\n\nLiming Dai 2015-18
\n\nWeihua Deng 2017, 2018
\n\nVincenzo Fogliano 2017, 2018
\n\nRon de Graaf 2014-18
\n\nHarald Haas 2017, 2018
\n\nFrancisco Herrera 2017, 2018
\n\nJaakko Kangasjärvi 2015-18
\n\nHamid Reza Karimi 2016-18
\n\nJunji Kido 2014-18
\n\nJose Luiszamorano 2015-18
\n\nYiqi Luo 2016-18
\n\nJoachim Maier 2014-18
\n\nAndrea Natale 2017, 2018
\n\nAlberto Mantovani 2014-18
\n\nMarjan Mernik 2017, 2018
\n\nSandra Orchard 2014, 2016-18
\n\nMohamed Oukka 2016-18
\n\nBiswajeet Pradhan 2016-18
\n\nDirk Raes 2017, 2018
\n\nUlrike Ravens-Sieberer 2016-18
\n\nYexiang Tong 2017, 2018
\n\nJim Van Os 2015-18
\n\nLong Wang 2017, 2018
\n\nFei Wei 2016-18
\n\nIoannis Xenarios 2017, 2018
\n\nQi Xie 2016-18
\n\nXin-She Yang 2017, 2018
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From\r\n1964 to 1974, he worked as Assistant in Biochemistry at the School of MedicineUniversidad Nacional de La Plata, Argentina. From 1974 to 1976, he was a Fellowof the National Institutes of Health (NIH) at the University of Connecticut, Health Center, USA. From 1985 to 2004, he served as a Full Professor oBiochemistry at the Universidad Nacional de La Plata, Argentina. He is Member ofthe National Research Council (CONICET), Argentina, and Argentine Society foBiochemistry and Molecular Biology (SAIB). His laboratory has been interested for manyears in the lipid peroxidation of biological membranes from various tissues and different species. Professor Catalá has directed twelve doctoral theses, publishedover 100 papers in peer reviewed journals, several chapters in books andtwelve edited books. Angel Catalá received awards at the 40th InternationaConference Biochemistry of Lipids 1999: Dijon (France). 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